U.S. patent application number 11/321093 was filed with the patent office on 2006-08-03 for compounds, formulations, and methods for treating or preventing rosacea.
Invention is credited to Jack DeJovin, Thomas M. Rossi.
Application Number | 20060171974 11/321093 |
Document ID | / |
Family ID | 33457481 |
Filed Date | 2006-08-03 |
United States Patent
Application |
20060171974 |
Kind Code |
A1 |
DeJovin; Jack ; et
al. |
August 3, 2006 |
Compounds, formulations, and methods for treating or preventing
rosacea
Abstract
In methods, compounds, and topical formulations for treatment of
rosacea incorporating compounds represented by the formulas below:
##STR1## wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, hologen, alkyl, or alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, or alkoxy; and each
of R.sub.6 and R.sub.7 is independently hydrogen, nitro, alkyl, or
alkoxy; wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl; and A.sub.2 is independently
hydrogen or hydroxy; and wherein each of B.sub.1, B.sub.2, and
B.sub.3 is independently hydrogen, hydroxy, or alkoxy; and each of
B.sub.4 and B.sub.5 is independently hydrogen or alkyl, applying
such compounds topically as sprays, mists, aerosols, solutions,
lotions, gels, creams, ointments, pastes, unguents, emulsions, and
suspensions to treat rosacea and its symptoms.
Inventors: |
DeJovin; Jack; (New
Brunswick, NJ) ; Rossi; Thomas M.; (Stockton,
NJ) |
Correspondence
Address: |
SONNENSCHEIN NATH & ROSENTHAL LLP
P.O. BOX 061080
WACKER DRIVE STATION, SEARS TOWER
CHICAGO
IL
60606-1080
US
|
Family ID: |
33457481 |
Appl. No.: |
11/321093 |
Filed: |
December 29, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10853585 |
May 25, 2004 |
|
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11321093 |
Dec 29, 2005 |
|
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60473611 |
May 27, 2003 |
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Current U.S.
Class: |
424/401 ;
514/249; 514/401; 514/651 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/498 20130101; A61P 7/10 20180101; A61K 31/00 20130101; A61P
17/10 20180101; A61K 9/0014 20130101; Y02A 50/30 20180101; A61K
9/06 20130101; A61K 31/4174 20130101; A61P 9/00 20180101; A61P
17/00 20180101; A61K 31/4164 20130101; A61P 29/00 20180101; A61K
31/137 20130101; A61K 31/4174 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/401 ;
514/249; 514/401; 514/651 |
International
Class: |
A61K 31/498 20060101
A61K031/498; A61K 31/4164 20060101 A61K031/4164; A61K 31/137
20060101 A61K031/137 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. The topical composition according to claim 167, wherein the
pharmaceutically acceptable carrier is an aqueous gel comprising
water, and a water-gelling amount of a pharmaceutically acceptable
gelling agent selected from the group including carbomers,
glycerine polyacrylate, and mixtures thereof, the topical
composition having a physiologically acceptable pH.
15. The topical composition according to claim 14, wherein the
brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof is present in an
amount in the range of about 0.01 to 5 weight percent.
16. The topical composition according to claim 14, wherein the pH
value of the composition is in the range of about 5 to 8.
17. The topical composition according to claim 14, further
comprising a preservative.
18. The topical composition according to claim 14, further
comprising a local anesthetic.
19. The topical composition according to claim 14, further
comprising a skin humectant.
20. A package for a topical composition suitable for treating or
preventing the symptoms of rosacea comprising brimonidine or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof and a pharmaceutically acceptable
carrier, comprising a container and instructions for use of the
topical composition.
21. The topical composition according to claim 167, wherein the
pharmaceutically acceptable carrier is at least one of a cream and
an ointment, comprising stearic acid, stearyl alcohol, cetyl
alcohol, glycerin, and water, the topical composition having a
physiologically acceptable pH.
22. The topical composition according to claim 21, wherein the
brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof is present in an
amount in the range of about 0.01 to 5 weight percent.
23. The topical composition according to claim 21, wherein the pH
value of the composition in the range of about 5 to 8.
24. The topical composition according to claim 21, further
comprising a preservative.
25. The topical composition according to claim 21, further
comprising a local anesthetic.
26. The topical composition according to claim 21, further
comprising a skin humectant.
27. The topical composition according to claim 166, wherein the
brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof is provided in a
concentration sufficient to decrease blood flow through the small
arteries or arterioles of the skin of the patient to which it is
applied.
28. The topical composition according to claim 166, wherein the
composition acts locally in the skin of the patient.
29. A method of treating or preventing rosacea and the symptoms
associated therewith, comprising topically administering to the
skin of a patient in need of such treatment or prevention a
composition comprising: a therapeutically effective amount of at
least one of an a adrenergic receptor agonist, a pharmaceutically
acceptable salt thereof, a prodrug thereof, an active metabolite
thereof, a derivative thereof, and an analog thereof; and a
pharmaceutically acceptable carrier.
30. The method according to claim 29, wherein the at least one of
an .alpha. adrenergic receptor agonist, a pharmaceutically
acceptable salt thereof, a prodrug thereof, an active metabolite
thereof, a derivative thereof, and an analog thereof is selected
from the group including the compounds shown below: ##STR30##
wherein each of R.sub.1, R.sub.2, and R.sub.3 is independently
hydrogen, halogen, alkyl, or alkoxy; each of R.sub.4 and R.sub.5 is
independently hydrogen, alkyl, or alkoxy; and each of R.sub.6 and
R.sub.7 is independently hydrogen, nitro, alkyl, or alkoxy; wherein
each of A.sub.1, A.sub.3, and A.sub.4 is independently hydrogen or
alkyl; and A.sub.2 is independently hydrogen or hydroxy; and
wherein each of B.sub.1, B.sub.2, and B.sub.3 is independently
hydrogen, hydroxy, or alkoxy; and each of B.sub.4 and B.sub.5 is
independently hydrogen or alkyl.
31. The method according to claim 30, wherein the compounds are
selected from the group including brimonidine, naphazoline,
tetrahydrozaline, oxymetazoline, xylometazoline, epinephrine,
nerepinephrine, phenylephrine, and methoxamine.
32. The method according to claim 29, wherein the at least one of
an .alpha. adrenergic receptor agonist, a pharmaceutically
acceptable salt thereof, a prodrug thereof, an active metabolite
thereof, a derivative thereof, and an analog thereof is a
reversible .alpha. adrenergic receptor agonist or a
pharmaceutically acceptable salt thereof or a prodrug thereof or an
active metabolite thereof or a derivative thereof or an analog
thereof.
33. The method according to claim 29, wherein the at least one of
an .alpha. adrenergic receptor agonist, a pharmaceutically
acceptable salt thereof, a prodrug thereof, an active metabolite
thereof, a derivative thereof, and an analog thereof is
administered in an amount sufficient to decrease blood flow through
the small arteries or arterioles of the skin of the patient.
34. The method according to claim 29, wherein the pharmaceutically
acceptable carrier is selected from the group including sprays,
mists, aerosols, solutions, lotions, gels, creams, ointments,
pastes, unguents, emulsions, and suspensions.
35. The method according to claim 29, wherein the composition acts
locally in the skin of the patient.
36. A topical composition intended for treating or preventing the
symptoms of rosacea, comprising: at least one of an .alpha.
adrenergic receptor agonist, a pharmaceutically acceptable salt
thereof, a prodrug thereof, an active metabolite thereof, a
derivative thereof, and an analog thereof, and a pharmaceutically
acceptable carrier.
37. The topical composition according to claim 36, wherein the
pharmaceutically acceptable carrier is selected from the group
including sprays, mists, aerosols, solutions, lotions, gels,
creams, ointments, pastes, unguents, emulsions, and
suspensions.
38. The topical composition according to claim 36, wherein the at
least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof is selected from the group including the compounds shown
below: ##STR31## wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, or alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, or alkoxy; and each
of R.sub.6 and R.sub.7 is independently hydrogen, nitro, alkyl, or
alkoxy; wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl; and A.sub.2 is independently
hydrogen or hydroxy; and wherein each of B.sub.1, B.sub.2, and
B.sub.3 is independently hydrogen, hydroxy, or alkoxy; and each of
B.sub.4 and B.sub.5 is independently hydrogen or alkyl.
39. The topical composition according to claim 36, wherein the at
least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof is selected from the group including brimonidine,
naphazoline, tetrahydrozoline, oxymetazoline, xylometazoline,
epinephrine, norepinephrine, phenylephrine, and methoxamine.
40. The topical composition according to claim 36, wherein the at
least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof is present in an amount in the range of about 0.01 to 5
weight percent.
41. The topical composition according to claim 36, wherein the pH
value of the composition is in the range of about 5 to 8.
42. The topical composition according to claim 37, wherein the
pharmaceutically acceptable carrier is an aqueous gel comprising
water, and a water-gelling amount of a pharmaceutically acceptable
gelling agent selected from the group including carbomers,
glycerine polyacrylate, and mixtures thereof, the topical
composition having a physiologically acceptable pH.
43. The topical composition according to claim 42, wherein the at
least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof is present in an amount in the range of about 0.01 to 5
weight percent.
44. The topical composition according to claim 42, wherein the pH
value of the composition is in the range of about 5 to 8.
45. The topical composition according to claim 42, further
comprising a preservative.
46. The topical composition according to claim 42, further
comprising a local anesthetic.
47. The topical composition according to claim 42, further
comprising a skin humectant.
48. A package for a topical composition suitable for treating or
preventing the symptoms of rosacea comprising at least one of an
.alpha. adrenergic receptor agonist, a pharmaceutically acceptable
salt thereof, a prodrug thereof, an active metabolite thereof, a
derivative thereof, and an analog thereof and a pharmaceutically
acceptable carrier, comprising a container and instructions for use
of the topical composition.
49. The topical composition according to claim 37, wherein the
pharmaceutically acceptable carrier is at least one of a cream and
an ointment comprising stearic acid, stearyl alcohol, cetyl
alcohol, glycerin, and water, the topical composition having a
physiologically acceptable pH.
50. The topical composition according to claim 49, wherein the at
least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof is present in an amount in the range of about 0.01 to 5
weight percent.
51. The topical composition according to claim 49, wherein the pH
value of the composition is in the range of about 5 to 8.
52. The topical composition according to claim 49, further
comprising a preservative.
53. The topical composition according to claim 49, further
comprising a local anesthetic.
54. The topical composition according to claim 49, further
comprising a skin humectant.
55. The topical composition according to claim 36, wherein the at
least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof is provided in a concentration sufficient to decrease blood
flow through the small arteries or arterioles of the skin of the
patient to which it is applied.
56. The topical composition according to claim 36, wherein the
composition acts locally in the skin of the patient.
57. A method of reducing or eliminating redness associated with an
inflammatory skin disorder comprising topically administering a
pharmaceutical composition comprising an effective amount of an
alpha adrenergic receptor agonist to the site of the redness on the
skin of a patient.
58. The method of claim 57, wherein the disorder is an inflammatory
facial skin disorder.
59. The method of claim 58, wherein the disorder is rosacea.
60. The method of claim 47, wherein the alpha adrenergic receptor
agonist is an .alpha..sub.2 adrenergic receptor agonist.
61. The method of claim 58, wherein the alpha adrenergic receptor
agonist is an .alpha..sub.2 adrenergic receptor agonist.
62. The method of claim 59, wherein the alpha adrenergic receptor
agonist is an .alpha..sub.2 adrenergic receptor agonist.
63. The method of claim 57, wherein the .alpha..sub.2 adrenergic
receptor agonist is a compound of the formula: ##STR32## wherein
each of R.sub.1, R.sub.2, and R.sub.3 is independently hydrogen,
halogen, alkyl, or alkoxy; each of R.sub.4 and R.sub.5 is
independently hydrogen, alkyl, or alkoxy; and each of R.sub.6 and
R.sub.7 is independently hydrogen, nitro, alkyl, or alkoxy; or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof.
64. The method of claim 58, wherein the .alpha..sub.2 adrenergic
receptor agonist is a compound of the formula: ##STR33## wherein
each of R.sub.1, R.sub.2, and R.sub.3 is independently hydrogen,
halogen, alkyl, or alkoxy; each of R.sub.4 and R.sub.5 is
independently hydrogen, alkyl, or alkoxy; and each of R.sub.6 and
R.sub.7 is independently hydrogen, nitro, alkyl, or alkoxy; or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof.
65. The method of claim 59, wherein the .alpha..sub.2 adrenergic
receptor agonist is a compound of the formula: ##STR34## wherein
each of R.sub.1, R.sub.2, and R.sub.3 is independently hydrogen,
halogen, alkyl, or alkoxy; each of R.sub.4 and R.sub.5 is
independently hydrogen, alkyl, or alkoxy; and each of R.sub.6 and
R.sub.7 is independently hydrogen, nitro, alkyl, or alkoxy; or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof.
66. The method of claim 57, wherein the .alpha..sub.2 adrenergic
receptor agonist is brimonidine or a pharmaceutically acceptable
salt or prodrug or active metabolite or derivative or analog
thereof.
67. The method of claim 58, wherein the .alpha..sub.2 adrenergic
receptor agonist is brimonidine or a pharmaceutically acceptable
salt or prodrug or active metabolite or derivative or analog
thereof.
68. The method of claim 59, wherein the .alpha..sub.2 adrenergic
receptor agonist is brimonidine or a pharmaceutically acceptable
salt or prodrug or active metabolite or derivative or analog
thereof.
69. The method of claim 57, wherein the alpha adrenergic receptor
agonist is administered in an amount sufficient to decrease blood
flow through the small arteries or arterioles of the skin of the
patient.
70. The method of claim 57, wherein the composition acts locally on
the skin of the patient.
71. The method of claim 57, wherein the alpha adrenergic receptor
agonist is an .alpha..sub.1 adrenergic receptor agonist.
72. The method of claim 58, wherein the alpha adrenergic receptor
agonist is an .alpha..sub.1 adrenergic receptor agonist.
73. The method of claim 59, wherein the alpha adrenergic agonist is
an .alpha..sub.1 adrenergic receptor agonist.
74. The method of claim 71, wherein the .alpha..sub.1 adrenergic
receptor agonist is a compound selected from the following
##STR35## wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl; and A.sub.2 is independently
hydrogen or hydroxy; and wherein each of B.sub.1, B.sub.2, and
B.sub.3 is independently hydrogen, hydroxy, or alkoxy; and each of
B.sub.4 and B.sub.5 is independently hydrogen or alkyl; or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof.
75. The method of claim 72, wherein the .alpha..sub.1 adrenergic
receptor agonist is a compound selected from the following
##STR36## wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl; and A.sub.2 is independently
hydrogen or hydroxy; and wherein each of B.sub.1, B.sub.2, and
B.sub.3 is independently hydrogen, hydroxy, or alkoxy; and each of
B.sub.4 and B.sub.5 is independently hydrogen or alkyl; or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof.
76. The method of claim 73, wherein the .alpha..sub.1 adrenergic
receptor agonist is a compound selected from the following
##STR37## wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl; and A.sub.2 is independently
hydrogen or hydroxy; and wherein each of B.sub.1, B.sub.2, and
B.sub.3 is independently hydrogen, hydroxy, or alkoxy; and each of
B.sub.4 and B.sub.5 is independently hydrogen or alkyl; or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof.
77. The method of claim 71, wherein the .alpha..sub.1 adrenergic
receptor agonist is naphazoline, tetrahydrozaline, oxymetazoline,
xylometazoline, epinephrine, nerepinephrine, phenylephrine, or
methoxamine, or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof.
78. The method of claim 72, wherein the .alpha..sub.1 adrenergic
receptor agonist is naphazoline, tetrahydrozaline, oxymetazoline,
xylometazoline, epinephrine, nerepinephrine, phenylephrine, or
methoxamine, or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof.
79. The method of claim 73, wherein the .alpha..sub.1 adrenergic
receptor agonist is naphazoline, tetrahydrozaline, oxymetazoline,
xylometazoline, epinephrine, nerepinephrine, phenylephrine, or
methoxamine, or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof.
80. A method of preventing or reducing the severity of a
stress-associated condition in a subject, comprising administering
to said subject an effective amount of brimonidine or a
pharmaceutically acceptable salt, ester, amide, sterioisomer or
racemic mixture thereof, wherein said stress-associated condition
is a dermatogical condition.
81. The method of claim 80, wherein said effective amount is
administered topically.
82. The method of claim 81, wherein the effective amount acts
locally in the skin of the patient.
83. A method for treating at least one condition selected from the
group consisting of rosacea, acne, skin redness or other conditions
characterized by discreet erythema of the skin in a subject in need
of such treatment, comprising administering topically to said
subject, for such period of time as is required to elicit the
desired therapeutic response, a therapeutically or cosmetically
effective amount of at least one alpha-1 adrenoreceptor
agonist.
84. The method according to claim 83, wherein said at least one
alpha-1 adrenoreceptor agonist is topically applied to the
skin.
85. The method according to claim 83, wherein said at least alpha-1
adrenoreceptor agonist comprises oxymetazoline.
86. The method according to claim 83, wherein said at least alpha-1
adrenoreceptor agonist comprises tetrahydrozoline.
87. The method according to claim 83, wherein said at least alpha-1
adrenoreceptor agonist comprises nephazoline.
88. The method according to claim 83, wherein said at least alpha-1
adrenoreceptor agonist comprises xylometazoline.
89. The method according to claim 83, wherein the treated condition
comprises rosacea.
90. The method according to claim 83, wherein the treated condition
comprises acne.
91. The method according to claim 83, wherein the treated condition
comprises other discreet erythemas.
92. A composition for topical administration to the skin for
treating rosacea comprising oxymetazoline HCl and an inert
carrier.
93. The method according to claim 83, wherein at least one alpha-1
adrenoreceptor agonist is co-administered with a therapeutically
effective amount of at least one other active agent selected from
the group consisting of antibacterial agents, antiparasitic agents,
antifungal agents, anti-inflammatory agents, antihistamines,
anti-pruriginous agents, anesthetics, antiviral agents, keratolytic
agents, anti free-radical agents, antiseborrheic agents,
antidandruff agents, antiacne agents, sunscreens and sun blocking
agents, and active agents which modify at least one of cutaneous
differentiation, proliferation, and pigmentation.
94. The method according to claim 83, wherein said at least one
alpha-1 adrenoreceptor agonist is administered in a
pharmacologically or cosmetically acceptable form selected from the
group consisting of solutions, gels, lotions creams, ointments,
foams, emulsions, microemulsions, milks, serums, aerosols, sprays,
dispersions, microcapsules, vesicles and microparticles
thereof.
95. The method according to claim 83, wherein said at least one
alpha-1 adrenoreceptor agonist is administered in a
pharmacologically or cosmetically acceptable form selected from the
group consisting of soaps and cleansing bars.
96. The method according to claim 83, wherein said skin redness,
rosacea, or discreet erythema is elicited by at least one factor
selected from the group consisting of intake of food, of hot or
alcoholic drinks, temperature variations, heat, exposure to
ultraviolet or infrared radiation, exposure to low relative
humidity, exposure of the skin to strong winds or currents of air,
exposure of the skin to surfactants, irritants, irritant
dermatological topical agents, or cosmetics.
97. A method of treating cutaneous flushing in humans caused by
abnormal, endogenously-induced vasomotor instability comprising
administering, to said human via topical dermatological
application, a composition comprising at least one selective
.alpha..sub.2 adrenergic receptor agonist admixed with a
dermatologically acceptable carrier, in an amount effective to
reduce, inhibit, reverse or prevent cutaneous facial flushing.
98. The method of claim 97, wherein the composition contains at
least one (2-imidazolin-2-ylamino) quinoxaline derivative.
99. The method of claim 97, wherein the cutaneous flushing is
facial flushing and the flushing re action is caused by acne
rosacea.
100. The method of claim 98, wherein the cutaneous flushing is
facial flushing and the flushing reaction is caused by acne
rosacea.
101. The method of claim 97, wherein the cutaneous flushing is
facial flushing and the flushing reaction is caused by
menopause-associated hot flashes.
102. The method of claim 98, wherein the cutaneous flushing is
facial flushing and the flushing reaction is caused by
menopause-associated hot flashes.
103. The method of claim 97, wherein the cutaneous flushing is
facial flushing and the flushing reaction is the result of hot
flashes following orchiectomy.
104. The method of claim 98, wherein the cutaneous flushing is
facial flushing and the flushing reaction is the result of hot
flashes following orchiectomy.
105. The method of claim 97, wherein the cutaneous flushing is
facial flushing and the flushing reaction is caused by ingestion of
a substance capable of inducing cutaneous facial flushing selected
from the group consisting of alcohol, chocolate, spice,
flavor-enhancing additives and mono-sodium glutamate.
106. The method of claim 98, wherein the cutaneous flushing is
facial flushing and the flushing reaction is caused by ingestion of
a substance capable of inducing cutaneous facial flushing selected
from the group consisting of alcohol, chocolate, spice,
flavor-enhancing additives and mono-sodium glutamate.
107. The method of claim 98, wherein the composition further
comprises an agent, or combination of agents, selected from the
group consisting of antibacterial agents, anthelmintic agents,
antioxidant agents, steroidal anti-inflammatory agents,
non-steroidal anti-inflammatory agents, antiangiogenic agents, and
derivatives of retinoic acid.
108. The method of claim 97, wherein the composition further
comprises an agent, or combination of agents, selected from the
group consisting of antibacterial agents, anthelmintic agents,
antioxidant agents, steroidal anti-inflammatory agents,
non-steroidal anti-inflammatory agents, antiangiogenic agents, and
derivatives of retinoic acid.
109. The method according to claim 98, wherein said at least one
(2-imidazolin-2-ylamino)quinoxaline derivative is brimonidine
tartrate.
110. The method of claim 98, wherein the composition further
comprises: aloe; compounds that act as sunscreens; or a combination
of aloe and compounds that act as sunscreens.
111. The method of claim 98, wherein the composition further
comprises a preservative.
112. The method of claim 98, wherein the composition further
comprises a halogen.
113. The method of claim 98, wherein the
(2-imidazolin-2-ylamino)quinoxaline derivative is combined with an
acidic group other than tartrate.
114. The method of claim 97, wherein the composition further
comprises an agent, or combination of agents, selected from the
group consisting of antibacterial agents, anthelmintic agents,
antioxidant agents, steroidal anti-inflammatory agents,
non-steroidal anti-inflammatory agents, antiangiogenic agents, and
derivatives of retinoic acid.
115. The method of claim 114, wherein the composition further
comprises: aloe; compounds that act as sunscreens; or a combination
of aloe and compounds that act as sunscreens.
116. The method of claim 115, wherein the composition further
comprises a preservative.
117. The method of claim 116, wherein the composition further
comprises a halogen.
118. A composition comprising at least one selective .alpha..sub.2
adrenergic receptor agonist admixed with a dermatologically
acceptable carrier and one or more agent selected from the group
consisting of antibacterial agents, anthelmintic agents,
antioxidant agents, steroidal anti-inflammatory agents,
non-steroidal anti-inflammatory agents, antiangiogenic agents,
derivatives of retinoic acid, aloe, compounds that act as
sunscreens, a combination of aloe and compounds that act as
sunscreens, preservatives, halogens and combinations of said
agents.
119. The composition according to claim 118, wherein the selective
.alpha..sub.2 adrenergic receptor agonist is a
(2-imidazolin-2-ylamino)quinoxaline derivative.
120. The composition according to claim 119 wherein said
(2-imidazolin-2-ylamino)quinoxaline derivative is brimonidine
tartrate.
121. The composition according to claim 119, wherein said at least
one selective adrenergic receptor agonist is selected from the
group consisting of guanabenz, guanfacine, alpha-methyl DOPA
(methydopamine), amphetamine, methylphenidate, lofexidine,
moxonidine, dexmedetomidine, mivazerol,
(2-imidazolin-2-ylamino)quinoxaline derivatives, brimonidine, and
combinations thereof.
122. A method for the treatment of flushing in an individual
comprising the administration of a composition comprising at least
one selective .alpha..sub.2 adrenergic receptor agonist and a
carrier in an amount sufficient to prevent, reduce, ameliorate, or
inhibit facial flushing.
123. The method of claim 120, wherein said at least one selective
adrenergic receptor agonist is selected from the group consisting
of guanabenz, guanfacine, alpha-methyl DOPA (methydopamine),
amphetamine, methylphenidate, lofexidine, moxonidine,
dexmedetomidine, mivazerol, (2-imidazolin-2-ylamino) quinoxaline
derivatives, brimonidine, and combinations thereof.
124. The method of claim 97, wherein said at least one selective
adrenergic receptor agonist is selected from the group consisting
of guanabenz, guanfacine, alpha-methyl DOPA (methydopamine),
amphetamine, methylphenidate, lofexidine, moxonidine,
dexmedetomidine, mivazerol, (2-imidazolin-2-ylamino) quinoxaline
derivatives, brimonidine, and combinations thereof.
125. A method of reducing or eliminating redness associated with
rosacea comprising topically administering an effective amount of
nephazoline or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof to the site of
the redness on the skin of a patient.
126. The method of claim 125, wherein the nephazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof is administered in an amount
sufficient to decrease blood flow through the small arteries or
arterioles of the skin of the patient.
127. The method of claim 125, wherein the nephazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof acts locally on the skin of the
patient.
128. A method of reducing or eliminating redness associated with
rosacea comprising topically administering an effective amount of
oxymetazoline or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof to the site of
the redness on the skin of a patient.
129. The method of claim 128, wherein the oxymetazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof is administered in an amount
sufficient to decrease blood flow through the small arteries or
arterioles of the skin of the patient.
130. The method of claim 128, wherein the oxymetazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof acts locally on the skin of the
patient.
131. A method of reducing or eliminating redness associated with
rosacea comprising topically administering an effective amount of
xylometazoline or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof to the site of
the redness on the skin of a patient.
132. The method of claim 131, wherein the xylometazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof is administered in an amount
sufficient to decrease blood flow through the small arteries or
arterioles of the skin of the patient.
133. The method of claim 131, wherein the xylometazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof acts locally on the skin of the
patient.
134. A topical composition intended for treating or preventing the
redness associated with rosacea comprising: nephazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof; and a pharmaceutically acceptable
carrier.
135. The topical composition according to claim 134, wherein the
pharmaceutically acceptable carrier is selected from the group
including sprays, mists, aerosols, solutions, lotions, gels,
creams, ointments, pastes, unguents, emulsions, and
suspensions.
136. The topical composition according to claim 134, wherein the pH
value of the composition is in the range of about 5 to 8.
137. A topical composition intended for treating or preventing the
redness associated with rosacea comprising: oxymetazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof; and a pharmaceutically acceptable
carrier.
138. The topical composition according to claim 137, wherein the
pharmaceutically acceptable carrier is selected from the group
including sprays, mists, aerosols, solutions, lotions, gels,
creams, ointments, pastes, unguents, emulsions, and
suspensions.
139. The topical composition according to claim 137, wherein the pH
value of the composition is in the range of about 5 to 8.
140. A topical composition intended for treating or preventing the
redness associated with rosacea comprising: xylometazoline or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof; and a pharmaceutically acceptable
carrier.
141. The topical composition according to claim 140, wherein the
pharmaceutically acceptable carrier is selected from the group
including sprays, mists, aerosols, solutions, lotions, gels,
creams, ointments, pastes, unguents, emulsions, and
suspensions.
142. The topical composition according to claim 140, wherein the pH
value of the composition is in the range of about 5 to 8.
143. A topical composition intended for treating or preventing the
redness associated with rosacea comprising: at least one of
nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof; and a pharmaceutically acceptable
carrier.
144. The topical composition according to claim 134, wherein the
pharmaceutically acceptable carrier is selected from the group
including sprays, mists, aerosols, solutions, lotions, gels,
creams, ointments, pastes, unguents, emulsions, and
suspensions.
145. The topical composition according to claim 144, wherein the
pharmaceutically acceptable carrier is an aqueous gel comprising
water, and a water-gelling amount of a pharmaceutically acceptable
gelling agent selected from the group including carbomers,
glycerine polyacrylate, and mixtures thereof, the topical
composition having a physiologically acceptable pH.
146. The topical composition according to claim 145, wherein the at
least one of nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof is present in an amount in the range
of about 0.01 to 5 weight percent.
147. The topical composition according to claim 145, wherein the pH
value of the composition is in the range of about 5 to 8.
148. The topical composition according to claim 145, further
comprising a preservative.
149. The topical composition according to claim 145, further
comprising a local anesthetic.
150. The topical composition according to claim 145, further
comprising a skin humectant.
151. A package for a topical composition suitable for treating or
preventing the symptoms of rosacea comprising at least one of
nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof, and a pharmaceutically acceptable
carrier, comprising a container and instructions for use of the
topical composition.
152. The topical composition according to claim 144, wherein the
pharmaceutically acceptable carrier is at least one of a cream and
an ointments comprising stearic acid, stearyl alcohol, cetyl
alcohol, glycerin, and water, the topical composition having a
physiologically acceptable pH.
153. The topical composition according to claim 152, wherein the at
least one of nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof, is present in an amount in the range
of about 0.01 to 5 weight percent.
154. The topical composition according to claim 152, wherein the pH
value of the composition in the range of about 5 to 8.
155. The topical composition according to claim 152, further
comprising a preservative.
156. The topical composition according to claim 152, further
comprising a local anesthetic.
157. The topical composition according to claim 152, further
comprising a skin humectant.
158. The topical composition according to claim 143, wherein the at
least one of nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof, is provided in a concentration
sufficient to decrease blood flow through the small arteries or
arterioles of the skin of the patient to which it is applied.
159. The topical composition according to claim 143, wherein the
composition acts locally in the skin of the patient.
160. A method of reducing or eliminating redness associated with
rosacea comprising topically administering a pharmaceutical
composition comprising an effective amount of at least one of
nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof, to the site of the redness on the
skin of a patient.
161. The method of claim 160, wherein the at least one of
nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof, is administered in an amount
sufficient to decrease blood flow through the small arteries or
arterioles of the skin of the patient.
162. The method of claim 160, wherein the at least one of
nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof, acts locally on the skin of the
patient.
163. A topical dermal composition intended for treating or
preventing the redness associated with rosacea comprising: at least
one of nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof; and a pharmaceutically acceptable
carrier.
164. The topical composition according to claim 163, wherein the
pharmaceutically acceptable carrier is selected from the group
including sprays, mists, aerosols, solutions, lotions, gels,
creams, ointments, pastes, unguents, emulsions, and
suspensions.
165. The topical composition according to claim 163, wherein the pH
value of the composition is in the range of about 5 to 8.
166. A topical dermal composition intended for treating or
preventing the redness associated with rosacea comprising:
brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof; and a
pharmaceutically acceptable carrier.
167. The topical composition according to claim 166, wherein the
pharmaceutically acceptable carrier is selected from the group
including sprays, mists, aerosols, solutions, lotions, gels,
creams, ointments, pastes, unguents, emulsions, and
suspensions.
168. The topical composition according to claim 166, wherein the pH
value of the composition is in the range of about 5 to 8.
169. A method of reducing or eliminating redness associated with
rosacea comprising topically administering a pharmaceutical
composition comprising an effective amount of brimonidine or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof to the site of the redness on the skin
of a patient.
170. The method of claim 169, wherein the brimonidine or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof is administered in an amount
sufficient to decrease blood flow through the small arteries or
arterioles of the skin of the patient.
171. The method of claim 169, wherein the brimonidine or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof acts locally on the skin of the
patient.
172. The topical composition according to claim 14, wherein the
topical composition comprises a formulation containing a suspension
of brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof such that the
solubilized portion of the drug is held constant at 100% saturation
solubility over the shelf life of the formulation and during
application.
173. The topical composition according to claim 21, wherein the
topical composition comprises a formulation containing a suspension
of brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof such that the
solubilized portion of the drug is held constant at 100% saturation
solubility over the shelf life of the formulation and during
application.
174. The topical composition according to claim 36, wherein the
topical composition comprises a formulation containing a suspension
of the at least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof such that the solubilized portion of the drug is held
constant at 100% saturation solubility over the shelf life of the
formulation and during application.
175. The topical composition according to claim 42, wherein the
topical composition comprises a formulation containing a suspension
of the at least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof such that the solubilized portion of the drug is held
constant at 100% saturation solubility over the shelf life of the
formulation and during application.
176. The topical composition according to claim 49, wherein the
topical composition comprises a formulation containing a suspension
of the at least one of an .alpha. adrenergic receptor agonist, a
pharmaceutically acceptable salt thereof, a prodrug thereof, an
active metabolite thereof, a derivative thereof, and an analog
thereof such that the solubilized portion of the drug is held
constant at 100% saturation solubility over the shelf life of the
formulation and during application.
177. The topical composition according to claim 145, wherein the
topical composition comprises a formulation containing a suspension
of the at least one of nephazoline, oxymetazoline, and
xylometazoline, or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof such that the
solubilized portion of the drug is held constant at 100% saturation
solubility over the shelf life of the formulation and during
application.
178. The topical composition according to claim 152, wherein the
topical composition comprises a formulation containing a suspension
of the at least one of nephazoline, oxymetazoline, and
xylometazoline, or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof such that the
solubilized portion of the drug is held constant at 100% saturation
solubility over the shelf life of the formulation and during
application.
179. The topical composition according to claim 14, wherein the
brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof is present in a
concentration in the range of from about 20% to about 200% of the
maximum equilibrium solubility of the drug in a delivery
vehicle.
180. The topical composition according to claim 21, wherein the
brimonidine or a pharmaceutically acceptable salt or prodrug or
active metabolite or derivative or analog thereof is present in a
concentration in the range of from about 20% to about 200% of the
maximum equilibrium solubility of the drug in a delivery
vehicle.
181. The topical composition according to claim 36, wherein the at
least one of an a adrenergic receptor agonist, a pharmaceutically
acceptable salt thereof, a prodrug thereof, an active metabolite
thereof, a derivative thereof, and an analog thereof is present in
a concentration in the range of from about 20% to about 200% of the
maximum equilibrium solubility of the drug in a delivery
vehicle.
182. The topical composition according to claim 42, wherein the at
least one of an a adrenergic receptor agonist, a pharmaceutically
acceptable salt thereof, a prodrug thereof, an active metabolite
thereof, a derivative thereof, and an analog thereof is present in
a concentration in the range of from about 20% to about 200% of the
maximum equilibrium solubility of the drug in a delivery
vehicle.
183. The topical composition according to claim 49, wherein the at
least one of an a adrenergic receptor agonist, a pharmaceutically
acceptable salt thereof, a prodrug thereof, an active metabolite
thereof, a derivative thereof, and an analog thereof is present in
a concentration in the range of from about 20% to about 200% of the
maximum equilibrium solubility of the drug in a delivery
vehicle.
184. The topical composition according to claim 145, wherein the at
least one of nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof is present in a concentration in the
range of from about 20% to about 200% of the maximum equilibrium
solubility of the drug in a delivery vehicle.
185. The topical composition according to claim 152, wherein the at
least one of nephazoline, oxymetazoline, and xylometazoline, or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof, is present in a concentration in the
range of from about 20% to about 200% of the maximum equilibrium
solubility of the drug in a delivery vehicle.
186. A method of treating or preventing redness associated with
rosacea comprising topically administering a pharmaceutical
composition comprising an effective amount of brimonidine or a
pharmaceutically acceptable salt or prodrug or active metabolite or
derivative or analog thereof to a site on the skin of a patient.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/853,585, filed May 25, 2004, which in turn
claims priority from U.S. Patent Application Ser. No. 60/473,611,
filed on May 27, 2003, both of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention is directed to compounds and methods
for treatment or prevention of rosacea. The compounds and methods
taught by the present invention are particularly useful for
treating or preventing rosacea and the symptoms of rosacea.
BACKGROUND OF THE INVENTION
[0003] Many people are affected by inflammatory skin disorders that
result in unsightly and painful rashes, acne, persistent red veins,
and acne-like skin eruptions, such as macules, nodules, and
pustules that may ooze or crust. Inflammatory skin disorders often
result in intense psychosocial distress. Rosacea is a common
inflammatory skin disorder affecting over 10 million people in the
United States. Rosacea generally involves the cheeks, nose, chin,
and forehead and the typical age of onset is 30 to 60 years. See
e.g., Zuber T. J., Rosacea: Beyond First Blush 32 HOSP. PRACT.
188-189 (1997); THE MERCK MANUAL 813-814 (Keryn A. G. Lane et al.
eds. 17.sup.th ed. 2001). Many people with early-stage rosacea
incorrectly assume that they suffer from adult acne, sun or
windburn, or the normal effects of aging.
[0004] Rosacea develops gradually starting as frequent blushing and
frequent irritation of the facial skin. More advanced rosacea is
characterized by a vascular stage where patients display
increasingly severe erythema (abnormal redness of the skin) and
telangiectasia (visible red lines due to abnormal dilatation of
capillary vessels and arterioles). Pimple-like eruptions, which may
be solid (called papules or nodules) or puss filled (known as
pustules) may develop. Such eruptions often look like acne, but
whiteheads or blackheads (common symptoms of acne) are not normally
present. Later-stage rosacea is characterized by rhinophyma
(enlargement of the nose). If left untreated, rosacea can progress
to irreversible disfigurement. Rosacea symptoms are often
aggravated by sun exposure, changes or extremes in temperature,
wind, and consumption of certain foods, such as spicy foods,
caffeine, and alcohol.
[0005] The exact pathogenesis of rosacea is unknown, but the
pathologic process is well described. For example, erythema
associated with rosacea is caused by dilation of the superficial
vasculature of the face. Zuber T. J., Rosacea: Beyond First Blush
32 HOSP. PRACT. 188-189 (1997).
[0006] There is no known cure for rosacea. Current treatments,
which are directed to control of redness, inflammation, and skin
eruptions, are of limited effectiveness in many patients and,
generally, can be used only for a limited duration. Standard
treatments include avoidance of triggers such as sun exposure, wind
exposure, alcohol consumption, spicy foods, and irritating facial
cleansers, lotions, and cosmetics. Antibiotics are the traditional
first line of therapy. Long-term treatment (5 to 8 weeks or more)
with oral antibiotics such as tetracycline, minocycline,
doxycycline or clarithromycin may control skin eruptions.
Alternative oral treatments include vitamin A medications, such as
isoretinoin and antifungal medications. Unfortunately, such oral
medications often cause side effects and many people have limited
tolerance. Topical treatments, such at topically applied
antibiotics and antifungals (such as metronidazole) or steroids,
are available but also have limited effectiveness and cannot treat
all symptoms. For example, isoretinoin has serious teratogenic
side-effects and female patients of child bearing age must use
effective birth control or avoid the therapy. Topical treatments
include topically applied metronidazole, topically applied
steroids, topically applied azelaic acid, topically applied
rentinoic acid or retinaldehyde, and topical vitamin C preparations
are available but have limited effectiveness and cannot treat all
symptoms. Surgery, such as the laser elimination of blood vessels,
is typically a last resort, but may be prescribed if other
treatments are ineffective. In patients with nose hyperplasia,
surgical reduction may improve the patient's cosmetic appearance,
but does not treat the disease itself. Mixed light pulse
(photoderm) therapy has proved somewhat effective for certain
rosacea symptoms in some patients. Thus, there remains a need for
topical formulations for treatment of rosacea and its symptoms.
[0007] Agonists of the .alpha..sub.2 adrenoceptors have been used
therapeutically for a number of conditions including hypertension,
congestive heart failure, angina pectoris, spasticity, glaucoma,
diarrhea, and for the suppression of opiate withdrawal symptoms (J.
P. Heible and R. R. Ruffolo Therapeutic Applications of Agents
Interacting with .alpha.-Adrenoceptors, p. 180-206 in Progress in
Basic and Clinical Pharmacology Vol. 8, P. Lomax and E. S. Vesell
Ed., Karger, 1991). Adrenoceptor agonists such as clonidine have
been primarily used orally, though a patch formulation is known.
The goal of existing formulations is to deliver a systemic internal
dose of the compound to the patient. The .alpha..sub.2 agonists are
known to mediate vasoconstriction both in the core and periphery of
a patient. In particular .alpha..sub.2 adrenoceptor agonists are
known to cause vasoconstriction of peripheral arterioles, in
response to stimulation due to cold or stress.
[0008] A number of patents describe the use of brimonidine for
treating ophthalmic conditions and eye diseases. In Canadian patent
No. CA2326690, there is described the use of topical ophthalmic
preparations for use only in the eyes, to treat eye diseases. The
Canadian patent discusses the problems with ophthalmic preparations
taken topically (in the eye), orally or parenterally, and their
systemic effects, including some serious, that limit their use.
These systemic effects include, cardiopulmonary effects of
.beta.-blockers like timolol; dryness of mouth, flush, fever, tachy
cardia, urinary retention, convulsion and irritability with
atropine; hypertension with phenylephine; increased salivation,
nausea, vomiting, diarrhea, stomach cramps, bronchial secretions,
brionchial constriction, asthma, bradycardia, paresthesia with
miotics; hypotension with clonidine; and dry mouth, fatigue and
drowsiness with apraclonidine and brimonidine.
[0009] There has been no composition containing .alpha..sub.2
adrenoceptor agonists that can deliver a dose of the agonist to the
patient, ameliorating the symptoms of rosacea, without causing
systemic side effects. There has also been no topical skin
composition containing .alpha..sub.2 adrenoceptor agonists that can
deliver a dose of the agonist to the skin of the patient,
ameliorating the symptoms of rosacea, without causing systemic side
effects.
SUMMARY OF THE INVENTION
[0010] The present invention provides methods, compounds, and
topical skin formulations for treatment of rosacea and its
symptoms. Compounds of the invention are .alpha..sub.2 adrenoceptor
agonists that act on the peripheral vasculature to cause
vasoconstriction and thereby ameliorate the symptoms of rosacea.
The compounds are delivered in a topical skin composition that
insures that the compounds are effective in the skin of a patient
but do not penetrate the skin in sufficient amounts to induce
serious systemic side effects.
[0011] Compounds of one embodiment of the invention are represented
by Formula I below: ##STR2##
[0012] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy;
and each of R.sub.6 and R.sub.7 is independently hydrogen, nitro,
alkyl, preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula I, R.sub.6 and R.sub.7 are both hydrogen. In another
preferred embodiment, R.sub.4 and R.sub.5 are both hydrogen.
[0013] To treat or prevent rosacea, according to the methods of the
invention, the compounds of this embodiment of the invention are
topically applied. Preferably the compounds of the invention are
delivered in a topical formulation. Formulations for topical
delivery of compounds of the invention are well-known in the art,
such as aqueous or non-aqueous solutions or suspensions, creams,
lotions, gels, or ointments.
[0014] Compounds of another embodiment of the invention are
represented by Formula II below: ##STR3##
[0015] Compounds of another embodiment of the invention are
represented by Formula III below: ##STR4##
[0016] Compounds of other embodiments of the invention are shown
below: ##STR5##
[0017] These and other features, aspects, and advantages of the
present invention will become better understood with reference to
the following detailed description, examples, and claims.
[0018] These and other features, aspects, and advantages of the
invention will become better understood with reference to the
following detailed description, examples, and appended claims.
DETAILED DESCRIPTION
1.1 COMPOUNDS OF THE INVENTION
[0019] In one embodiment, the invention is directed to compounds of
the Formula I: ##STR6##
[0020] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy;
and each of R.sub.6 and R.sub.7 is independently hydrogen, nitro,
alkyl, preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula I, R.sub.6 and R.sub.7 are both hydrogen. In another
preferred embodiment, R.sub.4 and R.sub.5 are both hydrogen.
[0021] In another embodiment, the invention is directed to
compounds of the Formula Ia; ##STR7##
[0022] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy;
and each of R.sub.6 and R.sub.7 is independently hydrogen, nitro,
alkyl, preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula Ia, R.sub.6 and R.sub.7 are both hydrogen. In another
preferred embodiment, R.sub.4 and R.sub.5 are both hydrogen. In
still another preferred embodiment of the compounds of Formula Ia,
R.sub.2 and R.sub.3 are both hydrogen and R.sub.1 is halo,
preferably, bromo.
[0023] In another embodiment, the invention relates to compounds of
the Formula Ib: ##STR8##
[0024] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy. In a preferred
embodiment of the compounds of Formula Ib, R.sub.2 and R.sub.3 are
both hydrogen and R.sub.1 is halo, preferably, bromo.
[0025] In another embodiment the invention relates to compounds of
the Formula Ic: ##STR9##
[0026] wherein R.sub.1 is hydrogen, halogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy. In
a preferred embodiment R.sub.1 is halo, more preferably, bromo; and
each of R.sub.4 and R.sub.5 is independently hydrogen, alkyl,
preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula Ic, at least one of R.sub.4 and R.sub.5 is hydrogen.
[0027] In another embodiment, the invention relates to compounds of
the Formula Id: ##STR10##
[0028] wherein R.sub.1 is hydrogen, halogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy.
In a preferred embodiment, R.sub.1 is halo, more preferably,
bromo.
[0029] In another embodiment, the invention relates to compounds of
the Formula II: ##STR11##
[0030] wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl, and A.sub.2 is hydrogen or
hydroxyl.
[0031] In another embodiment, the invention relates to compounds of
the Formula III: ##STR12##
[0032] wherein each of B.sub.1, B.sub.2, and B.sub.3 is
independently hydrogen, hydroxy, or methoxy; each of B.sub.4 and
B.sub.5 is independently hydrogen or alkyl.
[0033] Preferred compounds of the invention are listed in Table 1
below. TABLE-US-00001 TABLE 1 Compounds Of The Invention Compound
of the Invention Name ##STR13##
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H- imidazol-2-yl)-amine
(Brimonidine) ##STR14## (8-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-
imidazol-2-yl)-amine ##STR15##
(8-Bromo-quinoxalin-5-yl)-(4,5-dihydro-1H- imidazol-2-yl)-amine
##STR16## (5-Bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-
1H-imidazol-2-yl)-amine ##STR17##
(5-Bromo-2-methoxy-quinoxalin-6-yl)-(4,5-
dihydro-1H-imidazol-2-yl)-amine ##STR18##
(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl- quinoxalin-6-yl)-amine
##STR19## (4,5-dihydro-1H-imidazol-2-yl)-quinoxalin-5-yl- amine
##STR20## Tetrahydrozaline ##STR21## Naphazoline ##STR22##
Oxymetazoline ##STR23## Xylometazoline ##STR24## Epinephrine
##STR25## Norepinephrine ##STR26## Phenylephrine ##STR27##
Methoxyamine
[0034] The most preferred compound is
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
(commonly referred to as brimonidine) and pharmaceutically
acceptable salts thereof, particularly the tartrate salt. Other
compounds of the invention include naphazoline, tetra-hydrozaline,
oxymetazoline, xylometazoline, epinephrine, norepinephrine,
phenylephrine and methoxamine and their pharmaceutically acceptable
salts.
[0035] The compounds of the invention are well known in the art to
be .alpha..sub.2 adrenergic receptor agonists. As such the
compounds have powerful vasoconstricting effects when introduced
into the body of mammals, particularly humans.
1.2 SYNTHESIS OF COMPOUNDS OF THE INVENTION
[0036] The compounds of the invention can be prepared in accordance
with well-known synthetic procedures, for example, using the
general synthetic procedures outlined in U.S. Pat. No. 3,890,319
(issued Jun. 17, 1975) and U.S. Pat. No. 4,029,792 (issued Jun. 14,
1977) both of which patents are hereby incorporated herein by
reference. Scheme 1 below illustrates one method to synthesize
compounds of Formula I. ##STR28##
[0037] Compounds of the invention can be synthesized by reaction of
the appropriate quinoxalines 15 with thiophosgene 20 to form
corresponding isothiocyanates 25. The reaction with thiophosgene
can be carried out in aqueous solution or in dilute aqueous
hydrochloric acid at room temperature in a period of about 2 hours.
Alternatively, the thiophosgene 20 dissolved in a water-immiscible
solvent, such as chloroform, can be added to a basic aqueous
solution 20 (sodium carbonate) of quinoxalines 15 and stirred for
about two hours. In the first alternative, isothiocyanates 25
precipitate from the reaction mixture. Precipitation can be
completed by neutralization with excess aqueous base. Precipitated
isothiocyanates 25 are recovered by filtration and dissolved in a
suitable solvent, e.g., chloroform, to form a solution. The
solution is dried (e.g., MgSO.sub.4), filtered, and concentrated to
yield the isothiocyanates 25.
[0038] Isothiocyanates 25 are treated with an excess of the
appropriately substituted ethylene diamine 30 to form the
corresponding 3-quinoxalin-6-yl-thioureas 35. Isothiocyanates 25
are reacted with an excess (e.g., 5 moles to 1 mole) of ethylene
diamine 30 in a suitable solvent, e.g., diethyl ether, benzene,
chloroform or dioxane. The reaction is carried out at room
temperature for about 2 hours. 3-Quinoxalin-6-yl-thioureas 35
precipitate and are recovered by filtration and washing the filter
cake with solvent.
[0039] Cyclization of 3-quinoxalin-6-yl-thioureas 35 to afford
compounds of the invention 10 is effected by heating a suspension
of thioureas 35 with mercuric or cupric oxide in a suitable organic
solvent, e.g., ethanol. The mercuric or cupric oxide can be
replaced by an organic soluble mercuric or cupric salt, e.g.,
mercuric or cupric acetate. The reaction mixture is filtered, to
remove the mercuric or cupric sulfide by-product, and the filtrate
is concentrated to give compounds 10 in crude form. Compounds 10
are recrystallized as the free base or converted to an
acid-addition salt by conventional reaction with a suitable acid.
In certain cases, cyclization can be effected by simply refluxing
the thioureas 35 in a suitable organic solvent, e.g., methanol, in
the absence of mercuric or cupric oxide.
[0040] Quinoxalines 15 are synthesized by well-known synthetic
procedures, for example, the procedures disclosed in J. A. JOULE ET
AL., HETEROCYCLIC CHEMISTRY 189-224 (3rd ed. 1995), hereby
incorporated herein by reference.
1.3 TOPICAL FORMULATIONS OF THE INVENTION
[0041] In one embodiment, the compounds of the invention are
delivered to the affected area of the skin in a pharmaceutically
acceptable topical carrier. As used herein, a pharmaceutically
acceptable topical carrier is any pharmaceutically acceptable
formulation that can be applied to the skin surface for topical,
dermal, intradermal, or transdermal delivery of a pharmaceutical or
medicament. The combination of a pharmaceutically acceptable
topical carrier and a compound of the invention is termed a topical
formulation of the invention. Topical formulations of the invention
are prepared by mixing a compound of the invention with a topical
carrier according to well-known methods in the art, for example,
methods provided by standard reference texts such as, REMINGTON:
THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 1672-1673,
866-885(Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K.; et al.
TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), both of which
are hereby incorporated herein by reference.
[0042] The topical carriers useful for topical delivery of
compounds of the invention can be any carrier known in the art for
topically administering pharmaceuticals, for example, but not
limited to, pharmaceutically acceptable solvents, such as a
polyalcohol or water; emulsions (either oil-in-water or
water-in-oil emulsions), such as creams or lotions; micro
emulsions; gels; ointments; liposomes; powders; and aqueous
solutions or suspensions, such as standard ophthalmic
preparations.
1.3.1 Emulsions, Gels, and Ointments as Topical Carriers
[0043] In a preferred embodiment, the topical carrier used to
deliver a compound of the invention is an emulsion, gel, or
ointment. Emulsions, such as creams and lotions are suitable
topical formulations for use in the invention. An emulsion is a
dispersed system comprising at least two immiscible phases, one
phase dispersed in the other as droplets ranging in diameter from
0.1 .mu.m to 100 .mu.m. An emulsifying agent is typically included
to improve stability. When water is the dispersed phase and an oil
is the dispersion medium, the emulsion is termed a water-in-oil
emulsion. When an oil is dispersed as droplets throughout the
aqueous phase as droplets, the emulsion is termed an oil-in-water
emulsion. Emulsions, such as creams and lotions that can be used as
topical carriers and their preparation are disclosed in REMINGTON:
THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R. Gennaro
ed. 19th ed. 1995), hereby incorporated herein by reference.
[0044] In another embodiment, the topical carrier used to deliver a
compound of the invention is a gel, for example, a two-phase gel or
a single-phase gel. Gels are semisolid systems consisting of
suspensions of small inorganic particles or large organic molecules
interpenetrated by a liquid. When the gel mass comprises a network
of small discrete inorganic particles, it is classified as a
two-phase gel. Single-phase gels consist of organic macromolecules
distributed uniformly throughout a liquid such that no apparent
boundaries exist between the dispersed macromolecules and the
liquid. Suitable gels for use in the invention are disclosed in
REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso
R. Gennaro ed. 19th ed. 1995), hereby incorporated herein by
reference. Other suitable gels for use with the invention are
disclosed in U.S. Pat. No. 6,387,383 (issued May 14, 2002); U.S.
Pat. No. 6,517,847 (issued Feb. 11, 2003); and U.S. Pat. No.
6,468,989 (issued Oct. 22, 2002), each of which patents is hereby
incorporated herein by reference.
[0045] Polymer thickeners (gelling agents) that may be used include
those known to one skilled in the art, such as hydrophilic and
hydroalcoholic gelling agents frequently used in the cosmetic and
pharmaceutical industries. Preferably, the hydrophilic or
hydroalcoholic gelling agent comprises "CARBOPOL.RTM." (B.F.
Goodrich, Cleveland, Ohio), "HYPAN.RTM." (Kingston Technologies,
Dayton, N.J.), "NATROSOL.RTM." (Aqualon, Wilmington, Del.),
"KLUCEL.RTM." (Aqualon, Wilmington, Del.), or "STABILEZE.RTM.D"
(ISP Technologies, Wayne, N.J.). Preferably the gelling agent
comprises between about 0.2% to about 4% by weight of the
composition. More particularly, the preferred compositional weight
percent range for "CARBOPOL.RTM." is between about 0.5% to about
2%, while the preferred weight percent range for "NATROLSOL.RTM."
and "KLUCEL.RTM." is between about 0.5% to about 4%. The preferred
compositional weight percent range for both "HYPAN.RTM." and
"STABILEZE.RTM." is between 0.5% to about 4%.
[0046] "CARBOPOL.RTM." is one of numerous cross-linked acrylic acid
polymers that are given the general adopted name carbomer. These
polymers dissolve in water and form a clear or slightly hazy gel
upon neutralization with a caustic material such as sodium
hydroxide, potassium hydroxide, triethanolamine, or other amine
bases. "KLUCEL.RTM." is a cellulose polymer that is dispersed in
water and forms a uniform gel upon complete hydration. Other
preferred gelling polymers include hydroxyethylcellulose, cellulose
gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer, or a
combination thereof.
[0047] In another preferred embodiment, the topical carrier used to
deliver a compound of the invention is an ointment. Ointments are
oleaginous semisolids that contain little if any water. Preferably,
the ointment is hydrocarbon based, such as a wax, petrolatum, or
gelled mineral oil. Suitable ointments for use in the invention are
well known in the art and are disclosed in REMINGTON: THE SCIENCE
AND PRACTICE OF PHARMACY 1585-1591 (Alfonso R. Gennaro ed. 19th ed.
1995), hereby incorporated herein by reference.
1.3.2 Aqueous Topical Formulations of the Invention
[0048] In another embodiment, the topical carrier used in the
topical formulations of the invention is an aqueous solution or
suspension, preferably, an aqueous solution. Well-known ophthalmic
solutions and suspensions are suitable topical carriers for use in
the invention. Suitable aqueous topical formulations for use in the
invention are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF
PHARMACY 1563-1576 (Alfonso R. Gennaro ed. 19th ed. 1995), hereby
incorporated herein by reference. Other suitable aqueous topical
carrier systems are disclosed in U.S. Pat. No. 5,424,078 (issued
Jun. 13, 1995); U.S. Pat. No. 5,736,165 (issued Apr. 7, 1998); U.S.
Pat. No. 6,194,415 (issued Feb. 27, 2001); U.S. Pat. No. 6,248,741
(issued Jun. 19, 2001); U.S. Pat. No. 6,465,464 (issued Oct. 15,
2002), all of which patents are hereby incorporated herein by
reference.
[0049] The pH of the aqueous topical formulations of the invention
are preferably within the range of from about 6 to about 8, more
preferably, of from about 6.3 to about 6.5. To stabilize the pH,
preferably, an effective amount of a buffer is included. In one
embodiment, the buffering agent is present in the aqueous topical
formulation in an amount of from about 0.05 to about 1 weight
percent of the formulation. Acids or bases can be used to adjust
the pH as needed. Suitable buffering agents are listed below in
Section 1.3.3.
[0050] Tonicity-adjusting agents can be included in the aqueous
topical formulations of the invention. Examples of suitable
tonicity-adjusting agents include, but are not limited to, sodium
chloride, potassium chloride, mannitol, dextrose, glycerin, and
propylene glycol. The amount of the tonicity agent can vary widely
depending on the formulation's desired properties. In one
embodiment, the tonicity-adjusting agent is present in the aqueous
topical formulation in an amount of from about 0.5 to about 0.9
weight percent of the formulation.
[0051] Preferably, the aqueous topical formulations of the
invention have a viscosity in the range of from about 15 cps to
about 25 cps. The viscosity of aqueous solutions of the invention
can be adjusted by adding viscosity adjusting agents, for example,
but not limited to, polyvinyl alcohol, povidone, hydroxypropyl
methyl cellulose, poloxamers, carboxymethyl cellulose, or
hydroxyethyl cellulose.
[0052] In a preferred embodiment, the aqueous topical formulation
of the invention is isotonic saline comprising a preservative, such
as benzalkonium chloride or chlorine dioxide, a viscosity-adjusting
agent, such as polyvinyl alcohol, and a buffer system such as
sodium citrate and citric acid.
1.3.3 Excipients
[0053] The topical formulations of the invention can comprise
pharmaceutically acceptable excipients such as those listed in
REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885(Alfonso R.
Gennaro ed. 19th ed. 1995; Ghosh, T. K.; et al. TRANSDERMAL AND
TOPICAL DRUG DELIVERY SYSTEMS (1997), hereby incorporated herein by
reference, including, but not limited to, protectives, adsorbents,
demulcents, emollients, preservatives, antioxidants, moisturizers,
buffering agents, solubilizing agents, skin-penetration agents, and
surfactants.
[0054] Suitable protectives and adsorbents include, but are not
limited to, dusting powders, zinc sterate, collodion, dimethicone,
silicones, zinc carbonate, aloe vera gel and other aloe products,
vitamin E oil, allatoin, glycerin, petrolatum, and zinc oxide.
[0055] Suitable demulcents include, but are not limited to,
benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
and polyvinyl alcohol.
[0056] Suitable emollients include, but are not limited to, animal
and vegetable fats and oils, myristyl alcohol, alum, and aluminum
acetate.
[0057] Suitable preservatives include, but are not limited to,
quaternary ammonium compounds, such as benzalkonium chloride,
benzethonium chloride, cetrimide, dequalinium chloride, and
cetylpyridinium chloride; mercurial agents, such as phenylmercuric
nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents,
for example, chlorobutanol, phenylethyl alcohol, and benzyl
alcohol; antibacterial esters, for example, esters of
parahydroxybenzoic acid; and other anti-microbial agents such as
chlorhexidine, chlorocresol, benzoic acid and polymyxin. Chlorine
dioxide (ClO.sub.2), preferably, stabilized chlorine dioxide, is a
preferred preservative for use with topical formulations of the
invention. The term "stabilized chlorine dioxide" is well known in
the industry and by those skilled in the art. Stabilized chlorine
dioxide includes one or more chlorine dioxide precursors such as
one or more chlorine dioxide-containing complexes and/or one or
more chlorite-containing components and/or one or more other
entities capable of decomposing or being decomposed in an aqueous
medium to form chlorine dioxide. U.S. Pat. No. 5,424,078 (issued
Jun. 13, 1995), hereby incorporated herein by reference, discloses
a form of stabilized chlorine dioxide and a method for producing
same, which can be used as a preservative for aqueous ophthalmic
solutions and is useful in topical formulations of the invention.
The manufacture or production of certain stabilized chlorine
dioxide products is described in U.S. Pat. No. 3,278,447, hereby
incorporated herein by reference. A commercially available
stabilized chlorine dioxide which can be utilized in the practice
of the present invention is the proprietary stabilized chlorine
dioxide of BioCide International, Inc. of Norman, Okla., sold under
the trademark Purogene.TM. or Purite.TM.. Other suitable stabilized
chlorine dioxide products include that sold under the trademark
DuraKlor by Rio Linda Chemical Company, Inc., and that sold under
the trademark Antheium Dioxide by International Dioxide, Inc.
[0058] Suitable antioxidants include, but are not limited to,
ascorbic acid and its esters, sodium bisulfite, butylated
hydroxytoluene, butylated hydroxyanisole, tocopherols, and
chelating agents like EDTA and citric acid.
[0059] Suitable moisturizers include, but are not limited to,
glycerin, sorbitol, polyethylene glycols, urea, and propylene
glycol.
[0060] Suitable buffering agents for use with the invention
include, but are not limited to, acetate buffers, citrate buffers,
phosphate buffers, lactic acid buffers, and borate buffers.
[0061] Suitable solubilizing agents include, but are not limited
to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate,
lecithin, and polysorbates.
[0062] Suitable skin-penetration agents include, but are not
limited to, ethyl alcohol, isopropyl alcohol,
octylphenylpolyethylene glycol, oleic acid, polyethylene glycol
400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters
(e.g., isopropyl myristate, methyl laurate, glycerol monooleate,
and propylene glycol monooleate); and N-methyl pyrrolidone.
1.3.4 Pharmaceutical Additives
[0063] The topical formulations of the invention can include
pharmaceuticals or their pharmaceutically acceptable salts, for
example, but not limited to, topical corticosteroids and other
anti-inflammatory agents, such as betamethasone, diflorasone,
amcinonide, fluocinolone, mometasone, hydrocortisone, prednisone,
and triamcinolone; local anesthetics and analgesics, such as
camphor, menthol, lidocaine, and dibucaine, and pramoxine;
antifungals, such as ciclopirox, chloroxylenol, triacetin,
sulconazole, nystatin, undecylenic acid, tolnaftate, miconizole,
clotrimazole, oxiconazole, griseofulvin, econazole, ketoconozole,
and amphotericin B; antibiotics and anti-infectives, such as
mupirocin, erythromycin, clindamycin, gentamicin, polymyxin,
bacitracin, and silver sulfadiazine; and antiseptics, such as
iodine, povidine-iodine, benzalkonium chloride, benzoic acid,
chlorhexidine, nitrofurazine, benzoyl peroxide, hydrogen peroxide,
hexachlorophene, phenol, resorcinol, and cetylpyridinium
chloride.
1.4 DOSAGE
[0064] Dosages and dosing frequency will be determined by a trained
medical professional depending on the activity of the compound of
the invention, the characteristics of the particular topical
formulation, and the identity and severity of the dermatologic
disorder treated or prevented.
[0065] In general, a compound of the invention is present in a
formulation of the invention in an amount of from about 0.01
percent to about 5 percent of the total weight of the formulation,
preferably, of from about 0.05 percent to about 1 percent, more
preferably, of from about 0.1 percent to about 0.2 percent of the
total weight of the formulation.
[0066] To treat or prevent rosacea, the topical formulations of the
invention are topically applied directly to the affected area in
any conventional manner well known in the art. For example, by
dropper or applicator stick, as a mist via an aerosol applicator,
via an intradermal or transdermal patch, or by simply spreading a
formulation of the invention onto the affected area with fingers.
Generally the amount of a topical formulation of the invention
applied to the affected skin area ranges from about 0.1 g/cm.sup.2
of skin surface area to about 5 g/cm.sup.2, preferably, 0.2
g/cm.sup.2 to about 0.5 g/cm.sup.2 of skin surface area. Typically,
one to four applications per day are recommended during the term of
treatment.
1.5 USE OF TOPICAL FORMULATIONS OF THE INVENTION IN COMBINATION
WITH OTHER SKIN-DISORDER TREATMENTS
[0067] The formulations of the invention can be used in combination
with other treatments and medications to provide more effective
treatment or prevention of rosacea and its symptoms. In a preferred
embodiment, the topical formulations of the invention are used in
combination with treatment regimens and medications well known for
treatment of dermatologic disorders, such as those disclosed in THE
MERCK MANUAL 811-830 (Keryn A. G. Lane et al. eds. 17.sup.th ed.
2001), hereby incorporated herein by reference.
[0068] Using a formulation or compound of the invention in
combination with another medicament or treatment means
administering a compound of the invention and the other medicament
or treatment to a subject in a sequence and within a time interval
such that they can act together to treat or prevent rosacea and its
symptoms. For example, the compounds of the invention can be
administered at the same time as the other medicament in the same
or separate formulations or at different times.
[0069] Any suitable route of administration can be employed to
deliver the additional treatment or medication including, but not
limited to, oral, intraoral, rectal, parenteral, topical,
epicutaneous, transdermal, subcutaneous, intramuscular, intranasal,
sublingual, buccal, intradural, intraocular, intrarespiratory, or
nasal inhalation. Thus, the formulations of the invention can be
administered together or at separate times with other medications
or treatments.
[0070] In one embodiment, the topical formulations of the invention
are used in combination with systemic administration of antibiotics
or retinoids including, but not limited to, orally dosed
antibiotics, such as tetracycline, minocin, minocycline,
erythromycin, and doxycycline, and orally dosed retinoids such as
isotretinoins (e.g., Accutane or Roaccutance).
[0071] In another embodiment, the topical formulations of the
invention are used in combination with other topical treatments
including, but not limited to, topical formulations consisting of
metronidizole, hydrogen peroxide, benzoyl peroxide, lipoic acid,
and azelaic acid, and sulfur preparations; topically dosed
antibiotics, such as metronidazole, clindamycin, and erythromycin;
topical retinoids such as tretinoin, adapalene, tazarotene; or
topical steroids.
[0072] In another embodiment, the topical formulations of the
invention are used in combination with mixed light pulse therapy
(photoderm), pulsed dye laser treatment, or electrosurgery.
1.6 ARTICLE OF MANUFACTURE
[0073] Another aspect of the invention is an article of manufacture
that comprises a topical formulation of the invention in a suitable
container with labeling and instructions for use. The container can
be a dropper or tube with a suitable small orifice size, such as an
extended tip tube made of any pharmaceutically suitable
material.
[0074] The topical formulations of the invention can be filled and
packaged into a plastic squeeze bottle or tube. Suitable
container-closure systems for packaging a topical formulations of
the invention are commercially available for example, from Wheaton
Plastic Products, 1101 Wheaton Avenue, Millville, N.J. 08332.
[0075] Preferably, instructions are packaged with the formulations
of the invention, for example, a pamphlet or package label. The
labeling instructions explain how to administer topical
formulations of the invention, in an amount and for a period of
time sufficient to treat or prevent rosacea and its symptoms. The
labeling instructions are an important aspect of the invention in
that before a composition can be approved for any particular use,
it must be approved for marketing by the United States Food and
Drug Administration. Part of that process includes providing a
label that will accompany the pharmaceutical composition that is
ultimately sold. Preferably, the label includes the dosage and
administration instructions, the topical formulation's composition,
the clinical pharmacology, drug resistance, pharmacokinetics,
absorption, bioavailability, and contraindications.
1.7 EXAMPLES
[0076] The following examples are provided for illustrative
purposes only and are not to be construed as limiting the
invention's scope in any manner.
1.7.1 Example 1
Synthesis
of(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
[0077] To a stirred solution of 6-amino-5-bromoquinoxaline
hydrobromide (10 g) in distilled water (150 ml) is added
thiophosgene (3 ml). The solution is stirred for two hours at room
temperature and the resultant precipitate is collected by
filtration, washed with water, and dried to afford
5-bromo-6-isothiocyanato-quinoxaline.
[0078] The 5-bromo-6-isothiocyanato-quinoxaline (3.5 g.) is
directly dissolved in benzene (400 ml) and added dropwise to a
well-stirred solution of ethylene diamine (15 g.) in benzene (50
ml). During a period of about two hours, an oil separates as a
lower layer. The upper benzene layer is poured off and the oil is
washed with diethyl ether and then dissolved in methanol (500 ml).
The methanolic solution is refluxed until hydrogen sulfide
evolution ceases. The methanolic solution is concentrated in vacuo
to a volume of approximately 100 ml upon which a yellow solid
precipitates. The precipitate is collected by filtration and
recrystallized from methanol to afford of
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine:
m.p. 250-251 C.
1.7.2 Example 2
[0079] An aqueous solution topical formulation of the invention
comprises
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate
(brimonidine tartrate) (0.15 wt. %); Purite.RTM. (0.005%)
(stabilized chlorine dioxide) as a preservative; and the inactive
ingredients: boric acid; calcium chloride; magnesium chloride;
potassium chloride; purified water; sodium borate; sodium
carboxymethylcellulose; sodium chloride; with hydrochloric acid
and/or sodium hydroxide to adjust the pH to 5.6 to 6.6. The
osmolality is in the range of 250-350 mOsmol/kg.
1.7.3 Example 3
[0080] A aqueous solution topical formulation of the invention
comprises
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate-
, (brimonidine tartrate) (0.15 wt. %); benzalkonium chloride (0.005
wt. %) as a preservative; and the inactive ingredients: boric acid;
calcium chloride; magnesium chloride; potassium chloride; purified
water; sodium borate; sodium carboxymethylcellulose; sodium
chloride; with hydrochloric acid and/or sodium hydroxide to adjust
the pH to 5.6 to 6.6. The osmolality is in the range of 250-350
mOsmol/kg.
1.7.4 Example 4
[0081] A possible cream topical formulation of the invention is
described in the Table below. TABLE-US-00002 Possible Cream
Formulation Of The Invention (Hydrophilic Ointment USP) Ingredient
Weight Percent Brimonidine tartrate 0.15% Stearic acid 7% Stearyl
alcohol 5% Cetyl alcohol 2% Glycerin 10% Sodium lauryl sulfate 1%
Propylparaben 0.05% Methylparaben 0.25% Disodium edetate 0.055
Distilled water QS
[0082] Melt the stearyl alcohol and the white petrolatum on a steam
bath, and warm to about 75 degrees C. Add the other ingredients,
previously dissolved in the water and warmed to 75 degrees C., and
stir the mixture until it congeals. With stirring, allow the
mixture to cool and add brimonidine tartrate as a concentrated
solution.
1.7.5 Example 5
[0083] A possible ointment topical formulation of the invention is
described in the Table below. TABLE-US-00003 Possible Ointment
Formulation of the Invention (Hydrophilic Ointment USP) Ingredients
Weight Brimonidine tartrate 10 g Cholesterol 30 g Stearyl Alcohol
30 g White Wax 80 g White Petrolatum 850 g
[0084] Mix the stearyl alcohol and white wax together on a steam
bath, then add the cholesterol and stir until it completely
dissolves. Add the white petrolatum and mix. Remove from the bath,
and stir until the mixture congeals. Continue stirring and add
brimonidine tartrate as a concentrated slurry.
1.7.6 Example 6
[0085] A possible gel formulation of the invention is described in
the table below. TABLE-US-00004 Possible Gel Formulation of the
Invention Ingredients Weight % Brimonidine tartrate 1.0%
Methylparaben NF 0.15% Propylparaben NF 0.03% Hydroxyethylcellulose
NF 1.25% Disodium Edetate USP 0.05% Purified Water, USP QS 100%
1.7.7 Example 7
[0086] A possible gel formulation of the invention is described in
the Table below. TABLE-US-00005 Possible Gel Formulation of the
Invention Ingredients Weight % Brimonidine tartrate 1.0%
Methylparaben 0.20% Propylparaben 0.05% Carbomer 934P NF 1.0%
Sodium Hydroxide QS pH 7 Purified Water USP QS 100%
[0087] The ingredients are mixed together and aqueous sodium
hydroxide is slowly added to the mixture until a pH of about 7 is
reached and the gel is formed.
1.7.8 Example 8
[0088] A possible gel formulation of the invention is described in
the Table below. TABLE-US-00006 Possible Gel Formulation of the
invention Ingredients Weight % Brimonidine tartrate 1.0%
Methylparaben 0.2% Propylparaben 0.05% "CARBOPOL .RTM." 1.0%
Triethanolamine QS pH 7 Water QS 100%
[0089] The ingredients are mixed together and stirred.
Triethanolamine is added until a pH of about 7 is attained.
1.7.9 Example 9
[0090] Alphagan P (0.15% brimonidine tartrate in isotonic saline
and citrate buffer having a pH of 6.3 to 6.5) was supplied by
Allergan, Inc. having the composition disclosed in Example 2 above.
A study was conducted with four otherwise healthy persons who were
independently diagnosed with phase II rosacea (characterized by
transitory erythema of the mid-facial areas and early
telangiectasis). All subjects followed a morning protocol of
cleansing their face with soap and water. After a gentle towel
drying and air drying, Alphagan-P was administered by gently
rubbing onto areas of facial redness. The application area was
again allowed to air dry without any dressing.
[0091] Subject 1 is a 59 year old woman with a ten year history of
rosacea displaying symptoms of periodic redness flare-ups across
her cheeks that usually runs a course of three to four weeks before
subsiding under customary dermatological treatment. The subject
showed an immediate improvement after the first morning application
of Alphagan-P. All redness disappeared within 10 minutes and her
face remained symptom free for the entire first day. Daily
observation showed only mild return of redness after 24 hours.
Continued daily use resulted in completely eliminating the redness
due to rosacea in three days.
[0092] Subject 2 is a 54 year-old woman with an eight year history
of rosacea who suffers from everyday facial redness across her
cheeks with occasional severe flare-ups. The subject halted her
customary daily dermatological treatment to try the protocol
described above. The result was the same immediate removal of all
redness within ten minutes. The dramatic improvement lasted most of
the day with some mild redness re-occurring in the evening. For
this subject, redness returned the next day. Continued daily use
provided daily relief from redness.
[0093] Subject 3 is a 57 year-old man with a greater than ten-year
history of rosacea displaying symptoms of redness of the cheeks and
the nose. Although this subject's redness due to rosacea is always
present, his general ruddy complexion and lack of concern allows
him to forgo the daily use of customary dermatological treatment in
favor of occasional, ad hoc treatments. A single morning trial of
the Alphagan-P protocol described above resulted in dramatic
daylong relief of redness.
[0094] Subject 4 is a woman in her early forties with a diagnosis
of rosacea on her lower face and chin. Her condition includes some
thickening of skin. Upon trying the protocol, redness was greatly
reduced but not completely eliminated. Qualitatively the reduction
was described as 80% less red. An additional observation of reduced
skin thickening was reported.
[0095] These trials demonstrate that 0.15% brimonidine tartrate,
when used in a daily morning protocol, dramatically eliminates or
reduces redness due to rosacea. It is shown to be an effective
treatment to greatly accelerate the arrest of a rosacea flare-up.
It is further shown to be an effective daily treatment for chronic
rosacea redness.
1.7.10 Example 10
[0096] Use of oxymetazoline
[0097] An oxymetazoline solution (Afrin.RTM., 0.05% solution.
Schering-Plough HealthCare Products) The solution was placed onto a
cotton tipped swab and applied to approximately 4 cm.sup.2 of
naso-facial skin displaying rosacea induced erythema. Twenty two
minutes after application a lessening of erythema was observed.
1.7.11 Example 11
[0098] Use of Epinephrine
[0099] An epinephrine solution (Epipen.RTM., trademark of Dey.RTM.,
L.P.) containing approximately 0.3 mg of epinephrine was placed in
a glass container. The solution was placed onto a cotton tipped
swab and then applied to approximately 4 cm.sup.2 of naso-facial
skin displaying rosacea induced erythema. Within 5 minutes of
application a mottled whitening of the skin was observed. No
whitening was observed in skin outside of the application area. The
whitening effect began to fade after approximately 30 minutes.
1.7.12 Example 12
[0100] A tetrahydrozoline solution (Visine.RTM., 0.05% solution,
Pfizer) The solution was placed onto a cotton-tipped swab and
applied to approximately 4 cm.sup.2 of naso-facial skin displaying
rosacea induced erythema. Visual observation indicated no erythema
reduction using this concentration of tetrahydrozoline.
1.7.13 Example 13
[0101] Testing Procedure for Prevention of Redness By
.alpha.-Adrenergic Agonists:
[0102] A number of .alpha.-adrenergic agonists were evaluated for
their ability to topically suppress erythema in human skin induced
by methyl nicotinate. The erythema produced in the skin results
from the vasodilatory effect on the dermal vasculature by methyl
nicotinate. In this model, the minimum erythemal dose (MED)
produced on the forearm by methyl nicotinate is determined for each
test subject. The MED is defined as the minimal dose that results
in a defined circle of erythema. The MED was determined by
saturating five 19 mm Hill Top Chambers with 220 .mu.l of 1, 2, 3,
4, and 5 mm methyl nicotinate. The Hill Top Chambers were applied
to the volar forearm of each test subject, removed after 30 seconds
and excess liquid lightly blotted from the skin. The MED of methyl
nicotinate was selected 10 minutes after application, by
determining the minimal dose that resulted in a defined circle of
erythema. The .alpha.-adrenergic agonists were dissolved in alcohol
and topically applied (2 .mu.l/cm.sup.2) to selected sites on the
contralateral volar forearm for 30 minutes prior to challenge with
methyl nicotinate. Hill Top Chambers (19 mm) were saturated with
220 .mu.l of the dose of methyl nicotinate determined to produce a
MED for each test subject. The chambers were applied to the volar
forearm treated with vehicle or test compounds, removed after 30
seconds and excess liquid was lightly blotted from the skin. Ten
minutes after application of methyl nicotinate the test sites were
evaluated for erythema. A numerical grading scale of 0 to 3 was
used: 0=none, 0.5=barely perceptible, 1.0=mild, 1.5=mild+(mild to
moderate), 2.0=moderate, 2.5=moderate+(moderate to severe),
3.0=severe.
[0103] The test results are shown in the table below and indicate
that each of the tested compounds reduced the formation of the
Methyl Nicotinate induced redness (erythema) in the test subjects.
With both Oxymetazoline HCl and Naphazoline HCl the redness was
fully blocked for two of the three subjects pursuant to the test
conditions as described above. TABLE-US-00007 The Effect of
.alpha.-Adrenergic Agonists on Methyl Nicotinate-Induced Erythema
Pre-Treatment + Mean Methyl Nicotinate N Erythema Grade Alcohol
Vehicle Control 3 3.0 0.2% Naphazoline HCl 3 0.33 0.2%
Oxymetazoline HCl 3 1.0 0.2% Brimonidine 3 0.83
1.8 DEFINITIONS
[0104] The phrase "pharmaceutically acceptable salt(s)", as used
herein, means those salts of compounds of the invention that are
safe and effective for topical use in mammals and that possess the
desired biological activity. Pharmaceutically acceptable salts
include salts of acidic or basic groups present in compounds of the
invention. Pharmaceutically acceptable acid addition salts include,
but are not limited to, hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate,
isonicotinate, acetate, lactate, salicylate, citrate, tartrate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzensulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain
compounds of the invention can form pharmaceutically acceptable
salts with various amino acids. Suitable base salts include, but
are not limited to, aluminum, calcium, lithium, magnesium,
potassium, sodium, zinc, and diethanolamine salts. For a review on
pharmaceutically acceptable salts see BERGE ET AL., 66 J. PHARM.
SCI. 1-19 (1977), incorporated herein by reference.
[0105] The term "pharmaceutically acceptable topical formulation"
as used herein means any formulation which is pharmaceutically
acceptable for topical delivery of the compounds of the invention.
According to the invention, a "topical formulation" will comprise
at least a compound of the invention. The choice of topical
formulation will depend on several factors, including the nature of
the symptoms to be treated or prevented, the physiochemical
characteristics of the particular compound of the invention and of
other excipients present, their stability in the formulation,
available manufacturing equipment, and cost constraints.
[0106] As used herein, a "therapeutically effective amount of a
compound of the invention" means the minimum amount of the compound
that is effective to treat or prevent rosacea or its symptoms.
[0107] As used herein, the term "subject" means any animal,
preferably a mammal, to which will be or has been administered
compounds or topical formulations of the invention. The term
"mammal" as used herein, encompasses any mammal. Examples of
mammals include, but are not limited to, cows, horses, sheep, pigs,
cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans etc.,
more preferably, a human. Preferably, a subject is in need of
treatment or prevention of rosacea or its symptoms.
[0108] The term "analog" refers to a chemical compound that is
structurally similar to a parent compound and has chemical
properties or pharmaceutical activity in common with the parent
compound. Analogs include, but are not limited to, homologs, i.e.,
where the analog differs from the parent compound by one or more
carbon atoms in series; positional isomers; compounds that differ
by interchange of one or more atoms by a different atom, for
example, replacement of a carbon atom with an oxygen, sulfur, or
nitrogen atom; and compounds that differ in the identity of one or
more functional groups, for example, the parent compound differs
from its analog by the presence or absence of one or more suitable
substituents. Suitable substituents include, but are not limited
to, (C.sub.1-C.sub.8)alkyl; (C.sub.1-C.sub.8)alkenyl;
(C.sub.1-C.sub.8)alkynyl: aryl; (C.sub.2-C.sub.5)heteroaryl;
(C.sub.1-C.sub.6)heterocycloalkyl; (C.sub.3-C.sub.7)cycloalkyl;
O--(C.sub.1-C.sub.8)alkyl; O--(C.sub.1-C.sub.8)alkenyl;
O--(C.sub.1-C.sub.8)alkynyl; O-aryl; CN; OH; oxo; halo, C(O)OH;
COhalo; O(CO)halo; CF.sub.3, N.sub.3; NO.sub.2, NH.sub.2;
NH((C.sub.1-C.sub.8)alkyl); N((C.sub.1-C.sub.8)alkyl).sub.2;
NH(aryl); N(aryl).sub.2 N((C.sub.1-C.sub.8)alkyl)(aryl);
(CO)NH.sub.2; (CO)NH((C.sub.1-C.sub.8)alkyl);
(CO)N((C.sub.1-C.sub.8)alkyl).sub.2; (CO)NH(aryl);
(CO)N(aryl).sub.2; O(CO)NH.sub.2; NHOH;
NOH((C.sub.1-C.sub.8)alkyl); NOH(aryl);
O(CO)NH((C.sub.1-C.sub.8)alkyl);
O(CO)N((C.sub.1-C.sub.8)alkyl).sub.2; O(CO)NH(aryl);
O(CO)N(aryl).sub.2; CHO; CO((C.sub.1-C.sub.8)alkyl); CO(aryl);
C(O)O((C.sub.1-C.sub.8)alkyl); C(O)O(aryl);
O(CO)((C.sub.1-C.sub.8)alkyl); O(CO)(aryl);
O(CO)O((C.sub.1-C.sub.8)alkyl); O(CO)O(aryl);
S--(C.sub.1-C.sub.8)alkyl; S--(C.sub.1-C.sub.8)alkenyl;
S--(C.sub.1-C.sub.8)alkynyl; S-aryl; S(O)--(C.sub.1-C.sub.8)alkyl;
S(O)--(C.sub.1-C.sub.8)alkenyl; S(O)--(C.sub.1-C.sub.8)alkynyl; and
S(O)-aryl; S(O).sub.2--(C.sub.1-C.sub.8)alkyl;
S(O).sub.2--(C.sub.1-C.sub.8)alkenyl;
S(O).sub.2--(C.sub.1-C.sub.8)alkynyl; and S(O).sub.2-aryl. One of
skill in the art can readily choose a suitable substituent based
upon the stability and pharmacological activity of the compound of
the invention.
[0109] The term "alkyl" means a saturated, monovalent, unbranched
or branched hydrocarbon chain. Examples of alkyl groups include,
but are not limited to, (C.sub.1-C.sub.3)alkyl groups, such as
methyl, ethyl, propyl, isopropyl and (C.sub.4-C.sub.8)alkyl groups,
such as 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,
2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,
isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, heptyl,
and octyl. An alkyl group can be unsubstituted or substituted with
one or two suitable attachments.
[0110] The term "alkenyl" means a monovalent, unbranched or
branched hydrocarbon chain having one or more double bonds therein.
The double bond of an alkenyl group can be unconjugated or
conjugated to another unsaturated group. Suitable alkenyl groups
include, but are not limited to (C.sub.2-C.sub.8)alkenyl groups,
such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,
pentadienyl, hexadienyl,
2-ethylhexenyl,2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl.
An alkenyl group can be unsubstituted or substituted with one or
two suitable substituents.
[0111] The term "alkynyl" means monovalent, unbranched or branched
hydrocarbon chain having one or more triple bonds therein. The
triple bond of an alkynyl group can be unconjugated or conjugated
to another unsaturated group. Suitable alkynyl groups include, but
are not limited to, (C.sub.2-C.sub.8)alkynyl groups, such as
ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-1-butynyl,4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An
alkynyl group can be unsubstituted or substituted with one or two
suitable substituents.
[0112] The term "aryl" means a monocyclic or polycyclic-aromatic
group comprising carbon and hydrogen atoms. Examples of suitable
aryl groups include, but are not limited to, phenyl, tolyl,
anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as
benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or
substituted with one or two suitable substituents. Preferably, the
aryl group is a monocyclic ring, wherein the ring comprises 6
carbon atoms, referred to herein as "(C.sub.6)aryl".
[0113] The term "heteroaryl" means a monocyclic- or polycyclic
aromatic ring comprising carbon atoms, hydrogen atoms, and one or
more heteroatoms, preferably, 1 to 3 heteroatoms, independently
selected from nitrogen, oxygen, and sulfur. As is well known to
those skilled in the art, heteroaryl rings have less aromatic
character than their all-carbon counter parts. Thus, for the
purposes of the invention, a heteroaryl group need only have some
degree of aromatic character. Illustrative examples of heteroaryl
groups include, but are not limited to, pyridinyl, pyridazinyl,
pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl,
(1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl,
isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted
or substituted with one or two suitable substituents. Preferably, a
heteroaryl group is a monocyclic ring, wherein the ring comprises 2
to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as
"(C.sub.2-C.sub.5)heteroaryl".
[0114] The term "cycloalkyl" means a non-aromatic, monocyclic or
polycyclic ring comprising carbon and hydrogen atoms. A cycloalkyl
group can have one or more carbon-carbon double bonds in the ring
so long as the ring is not rendered aromatic by their presence.
Examples of cycloalkyl groups include, but are not limited to,
(C.sub.3-C.sub.7)cycloalkyl groups, such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated
cyclic and bicyclic terpenes and (C.sub.3-C.sub.7)cycloalkenyl
groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and
bicyclic terpenes. A cycloalkyl group can be unsubstituted or
substituted by one or two suitable substituents. Preferably, the
cycloalkyl group is a monocyclic ring or bicyclic ring.
[0115] The term "heterocycloalkyl" means a non-aromatic monocyclic
or polycyclic ring comprising carbon and hydrogen atoms and at
least one heteroatom, preferably, 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulfur. A heterocycloalkyl group can have one
or more carbon-carbon double bonds or carbon-heteroatoms double
bonds in the ring as long as the ring is not rendered aromatic by
their presence. Examples of heterocycloalkyl groups include
aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino,
piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl,
thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl,
tetrahydropyranyl, and pyranyl. A heterocycloalkyl group can be
unsubstituted or substituted with one or two suitable substituents.
Preferably, the heterocycloalkyl group is a monocyclic or bicyclic
ring, more preferably, a monocyclic ring, wherein the ring
comprises from 2 to 6 carbon atoms and from 1 to 3 heteroatoms,
referred to herein as (C.sub.1-C.sub.6)heterocycloalkyl.
[0116] The term "halogen" means fluorine, chlorine, bromine, or
iodine. Correspondingly, the term "halo" means fluoro, chloro,
bromo, and iodo.
[0117] The term "derivative" refers to an analog, as defined above,
that is synthesized in one or more chemical reactions from its
parent compound.
[0118] As used herein, the term "hydrate" means a compound of the
invention, or a pharmaceutically acceptable salt thereof that
further includes a stoichiometric or non-stoichiometric amount of
water bound to it by non-covalent intermolecular forces.
[0119] In one embodiment, "treatment" or "treating" refers to an
amelioration, prophylaxis, or reversal of a disease or disorder, or
at least one discernible symptom thereof. For example, treating
rosacea or its symptoms by lessening the redness of the skin. In
another embodiment, "treatment" or "treating" refers to an
amelioration, prophylaxis, or reversal of at least one measurable
physical parameter related to the disease or disorder being
treated, not necessarily discernible in or by the mammal. In yet
another embodiment, "treatment" or "treating" refers to inhibiting
or slowing the progression of a disease or disorder, either
physically, e.g., stabilization of a discernible symptom,
physiologically, e.g., stabilization of a physical parameter, or
both. In yet another embodiment, "treatment" or "treating" refers
to delaying the onset of a disease or disorder.
[0120] In certain embodiments, the compounds of the invention are
administered as a preventative measure. As used herein,
"prevention" or "preventing" refers to a reduction of the risk of
acquiring a given disease or disorder. In a preferred mode of the
embodiment, the compounds of the invention are administered as a
preventative measure to a subject having a predisposition to
rosacea even though symptoms of the disorder are absent or
minimal.
[0121] In view of the above Background, Summary, Figures, and
Detailed Description, it is clear that in certain embodiments, the
invention comprises a method of treating or preventing rosacea and
its symptoms, comprising topically administering to the skin of a
subject in need of such treatment or prevention a compound of a
formula: ##STR29##
[0122] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, or alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, or alkoxy; and each
of R.sub.6 and R.sub.7 is independently hydrogen, nitro, alkyl, or
alkoxy;
[0123] wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl; and A.sub.2 is independently
hydrogen or hydroxy; and
[0124] wherein each of B.sub.1, B.sub.2, and B.sub.3 is
independently hydrogen, hydroxy, or alkoxy; and each of B.sub.4 and
B.sub.5 is independently hydrogen or alkyl.
[0125] All citations (e.g., scientific journal publications,
patents, and other reference material) mentioned herein are hereby
incorporated herein by reference to the same extent as if each
individual citation was specifically and individually indicated to
be incorporated by reference. One of ordinary skill in the art can
make many variations and modifications to the above-described
embodiments of the invention without departing from the spirit or
scope of the appended claims. Accordingly, all such variations and
modifications are within the scope of the appended claims.
* * * * *