U.S. patent application number 11/839512 was filed with the patent office on 2008-05-15 for use of 2,5-dihydroxybenzene derivatives for treating dermatitis.
This patent application is currently assigned to Action Medicines. Invention is credited to Javier Angulo Frutos, Pedro Cuevas Sanchez, Guillermo Gimenez Gallego, Rosa Maria Lozano Puerto, Antonio Romero Garrido, Inigo Saenz de Tejada Morgan, Serafin Valverde Lopez.
Application Number | 20080114075 11/839512 |
Document ID | / |
Family ID | 38582009 |
Filed Date | 2008-05-15 |
United States Patent
Application |
20080114075 |
Kind Code |
A1 |
Cuevas Sanchez; Pedro ; et
al. |
May 15, 2008 |
Use of 2,5-Dihydroxybenzene Derivatives for Treating Dermatitis
Abstract
The present invention relates to the use of a
2,5-dihydroxybenzene derivative represented by Formula (I) or a
pharmaceutically acceptable salt, solvate, isomer, or prodrug
thereof for the therapeutic and/or prophylactic treatment of, inter
alia, dermatitis.
Inventors: |
Cuevas Sanchez; Pedro;
(Madrid, ES) ; Gimenez Gallego; Guillermo;
(Madrid, ES) ; Saenz de Tejada Morgan; Inigo;
(Madrid, ES) ; Angulo Frutos; Javier; (Madrid,
ES) ; Valverde Lopez; Serafin; (Madrid, ES) ;
Romero Garrido; Antonio; (Madrid, ES) ; Lozano
Puerto; Rosa Maria; (Madrid, ES) |
Correspondence
Address: |
FROMMER LAWRENCE & HAUG
745 FIFTH AVENUE- 10TH FL.
NEW YORK
NY
10151
US
|
Assignee: |
Action Medicines
Madrid
ES
|
Family ID: |
38582009 |
Appl. No.: |
11/839512 |
Filed: |
August 15, 2007 |
Current U.S.
Class: |
514/709 |
Current CPC
Class: |
A61K 31/222 20130101;
A61P 23/00 20180101; A61K 8/466 20130101; A61P 31/00 20180101; A61P
37/02 20180101; A61K 31/60 20130101; A61K 31/10 20130101; A61K
8/368 20130101; A61P 3/04 20180101; A61P 29/00 20180101; A61K
31/192 20130101; A61P 17/00 20180101; A61Q 17/04 20130101; A61K
31/225 20130101; A61P 35/00 20180101; A61Q 19/08 20130101; A61K
31/618 20130101; A61P 37/06 20180101; A61K 31/185 20130101; A61K
45/06 20130101 |
Class at
Publication: |
514/709 |
International
Class: |
A61K 31/10 20060101
A61K031/10; A61P 17/00 20060101 A61P017/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 16, 2006 |
ES |
ES P200602219 |
Jul 2, 2007 |
ES |
ES P200701857 |
Claims
1. A method for the treatment or prophylaxis of dermatitis,
comprising administering to a subject in need thereof, an effective
amount of a 2,5-dihydroxybenzene derivative represented by Formula
(I) or a pharmaceutically acceptable salt, solvate, isomer, or
prodrug thereof, wherein the compound of Formula (I) is:
##STR00006## wherein: R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pZ; Y is --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --PO.sub.3H,
--PO.sub.3.sup.-.X.sup.+, or --PO.sub.3R.sub.3, wherein when Y is
--SO.sub.3H, --SO.sub.3.sup.-.X.sup.+ or --SO.sub.3R.sub.3, then
R.sub.9 and R.sub.9' are independently selected from --OH and
--OR.sub.2, wherein at least one of R.sub.9 and R.sub.9' is a
substituted or unsubstituted alkylsulfonyloxy group, a substituted
or unsubstituted arylsulfonyloxy group, a substituted or
unsubstituted alkylcarbonyloxy group or a substituted or
unsubstituted arylcarbonyloxy group; Z is --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --PO.sub.3H,
--PO.sub.3.sup.-.X.sup.+, --P0.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ or --C0.sub.2R.sub.3; X.sup.+ is an
organic cation or an inorganic cation, such that the general charge
of the compound is neutral; R.sub.9 and R.sub.9' are independently
selected from --OH and --OR.sub.2, wherein when R.sub.9 and
R.sub.9' are both --OR.sub.2, then said R.sub.9 and R.sub.9' can be
the same or different; R.sub.2 is a substituted or unsubstituted
alkyl group, a substituted or unsubstituted aryl group, a
substituted or unsubstituted alkylsulfonyl group, a substituted or
unsubstituted arylsulfonyl group, a substituted or unsubstituted
alkylcarbonyl group or a substituted or unsubstituted arylcarbonyl
group; R.sub.3 is a substituted or unsubstituted alkyl group or a
substituted or unsubstituted aryl group; a is a number selected
from 0, 1, 2, 3, 4, 5 and 6; and p is an integer selected from 0,
1, 2, 3, 4, 5 and 6.
2. The method of claim 1, wherein R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pY.
3. The method of claim 2, wherein Y is selected from --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3.
4. The method of claim 3, wherein R.sub.3 is selected from methyl
and ethyl.
5. The method of claim 1, wherein R.sub.9 and R.sub.9' are,
independently, a substituted or unsubstituted alkylsulfonyloxy
group, a substituted or unsubstituted arylsulfonyloxy group, a
substituted or unsubstituted alkylcarbonyloxy group or a
substituted or unsubstituted arylcarbonyloxy group.
6. The method of claim 1, wherein R.sub.2 is selected from
methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,
benzylsulfonyl, benzyl and phenyl
7. The method of claim 1, wherein the compound of Formula (I) is
selected from the group consisting of:
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
2-(acetyloxy)-5-hydroxybenzenesulfonic acid;
5-(acetyloxy)-2-hydroxybenzenesulfonic acid;
2,5-bis(acetyloxy)benzenesulfonic acid;
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; 2,5-bis {[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; 2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;
5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;
2,5-bis(acetyloxy)benzenehomosulfonic acid;
3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic
acid)
3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid;
3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; 3-(2,5-bis {[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; 3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;
3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;
3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;
3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;
3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;
3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceutically
acceptable salts, solvates and prodrugs thereof.
8. The method of claim 7, wherein the compound of Formula (I) is
selected from: 2-(acetyloxy)-5-hydroxybenzenesulfonic acid,
5-(acetyloxy)-2-hydroxybenzenesulfonic acid and
2,5-bis(acetyloxy)benzenesulfonic acid.
9. The method of claim 1, wherein the dermatitis is selected from
the group consisting of: actinic dermatitis, allergic contact
dermatitis, atopic dermatitis, carcinomatous dermatitis, contact
dermatitis, diaper dermatitis, stasis dermatitis, neurodermatitis,
dermatomyositis and radiation-induced dermatitis.
10. The method of claim 1, wherein the compound of Formula (I) is
administered topically.
11. The method of claim 10, wherein the compound of Formula (I) is
administered orally, buccally, transdermally, by inhalation, or
otically.
12. The method of claim 1, further comprising administration of at
least one additional therapeutic agent.
13. The method of claim 12, wherein the at least one additional
therapeutic agent is selected from the group consisting of:
diclofenac, T4 endonuclease, isotretinoin, acitretin, cidofoir, a
corticosteroid, an antibiotic, an analgesic, an immunomodulator,
including oral immunomodulator such as tacrolimus and pimecrolimus,
and topical immunomodulators; an immunosuppressant, an
anti-angiogenic; a leukotriene modifier, an aminosalicylate, an
anesthetic, a non-steroidal anti-inflammatory, a modifier of a
solubilized interleukin receptor, an inhibitor of a tyrosine-kinase
receptor, a protein kinase C inhibitor, and a combination of two or
more thereof.
17. The method of claim 10, wherein the compound is administered at
least once per week.
18. The method of claim 17, wherein the compound is administered at
least once per day.
19. The method of claim 18, wherein the compound is administered at
least twice per day.
20. The method of claim 10, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 1%
w/w.
21. The method of claim 20, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 2.5%
w/w.
22. The method of claim 21, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 5%
w/w.
23. The method of claim 22, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 10%
w/w.
24. The method of claim 23, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 15%
w/w.
25. The method of claim 10, wherein the compound is administered
over a period of at least about one week.
26. The method of claim 25, wherein the compound is administered
over a period of at least about four weeks.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119 of ES Application No. P200602219, filed Aug. 16,
2006 and of ES Application No. P200701857, filed Jul. 2, 2007. The
foregoing applications, and all documents cited therein, are hereby
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the use of
2,5-dihydroxybenzene derivatives to manufacture medicaments useful
to prevent skin aging due to exposure to ultraviolet B rays (UVB),
or to exposure to sun rays in general, to treat pathologies
associated to said skin photoaging such as seborrheic keratosis, as
well as to treat dermatitis.
BACKGROUND OF THE INVENTION
[0003] Chronic exposure to ultraviolet B rays (UVB: 290-320 nm
wavelength), or solar rays, in general (comprising, among other
wavelengths, that of UVB radiation) produces skin aging
(photoaging) due to the accumulation of DNA damage and on the
structural proteins of the skin, evidencing in the form of fine
wrinkles, laxity with loss of skin elasticity, elastosis, yellowish
staining with localizad areas of melanin hyperpigmentation (solar,
actinic or senile lentigo). Besides, skin photoaging is associated
with the appearance of comedoes that are more evident in the "cutis
romboidalis" at the rear part of the neck. In the histological
test, an epidermic atrophy and degenerative changes in elastic
fibers of the dermis may be observed (Pearse A D, Gaskell S A,
Marks R. J Invest Dermatol 1987; 88 83-87; Berton T R, Mitchell D
L, Fischer S M, Looniskar M F. J Invest Dermatol 1997; 109:
340-347). Furthermore, chronic exposure to UVB rays is a risk
factor for the appearance of benign lesions, such as seborrheic
keratosis, and premalignant lesions such as actinic keratosis
(Kripke M L. Cancer Res 1994; 54: 6102-6105). Currently, there is
no effective treatment for skin photoaging (Dermatol Surg. Special
Issue: Cosmeceuticals. Invited editors: Draelos Z D, Brody H J.
2005).
[0004] On the other hand, the hair follicle is the functional unit
for hair elongation. Hirsutism is a clinical condition in which
there in an excessive hair growth with an androgenic-type pattern
(face, thorax, areolas, linea alba, lower part of the back,
buttocks, limbs and external genitals) produced by an increase in
the androgenic activity. Hypertricosis is a condition in which
there is an excessive hair growth in areas sensitive and
non-sensitive to androgens.
[0005] Obesity is a disease produced when the energy intake exceeds
and produces an excess of adipose tissue. This process is regulated
by the control on the intake, on the energy expenditure and
efficiency and on the adipogenesis). (Gregoire F M. Exp Biol Med,
2001, 226: 997-1002; Palou A et al. Eur J Nutr, 2000, 39: 127-144).
Prevention and/or treatment of obesity is a very important factor
to reduce morbidity and mortality rates associated to
cardiovascular disorders and to type 2 diabetes, which represent a
high health and social cost in industrialized countries. Currently,
there is no effective treatment for obesity. The effective
therapies to treat obesity should interfere with the development of
adipose tissue. To increase the adipose tissue mass, it is
essential that preadipocytes are differentiated in a mature
adipocyte phenotype. Besides morphological changes, the
differentiation process of preadipocyte into adipocyte is
accompanied by metabolic processes such as the capacity of storing
energy in the form of triglycerides (McDougald O A, Lane M D. Annu
Rev Biochem, 1995, 345-373; Spiegelman B M, Flier J S. Cell 1996,
87: 377-389). Therefore, the pharmacological inhibition of the
differentiation of preadipocytes into adipocytes represents a
therapeutic strategy to treat obesity.
[0006] There is a need to find alternative treatments to the
current ones for skin aging and photoaging, both from the aesthetic
and therapeutic points of view, based on the use of active
principles.
SUMMARY OF THE INVENTION
[0007] Surprisingly, the inventors have found that
2,5-dihydroxybenzene derivatives, the pharmaceutically acceptable
salts and solvates thereof, as well as isomers and prodrugs thereof
are useful to prevent and/or therapeutically treat skin aging due
to exposure to ultraviolet rays B (UVB), or to exposure to sun rays
in general, to treat pathologies associated to said skin photoaging
such as seborrheic keratosis. In addition said derivatives are
useful to prevent and/or therapeutically treat dermatitis.
[0008] In certain embodiments, the invention provides a method for
the treatment or prophylaxis of dermatitis, comprising
administering to a subject in need thereof, an effective amount of
a 2,5-dihydroxybenzene derivative represented by Formula (I) or a
pharmaceutically acceptable salt, solvate, isomer, or prodrug
thereof, wherein the compound of Formula (I) is:
##STR00001##
wherein: [0009] R.sub.1 is --(CH.sub.2).sub.a or
--CH.dbd.CH--(CH.sub.2).sub.pZ; [0010] Y is --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --PO.sub.3H,
--PO.sub.3.sup.-X.sup.+, or --PO.sub.3R.sub.3, wherein when Y is
--SO.sub.3H, --SO.sub.3.sup.-..sup.+ or --SO.sub.3R.sub.3, then
R.sub.9 and R.sub.9' are independently selected from --OH and
--OR.sub.2, wherein at least one of R.sub.9 and R.sub.9' is a
substituted or unsubstituted alkylsulfonyloxy group, a substituted
or unsubstituted arylsulfonyloxy group, a substituted or
unsubstituted alkylcarbonyloxy group or a substituted or
unsubstituted arylcarbonyloxy group; [0011] Z is --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --PO.sub.3H,
--PO.sub.3.sup.-.X.sup.+, --PO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ or --CO.sub.2R.sub.3; [0012] X.sup.+ is an
organic cation or an inorganic cation, such that the general charge
of the compound is neutral; [0013] R.sub.9 and R.sub.9' are
independently selected from --OH and --OR.sub.2, wherein when
R.sub.9 and R.sub.9' are both --OR.sub.2, then said R.sub.9 and
R.sub.9' can be the same or different; [0014] R.sub.2 is a
substituted or unsubstituted alkyl group, a substituted or
unsubstituted aryl group, a substituted or unsubstituted
alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl
group, a substituted or unsubstituted alkylcarbonyl group or a
substituted or unsubstituted arylcarbonyl group; [0015] R.sub.3 is
a substituted or unsubstituted alkyl group or a substituted or
unsubstituted aryl group; [0016] a is a number selected from 0, 1,
2, 3, 4, 5 and 6; and [0017] p is an integer selected from 0, 1, 2,
3, 4, 5 and 6.
[0018] In certain embodiments, R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pY. In other embodiments, Y is selected
from --SO.sub.3H, --SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3. In
yet other embodiments, R.sub.3 is selected from methyl and ethyl.
In some embodiments, R.sub.9 and R.sub.9' are, independently, a
substituted or unsubstituted alkylsulfonyloxy group, a substituted
or unsubstituted arylsulfonyloxy group, a substituted or
unsubstituted alkylcarbonyloxy group or a substituted or
unsubstituted arylcarbonyloxy group. In some embodiments, R.sub.2
is selected from methylcarbonyl, phenylsulfonyl,
4-methylphenylsulfonyl, benzylsulfonyl, benzyl and phenyl
[0019] In certain embodiments, the compound of Formula (I) is
selected from the group consisting of:
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
2-(acetyloxy)-5-hydroxybenzenesulfonic acid;
5-(acetyloxy)-2-hydroxybenzenesulfonic acid;
2,5-bis(acetyloxy)benzenesulfonic acid;
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; 2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; 2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid;
5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid;
2,5-bis(acetyloxy)benzenehomosulfonic acid;
3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic
acid);
3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid;
3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; 3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; 3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid;
3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid;
3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid;
3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid;
3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid;
3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceutically
acceptable salts, solvates, and prodrugs thereof.
[0020] In certain embodiments, the compound of Formula (I) is
selected from: 2-(acetyloxy)-5-hydroxybenzenesulfonic acid,
5-(acetyloxy)-2-hydroxybenzenesulfonic acid and
2,5-bis(acetyloxy)benzenesulfonic acid.
[0021] In certain embodiments, the invention provides a method for
the treatment or prophylaxis of dermatitis, wherein the dermatitis
is selected from the group consisting of: actinic dermatitis,
allergic contact dermatitis, atopic dermatitis, carcinomatous
dermatitis, contact dermatitis, diaper dermatitis, stasis
dermatitis, neurodermatitis, dermatomyositis and radiation-induced
dermatitis.
[0022] Advantageously, a compound of Formula (I) is administered
topically. In certain embodiments, the compound of Formula (I) is
administered orally, buccally, transdermally, by inhalation, or
otically.
[0023] In certain embodiments, the invention provides a method for
the treatment or prophylaxis of dermatitis further comprising
administration of at least one additional therapeutic agent.
[0024] Examples of suitable additional therapeutic agents include
diclofenac, T4 endonuclease, isotretinoin, acitretin, cidofoir, a
corticosteroid, an antibiotic, an analgesic, an immunomodulator,
including oral immunomodulator such as tacrolimus and pimecrolimus,
and topical immunomodulators; an immunosuppressant, an
anti-angiogenic, including anti-VEGF, anti-FGF, anti-EGF and
anti-HGF; a leukotriene modifier, an aminosalicylate, an
anesthetic, a non-steroidal anti-inflammatory, a modifier of a
solubilized interleukin receptor, an inhibitor of a tyrosine-kinase
receptor, a protein kinase C inhibitor, and a combination of two or
more thereof.
[0025] In certain embodiments, the invention provides for
administration of a compound of Formula (I) for the treatment
and/or prophylaxis of dermatitis, wherein the compound is
administered at least once per week. In other embodiments, the
compound is administered at least once per day or at least twice
per day.
[0026] In certain embodiments, a compound of Formula (I) is present
in a pharmaceutical composition in an amount of at least about 1%
w/w. In other embodiments, the compound is present in a
pharmaceutical composition in an amount of at least about 2.5% w/w,
at least about 5% w/w, at least about 10% w/w, or at least about
15% w/w.
[0027] In yet other embodiments, a compound of Formula (I) is
administered over a period of at least about one week. In certain
embodiments, the compound is administered over a period of at least
about four weeks.
[0028] These and other aspects of the present invention are
described in detail herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1. Inhibitory effect of 2,5-dihydroxybenzenesulfonic
acid (DHBS) on dermatitis induced by the application of
benzalkonium chloride on the rat ears. Dermatitis was induced in
both ears, and only the right ear was treated topically with a
cream containing 5% DHBS; the left ear was used as control. The
intravenous injection of Evans blue dye revealed the extent of
dermatitis in the ears. The application of the cream containing
DHBS remarkably reduced dye extravasation caused by the dermatitis,
as shown in photographs (A-F) of the treated ears in the 6 rats
that, 4 hours after dermatitis induction, exhibited a colored
extent lower than untreated ears.
[0030] FIG. 2. Quantification of the inhibitory effect of
2,5-dihydroxybenzenesulfonic acid (DHBS) on dermatitis induced by
the application of benzalkonium chloride on the ears of the rats
shown in FIG. 1. The abscissa axis represents the percentage of the
blue-colored area compared to the total area of the ear, as a
marker of the dermatitis extent. Data is expressed as the
mean.+-.SEM of the corresponding values of the six rats shown in
FIG. 1. As shown in the graphs, topical application of 5% DHBS
(black bars) significantly reduced dermatitis extent as observed 4
hours later (A) and 24 hours (B) after induction thereof.
[0031] FIG. 3. Appearance of two rat ears on which benzalkonium
chloride was applied to induce dermatitis. One of the rats (A), was
treated topically with glycerol in both ears, while the other rat
(B) was treated topically with a solution of glycerol containing
2.5% of 2,5-diacetoxybenzenesulfonic acid (DABS). The erythema
caused by the dermatitis is milder in the mouse treated with
DABS.
[0032] FIG. 4. Representative examples of the histological study of
the effect of a topical treatment with 2.5%
2,5-diacetoxybenzenesulfonic acid (DABS) on the dermatitis induced
by benzalkonium chloride on the ear of the rat. The microphotograph
shows a clear tissular edema on the ear of a rat with dermatitis
and treated only with the vehicle (anhydrous glycerol) (a). This
edema is not observed in a rat with dermatitis but treated with
2.5% DABS in glycerol (b). In the ear treated with the vehicle, a
considerable leukocyte infiltration in the tissue (c) may be
observed, and it is noticeably milder in the ear of a rat treated
topically with 2.5% DABS (d). The magnification of the area marked
with a box in c and d shows that in the capillaries of the rat
treated with vehicle there are granulocytes adhered to the
endothelial cells that roll and extravasate to infiltrate the
surrounding tissue (e), this is not observed in the vessels of the
rat treated with DABS (f). The tissues were fixed 24 hours after
dermatitis induction.
[0033] FIG. 5. Effect of the topical treatment with
2,5-dihydroxybenzenesulfonic acid (DHBS),
2,5-diacetoxybenzenesulfonic acid (DABS) or vehicle (anhydrous
glycerol) over the increase of the myeloperoxidase (MPO) activity
as a result of dermatitis induced by benzalkonium chloride on the
ear of the rat. Once dermatitis was induced, the ears were treated
with vehicle (anhydrous glycerol), a 5% DHBS cream, or with 2.5%
DABS solution in anhydrous glycerol. Twenty-four hours after the
dermatitis induction, the ears were removed and frozen. The control
group corresponds to ears of rats in which dermatitis had not been
induced. The MPO activity is expressed as the mean.+-.SEM of the
absorbance at 460 nm normalized by the mg of the tissue of the
corresponding ear. The number of animals used in each group is
stated between brackets. ** indicates p<0.01 vs. control,
.dagger. p<0.05, .dagger..dagger. p<0.01 vs. vehicle.
[0034] FIG. 6. Inhibitory effect of
2-acetoxy-5-hydroxybenzenesulfonic acid (2A-5HBS) on dermatitis
induced by the application of benzalkonium chloride on the rat
ears. Dermatitis was induced in both ears, and only the right ear
was treated topically with a solution containing 5% 2A-5HBS in
glycerol; the left ear was used as control. The intravenous
injection of Evans blue dye revealed the extent of dermatitis in
the ears. The application of the solution containing 5% 2A-5HBS
remarkably reduced dye extravasation caused by the dermatitis, as
shown in photographs (A-E) of the treated ears in the 5 rats that,
24 hours after dermatitis induction, exhibited a colored extent
lower than untreated ears.
[0035] FIG. 7. Inhibitory effect of
5-acetoxy-2-hydroxybenzenesulfonic acid (5A-2HBS) on dermatitis
induced by the application of benzalkonium chloride on the rat
ears. Dermatitis was induced in both ears, and only the right ear
was treated topically with a solution containing 5% 5A-2HBS in
glycerol; the left ear was used as control. The intravenous
injection of Evans blue 7 00473825 dye revealed the extent of
dermatitis in the ears. The application of the solution containing
5% 5A-2HBS remarkably reduced dye extravasation caused by the
dermatitis, as shown in photographs (A-D) of the treated ears in
the 4 rats that, 24 hours after dermatitis induction, exhibited a
colored extent lower than untreated ears.
[0036] FIG. 8. Quantification of the inhibitory effect of
2-acetoxy-5-hydroxybenzenesulfonic acid (2A-5HBS) on dermatitis
induced by the application of benzalkonium chloride on the ears of
the rats shown in FIG. 6. The abscissa axis represents the
percentage of the blue-colored area compared to the total area of
the ear, as a marker of the dermatitis extent. Data are expressed
as the mean.+-.SEM of the corresponding values from the five rats
shown in FIG. 6. As shown in the graphs, topical application of 5%
2A-5HBS (stripped bar) significantly reduced dermatitis extent 24
hours after induction thereof.
[0037] FIG. 9. Quantification of the inhibitory effect of
5-acetoxy-2-hydroxybenzenesulfonic acid (5A-2HBS) on dermatitis
induced by the application of benzalkonium chloride on the ears of
the rats shown in FIG. 7. The abscissa axis represents the
percentage of the blue-colored area compared to the total area of
the ear, as a marker of the dermatitis extent. Data are expressed
as the mean.+-.SEM of the corresponding values from the four rats
shown in FIG. 7. As shown in the graphs, topical application of 5%
2A-5HBS (gray bar) significantly reduced dermatitis extent 24 hours
after induction thereof.
[0038] FIG. 10. Co-crystallized potassium
5-acetoxy-2-hydroxybenzenesulfonic acid with fibroblast growth
factor-1. The electron density of the compound, contoured at
1.sigma. (panel C), enables the localization and recognition of the
compound orientation regarding the protein (panels A and B), as
well as the confirmation that the compound maintains the acetoxyl
group in position 2 when it binds to the protein. The compound is
located at a site very close to the site that, as described, is
occupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic
ring forms a cation-.pi. bond with the N.sup..epsilon. group of
lysine 132, marked in panel A as reference. Panel B shows, in the
form of a mesh, the Van der Waals volume of
2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped to its
representation in the form of rods. In panels A and B, the protein
surface is colored according to its electrostatic potential (light
grey: negative charge; dark grey: positive charge; white: lack of
charge).
[0039] FIG. 11. Co-crystallized potassium
5-acetoxy-2-hydroxybenzenesulfonic acid with fibroblast growth
factor-1. The electron density of the compound, contoured at
1.sigma. (panel C), enables the localization and recognition of the
compound orientation regarding the protein (panels A and B) as well
as the confirmation that the compound maintains the acetoxyl group
in position 5 when it binds to the protein. The compound is located
at a site very close to the site that, as described, is occupied by
the 2,5-dihydroxybenzenesulfonic acid, which aromatic ring forms a
cation-.pi. bond with the N.sup..epsilon. group of lysine 132,
marked in panel A as reference. Panel B shows, in the form of a
mesh, the Van der Waals volume of
2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped to its
representation in the form of rods. In panels A and B, the protein
surface is colored according to its electrostatic potential (light
grey: negative charge; dark grey: positive charge; white: lack of
charge).
[0040] FIG. 12. Co-crystallized potassium
5-acetoxy-2-hydroxybenzenesulfonic acid with fibroblast growth
factor-1. The electron density of the compound, contoured at
1.sigma. (panel C), enables the localization and recognition of the
compound orientation regarding the protein (panels A and B), as
well as the confirmation that the compound maintains the acetoxyl
group in position 2 when it binds to the protein. The compound is
located at a site very close to the site that, as described, is
occupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic
ring forms a cation-.pi. bond with the N.sup..epsilon. group of
lysine 132, marked in panel A as reference. Panel B shows, in the
form of a mesh, the Van der Waals volume of
2-acetoxy-5-hydroxybenzenesulfonic acid, overlapped to its
representation in the form of rods. In panels A and B, the protein
surface is colored according to its electrostatic potential (light
grey: negative charge; dark grey: positive charge; white: lack of
charge).
DETAILED DESCRIPTION OF THE INVENTION
[0041] The definitions of the terms and the chemical groups
comprised in the formulas herein are as follows:
[0042] The term "patient" refers to animals, preferably mammals,
and more preferably humans, and includes males and females,
children and adults.
[0043] The expression "effective amount" refers to the amount of
compound and/or composition effective to achieve the desired
purpose.
[0044] The terms "treat" or "treatment" refer to the prophylactic
use of compounds or compositions of the present invention to avoid
the symptoms of the disease or condition, or the therapeutical use
to improve an existing condition.
[0045] "Alkyl" refers to a linear or branched chain hydrocarbon
radical comprising carbon atoms and hydrogen, with no
unsaturations, with one to twelve, preferably one to eight, more
preferably one to six carbon atoms, bound to the rest of the
molecule by a single bond, for example, methyl, ethyl, n-propyl,
i-propyl, n-butyl, t-butyl, n-pentyl, etc.
[0046] "Alkenyl" refers to a linear or branched chain hydrocarbon
radical comprising carbon atoms and hydrogen atoms, containing at
least one unsaturation, with two to twelve, preferably two to
eight, more preferably two to six carbon atoms, bound to the rest
of the molecule by a single bond.
[0047] "Cycloalkyl" refers to a saturated carbocyclic ring having
between three and eight, preferably three to six carbon atoms. They
may exhibit a bridged structure. Suitable cycloalkyl groups
include, but are not limited to, cycloalkyl groups such as
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0048] "Alkynyl" refers to a linear or branched chain hydrocarbon
radical comprising carbon atoms and hydrogen, containing at least
one triple carbon-carbon bond, whether conjugated or not, with two
to twelve, preferably two to eight, more preferably two to six
carbon atoms, bound to the rest of the molecule by a single bond
such as --CCH, --CH.sub.2CCH, --CCCH.sub.3,
--CH.sub.2CCCH.sub.3.
[0049] "Aryl" refers to an aromatic hydrocabon radical containing
from six to ten carbon atoms such as phenyl or naphthyl.
[0050] "Aralkyl" refers to an aryl group bound to the rest of the
molecule by an alkyl group such as benzyl and phenetyl.
[0051] "Heterocycle" refers to a stable 3 to 15-membered ring
comprised of carbon atoms and between one and five heteroatoms
selected from the group consisting of nitrogen, oxygen and sulfur,
preferably a 4 to 8-membered ring with two, three or four
heteroatoms, more preferably a 5 or 6-membered ring with one, two
or three heteroatoms. For the purpose of the present invention, the
heterocycle may be a monocyclic, bicyclic or tryciclic ring system
that may include fused ring systems; bridged structures; and the
nitrogen, carbon or sulfur atoms in the heterocyclic radical may be
optionally oxidized; the nitrogen atom may be optionally
quaternized; and the heterocyclic radical may be partially or
completely saturated or it may be aromatic. Examples of such
heterocycles include, but are not limited to, azepines,
benzimidazole, benzothiazole, furan, isothiazole, imidazole,
indole, piperidine, piperazine, quinoline, thiadiazol,
tetrahydrofuran.
[0052] Unless otherwise specified, the alkyl, cycloalkyl, alkenyl,
alkynyl, aryl, aralkyl and heterocycle radicals may be optionally
substituted by one, two or three substituents such as halo, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, hydroxy, alkoxy, sulfoxy,
O-Benzyl, O-Benzoyl, carboxyl, alkylcarboxyl, arylcarboxyl,
alkylcarbonyl, arylcarbonyl, cyano, carbonyl, acyl, alkoxycarbonyl,
amino, alkylamino, dialkylamino, arylamino, diarylamino,
alkylarylamino, imino, alkylsulphinyl, amidyl, carbamoyl,
sulfonamido, nitro, nitrite, nitrate, thionitrate and
carboxamido.
[0053] The term "alkoxycarbonyl" refers to a compound having the
formula --C(.dbd.O)O--, where the C-terminal is bound to the
molecule and the 0-terminal is bound to a carbon atom to form an
ester function. Said carbon atom may be part of an alkyl, alkenyl,
cycloalkyl, alkynyl, aryl, aralkyl or heterocyclic group.
[0054] The term "alkoxycarbonylalkyl" refers to a compound of the
previously defined formula --C(.dbd.O)O--, wherein the C-terminal
binds to a molecule through an alkyl group. The terms "aryloxy-
arylalkoxy- or alkylaryloxy-carbonylalkyl" will be understood
similarly to "alkoxycarbonylalkyl".
[0055] The term "arylalkyl" refers to an aryl radical, as defined
herein, bound to an alkyl radical, as defined herein. The exemplary
arylalkyl groups include benzyl, phenylethyl, 4-hydroxybenzyl,
3-fluorobenzyl, 2-fluorophenylethyl and the like.
[0056] The term "alkylaryl" refers to an alkyl group, as defined
herein, to which an aryl group is bound, as defined herein. The
exemplary alkylaryl groups include benzyl, phenylethyl,
hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the like.
[0057] The term "alkylsulfonyl" refers to a R.sub.50--S(O).sub.2--,
wherein R.sub.50 is a lower alkyl group, as defined herein.
[0058] The term "arylsulfonyl" refers to a R.sub.55--S(O).sub.2--,
wherein R55 is an aryl group, as defined herein.
[0059] The term "alkylsulphinyl" refers to a
R.sub.55--S(O).sub.2--, wherein R55 is an aryl group, as defined
herein.
[0060] The term "arylsulphinyl" refers to a R.sub.55--S(O).sub.2--,
wherein R.sub.55 is an aryl group, as defined herein.
[0061] The term "sulfonamide" refers to a
--S(0).sub.2--N(R.sub.51)(R.sub.57), wherein R.sub.51 and R.sub.57
are each independently a hydrogen atom, an alkyl group, an aryl
group, heterocycle, as defined herein, or else R.sub.51 and
R.sub.57 together form a heterocyclic ring, a cycloalkyl group or a
bridged cycloalkyl group, as defined herein.
[0062] The term "alkylsulfonamide" refers to a sulfonamido group,
as defined herein, bound to an alkyl group, as defined herein.
[0063] The term "arylsulfonamide" refers to a sulfonamido group, as
defined herein, bound to an aryl group, as defined herein.
[0064] The term "alkylcarbonyl" refers to a R.sub.52--C(O).sub.2--,
wherein R.sub.52 is an alkyl group, as defined herein.
[0065] The term "arylcarbonyl" refers to the R.sub.55--S(O).sub.2--
radical, wherein R55 is an aryl group, as defined herein.
[0066] The term "carboxamide" refers to a
--C(O)N(R.sub.52)(R.sub.58) radical, wherein R.sub.52 and R.sub.58
are each independently a hydrogen atom, an alkyl group, an aryl
group or an heterocyclic group, as defined herein or else R.sub.51
and R.sub.57 together form an heterocyclic ring, a cycloalkyl
group, or a bridged cycloalkyl group, as defined herein.
[0067] The term "carboxylic ester" refers to --C(O)OR.sub.59,
wherein R.sub.59 is an alkyl group an aryl group or an heterocyclic
group, as defined herein.
[0068] The term "alcoxyalkyl" refers to an alcoxy group, as defined
herein, bound to an alkyl group, as defined herein. Examples of
alcoxyalkyl groups are methoxymethyl, methoxyethyl,
isopropoximethyl and the like.
[0069] The term "amine" refers to any organic compound containing
at least one basic nitrogen atom.
[0070] The term "organic cation" refers to a positively charged
organic ion. The exemplary organic cations include ammonium cations
unsubstituted or substituted with alkyl, primary, secondary o
tertiary amines, alkylamines, arylamines, cyclic amines,
N,N'-dibenzylethylenediamine, and the like.
[0071] The term "inorganic cation" refers to a positively charged
metal ion. The exemplary inorganic cations include Group I metal
cations such as sodium, potassium, magnesium, calcium and the
like.
[0072] The term "prodrug" refers to compounds that rapidly convert
in vivo into pharmacologically active compounds. Prodrug design is
generally studied in Hardma et al. (eds.), Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 9th ed., pages 11-16 (1996).
A thorough study is presented in Higuchi et al., Prodrugs as Novel
Delivery Systems, vol. 14, ASCD Symposium Series, and in Roche
(ed.), Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987).
[0073] The term "ester derivative of a compound of formula (I)"
refers to the compound of formula (I) wherein at least one of
R.sub.9 and R.sub.9' is an ester group. For example, the ester
derivative of 2,5-dihydroxybezene sulfonic acid or dobesilate ester
derivative refers to the compound 2,5-dihydroxybezene sulfonic acid
(dobesilate) wherein at least one of the hydroxyl groups has been
esterified.
[0074] The term "ester of a compound of formula (I)" refers to an
ester of the sulfonic or carboxylic acid group at position 1. For
example, the ester of 2,5-dihydroxybenzensulfonic acid or ester of
dobesilate refers to an ester of the sulfonic acid group at
position 1.
[0075] The compounds of the invention having one or more asymmetric
carbon atoms may exist as optically pure enantiomers, pure
diastereomers, mixtures of enantiomers, mixtures of diastereomers,
racemic mixtures of enantiomers, diastereomeric racemates or
mixtures of diastereomeric racemates. It should be clearly
understood that the invention contemplates and includes these
isomers and mixtures thereof within its scope.
[0076] The term "topical" refers to the administration of a
compound by applying it on the body surface and includes, but is
not limited to, transdermal administration and administration
through the mucosa.
[0077] The term "transdermal" refers to the delivery of a compound
that enters into the bloodstream through the skin.
[0078] The expression "through the mucosa" refers to the delivery
of a compound that enters into the bloodstream through the mucous
tissue.
[0079] The term "parenteral" refers to the administration of a
compound by means of a subcutaneous, intravenous, intramuscular,
intracardiac, intradermal, intraperitoneal, intrathecal or
intrastemal injection; and also includes local or systemic infusion
techniques.
[0080] The expression "penetration enhancement" or "permeation
enhancement" refers to the increase in the permeability of the skin
or mucous tissue to a pharmacologically active compound selected in
such a way that it increases the penetration rate through the skin
or mucous tissue.
[0081] "Excipients" or "vehicles" refers to the vehicle materials
suitable for compound administration and include any such material
known in the art such as, for example, any liquid, gel, solvent,
liquid diluent, solubilizer, or the like, which is non-toxic and
which does not show harmful interaction with any component of the
composition.
[0082] The expression "sustained release" refers to the release of
an active compound and/or composition such that the blood levels of
the active compound are maintained within a desirable therapeutic
range over a period of time. The sustained release formulation may
be prepared using any conventional known method by a skilled in the
art in order to obtain the desired release characteristics.
[0083] The term "Dermatitis" refers to a inflammatory skin
disease.
[0084] "Atopic dermatitis" refers to a chronic disease affecting
the skin. Atopic dermatitis is produced by a combination of genetic
and environmental factors and associated with excessive IgE
antibody formation.
[0085] "Contact dermatitis" refers to an inflammation of the skin
that is induced by external contact with substances that damage the
skin by direct chemical action or through an immunological
mechanism. Contact dermatitis is associated with lesions produced
on the skin upon contacting an antigen or irritating solution.
[0086] "Stasis dermatitis" refers to a dermatitis in which stasis
is merely one factor in eczema of the lower leg; edema of
nutritional or other origin, infection, and reaction to topical
medicaments are important factors.
[0087] "Actinic dermatitis" or "photodermatitis" refer to
dermatitis provoked by exposure to sunlight
[0088] "Neurodermatitis" refers to a skin disorder of psychosomatic
genesis or in which psychological factors play an important part,
as when rubbing and scratching induce circumscribed patches of
thickened skin.
[0089] "Allergic contact dermatitis" refers to an acute
inflammatory condition of the skin following topical exposure to an
allergen to which the subject shows delayed hypersensitivity.
[0090] "Carcinomatous dermatitis" refers to an inflammatory
alteration of the skin due to underlying carcinoma.
[0091] "Diaper dermatitis" refers to any eruption occurring in the
skin that is usually covered by the diaper and is often induced by
prolonged contact with urine or feces.
[0092] The term "dermatomyositis" refers to a collagen vascular
disease characterized by skeletal muscle inflammation and by
erythema and edema of the skin, notably on the eyelids, backs of
the hands, and the extensor aspects of the limbs.
[0093] "Seborrheic keratosis" refers to non-cancerous growth of the
external layer of the skin.
[0094] The term "therapeutic agent" includes any active agent that
can be used to treat or prevent a disease described herein.
"Therapeutic agents" include but are not limited to
immunomodulatory treatments, such as a tacrolimus ointment or a
pimecrolimus cream and the like; topical corticosteroids (cream,
unguents, ointments or gels) or systemic corticosteroids; topical
or systemic immunosupressants, such as, for example, cyclosporine,
metrotrexate, azathioprine, and the like; phototherapy; emollients
such as for example, white petrolatum, eucerin, urea cream, mineral
oil, aluminum acetate, and the like; barrier creams, sucha as, for
example, zinc oxide paste, and the like; moisturizing agents, such
as, for example, menthol, camphor, and the like; local anesthetics,
such as, for example, lidocaine, and the like; topical corticoids,
such as, for example, triamcinolone acetate, and the like; systemic
corticoids, such as, for example, prednisone, and the like;
antihistamines, such as, for example, diphenhydramine, hydroxyzine,
and the like; podophylline resin, locally applied; cantharin, only
combined with podophylline; salicylic acid, locally applied;
imiquimod; bleomycin; exfoliating agents, such as, for example,
alpha hydroxy acids (glycolic acid, salicylic acid, lactic acid),
trichloroacetic, phenols (carbolic acid, croton oil, and the like;
diclofenac gel; 5-fluorouracyl, bleaching agents and
photoprotectors, and the like. A therapeutic agent includes
pharmaceutically acceptable salts thereof, prodrugs and
pharmaceutical derivatives thereof.
[0095] In a first aspect, the present invention relates to the use
of a compound of Formula (I) or a pharmaceutically acceptable salt
or solvate, isomer or prodrug thereof to prepare a drug for the
cosmetic, therapeutic and/or prophylactic treatment of dermatitis
or seborrheic keratosis, wherein the compound of the Formula (I)
is:
##STR00002##
wherein: [0096] R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pZ; [0097] Y is --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --PO.sub.3H,
--PO.sub.3--.X.sup.+, --PO.sub.3R.sub.3; [0098] Z is --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --PO.sub.3H,
--PO.sub.3--.X.sup.+, --PO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ or --CO.sub.2R.sub.3; [0099] X+is an
organic cation or an inorganic cation, such that the general charge
of the compound is neutral; [0100] R.sub.9 and R.sub.9' are
independently selected from --OH and --OR.sub.2, wherein when
R.sub.9 and R.sub.9' are both --OR.sub.2, then said R.sub.9 and
R.sub.9' can be the same or different; [0101] R.sub.2 is a
substituted or unsubstituted alkyl group, a substituted or
unsubstituted aryl group, a substituted or unsubstituted arylalkyl
group, a substituted or unsubstituted alkylsulfonyl group, a
substituted or unsubstituted arylsulfonyl group, a substituted or
unsubstituted alkylarylsulfonyl group, a substituted or
unsubstituted arylalkysulfonyl group, a substituted or
unsubstituted aryloxyalkyl group, a substituted or unsubstituted
alkylcarbonyl group or an arylcarbonyl group, a carboxyl group, a
substituted or unsubstituted alkoxycarbonyl group, a substituted or
unsubstituted carboxyalkyl group, in particular --CH.sub.2--COOH,
or a substituted or unsubstituted alkoxy- aryloxy- arylalkoxy- or
alkylaryloxy-carbonylalkyl, in particular --CH.sub.2--COOR.sub.3;
[0102] R.sub.3 is a substituted or unsubstituted alkyl group or a
substituted or unsubstituted aryl group; [0103] a is number
selected from 0, 1, 2, 3, 4, 5 and 6; [0104] p is an integer
selected from 0, 1, 2, 3, 4, 5 and 6, with the proviso that when Y
is --SO.sub.3H, --SO.sub.3.sup.-.X.sup.+ or --SO.sub.3R.sub.3, then
R.sub.9 and R.sub.9' are independently selected from --OH and
--OR.sub.2, wherein at least one of R.sub.9 and R.sub.9' is a
substituted or unsubstituted alkylsulfonyloxy group, a substituted
or unsubstituted arylsulfonyloxy group, a substituted or
unsubstituted alkylcarbonyloxy group or a substituted or
unsubstituted arylcarbonyloxy group.
[0105] In a particular embodiment, 2,5-dihydroxybenzene derivatives
of the invention or any of the pharmaceutically acceptable salts
thereof are those that are represented by Formula (I) comprising
dobesilate ester derivatives and the pharmaceutically acceptable
salts thereof for the treatment of dermatitis.
[0106] More particularly, the dermatitis is selected from the group
consisiting of actinic dermatitis, allergic contact dermatitis,
atopic dermatitis, carcinomatous dermatitis, contact dermatitis,
diaper dermatitis, stasis dermatitis, neurodermatitis,
dermatomyositis and radiation-induced dermatitis.
[0107] The X.sup.+ cation in the compound of Formula (I) may be any
physiologically acceptable cation known in the art, that includes
but is not limited to those described in P. Heinrich Stahl, Camille
G. Wermuth (eds.), "Handbook of Pharmaceutical Salts Properties,
Selections and Use", Verlag Helvetica Chimica Acta, Zurich,
Switzerland, Wiley-VCH, Weinheim, Germany, 2002.
[0108] The X.sup.+ cation is typically selected in such a way that
the general charge of Formula (I) is neutral.
[0109] In a particular embodiment of the invention R1 is
--(CH.sub.2).sub.aY or --CH.dbd.CH--(CH.sub.2).sub.pY. More
particularly, Y is selected from --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, and --SO.sub.3R.sub.3.
[0110] In another particular embodiment of the invention, R.sub.3
is selected from methyl, ethyl, isopropyl or C.sub.6H.sub.5--, more
preferably from methyl and ethyl.
[0111] In another particular embodiment, R.sub.1 is
--(CH.sub.2).sub.aY or --CH.dbd.CH--(CH.sub.2).sub.pY.
[0112] In another particular embodiment, at least one of R.sub.9
and R.sub.9' are, independently, a substituted or unsubstituted
alkylsulfonyloxy group, a substituted or unsubstituted
arylsulfonyloxy group, a substituted or unsubstituted
alkylcarbonyloxy group or a substituted or unsubstituted
arylcarbonyloxy group.
[0113] In another particular mebodiment, R.sub.2 is selected from
methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,
benzylsulfonyl, benzyl and phenyl
[0114] In another particualr embodiment, R.sub.2 is selected from
methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,
benzylsulfonyl, benzyl and phenyl.
[0115] In another particualr embodiment of the invention, R.sub.2
is selected from acetyl (--C(O)CH.sub.3), tosyl
(--SO.sub.2--C.sub.6H.sub.4--CH.sub.3) or p-chlorophenoxyisobutyryl
(--C(O)--C(CH.sub.3).sub.2--O--C6H.sub.4Cl).
[0116] In a preferred embodiment of the invention, the inorganic
cation is sodium, potassium, lithium, calcium, or magnesium.
[0117] In another preferred embodiment of the invention, the
organic cation is [NH.sub.4-pR.sub.p].sup.+: wherein p is an
integer between 0 and 4 and R is an alkyl group having one to six
carbon atoms such as, for example, methyl, ethyl, n-propyl,
i-propyl, t-butyl or n-pentyl.
[0118] In another preferred embodiment of the invention, the
organic cation is the diethylamine
[H.sub.2N.sup.+(C.sub.2H.sub.5).sub.2], piperazine or pyridine
group.
[0119] In another preferred embodiment of the invention, the
compound of Formula (I) and acceptable salts thereof are:
##STR00003## ##STR00004## ##STR00005##
wherein: [0120] n is a number selected from 1 and 2; [0121] m is a
number selected from 1 and 2; and [0122] X, R.sub.2 and R.sub.3 are
as defined in the present invention.
[0123] In a more preferred embodiment of the invention, the
compound of Formula I is: [0124]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
[0125] 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0126] 2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0127] 2-(acetyloxy)-5-hydroxybenzenesulfonic acid; [0128]
5-(acetyloxy)-2-hydroxybenzenesulfonic acid; [0129]
2,5-bis(acetyloxy)benzenesulfonic acid; [0130]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0131]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0132]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;
[0133] 2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid; [0134]
5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid; [0135]
2,5-bis(acetyloxy)benzenehomosulfonic acid; [0136]
3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic
acid); [0137]
3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; [0138] 3-(2-hydroxy-5-
{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid; [0139]
3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;
[0140] 3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid; [0141]
3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0142]
3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid; [0143]
3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid; [0144]
3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0145]
3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid;
[0146] and pharmaceutically acceptable salts, solvates and prodrugs
thereof.
[0147] Particularly preferred are the compounds
2-(acetyloxy)-5-hydroxybenzenesulfonic acid;
5-(acetyloxy)-2-hydroxybenzenesulfonic acid and 2,5-bis(acetyloxy)
benzenesulfonic acid.
[0148] 2,5-dihydroxybenzene derivatives may be optionally used
combined with each other. In this manner and as an example, it is
possible to combine a dobesilate ester derivative with a
homodobesilate ester derivative, and the like in the same or in a
different ratio. Said combinations may be in the same formulation
or in formulations that would be used sequentially.
[0149] The compounds of Formula (I) may be synthesized by one
skilled in the art using conventional and commercially available
methods. The synthesis of the compounds of Formula (I) is disclosed
in, for example, U.S. Pat. No. 5,082,941; and "The Merck Index"
13th. edition, Merck & Co., R. Railway, N.J., USA, 2001; U.S.
Pat. Nos. 5,082,841, 4,814,110, 4,613,332 and 4,115,648; the
disclosures which are incorporated herein by reference in their
entirety.
[0150] Compounds of Formula (I) also may be in the form of
solvates, particularly in the form of hydrates. The preparation of
the compounds of Formula (I), as well as the solvates thereof may
be carried out by one skilled in the art using conventional methods
and commercially available reagents.
[0151] Even as it has been previously mentioned in one of the
preferred embodiments with respect to the definition of X.sup.+
cation, the scope of the present invention encompasses any salt
thereof, especially any pharmaceutically acceptable salt of the
compound. The phrase "pharmaceutically acceptable salts" includes
metal salts or the addition salts that may be used in
pharmaceutical forms. For example, the pharmaceutically acceptable
salts of the compounds provided herein may be acid addition salts,
base addition salts or metal salts and they may be synthesized from
the parenteral compounds containing a base or acid residue using
conventional chemical processes. Generally, those salts are
prepared, for example, by the reaction of free base or acid forms
of these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
both. Generally, non aqueous mediums such as ether, ethyl acetate,
ethanol, isopropanol or acetonitrile are preferred. The examples of
acid addition salts include addition salts of mineral acids such
as, for example, hydrochloride, bromhydrate, iodide hydrate,
sulfate, nitrate, phosphate, addition salts of organic acids such
as, for example, acetate, maleate, fumarate, citrate, oxalate,
succinate, tartrate, malate, mandelate, methanesulfonate and
p-toluenesulfonate. The examples of alkali addition salts include
inorganic salts such as, for example, ammonium salts and organic
alkaline salts such as, for example, diethylamine, ethylenediamine,
ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine
and basic amino acid salts. The examples of metal salts include,
for example, sodium, potassium, calcium, magnesium, aluminum, and
lithium salts.
[0152] In some embodiments, the invention provides a composition
comprising an ester derivative of a compound of Formula (I),
especially an dobesilate ester derivative, such as
2-acetyloxy-5-hydroxybenzenesulfonic acid,
5-acetyloxy-2-hydroxybenzenesulfonic acid, or
2,5-bis-acetyloxybenzenesulfonic acid. In some embodiments, it will
be desirable to formulate a composition of the invention with an
active principle such as a dobesilate ester derivative, for
example, wherein the ester derivative shows more therapeutic
efficacy than the original compound in the treatment or prevention
of a condition described herein. In other embodiments, the
invention includes the use of a dobesilate ester derivative as a
prodrug, for example, to treat a condition described herein,
wherein the ester derivative is metabolized to the original
compound in a patient to achieve therapeutic efficacy in the
patient.
[0153] The phrase "pharmaceutically acceptable" refers to
physiologically tolerable molecular entities and compositions which
do not typically produce an allergic or similar adverse reaction,
such as gastric upset, dizziness, and the like, when administered
to a human. Preferably, as used herein, the term "pharmaceutically
acceptable" means that it is approved by a regulatory agent of the
Federal or a state government or listed in the U.S. Pharmacopeia or
other generally recognized pharmacopoeia as suitable for use in
animals, and more particularly, in humans.
[0154] It would be obvious to those skilled in the art that the
scope of the present invention also encompasses salts that are not
pharmaceutically acceptable as possible media to obtain
pharmaceutically acceptable salts.
[0155] As used herein, the term "solvate" shall refer to any form
of the active compound according to the invention that exhibits
another molecule (most probably, a polar solvent) bound to it
through a non-covalent bond. Examples of solvates include hydrates
and alcoholates, preferably, C.sub.1-C.sub.6 alcoholates, for
example, methanolate.
[0156] The pharmaceutically acceptable salts of Formula (I) may be
prepared from organic or inorganic acids or basis by conventional
methods through the reaction of the appropriate acid or base with
the compound.
[0157] In a particular embodiment, 2,5-dihydroxybenzenic
derivatives of the invention may be used optionally and jointly
with at least one of the following therapeutic agents: diclofenac,
T4 endonuclease, isotretinoin, acitretin, cidofoir, a
corticosteroid, an antibiotic, an analgesic, an immunomodulator,
including oral immunomodulator such as tacrolimus and pimecrolimus,
and topical immunomodulators; an immunosuppressant, an
anti-angiogenic, including anti-VEGF, anti-FGF, anti-EGF and
anti-HGF; a leukotriene modifier, an aminosalicylate, an
anesthetic, a non-steroidal anti-inflammatory, a therapy of the
solubilized interleukin receptor, inhibitors of tyrosin-kinase
receptors, protein kinase C inhibitors, and combinations of two or
more thereof.
[0158] A medicament comprising a compound of formula (I) of the
invention may be presented in any suitable form for administration,
for example, for systemic, transdermal, oral, parenteral, buccal,
nasal (e.g., by inhalation), topical, rectal, intravaginal,
intraocular or otical administration; therefore, a medicament of
the invention may include the acceptable pharmaceutical excipients
or vehicles necessary to be formulated in the desired form of
administration. In a preferred embodiment, the pharmaceutical
composition is administered topically.
[0159] Thus, in one preferred aspect, the present invention refers
to a method for the treatment and/or prophylaxis of dermatitis in a
patient in need of the treatment and it comprises the
administration to the patient of an effective amount of the
described compounds and/or compositions of Formula (I).
[0160] The compounds of formula (I) may be optionally administered
together with at least one therapeutic agent, such as, diclofenac,
T4 endonuclease, isotretinoin, acitretin, cidofoir, a
corticosteroid, an antibiotic, an analgesic, an immunomodulator,
including oral immunomodulator such as tacrolimus and pimecrolimus,
and topical immunomodulators; an immunosuppressant, an
anti-angiogenic, including anti-VEGF, anti-FGF, anti-EGF and
anti-HGF; a leukotriene modifier, an aminosalicylate, an
anesthetic, a non-steroidal anti-inflammatory, a therapy of the
solubilized interleukin receptor, inhibitors of tyrosin-kinase
receptors, protein kinase C inhibitors, and combinations of two or
more thereof.
[0161] In other embodiments, the application of the
2,5-dihydroxybenzene compounds represented by Formula (I) may be
made independently or, in a preferred aspect, simultaneously with
the use of equivalent or different mixes of other
2,5-dihydroxybenzene compounds represented by Formula (I)
(including pharmaceutically acceptable salts and esters) and these
compounds may be in the same formulation or in independent
formulations that would be simultaneously or sequentially
administered.
[0162] In another aspect, the present invention refers to a
cosmetic product comprising 2,5-dihydroxybenzene derivatives or any
of the pharmaceutically acceptable salts thereof represented by
Formula (I).
[0163] In an embodiment, the present invention refers to a cosmetic
product that comprises 2,5-dihydroxybenzene derivatives or any of
the pharmaceutically acceptable salts thereof represented by
Formula (I) characterized in that the compound of Formula (I) is an
ester derivative of 2,5-dihydroxybenzenesulfonic acid or
pharmaceutically acceptable salts or esters thereof.
[0164] In another embodiment, the present invention refers to a
cosmetic product that comprises 2,5-dihydroxybenzene derivatives or
any of the pharmaceutically acceptable salts thereof represented by
Formula (I) characterized in that the compound of Formula (I) is an
ester derivative of 2,5-dihydroxybenzene homosulfonic acid or
pharmaceutically acceptable salts or esters thereof.
[0165] In another embodiment, the present invention refers to a
cosmetic product characterized in that the compound of Formula (I)
is an ester derivative of 2,5-dihydroxybenzenesulfonic acid or the
pharmaceutically acceptable salts or esters thereof characterized
in that it consists of a formulation for dermatitis or seborrheic
keratosis.
[0166] In another embodiment, the present invention refers to a
cosmetic product according to any of the previous aspects
characterized in that it is presented in the form of cream,
ointment, unguent, microsomes, bandages, or patches.
[0167] In another embodiment, the present invention refers to a
cosmetic product according to any of the previous aspects
characterized in that it contains an amount of 5% of an ester
derivative of 2,5-dihydroxybenzene sulfonic acid.
[0168] In another embodiment, the present invention refers to a
cosmetic product according to any of the previous aspects
characterized in that it comprises as excipients: cetyl alcohol
(2.5%), stearyl alcohol (2.5%), liquid vaseline (30%), filante
vaseline (20%), sorbitan monooleate (5%) and distilled water (q.s.
to 100 g).
[0169] In another embodiment, the present invention refers to the
use of 2,5-dihydroxybenzene derivatives or any of the
pharmaceutically acceptable esters or salts thereof represented by
Formula (I) to prepare a formulation intended to be cosmetically
used.
[0170] In another embodiment, the present invention refers to a
method for cosmetic or therapeutic treatment of dermatitis,
comprising the administration to a patient of a composition
comprising a compound of Formula (I).
[0171] In one embodiment, the present invention refers to the use
of 2,5-dihydroxybenzene derivatives or any pharmaceutically
acceptable esters or salts thereof represented by Formula (I)
wherein the compound of Formula (I) is an ester derivative of
2,5-dihydroxybenzensulfonic acid or the salts or esters thereof, to
prepare a drug or medicine intended for the cosmetic or therapeutic
treatment of dermatitis.
[0172] In one embodiment, the present invention refers to the use
of 2,5-dihydroxybenzene derivatives or any pharmaceutically
acceptable esters or salts thereof represented by Formula (I)
wherein the compound of Formula (I) is an ester derivative of
2,5-dihydroxybezene homosulfonic acid or the salts and esters
thereof, to prepare a drug or medicine intended for the cosmetic or
therapeutic treatment of dermatitis.
[0173] Another aspect of the present invention refers to a method
for the cosmetic treatment of any of the diseases comprised in the
following group: seborrheic keratosis, atopic dermatitis or contact
dermatitis, comprising the administration to a patient of a
composition comprising Formula (I), or the pharmaceutically
acceptable salts or esters thereof.
[0174] Another aspect of the present invention refers to a method
for therapeutic treatment of dermatitis, comprising the
administration to a patient of a composition comprising Formula
(I), or the pharmaceutically acceptable salts or esters
thereof.
[0175] The duration of treatment will typically depend on the
particular condition, its severity, the condition of the patient,
and the like, and will readily be determined by one of skill in the
art. Illustrative courses of therapy include 1 week, 2 weeks, 3
weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10
weeks, 11 weeks, 12 weeks, 3.5 months, 4 months, 4.5 months, 5
months, 6 months, 9 months, a year, or longer as needed.
[0176] In treating a subject suffering from a disorder described
herein, treatment may be continued until at least a 10% improvement
is effected in a symptom associated with the condition. In other
embodiments, treatment is continued until the subject in need of
such treatment experiences an improvement of at least about 20%, at
least about 30%, at least about 40%, preferably at least about 50%,
preferably at least about 60%, more preferably at least about 70%,
more preferably at least about 80%, even more preferably 90% or
greater in a symptom associated with a disorder described
herein.
[0177] In a particular embodiment of the invention, a compound of
formula (I) is administered at least once per week. In other
embodiments, a compound of formula (I) is administered at least
once per day. In yet other embodiments, a compound of formula (I)
is administered twice per day. In another particular embodiment, a
compound of formula (I) is administered over a period of at least
about one week. In other embodiments, a compound of formula (I) is
administered over a period of at least about four weeks.
[0178] Therapeutic amounts can be empirically determined and will
vary with the particular condition being treated, the subject, the
particular formulation components, dosage form, and the like.
[0179] In a particular embodiment, a compound of formula (I) is
present in a pharmaceutical composition in an amount of at least
about 1% W/W. In other embodiments, a compound of formula (I) is
present in a pharmaceutical composition in an amount of at least
about 2.5% w/w, at least about 5% w/w, at least about 10% w/w, or
at least about 15% w/w.
[0180] In another particular embodiment of the invention, the
inventive 2,5-dihydroxybenzene compounds of Formula (I) may be
administered topically in a formulation comprising from about
0.001% to about 30% (w/w) of the inventive 2,5-dihydroxybenzene
compounds of Formula (I). In a preferred aspect of the invention,
the inventive 2,5-dihydroxybenzene compounds of Formula (I) may be
administered topically in a formulation comprising from about 0.01%
to about 20% (w/w) of the inventive 2,5-dihydroxybenzene compounds
of Formula (I). In another preferred aspect of the invention, the
inventive 2,5-dihydroxybenzene compounds of Formula (I) may be
administered topically in a formulation comprising from about 0.1%
to about 15% (w/w) of the inventive 2,5-dihydroxybenzene compounds
of Formula (I). In a preferred aspect of the invention, the
inventive 2,5-dihydroxybenzene compounds of Formula (I) may be
administered topically in a formulation comprising from about 0.5%
to about 10% (w/w) of the inventive 2,5-dihydroxybenzene compounds
of Formula (I). In another preferred aspect of the invention, the
inventive 2,5-dihydroxybenzene compounds of Formula (I) may be
administered topically in a formulation comprising from about 1% to
about 5% (w/w) of the inventive 2,5-dihydroxybenzene compounds of
Formula (I). In another preferred aspect of the invention, the
inventive 2,5-dihydroxybenzene derivatives: of Formula (I) may be
administered topically in a formulation comprising from about 2.5%
to about 4% (w/w) of the inventive 2,5-dihydroxybenzene compounds
of Formula (I). The topic formulation of the compounds comprised in
the inventive 2,5-dihydroxybenzene compounds: of Formula (I) may be
administered as a single dose once a day or in multiple doses
several times a day. In a preferred aspect of the invention, the
topical formulation which comprises 30%, 20%, 15%, 10%, 5%, 2.5%,
1%, 0.5%, 0.1% or 0.001% of the inventive 2,5 dihydroxybenzene
compounds of Formula (I), is administered four times a day. In
another preferred aspect of the invention, the topical formulation
which comprises about 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1%
or 0.001% of the inventive 2,5 dihydroxybenzene compounds of
Formula (I), is administered three times a day. In another
preferred aspect of the invention, the topical formulation which
comprises about 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or
0.001% of the inventive 2,5 dihydroxybenzene compounds of Formula
(I), is administered twice a day. In another preferred aspect of
the invention, the topical formulation which comprises about 30%,
20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the inventive
2,5 dihydroxybenzene compounds of Formula (I), is administered once
a day.
Topical Compositions
[0181] The product of the present invention is useful for topical
application on the skin. The compositions comprise an effective
amount of the inventive compounds: of Formula (I), preferably from
about 0.001 to 30%. Furthermore, the composition comprises a
pharmaceutical acceptable vehicle. The appropriate vehicles remain
in the place of application on the skin forming a continuous film
resistant to water immersion and perspiration. Generally, the
vehicle is organic and capable of containing the formulation of the
invention in a diluted or dispersed form. Lotions, creams,
solutions, gels and solids are the usual physical forms of the
composition.
[0182] Topical application means depositing or spreading the
compound and the compositions over the epidermic tissue (including
skin and oral, gingival, nasal, etc. tissues).
Lotions
[0183] Lotions contain from about 0.001% to about 30% of the
inventive compounds of Formula: (I) from 1% to 25% of an emollient
and the appropriate amount of water. Examples of emollients are:
[0184] I. Hydrocarbon waxes and oils such as mineral oils,
petrolatum, paraffin, ceresin, microcrystalline wax, polyethylene
and perhydrosqualene. [0185] II. Silicone oils such as
dimethylpolysiloxanes, methylphenylpolysiloxanes and water-soluble
and alcohol-soluble glycol-silicone copolymers. [0186] III.
Triglycerides, such as animal and vegetable fats and oils. Examples
include, but are not limited to, castor oil, cod liver oil, corn
oil, olive oil, almond oil, palm oil, sesame oil, cotton seed oil
and soybean oil. [0187] IV. Acetoglyceride esters, such as
acetylated monoglycerides. [0188] V. Ethoxylated glycerides, such
as ethoxylated glycerol monostearate. [0189] VI. Alkyl esters of
fatty acids having 10 to 20 carbon atoms. Methyl, isopropyl and
butyl esters of fatty acids are useful herein. Examples inclue, but
are not limited to, hexyl laurate, isohexyl laurate, isohexyl
palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate,
hexadecyl stearate, decyl stearate, isopropyl isostearate,
diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate,
diisopropyl sebacate, lauryl lactate, myristoyl lactate and cetyl
lactate. [0190] VII. Alkenyl esters of fatty acids having 10 to 20
carbon atoms. Examples thereof include, but are not limited to,
oleyl myristate, oleyl stearate and oleyl oleate. [0191] VIII.
Fatty acids having 10 to 20 carbon atoms. Suitable examples
include, but are not limited to, pelargonic, lauric, myristic,
palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic,
ricinoleic, arachidonic, behenic and erucic acids. [0192] IX. Fatty
alcohols having 10 to 20 carbon atoms. Lauryl, myristoyl,
palmitoyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl,
behenyl, erucyl and 2-octyl dodecanol alcohols are appropriate
examples of fatty alcohols. [0193] X. Fatty alcohol ethers.
Ethoxylated fatty alcohols having 10 to 20 carbon atoms include,
but are not limited to, lauryl, cetyl, stearyl, isostearyl, oleyl
and cholesterol alcohols having attached thereto from 1 to 50
ethylene oxide groups or 1 to 50 propylene oxide groups. [0194] XI.
Ether-esters, such as fatty acid esters of ethoxylated fatty
alcohols. [0195] XII. Lanolin and derivatives. Lanolin, lanolin
oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl
lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols,
ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated
lanolin, acetylated lanolin alcohols, lanolin alcohols linoleates,
lanolin alcohols ricinoleate, acetate of lanolin alcohols
ricinoleate, hydrogenolysis of lanolin, and liquid or semisolid
lanolin absorption bases are illustrative examples of lanolin
derived emollients. [0196] XIII. Polyhydric alcohols and polyether
derivatives. Propylene glycol, dipropylene glycol, polypropylene
glycol 2000 and 4000, polyoxyethylene polypropylene glycols,
glycerol, ethoxylated glycerol, propoxylated glycerol, sorbitol,
ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol
200-6000, methoxy polyethylene glycols 350, 550, 750, 2000, 5000,
poly(ethylene oxide) homopolymers (100,000-5,000,000), polyalkylene
glycols and derivatives, hexylene glycol
(2-methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6-hexanetriol,
ethohexadiol USP (2-ethyl-1,3-hexanediol), and polyoxypropylene
derivatives of trimethylolpropane are suitable examples. [0197]
XIV. Polyhydric alcohol esters. Mono- and di-acyl esters of
ethylene glycol, mono- and di-acyl esters of diethylene glycol,
mono- and di-acyl esters of polyethylene glycol (200-6000), mono-
and di-acyl esters of propylene glycol, polypropylene glycol 2000
monooleate, polypropylene glycol 2000 monostearate, ethoxylated
propylene glycol monostearate, mono- and di-acyl esters of
glycerol, poly-acyl esters of poly glycerol, ethoxylated glycerol
monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol
distearate, acyl ester of polyoxyethylene polyol, acyl esters of
sorbitan, and acyl esters of polyoxyethylene sorbitan are suitable
examples. [0198] XV. Waxes such as beeswax, spermaceti, myristoyl
myristate and stearyl stearate. [0199] XVI. Beeswax derivatives,
such as polyoxyethylene sorbitol beeswax. These are reaction
products of beeswax with ethoxylated sorbitol of varying ethylene
oxide content that form a mixture of ether-esters. [0200] XVII.
Vegetable waxes, including, but not limited to, carnauba and
candelilla waxes. [0201] XVIII. Phospholipids such as lecithin and
derivatives. [0202] XIX. Sterols. Examples include, but are not
limited to, cholesterol and acyl esters of cholesterol. [0203] XX.
Amides, such as fatty acid amides, ethoxylated acyl amides and
solid fatty acid alkanolamides.
[0204] The lotions of the invention would further contain from 1%
to 30% of an emulsifier. The emulsifiers can be anionic, cationic
or non-ionic. Examples of non-ionic emulsifiers include, but are
not limited to, fatty alcohols having 10 to 20 carbon atoms, fatty
alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles
of ethylene oxide or propylene oxide, alkyl phenols with 6 to 12
carbons in the alkyl chain condensed with 2 to 20 moles of ethylene
oxide, mono- and di-acyl esters of ethylene glycol, wherein the
fatty acid contains from 10 to 20 carbons, monoglycerides wherein
the fatty acid contains from 10 to 20 carbons, diethylene glycol,
polyethylene glycols of molecular weight 200 to 6000, polypropylene
glycol of molecular weight 200 to 3000, glycerol, sorbitol,
sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and
hydrophilic wax esters. Suitable anionic emulsifiers include, but
are not limited to, fatty acids saponified (soaps) with potassium,
sodium, or triethanolamine, wherein the fatty acid contains from 10
to 20 carbons. Other suitable anionic emulsifiers include, but are
not limited to, alkali metals, ammonium or substituted ammonium
with alkyl sulfates, alkyl arylsulfonates and alkyl ethoxy ether
sulfonates having 10 to 30 carbons in the alkyl chain and from 1 to
50 ethylene oxide units. Suitable cationic emulsifiers include
quaternary ammonium and morpholinium and pyridinium compounds.
[0205] Some emollients previously described also have emulsifying
properties. When a lotion contains one of these emollients, an
additional emulsifier is not needed, though it can be included in
the formulation.
[0206] The balance of the composition is water. The lotions are
formulated by simply admixing all of the components together.
Preferably, the compounds of Formula I are dissolved in the
emollient and the resulting mixture is added into the water.
Optional components such as the emulsifier or common additives may
be included in the composition. A common additive is a thickening
agent included at a level of 1% to 30% by weight of the
composition. Examples of suitable thickening agents are:
Cross-linked carboxypolymethylene polymers, methyl cellulose,
polyethylene glycols, gums and bentonite.
Creams
[0207] The compositions of the present invention may be also
formulated in the form of a cream. Creams contain from 0.001% to
30% of the inventive compounds of Formula (I), from 5% to 50% of an
emollient and the remainder is water. The emollients, as described
above, can also be used in the cream formulation. Optionally, the
cream may contain an emulsifier at a level from 3% to 50%. The
previously described emulsifiers would also be adequate in this
case.
Solutions
[0208] The compositions of the present invention may also be
formulated in the form of a solution. Solutions contain from 0.001%
to 30% of the inventive compounds: of Formula (I), and the adequate
amount of an organic solvent. Organic substances useful as the
solvent or a part of the solvent system are as follows: propylene
glycol, polyethylene glycol (200-600), polypropylene glycol
(425-2025), glycerine, sorbitol esters, 1,2,6-hexanetriol, ethanol,
isopropanol, diethyl tartrate, butanediol, and mixtures thereof.
Such solvent systems can also contain water. These compositions are
applied on the skin in the form of a solution, or solutions are
formulated in the form of aerosol and applied on the skin as a
spray. Compositions in the form of aerosol additionally contain
from 25% to 80% of a suitable propellant. Examples of propellants
include, but are not limited to: chlorinated, fluorinated and
fluorochlorinated low molecular weight hydrocarbons. Nitrous oxide
and carbon dioxide are also used as propellant gases. Enough
quantity to expel the content of the cartridge is used.
Gels
[0209] The composition in the form of gel might be simply obtained
by the addition of a suitable thickening agent to the composition
in the form of a solution as described above. Suitable thickening
agents have been described in the chapter referring to lotions.
[0210] Gel formulations contain from about 0.001% to about 30% of
the compounds of Formula (I), 5% to 75% of a suitable organic
solvent, 0.5% to 20% of a suitable thickening agent and the
required amount of water.
Solids
[0211] The compositions in the present invention may also be
formulated in solid form. Such forms have the shape of a bar
intended for the application on the lips or other parts of the
body. These compositions contain from about 0.001% to about 30% of
the inventive compounds: of Formula (I), and from about 50% to
about 98% of an emollient such as the one already described. The
composition may be further contain from about 1% to about 20% of a
suitable thickening agent, such as those already described, and,
optionally, emulsifiers and water.
[0212] Additives usually found in topical compositions, such as
preservatives (for example, methyl and ethyl paraben), dyes and
perfumes may be included in any of the formulations described
herein.
Application Method
[0213] The effective amount of compounds of Formula (I) used
topically will vary according to the specific circumstances of
application, the duration of exposure and similar considerations.
Generally, the amount will vary from 0.01 microgram to 50
milligrams of the compounds of Formula (I), per square centimeter
of the epidermis area. The amount of topical composition (the
compounds of Formula (I) and the vehicle) applied on the affected
area may be easily determined according to the amount of compounds
of Formula (I) contained therein.
Kits
[0214] In yet other embodiments, the invention provides a kit or
package comprising a compound of formula (I), in packaged form,
accompanied by instructions for use. The compound of formula (I)
may be packaged in any manner suitable for administration, so long
as the packaging, when considered along with the instructions for
administration, indicates the manner in which the compound of
formula (I) is to be admininistered.
[0215] For example, a kit may comprise a compound of formula (I) in
unit dosage form, along with instructions for use. For example,
such instructions may indicate that administration of a compound of
formula (I) is useful in the treatment of dermatitis. The compound
of formula (I) may be packaged in any manner suitable for
administration. For example, when the compound of formula (I) is in
oral dosage form, e.g., is in the form of a coated tablet, then the
kit may comprise a sealed container of coated tablets, blister
strips containing the tablets, or the like.
[0216] Various embodiments according to the above may be readily
envisioned, and would depend upon the particular dosage form,
recommended dosage, intended patient population, and the like. The
packaging may be in any form commonly employed for the packaging of
pharmaceuticals, and may utilize any of a number of features such
as different colors, wrapping, tamper-resistant packaging, blister
packs or strips, and the like.
[0217] The following non-limiting examples further describe and
enable one of ordinary skill in the art to make and use the present
invention.
EXAMPLES
Example 1
Effect of 2,5-dihydroxybenzenesulfonate and the Ester Thereof,
2,5-diacetoxybenzenesulfonate on Dermatitis
[0218] Dermatitis was induced by the application of benzalkonium
chloride, 5% solution (w/v) (1:5 olive oil:acetone) on the entire
extent of the back part of the ear (40 .mu.L/ear) in anesthetized
rats. Dermatitis was induced in both ears. In the assay of
2,5-dihydroxybenzenesulfonate (DHBS), a cream containing 5% of DHBS
(w/w) was applied topically only on the back part of the right ear,
30 minutes after the application of benzalkonium chloride. Fifteen
minutes later, 0.5% by weight of Evans blue dye solution (400 .mu.L
per animal) was injected into the jugular vein. This dye only
stains in blue the areas of the skin that exhibit an alteration of
the vascular permeability which enables the extravasation of the
dye, as would correspond to a dermatitis process. Four hours after
inducing dermatitis in both ears, the left ear of the studied rats
(n=6) which had not been treated, exhibited a vast and intense blue
stain, as shown in FIG. 1. Nevertheless, the right ear of all the
rats treated with 5% DHBS exhibited a clearly smaller blue stain
than the one in the respective left ear of each case (FIG. 1).
Therefore, it can be stated that topical application of 5% DHBS
reduced the dermatitis extent.
[0219] This observation was confirmed upon quantification of
dermatitis extent based on the area of the ear stained in blue with
respect to the total area of the ear. Identically obtained
photographs of the extended ears were processed in order to
determine the stained area and the total area of the ear using a
computer program to analyze images (Motic Image). The stained area
of each ear was related to the total area to obtain the percentage
of the ear affected by the dermatitis. The statistic analysis of
the resulting values, 4 hours after the application of benzalkonium
chloride on the treated and untreated ears, revealed that the
treatment with cream containing DHBS at 5% by weight significantly
reduced the percentage of the area stained in blue, as shown in
FIG. 2A, thus, showing an inhibitory effect of DHBS on the
development of dermatitis. 24 hours after dermatitis induction
(FIG. 2B), these values were very similar.
[0220] Using the same model, dermatitis was induced on both ears of
two rats, following the same process described above. In this case,
30 minutes after the application of benzalkonium chloride, a rat
was treated in both ears with a glycerol solution (FIG. 3A), while
the other one was treated in both ears with a glycerol solution
containing 2.5% (w/v) of 2,5-diacetoxybenzenesulfonate (DABS) (FIG.
3B). The topical treatment with DABS reduced benzalkonium chloride
induced dermatitis, as evidenced by the fact that the ears of the
rats treated with the vehicle (glycerol) exhibit a much more
intense erythema than that corresponding to the rats treated with
DABS. The histological study of these ears evidences that the
topical treatment with 2.5% of DABS reduces the edema and the
leukocyte infiltration (FIG. 4). The ears treated with DABS show a
significant reduction of the presence of granulocytes adhered to
the capillary endothelial cells, in its step previous to
extravasation towards the subjacent tissue (FIGS. 4e and 4f).
[0221] In this same model (Hyun E et al. Br J Pharmacol, 2004),
dermatitis induction has been associated to an increase in the
myeloperoxidase (MPO) activity in the ear, as a marker of leukocyte
infiltration in the tissue affected with dermatitis. Based on these
evidences, the effect of hidroxybenzene derivatives on the activity
of the MPO in the model described in this example was established.
The MPO activity was determined in the ears of control rats
(without dermatitis) and in ears on which dermatitis had been
induced with benzalkonium chloride and had been treated with
vehicle (anhydrous glycerol), 5% DHBS cream or DABS 2.5% solution
in glycerol. The ears were frozen in liquid nitrogen 24 hours after
the induction of dermatitis and were kept at -80.degree. C. until
determination of MPO activity. To determine the MPO activity, the
frozen ears were homogenized in phosphate buffer with 0.5% of
hexadecyltrimethylammonium bromide. After several
freezing/thawing/sonication cycles, the samples were centrifuged at
13,000.times.g during 20 minutes at 4.degree. C. H.sub.20.sub.2 and
0-dianisidine were added into the supernatants and the absorbance
was measured at 460 nm in a spectrophotometer 1 hour after
incubation at room temperature. The MPO activity is expressed as
absorbance units per mg of tissue.
[0222] 24 hours later, the dermatitis produces a significant
increase in the MPO activity in the ear which is significantly
reduced by the topical treatment with 5% DHBS (FIG. 5). The topical
application of 2.5% of DABS also significantly reduces the increase
of MPO activity caused by the dermatitis. In fact, when the DABS
topical formulation contained half of the amount of active
principle contained in the DHBS, its efficacy was slightly higher
(FIG. 5).
[0223] This example shows the efficacy of the topical application
of DHBS and of the diacetylated form thereof, DABS, for the
treatment of dermatitis in an animal model.
[0224] As the foregoing example illustrates, in certain
embodiments, the esters of 2,5-dihydroxybenzene sulfonate described
in the present invention surprisingly exert pharmacological actions
of interest in the present invention by themselves, without needing
to be first converted into 2,5-dihydroxybenzenesulfonate in order
to exert such actions.
Example 2
Effect of Monoesters of 2,5-dihydroxybenzenesulfonate on
Dermatitis
[0225] Using the same procedure as in the former example,
dermatitis was induced by the application of benzalkonium chloride,
5% solution (w/v) (1:5 olive oil:acetone) on the entire extent of
the back part of the ear (40 .mu.L/ear) in anesthetized rats.
Dermatitis was induced in both ears. A cream containing 5% (w/v) of
either 2-acetoxy-5-hydroxybenzenesulfonate (2A-5HBS) or
5-acetoxy-2-hydroxybenzenesulfonate (5A-2HBS) was applied topically
only on the back part of the right ear, 30 minutes after the
application of benzalkonium chloride. Fifteen minutes later, 0.5%
(w/v) of Evans blue dye solution (400 .mu.L per animal) was
injected into the jugular vein. This dye only stains in blue the
areas of the skin that exhibit an alteration of the vascular
permeability which enables the extravasation of the dye, as would
correspond to a dermatitis process. Twenty four hours after
inducing dermatitis in both ears, the left ear of the studied rats
(n=5) which had not been treated, exhibited a vast and intense blue
stain, as shown in FIG. 6. Nevertheless, the right ear of all the
rats treated with 5% 2A-5HBS exhibited a clearly smaller blue stain
than the one in the respective left ear of each case (FIG. 6). In
the same way, rats treated with 5% 5A-2HBS presented marked blue
stain in the left (untreated) ears while the extent of the staining
in the right (treated) ears was notably reduced (FIG. 7).
Therefore, it can be stated that topical application of 5% 2A-5HBS
and 5% 5A-2HBS reduced the dermatitis extent.
[0226] This observation was confirmed upon quantification of
dermatitis extent based on the area of the ear stained in blue with
respect to the total area of the ear. Identically obtained
photographs of the extended ears were processed in order to
determine the stained area and the total area of the ear using a
computer program to analyze images (Motic Image). The stained area
of each ear was related to the total area to obtain the percentage
of the ear affected by the dermatitis. The statistic analysis of
the resulting values, 24 hours after the application of
benzalkonium chloride on the treated and untreated ears, revealed
that the treatment with 2A-5HBS solution at 5% by weight
significantly reduced the percentage of the area stained in blue,
as shown in FIG. 8, as well as did it the treatment with 5% (w/v)
5A-2HBS solution (FIG. 9) thus, showing an inhibitory effect of the
monoesters of 2,5-dihydroxybenzesulfonate at positions 2 (2A-5HBS)
or 5 (5A-2HBS) on the development of dermatitis.
Example 3
Analysis of the Structural Interaction of the Esters of
2,5-dihydroxybenzenesulfonate with the Fibroblast Growth Factor-1
(FGF-1)
[0227] As of the diffraction from complex crystals of FGF-1:
2-acetoxy-5-hydroxybenzenesulfonic acid, FGF-1:
5-acetoxy-2-hydroxybenzenesulfonic acid and FGF-1:
2,5-diacetoxybenzenesulfonic acid, the complex structures were
calculated and represented. In FIGS. 10, 11 and 12, representing
the surface of the protein cloured according to its electrostatic
potential (light grey: negative charge, dark grey: positive charge,
white: areas with no charge), the interaction form of the
2-acetoxy-5-hydroxybenzenesulfonic acid,
5-acetoxy-2-hydroxybenzenesulfonic acid and
2,5-diacetoxybenzenesulfonic acid, respectively, with the FGF-1 may
be observed. The electronic density of the compound, contoured at
1.sigma. (FIGS. 10-12, panels C), enabled the localization and
determination of the orientations of the compounds regarding the
protein (FIGS. 10-12, panels A and B), as well as the confirmation
that the compounds keep the acetoxyl groups in positions 2, 5 and,
2 and 5, respectively, when they bind to the protein. The compounds
are located at a site very close to the site that, as described, is
occupied by the 2,5-dihydroxybenzenesulfonic acid, which aromatic
ring forms a cation-.pi. bond with the N.sup..epsilon. group of
lysine 132, marked in FIGS. 10-12, panels A, as reference.
[0228] Each patent, patent application, and publication cited or
described in the present application is hereby incorporated by
reference in its entirety as if each individual patent, patent
application, or publication was specifically and individually
indicated to be incoporated by reference.
[0229] While specific embodiments of the subject invention have
been discussed, the above specification is illustrative and not
restrictive. One skilled in the art will appreciate that numerous
changes and modifications can be made to the invention, and that
such changes and modifications can be made without departing from
the spirit and scope of the invention. The full scope of the
invention should be determined by reference to the claims, along
with their full scope of equivalents, and the specification, along
with such variations.
* * * * *