U.S. patent application number 11/839529 was filed with the patent office on 2008-05-15 for use of 2,5-dihydroxybenzene derivatives for the treatment of tissue reactive diseases.
This patent application is currently assigned to Action Medicines. Invention is credited to Tomas Fernado Fernandez Jaen, Javier Angulo Frutos, Guillermo Gimenez Gallego, Serafin Valverde Lopez, Rosa Maria Lozano Puerto, Francisco Javier Moreno Nuncio, Luis Ignacio Rivas Lopez, Antonio Romero Garrido, Inigo Saenz de Tejada Gorman, Pedro Cuevas Sanchez.
Application Number | 20080114063 11/839529 |
Document ID | / |
Family ID | 38515369 |
Filed Date | 2008-05-15 |
United States Patent
Application |
20080114063 |
Kind Code |
A1 |
Sanchez; Pedro Cuevas ; et
al. |
May 15, 2008 |
Use of 2,5-Dihydroxybenzene Derivatives for the Treatment of Tissue
Reactive Diseases
Abstract
The present invention relates to the use of a compound of
Formula (I') or pharmaceutically acceptable salt, solvate, isomer,
or prodrug thereof for the treatment and/or prophylaxis of any of
the diseases selected from the group consisting of benign prostatic
hyperplasia, Barrett's disease, asthma, skeletal muscle and tendon
repair, Crohn's disease, ulcerative colitis and leishmaniasis.
Inventors: |
Sanchez; Pedro Cuevas;
(Madrid, ES) ; Gimenez Gallego; Guillermo;
(Madrid, ES) ; Saenz de Tejada Gorman; Inigo;
(Madrid, ES) ; Frutos; Javier Angulo; (Valdermo,
ES) ; Rivas Lopez; Luis Ignacio; (Madrid, ES)
; Moreno Nuncio; Francisco Javier; (Madrid, ES) ;
Fernandez Jaen; Tomas Fernado; (Madrid, ES) ; Lozano
Puerto; Rosa Maria; (Madrid, ES) ; Romero Garrido;
Antonio; (Madrid, ES) ; Lopez; Serafin Valverde;
(Madrid, ES) |
Correspondence
Address: |
FROMMER LAWRENCE & HAUG
745 FIFTH AVENUE- 10TH FL.
NEW YORK
NY
10151
US
|
Assignee: |
Action Medicines
Madrid
ES
|
Family ID: |
38515369 |
Appl. No.: |
11/839529 |
Filed: |
August 15, 2007 |
Current U.S.
Class: |
514/546 ;
514/548; 514/553 |
Current CPC
Class: |
A61P 11/00 20180101;
Y02A 50/30 20180101; A61P 35/00 20180101; A61P 1/00 20180101; A61P
29/00 20180101; A61K 31/10 20130101; A61P 21/00 20180101; Y02A
50/409 20180101; A61P 43/00 20180101; A61P 19/02 20180101; A61P
17/06 20180101; A61P 11/06 20180101; A61P 27/02 20180101; A61P
33/00 20180101; A61P 31/04 20180101; A61K 31/192 20130101; A61K
31/60 20130101; A61P 15/00 20180101; A61K 31/618 20130101; A61P
17/00 20180101; A61P 13/12 20180101; A61P 27/00 20180101; A61P
31/10 20180101; A61P 13/00 20180101; A61P 13/08 20180101 |
Class at
Publication: |
514/546 ;
514/548; 514/553 |
International
Class: |
A61K 31/22 20060101
A61K031/22; A61K 31/225 20060101 A61K031/225; A61K 31/185 20060101
A61K031/185 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 16, 2006 |
ES |
ES P200602217 |
Jul 2, 2007 |
ES |
ES P200701855 |
Claims
1. A method for the treatment or prophylaxis of one more diseases
selected from the group consisting of: benign prostatic
hyperplasia, Barrett's disease, asthma, skeletal muscle and tendon
repair, Crohn's disease, ulcerative colitis and leishmaniasis,
comprising administering to a subject in need thereof, an effective
amount of a compound of Formula (I') or pharmaceutically acceptable
salt, solvate, isomer, or prodrug thereof, wherein the compound of
Formula (I') is: ##STR00018## wherein: R.sub.1 is
--(CH.sub.2).sub.aY or --CH.dbd.CH--(CH.sub.2).sub.pY; 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.+, --PO.sub.3R.sub.3,
--CO.sub.2H, --CO.sub.2.sup.-.X.sup.+ or --CO.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 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 Y is selected from --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ and --CO.sub.2R.sub.3.
3. The method of claim 1 or claim 2, 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
4. The method of claim 1 or claim 2, wherein R.sub.2 is selected
from methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,
benzylsulfonyl, benzyl and phenyl
5. The method of claim 1, wherein the compound of Formula (I') is
selected from the group consisting of: 2,5-dihydroxybenzenesulfonic
acid (Dobesilate),
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;
2-(benzyloxy)-5-hydroxybenzenesulfonic acid;
5-(benzyloxy)-2-hydroxybenzenesulfonic acid;
2,5-bis(benzyloxy)benzenesulfonic acid; 2,5-dihydroxybenzene
homosulfonic acid (homodobesilate)
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;
2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid;
5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid;
2,5-bis(benzyloxy)benzenehomosulfonic acid; 2,5-dihydroxybenzoic
acid (gentisic acid),
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;
2-(acetyloxy)-5-hydroxybenzoic acid; 5-(acetyloxy)-2-hydroxybenzoic
acid; 2,5-bis(acetyloxy)benzoic acid;
2-(benzyloxy)-5-hydroxybenzoic acid; 5-(benzyloxy)-2-hydroxybenzoic
acid; 2,5-bis(benzyloxy)benzoic acid; 2,5-dihydroxyhomobenzoic acid
(homogentisic acid),
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;
2-(acetyloxy)-5-hydroxyhomobenzoic acid;
5-(acetyloxy)-2-hydroxyhomobenzoic acid;
2,5-bis(acetyloxy)homobenzoic acid;
2-(benzyloxy)-5-hydroxyhomobenzoic acid;
5-(benzyloxy)-2-hydroxyhomobenzoic acid;
2,5-bis(benzyloxy)homobenzoic 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-propenoic 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.
6. The method of claim 1, wherein the compound of Formula (I')
comprises an ester at position 1.
7. The method of claim 5, 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.
8. The method of claim 5, wherein the compound of Formula (I') is
selected from the group consisting of: calcium
2,5-dihydroxybenzenesulfonate (calcium Dobesilate); potassium
2,5-dihydroxybenzenesulfonate (potassium Dobesilate); magnesium
2,5-dihydroxybenzenesulfonate (magnesium Dobesilate); diethylamine
2,5-dihydroxybenzenesulfonate (Ethamsylate);
9. The method of claim 1, wherein the compound of Formula (I') is
administered topically, orally, buccally, transdermally,
parenterally or rectally.
10. The method of claim 1, further comprising administration of at
least one additional therapeutic agent.
11. The method of claim 10, wherein the at least one additional
therapeutic agent is selected from the group consisting of: a
chemotherapeutic agent, a corticosteroid, an antibiotic, an
analgesic, an alpha-adrenergic blocker, a beta-adrenergic agonist,
an anticholinergic, an inhibitor of 5-alpha-reductase, an
antiandrogen, an oral contraceptive, an immunomodulator, an
immunosuppressant, an anti-angiogenic, a bronchodilator, a
leukotriene modifier, an aminosalicylate, an anesthetic, a
non-steroidal anti-inflammatory, an antiparasitic, a proton pump
inhibitor, an H2-receptor antagonist, a modifier of a solubilized
interleukin receptor, intramuscular gold, a cytotoxic agent, an
antioxidant, and a combination of two or more thereof.
12. The method of claim 1, wherein the compound is administered at
least once per week.
13. The method of claim 12, wherein the compound is administered at
least once per day.
14. The method of claim 13, wherein the compound is administered at
least twice per day.
15. The method of claim 1, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 1%
w/w.
16. The method of claim 15, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 2.5%
w/w.
17. The method of claim 16, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 5%
w/w.
18. The method of claim 17, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 10%
w/w.
19. The method of claim 18, wherein the compound is present in a
pharmaceutical composition in an amount of at least about 15%
w/w.
20. The method of claim 1, wherein the compound is administered
over a period of at least about one week.
21. The method of claim 20, 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. P200602217, filed Aug. 16,
2006 and of ES Application No. P200701855, 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 invention relates to the use of 2,5 dihydroxybenzene
compounds and derivatives thereof, its pharmaceutically acceptable
salts and solvates, as well as the isomers and prodrugs thereof for
the treatment of certain diseases, specifically, for the treatment
of hemangiomas, hemangioblastomas, benign prostatic hyperplasia,
Barrett's disease, asthma, skeletal muscle and tendon repair,
Crohn's disease, ulcerative colitis (proctitis, proctosigmoiditis,
pancolitis), leishmaniasis, pain and arthritis; through the
administration of a compound including at least one
2,5-dihydroxybenzene compound or a pharmaceutically acceptable salt
thereof and, optionally, at least one additional therapeutic
agent.
BACKGROUND OF THE INVENTION
[0003] The hemangioma is the most frequent tumor in childhood.
Besides surgery which, sometimes is difficult to carry out due to
the extent or localization of the tumors, there are no effective
treatments approved by health authorities to treat hemangiomas.
Likewise, other vascular tumors such as the hemangioblastoma are
difficult to treat.
[0004] Barrett's disease is originated by gastroesophageal reflux
that transforms the esophagus normal squamous epithelium into a
columnar epithelium. This process may produce adenocarcinomas.
[0005] Ulcerative colitis (proctitis, proctosigmoiditis,
pancolitis) is a disease that causes ulcers in the rectum and colon
producing bleeding and diarrhea.
[0006] Crohn's disease is an autoimmune chronic disease producing
intestinal inflammation. Even if it may affect the whole
gastrointestinal tract, most frequently it affects the ileum.
[0007] Arthritis is a usually chronic condition that causes
stiffness, pain and sometimes joint swelling (it includes
osteoarthritis, rheumatoid arthritis, gouty arthritis,
lupus-related arthritis, and the like).
[0008] Asthma is a chronic disease that affects the airways
constricting them. Current therapies for asthma are partially
effective, and it is still one of the main causes of infant
mortality.
[0009] Benign prostatic hyperplasia is a disease in which the
prostate gland is considerably enlarged and may cause
urination-related conditions. Even if there are pharmacological
treatments for benign prostatic hyperplasia, their efficacy is
limited and, in the end, many patients require surgery with at
least a partial resection of the gland.
[0010] Every year, in the United States, 6 million people suffer
from musculoskeletal diseases, mainly, fiber tearing (McClatchey K
D. Arch Pathol Lab Med, 2004). Regeneration of damaged muscle
implies a process that frequently causes alterations in the
muscular function. Currently, there are no effective therapies to
treat muscle injuries.
[0011] Leishmaniasis, produced by the parasitation of species of
the genus Leishmania gender, is the third most important disease
among vector-transmitted diseases. It is transmitted to mammals,
including humans, by the bite of mosquitoes of the genus
Phlebotomus. It is estimated that every year, there are 1.5-2
million cases of leishmaniasis worldwide, and that 350 million
people are in risk of suffering from the disease. Leishmaniasis is
associated to a wide variety of clinical symptoms that include,
skin ulcerative lesions in the area of the bite (localized
cutaneous leishmaniasis), multiple non-ulcerative nodules (diffuse
cutaneous leishmaniasis), inflammation and destruction of the
mucosa (mucosal leishmaniasis) and disseminated visceral infection,
potentially fatal (leishmaniasis visceral) (Murray et al. Lancet,
2005). The current treatment for leishmaniasis comprises
pentavalent antimonial salts, mainly Pentosam (sodium
stibogluconate) and Glucantime (N-methylglucamine antimoniate).
These treatments are associated with important side effects
affecting the kidney, the liver and the heart (Ouellete M J et al.
Drug Resist Updates, 2004). Therefore, there is a considerable
clinical interest in finding new, safe and efficient treatments for
leishmaniasis.
[0012] Pain is an unpleasant emotional (subjective) and sensorial
(objective) experience associated to a lesion. This is the main
reason why patients visit the doctor's.
[0013] Therefore and in spite of the recent scientific advances and
of knowledge about the etiology of many diseases described in this
invention, there are not really effective treatments for those
diseases.
SUMMARY OF THE INVENTION
[0014] The inventors have surprisingly found that
2,5-dihydroxybenzene derivatives, pharmaceutically accepted salts
and solvates, as well as isomers and prodrugs thereof are useful
for the treatment and/or prophylaxis of hemangiomas,
hemangioblastomas, benign prostatic hyperplasia, Barrett's disease,
asthma, skeletal muscle and tendon repair, Crohn's disease,
ulcerative colitis (proctitis, proctosigmoiditis, pancolitis),
leishmaniasis, pain and arthritis.
[0015] In certain embodiments, the present invention provides a
method for the treatment and/or prophylaxis of one more diseases
selected from the group consisting of: benign prostatic
hyperplasia, Barrett's disease, asthma, skeletal muscle and tendon
repair, Crohn's disease, ulcerative colitis and leishmaniasis,
comprising administering to a subject in need thereof, an effective
amount of a compound of Formula (I') or pharmaceutically acceptable
salt, solvate, isomer, or prodrug thereof, wherein the compound of
Formula (I') is:
##STR00001##
[0016] wherein: [0017] R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pY; [0018] 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.+, --PO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ or --CO.sub.2R.sub.3; [0019] X.sup.+ is an
organic cation or an inorganic cation, such that the general charge
of the compound is neutral; [0020] 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; [0021] 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; [0022] R.sub.3 is
a substituted or unsubstituted alkyl group or a substituted or
unsubstituted aryl group; [0023] a is number selected from 0, 1, 2,
3, 4, 5 and 6; and [0024] p is an integer selected from 0, 1, 2, 3,
4, 5 and 6.
[0025] In certain embodiments, Y is selected from --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ and --CO.sub.2R.sub.3. In other
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 yet other embodiments, R.sub.2 is
selected from methylcarbonyl, phenylsulfonyl,
4-methylphenylsulfonyl, benzylsulfonyl, benzyl and phenyl
[0026] In certain embodiments, the compound of Formula (I') is
selected from the group consisting of: 2,5-dihydroxybenzenesulfonic
acid (Dobesilate),
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;
2-(benzyloxy)-5-hydroxybenzenesulfonic acid;
5-(benzyloxy)-2-hydroxybenzenesulfonic acid;
2,5-bis(benzyloxy)benzenesulfonic acid; 2,5-dihydroxybenzene
homosulfonic acid (homodobesilate);
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;
2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid;
5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid;
2,5-bis(benzyloxy)benzenehomosulfonic acid; 2,5-dihydroxybenzoic
acid (gentisic acid);
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid;
2-(acetyloxy)-5-hydroxybenzoic acid; 5-(acetyloxy)-2-hydroxybenzoic
acid; 2,5-bis(acetyloxy)benzoic acid;
2-(benzyloxy)-5-hydroxybenzoic acid; 5-(benzyloxy)-2-hydroxybenzoic
acid; 2,5-bis(benzyloxy)benzoic acid; 2,5-dihydroxyhomobenzoic acid
(homogentisic acid);
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid;
2-(acetyloxy)-5-hydroxyhomobenzoic acid;
5-(acetyloxy)-2-hydroxyhomobenzoic acid;
2,5-bis(acetyloxy)homobenzoic acid;
2-(benzyloxy)-5-hydroxyhomobenzoic acid;
5-(benzyloxy)-2-hydroxyhomobenzoic acid;
2,5-bis(benzyloxy)homobenzoic 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-propenoic 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.
[0027] In certain embodiments, the compound of Formula (I')
comprises an ester at position 1.
[0028] In other 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.
[0029] In certain embodiments, the compound of Formula (I') is
selected from the group consisting of: calcium
2,5-dihydroxybenzenesulfonate (calcium Dobesilate); potassium
2,5-dihydroxybenzenesulfonate (potassium Dobesilate); magnesium
2,5-dihydroxybenzenesulfonate (magnesium Dobesilate); and
diethylamine 2,5-dihydroxybenzenesulfonate (Ethamsylate).
[0030] In certain embodiments, the present invention provides a
method for the treatment and/or prophylaxis of one more diseases
selected from the group consisting of: benign prostatic
hyperplasia, Barrett's disease, asthma, skeletal muscle and tendon
repair, Crohn's disease, ulcerative colitis and leishmaniasis,
wherein the compound of Formula (I') is administered topically,
orally, buccally, transdermally, parenterally or rectally.
[0031] In certain embodiments, the present invention provides a
method for the treatment and/or prophylaxis of one more diseases
selected from the group consisting of: benign prostatic
hyperplasia, Barrett's disease, asthma, skeletal muscle and tendon
repair, Crohn's disease, ulcerative colitis and leishmaniasis,
further comprising administration of at least one additional
therapeutic agent.
[0032] Examples of suitable therapeutic agents include those
selected from the group consisting of: a chemotherapeutic agent, a
corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic
blocker, a beta-adrenergic agonist, an anticholinergic, an
inhibitor of 5-alpha-reductase, an antiandrogen, an oral
contraceptive, an immunomodulator, an immunosuppressant, an
anti-angiogenic, a bronchodilator, a leukotriene modifier, an
aminosalicylate, an anesthetic, a non-steroidal anti-inflammatory,
an antiparasitic, a proton pump inhibitor, an H2-receptor
antagonist, a modifier of a solubilized interleukin receptor,
intramuscular gold, a cytotoxic agent, an antioxidant, and a
combination of two or more thereof.
[0033] In certain embodiments, a compound of Formula (I') 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.
[0034] 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.
[0035] In some embodiments, a compound of Formula (I') is
administered over a period of at least about one week. In other
embodiments, the compound is administered over a period of at least
about four weeks.
[0036] These and other aspects of the present invention are
described in detail herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1. Hemangioma.
[0038] Photographs of a child showing the effects of the topical
treatment with a cream comprising 2,5-dihydroxybenzenesulfonic
(DHBS) (2.5%) in a baby suffering infantile hemangioma. Panel A
shows the appearance of the child before treatment, and Panels B, C
and D show the child after the topical treatment with 2,5
dihydroxybenzenesulfonic (DHBS) twice a day for 1, 2 and 3 months
respectively.
[0039] FIG. 2. Hemangioblastoma.
[0040] Photographs showing the effects of a topical treatment with
a cream comprising 2,5-dihydroxybenzenesulfonic (DHBS) in a child
suffering from Nakagawa angioblastoma. Panel A shows the appearance
of the child before treatment, and Panel B shows the child after
the topical treatment with 2,5 dihydroxybenzenesulfonic (DHBS)
twice a day for 1 month. A decrease in the intensity of the
coloration of the hemangioblastoma may be clearly observed.
[0041] FIG. 3. Intestinal Inflammatory Disease.
[0042] Effect of potassium 2,5-diacetoxybenzene sulfonate on body
weight loss in mice with experimentally induced intestinal
inflammatory disease in a model applicable to the evaluation of
treatments for ulcerative colitis and Crohn's disease. The mice
were subject to two 7-day cycles of exposure to dextran sulfate
sodium (DSS) (from day 1 to 7 and from day 14 to 21) and in the
drinking water separated by 7 days in which regular water was
provided (from 7 to 14). One group was treated with vehicle (0.9%
NaCl), another with Solu-Medrol (10 mg/kg/day i.m.), and the other
two groups with potassium 2,5-diacetoxybenzene sulfonate (DABS),
one of them with 100 mg/kg/day i.p. and the other with 125
mg/kg/day, orally (p.o.). The body weight was normalized on day 0.
Data are expressed as the mean .+-.S.D of the percentage of the
basal weight (day 0) of 10 mice per group. All the treatments had a
significant effect on the body weight compared to the group treated
with vehicle.
[0043] FIG. 4. Intestinal Inflammatory Disease
[0044] Effect of potassium 2,5-diacetoxybenzene sulfonate on the
clinical score of the disease in mice with experimentally induced
intestinal inflammatory disease in a model applicable to the
evaluation of treatments for ulcerative colitis and Crohn's
disease. The mice were subject to two 7-day cycles of exposure to
dextran sulfate sodium (DSS) (from day 1 to 7 and from day 14 to
21) and in the drinking water separated by 7 days in which regular
water was provided (from 7 to 14). One group was treated with
vehicle (0.9% NaCl), another with Solu-Medrol (10 mg/kg/day i.m.),
and the other two groups with potassium 2,5-diacetoxybenzene
sulfonate (DABS), one of them with 100 mg/kg/day i.p. and the other
with 125 mg/kg/day, orally (p.o.) Data are expressed as the mean
.+-.S.D of clinical score of the disease continuously obtained from
10 mice per each group.
[0045] FIG. 5. Asthma
[0046] Effect of potassium 2,5-diacetoxybenzene sulfonate (DABS) on
bronchoconstriction in asthmatic mice treated with methacholine.
All the mice were exposed to nebulized methacholine (MC; 5 and 20
mg/ml). Bronchoconstriction was determined as the enhanced pause.
(P.sub.enh), calculated as described in the corresponding example
(example 13). As control, the background and the exposure to
nebulized saline (0.9% NaCl) are shown. * p<0.05 vs. saline. The
groups of mice treated with Combivent or DABS do not show a
significant increase of the P.sub.enh after exposure to MC.
[0047] FIG. 6. Asthma
[0048] Effect of potassium 2,5-diacetoxybenzene sulfonate (DABS) on
the inflammatory cell count in the bronchoalveolar lavage (BAL) in
asthmatic mice. The data are expressed as mean .+-.SEM of the total
number of detected cells in the BAL of the right lung of each
animal. * p<0.05, *** p<0.001 vs. group treated with
vehicle.
[0049] FIG. 7. Skeletal Muscle.
[0050] A and B are, respectively, front and cross sectional
magnetic resonance images showing the breaking of the left
quadriceps in a patient, immediately before treatment. The presence
of a large hematoma, indicated by arrows, may be observed. C and D
are, respectively, front and cross sectional magnetic resonance
images showing the quadriceps of the same patient after treatment
with 2,5-dihydroxybenzene sulfonic acid (DHBS) (500 mg/day p.o. for
two weeks). It may be observed that the hematoma has disappeared. 1
indicates the femur and 2 indicates the femoral vessels.
[0051] FIG. 8. Skeletal Muscle.
[0052] Images showing an almost complete flexion (A) and extension
(B) capacity of the right lower limb in a patient (the same to
which correspond the images of FIG. 7) with quadriceps breaking,
after two weeks of oral treatment with 2,5 dihydroxybenzene
sulfonic acid (DHBS) (500 mg/day).
[0053] FIG. 9. Skeletal Muscle.
[0054] A is a Magnetic Resonance Image (MRI) of a patient showing
the breaking of the right arm brachial biceps one day after the
lesion and immediately before the treatment. B is the MRI of the
same patient after being treated with 2,5-dihydroxybenzene sulfonic
acid (DHBS) (1500 mg/day p.o. for 20 days) A remarkable reduction
in the size of the lesion may be observed.
[0055] FIG. 10. Skeletal Muscle.
[0056] Images show the clinical manifestation of the patient
referred to in FIG. 9. Before the treatment (1 day after the
lesion) a large hematoma (A) and limited flexion (B) and extension
(C) of the elbow are observed. After 20 days of oral treatment with
2,5-dihydroxybenzene sulfonic acid (DHBS) (1500 mg/day) the
hematoma has disappeared and the flexion (D) and extension (E)
capacity of the elbow have been recovered.
[0057] FIG. 11. Skeletal Muscle.
[0058] It is a Magnetic Resonance Image (MRI) of a patient showing
the tear of left leg semitendinosus muscle 9 day after the lesion
and immediately before starting the treatment. B is the MRI of the
same patient after being treated with 2,5-dihydroxybenzene sulfonic
acid (DHBS) (1500 mg/day p.o. for 11 days) A remarkable reduction
in the size of the lesion may be observed.
[0059] FIG. 12. Skeletal Muscle.
[0060] A is a Magnetic Resonance Image (MRI) of a patient showing
the Achilles tendon rupture just before being treated. B is the MRI
of the same patient after being treated with 2,5-dihydroxybenzene
sulfonic acid (DHBS) (1500 mg/day p.o. for 2 months) A remarkable
reduction in the size of the lesion may be observed (marked with
arrows in both images).
[0061] FIG. 13. Leishmaniasis.
[0062] Reduction in the size of the lesion caused by massive
inoculation of Leishmania major promastigotes in the plantar pad of
the back paw of BALB/c female mice after the daily intraperitoneal
treatment with potassium 2,5-dihydroxybenzenesulfonate (DHBS, 200
mg/kg) for 14 days from the third week after infection. The vehicle
group consisted of infected animals that received daily injections
of saline serum (0.9% NaCl) during the same period as DHBS. Results
are expressed as the mean .+-.the standard deviation of the
increases in size of the inoculated paw (right) compared to the
non-inoculated paw (left) in mm obtained with a Vernier caliper
each week from 0 to 10. ** indicates p<0.01 vs. the
vehicle-treated group by a Student t-test. 6 animals were used for
each group.
[0063] FIG. 14. Leishmaniasis.
[0064] Reduction in the size of the lesion caused by massive
inoculation of Leishmania major promastigotes in the plantar pad of
the back paw of BALB/c female mice after the daily intraperitoneal
treatment with potassium 2,5-diacetoxybenzenesulfonate (DABS, 200
mg/kg) from the moment of the infection. The vehicle group
consisted of infected animals that received daily injections of
saline serum (0.9% NaCl) from the moment of the infection, while
the control group consisted of non-infected animals. Results are
expressed as the mean .+-.the standard deviation of the increases
in size of the inoculated paw (right) compared to the
non-inoculated paw (left) in mm obtained with a Vernier caliper
each week from 0 to 9. * indicates p<0.05 vs. the
vehicle-treated group by a Student t-test. 7 animals were used for
each group.
[0065] FIG. 15. Leishmaniasis.
[0066] Reduction in the size of the lesion caused by massive
inoculation of Leishmania major promastigotes in the plantar pad of
the back paw of BALB/c female mouse after the daily intreperitoneal
treatment with potassium 2,5-diacetoxybenzenesulfonate (DABS, 200
mg/kg) from the third week after the infection. The vehicle group
consisted of infected animals that received daily injections of
saline serum (0.9% NaCl) from the third week after the infection.
Results are expressed as the mean .+-.the standard deviation of the
increases in size of the inoculated paw (right) compared to the
non-inoculated paw (left) in mm obtained with a Vernier caliper
each week from 0 to 9. * indicates p<0.05 vs. the
vehicle-treated group by a Student t-test. 7 animals were used for
each group.
[0067] FIG. 16. Inhibition of the mitogenesis induced by
fibroblasts growth factor-1 in Balb/c 3T3 fibroblasts quiescent
cultures by calcium 2-acetoxy-5-hydroxybenzenesulfonate (2A-5HBS)
and potassium 2,5-dihydroxybenzenesulfonate (DHBS).
[0068] FIG. 17. Inhibition of the mitogenesis induced by
fibroblasts growth factor-1 in Balb/c 3T3 fibroblasts quiescent
cultures by potassium 5-acetoxy-2-hydroxybenzenesulfonate (5A-2HBS)
and potassium 2,5-dihydroxybenzenesulfonate (DHBS).
[0069] FIG. 18. Inhibition of the mitogenesis induced by
fibroblasts growth factor-1 in Balb/c 3T3 fibroblasts quiescent
cultures by potassium 2,5-diacetoxybenzene sulfonate (DABS) and
potassium 2,5-dihydroxybenzene sulfonate (DHBS).
[0070] FIG. 19. Shows the effect of the treatment with potassium
5-acetoxy-2-hydroxybenzenesulfonate (5A-2HBS) and the potassium
2-acetoxy-5-hydroxybenzenesulfonate (2A-5HBS) on the proliferation
of rat C6 glioma cells. 5A-2HBS and 2A-5HBS were administered or
not (control) after seeding C6 cells in 24 well plates (10.sup.4
per well) until they were fixed 48 hours later. Data are expressed
as the mean .+-.SEM of the percentage of absorbance at 595 nm
obtained in control cultures, which is proportional to the number
of cells stained with crystal violet. Data were obtained from 3
cultures for each treatment and 6 control cultures. The white bar
represents the value of the control cells, whereas the black bar
shows the value in presence of 5A-2HBS (500 .mu.M), and the
stripped bar shows the value in the presence of 2A-5HBS (500
.mu.M). *** indicates p<0.001 with respect to control by a
one-factor analysis of variance (ANOVA) followed by a
Student-Newmann-Keuls post-analysis.
[0071] FIG. 20. 2-acetoxy-5-hydroxybenzenesulfonic acid
co-crystallized with fibroblast growth factor-1. The electron
density of the compound, contoured at 1.sigma. (panel C), allows
locating and determining the orientation of the compound with
respect to the protein (panels A and B), as well as asserting that
the compound conserves the acetoxyl group in position 2 when it
binds to the protein. The compound occupies a place that is very
close to that described occupied by 2,5-dihydroxybenzenesulfonic
acid, the aromatic ring of which forms a cation-.PI. bond with the
N.sup..epsilon. group of lysine 132, which is 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, superimposed
with 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).
[0072] FIG. 21. 5-acetoxy-2-hydroxybenzenesulfonic acid
co-crystallized with fibroblast growth factor-1. The electron
density of the compound, contoured at Icy (panel C), allows
locating and determining the orientation of the compound with
respect to the protein (panels A and B), as well as asserting that
the compound conserves the acetoxyl group in position 5 when it
binds to the protein. The compound occupies a place that is very
close to that described occupied by 2,5-dihydroxybenzenesulfonic
acid, the aromatic ring of which forms a cation-.pi. bond with the
N.sup..epsilon. group of lysine 132, which is 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, superimposed
with 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).
[0073] FIG. 22. 2,5-diacetoxybenzenesulfonic acid co-crystallized
with fibroblast growth factor-1. The electron density of the
compound, contoured at 1.sigma. (panel C), allows locating and
determining the orientation of the compound with respect to the
protein (panels A and B), as well as asserting that the compound
conserves the acetoxyl groups in positions 2 and 5 when it binds to
the protein. The compound occupies a place that is very close to
that described occupied by 2,5-dihydroxybenzenesulfonic acid, the
aromatic ring of which forms a cation-.pi. bond with the
N.sup..epsilon. group of lysine 132, which is marked in panel A as
reference. Panel B shows, in the form of a mesh, the Van der Waals
volume of 2,5-diacetoxybenzenesulfonic acid, superimposed with 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
[0074] As used in the description, it must be understood that,
unless otherwise specified, the following terms shall have the
meanings set forth below:
[0075] The term "patient" refers to animals, preferably mammals,
and more preferably humans, and includes males and females,
children and adults.
[0076] The expression "effective amount" refers to the amount of
the compound and/or composition effective to achieve the desired
purpose.
[0077] The terms "treat" or "treatment" refer to the use of the
compounds or compositions of the present invention,
prophylactically to avoid the symptoms of the disease or disorder,
or therapeutically to improve an existing condition.
[0078] 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
corticosteroids, antibiotics, analgesics, alpha-adrenergic
blockers, beta-adrenergic agonists, anticholinergics, inhibitors of
5-alpha-reductase, antiandrogens, oral contraceptives,
immunomodulators, immunosuppressants, anti-angiogenics,
bronchodilators, leukotriene modifiers, aminosalicylates,
anesthetics, non-steroidal anti-inflammatories, antiparasitics,
antioxidants, proton pump inhibitors, H2-receptor antagonists,
therapy of the solubilized interleukin receptor, intramuscular
gold, cytotoxics, chemotherapy agents, and combinations of two or
more thereof.
[0079] A therapeutic agent includes pharmaceutically acceptable
salts thereof, prodrugs and pharmaceutical derivatives thereof.
[0080] The term "hemangioma" refers to a vascular tumor that
appears during childhood.
[0081] The term "hemangiomablastoma" refers to another vascular
tumor that appears during childhood.
[0082] The term "prostate benign hyperplasia" refers to a disease
in which the prostate gland increases considerably and may cause
urination-related conditions.
[0083] The term "Barrett's disease" refers to a
metaplasia/dysplasia process of the esophagic epithelium.
[0084] The term "ulcerative colitis (proctitis, proctosigmoiditis,
pancolitis)" refers to a disease that causes ulcers in the rectum
and colon producing bleeding and diarrhea.
[0085] The term "Crohn's disease" refers to an autoimmune chronic
disease producing intestinal inflammation. Even if it may affect
the whole gastrointestinal tract, most frequently it affects the
ileum.
[0086] The term "pain" refers to an unpleasant emotional
(subjective) and sensorial (objective) experience associated to an
injury.
[0087] The term "asthma" refers to a chronic disease that affects
the airways, constricting them.
[0088] The term "arthritis" refers to a condition, usually chronic,
that causes stiffness, pain and sometimes joint swelling; it
includes osteoarthritis, rheumatoid arthritis, polyarthritis, gouty
arthritis, lupus-related arthritis, psoriasis-related arthritis,
and the like).
[0089] The term "skeletal muscle diseases" refers to lesions
thereof, like breakings and traumas.
[0090] The term "leishmaniasis" refers to the parastitation by
species of Leishmania genus in human and pets that causes a disease
affecting the skin, mucosa o visceras.
[0091] The term "topical" refers to the administration of a
compound by applying it on the body surface and includes, but is
not limited to, the transdermal administration and the
administration through the mucosa.
[0092] The term "transdermal" refers to the administration of a
compound that enters into the bloodstream through the skin.
[0093] The expression "through the mucosa" refers to the
administration of a compound that enters into the bloodstream
through the mucous tissue.
[0094] The term "parenteral" refers to the administration of a
compound by means of a subcutaneous, intravenous, intramuscular,
intracardiac, intradermic, intraperitoneal, intrathecal or
intrasternal injection; and also includes local or systemic
infusion techniques.
[0095] The expression "penetration enhancement" or "permeation
enhancement" refers to an increase in the permeability of the skin
or mucous tissue to a pharmacologically active compound such that
it increases the rate and/or amount of said compound that
penetrates into, or through the skin or mucous tissue.
[0096] "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 interact harmfully with any component of the
composition.
[0097] 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.
[0098] 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-dihydroxybenzene sulfonic acid or dobesilate
ester derivative refers to the compound 2,5-dihydroxybenzene
sulfonic acid (dobesilate) wherein at least one of the hydroxyl
groups has been esterified.
[0099] 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.
[0100] In the definitions of the compounds described herein, the
following terms mean:
[0101] "Alkyl" means 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.
[0102] "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.
[0103] "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.
[0104] "Aryl" refers to an aromatic hydrocarbon radical containing
from six to ten carbon atoms such as phenyl or naphthyl.
[0105] "Aralkyl" refers to an aryl group bound to the rest of the
molecule by an alkyl group such as benzyl and phenetyl.
[0106] "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 one, 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 tricyclic 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, purine, quinoline, thiadiazol,
tetrahydrofuran.
[0107] 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, 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.
[0108] The term "alkoxycarbonyl" refers to a compound having the
formula --C(.dbd.O)O--, wherein the C-terminal is bound to the
molecule and the O-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.
[0109] 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".
[0110] 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.
[0111] 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.
[0112] 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.
[0113] The term "arylsulfonyl" refers to R.sub.55--S(O).sub.2--,
wherein R.sub.55 is an aryl group, as defined herein.
[0114] The term "alkylsulphinyl" refers to R.sub.55--S(O)--,
wherein R.sub.55 is an aryl group, as defined herein.
[0115] The term "arylsulphinyl" refers to R.sub.55--S(O)--, wherein
R.sub.55 is an aryl group, as defined herein.
[0116] The term "sulfonamide" refers to
--S(O).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.
[0117] The term "alkylsulfonamido" refers to a sulfonamido group,
as defined herein, bound to an alkyl group, as defined herein.
[0118] The term "arylsulfonamido" refers to a sulfonamido group, as
defined herein, bound to an aryl group, as defined herein.
[0119] The term "alkylcarbonyl" refers to R.sub.52--C(O).sub.2--,
wherein R.sub.52 is an alkyl group, as defined herein.
[0120] The term "arylcarbonyl" refers to the R.sub.55--S(O)--
radical, wherein R.sub.55 is an aryl group, as defined herein.
[0121] The term "carboxamide" refers to the
--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.
[0122] 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.
[0123] 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.
[0124] The term "amine" refers to any organic compound containing
at least one basic nitrogen atom.
[0125] 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.
[0126] 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.
[0127] The term "prodrug" refers to compounds that rapidly convert
in vivo into pharmacologically active compounds. The prodrugs
design is generally studied at Hardma et al. (eds.), Goodman and
Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pages
11-16 (1996). A detailed study is disclosed in Higuchi et al.,
Prodrugs as Novel Delivery Systems, vol. 14, ASCD Symposium Series,
y en Roche (ed.), Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987).
[0128] 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.
[0129] According to a first aspect, the present invention refers to
the use of a compound of Formula (I) or pharmaceutically acceptable
salt or solvate, isomers or prodrugs thereof in the manufacturing
of a medicament for the treatment and/or prophylaxis of hemangiomas
or hemangioblastomas, where the compound of Formula (I):
##STR00002##
[0130] wherein: [0131] R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pY; [0132] 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.+, --PO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ or --CO.sub.2R.sub.3; [0133] X.sup.+ is an
organic cation or an inorganic cation, such that the general charge
of the compound is neutral; [0134] R.sub.9 and R.sub.9' are
individually 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; [0135] 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;
[0136] R.sub.3 is a lower alkyl group, an aryl group, an arylalkyl
group or an alkylaryl group; [0137] a is number selected from 0, 1,
2 , 3, 4, 5 and 6; [0138] p is an integer selected from 0, 1, 2, 3,
4, 5 and 6.
[0139] 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 esters derivatives or pharmaceutically acceptable salts
or esters thereof for the treatment of hemangiomas or
hemangioblastomas.
[0140] The X.sup.+ cation in the Compounds of Formula (I) may be
any physiologically acceptable cation known by a skilled in the art
and includes, but is not limited to, those described in 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; the
disclosures of which are incorporated herein by reference in their
entirety. The X.sup.+ cation is selected in such a way that the
total charge of the compounds of Formula (I) is neutral.
[0141] In a particular embodiment of the invention in the compound
of formula (I) Y is selected from --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ and --CO.sub.2R.sub.3.
[0142] In another particular embodiment, in the compound of formula
(I) 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.
[0143] In another particular embodiment, R.sub.2 is selected from
methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,
benzylsulfonyl, benzyl and phenyl.
[0144] In another 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) and
p-chlorophenoxyisobutyryl
(--C(O)--C(CH.sub.3).sub.2--O--C.sub.6H.sub.4Cl).
[0145] In another embodiment, R.sub.3 is selected from methyl,
ethyl, isopropyl and C.sub.6H.sub.5--, more particularly from
methyl and ethyl.
[0146] In one embodiment of the invention, the inorganic cation is
sodium, potassium, lithium, calcium, or magnesium.
[0147] In another embodiment of the invention, the organic cation
is [NH.sub.4-pR.sub.p].sup.+: wherein p is in each case selected
independently from an integer number from 0 to 4, both included;
and R is an alkyl group of one to six carbon atoms such as, for
example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, or
n-pentyl.
[0148] In another embodiment of the invention, the organic cations
are a diethylamine [H.sub.2N.sup.+(C.sub.2H.sub.5).sub.2],
piperazine or pyridine group.
[0149] In other embodiments of the invention, the compounds of
Formula (I) and pharmaceutically acceptable salts thereof are:
##STR00003## ##STR00004## ##STR00005## ##STR00006##
##STR00007##
wherein: n is an integer selected from 1 and 2; m is an integer
selected from 1 and 2; and
X, R.sub.2 and R.sub.3 are as defined herein.
[0150] In one preferred embodiment, the compound of Formula (I) is
selected from the group consisting of: [0151]
2,5-dihydroxybenzenesulfonic acid (Dobesilate), [0152]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
[0153] 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0154] 2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0155] 2-(acetyloxy)-5-hydroxybenzenesulfonic acid; [0156]
5-(acetyloxy)-2-hydroxybenzenesulfonic acid; [0157]
2,5-bis(acetyloxy)benzenesulfonic acid; [0158]
2-(benzyloxy)-5-hydroxybenzenesulfonic acid; [0159]
5-(benzyloxy)-2-hydroxybenzenesulfonic acid; [0160]
2,5-bis(benzyloxy)benzenesulfonic acid; [0161] 2,5-dihydroxybenzene
homosulfonic acid (homodobesilate) [0162]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0163]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0164]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;
[0165] 2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid; [0166]
5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid; [0167]
2,5-bis(acetyloxy)benzenehomosulfonic acid; [0168]
2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid; [0169]
5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid; [0170]
2,5-bis(benzyloxy)benzenehomosulfonic acid; [0171]
2,5-dihydroxybenzoic acid (gentisic acid), [0172]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; [0173]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; [0174]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; [0175]
2-(acetyloxy)-5-hydroxybenzoic acid; [0176]
5-(acetyloxy)-2-hydroxybenzoic acid; [0177]
2,5-bis(acetyloxy)benzoic acid; [0178]
2-(benzyloxy)-5-hydroxybenzoic acid; [0179]
5-(benzyloxy)-2-hydroxybenzoic acid; [0180]
2,5-bis(benzyloxy)benzoic acid; [0181] 2,5-dihydroxyhomobenzoic
acid (homogentisic acid), [0182]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; [0183]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; [0184]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; [0185]
2-(acetyloxy)-5-hydroxyhomobenzoic acid; [0186]
5-(acetyloxy)-2-hydroxyhomobenzoic acid; [0187]
2,5-bis(acetyloxy)homobenzoic acid; [0188]
2-(benzyloxy)-5-hydroxyhomobenzoic acid; [0189]
5-(benzyloxy)-2-hydroxyhomobenzoic acid; [0190]
2,5-bis(benzyloxy)homobenzoic acid; [0191]
3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic
acid); [0192]
3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; [0193]
3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; [0194]
3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;
[0195] 3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenoic acid; [0196]
3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0197]
3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid; [0198]
3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid; [0199]
3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0200]
3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid;
[0201] and pharmaceutically acceptable salts and solvates thereof,
isomers, prodrugs and esters.
[0202] In another particular embodiment, the compounds of Formula
(I) are in the form of esters at position 1, in particular methyl
and ethyl esters.
[0203] Preferred compounds of formula I are those selected from
2-(acetyloxy)-5-hydroxybenzenesulfonic acid;
5-(acetyloxy)-2-hydroxybenzenesulfonic acid and
2,5-bis(acetyloxy)benzenesulfonic acid.
[0204] Other preferred compounds of Formula (I) are those selected
from the group consisting of: [0205] calcium
2,5-dihydroxybenzenesulfonate (calcium Dobesilate); [0206]
potassium 2,5-dihydroxybenzenesulfonate (potassium Dobesilate);
[0207] magnesium 2,5-dihydroxybenzenesulfonate (magnesium
Dobesilate); [0208] diethylamine 2,5-dihydroxybenzenesulfonate
(Ethamsylate).
[0209] The invention provides compositions comprising at least one
compound of Formula (I) and at least one additional therapeutic
agent, including but not limited to chemotherapeutic agent, a
corticosteroid, an antibiotic, an analgesic, an antiandrogen, an
immunomodulator, an anti-angiogenic, including anti-VEGF, anti-FGF,
anti-EGF and anti-HGF; inhibitors of tyrosin-kinase receptors,
protein kinase C inhibitors, a non-steroidal anti-inflammatory, a
therapy of the solubilized interleukin receptor, a cytotoxic, an
antioxidant and combinations of two or more thereof.
[0210] The compounds of Formula (I) can optionally be used together
with one or more additional therapeutic agents, such as
chemotherapeutic agent, a corticosteroid, an antibiotic, an
analgesic, an antiandrogen, an immunomodulator, an anti-angiogenic,
including anti-VEGF, anti-FGF, anti-EGF and anti-HGF; inhibitors of
tyrosin-kinase receptors, protein kinase C inhibitors, a
non-steroidal anti-inflammatory, a therapy of the solubilized
interleukin receptor, a cytotoxic, an antioxidant and combinations
of two or more thereof.
[0211] In a second aspect, the present invention relates to the use
of a compound of Formula (I') or pharmaceutically acceptable salt
or solvate, isomer or prodrug thereof in the manufacturing of a
medicament for the treatment and/or prophylaxis of any of the
diseases selected from the group consisting of benign prostatic
hyperplasia, Barrett's disease, asthma, skeletal muscle and tendon
repair, Crohn's disease, ulcerative colitis and leishmaniasis,
wherein the compound of Formula (I'):
##STR00008##
[0212] wherein: [0213] R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pY; [0214] 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.+, --PO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ or --CO.sub.2R.sub.3; [0215] X.sup.+ is an
organic cation or an inorganic cation, such that the general charge
of the compound is neutral; [0216] 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;
[0217] 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;
[0218] R.sub.3 is a substituted or unsubstituted alkyl group or a
substituted or unsubstituted aryl group; [0219] a is number
selected from 0, 1, 2, 3, 4, 5 and 6; [0220] p is an integer
selected from 0, 1, 2, 3, 4, 5 and 6.
[0221] 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 esters derivatives or pharmaceutically acceptable salts
or esters thereof for the treatment of benign prostatic
hyperplasia, Barrett's disease, asthma, skeletal muscle and tendon
repair, Crohn's disease, ulcerative colitis or leishmaniasis.
[0222] The X.sup.+ cation in the Compounds of Formula (I') may be
any physiologically acceptable cation known by a skilled in the art
and includes, but is not limited to, those described in 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; the
disclosures of which are incorporated herein by reference in their
entirety. The X.sup.+ cation is selected in such a way that the
total charge of the compounds of Formula (I') is neutral.
[0223] In a particular embodiment of the invention in the compound
of formula (I') Y is selected from --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+, --SO.sub.3R.sub.3, --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ and --CO.sub.2R.sub.3.
[0224] In another particular embodiment, in the compound of formula
(I') 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.
[0225] In another particular embodiment, R.sub.2 is selected from
methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,
benzylsulfonyl, benzyl and phenyl.
[0226] In another 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) and
p-chlorophenoxyisobutyryl
(--C(O)--C(CH.sub.3).sub.2--O--C.sub.6H.sub.4Cl).
[0227] In another embodiment, R.sub.3 is selected from methyl,
ethyl, isopropyl and C.sub.6H.sub.5--, more particularly from
methyl and ethyl.
[0228] In one embodiment of the invention, the inorganic cation is
sodium, potassium, lithium, calcium, or magnesium.
[0229] In another embodiment of the invention, the organic cation
is [NH.sub.4-pR.sub.p].sup.+: wherein p is in each case selected
independently from an integer number from 0 to 4, both included;
and R is an alkyl group of one to six carbon atoms such as, for
example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, or
n-pentyl.
[0230] In another embodiment of the invention, the organic cations
are a diethylamine [H.sub.2N.sup.+(C.sub.2H.sub.5).sub.2],
piperazine or pyridine group.
[0231] In other embodiments of the invention, the compounds of
Formula (I') and pharmaceutically acceptable salts thereof are:
##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013##
wherein: n is an integer selected from 1 and 2; m is an integer
selected from 1 and 2; and
X, R.sub.2 and R.sub.3 are as defined herein.
[0232] In one preferred embodiment, the compound of Formula (I') is
selected from the group consisting of: [0233]
2,5-dihydroxybenzenesulfonic acid (Dobesilate), [0234]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
[0235] 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0236] 2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0237] 2-(acetyloxy)-5-hydroxybenzenesulfonic acid; [0238]
5-(acetyloxy)-2-hydroxybenzenesulfonic acid; [0239]
2,5-bis(acetyloxy)benzenesulfonic acid; [0240]
2-(benzyloxy)-5-hydroxybenzenesulfonic acid; [0241]
5-(benzyloxy)-2-hydroxybenzenesulfonic acid; [0242]
2,5-bis(benzyloxy)benzenesulfonic acid; [0243] 2,5-dihydroxybenzene
homosulfonic acid (homodobesilate) [0244]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0245]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0246]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;
[0247] 2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid; [0248]
5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid; [0249]
2,5-bis(acetyloxy)benzenehomosulfonic acid; [0250]
2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid; [0251]
5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid; [0252]
2,5-bis(benzyloxy)benzenehomosulfonic acid; [0253]
2,5-dihydroxybenzoic acid (gentisic acid), [0254]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; [0255]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; [0256]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; [0257]
2-(acetyloxy)-5-hydroxybenzoic acid; [0258]
5-(acetyloxy)-2-hydroxybenzoic acid; [0259]
2,5-bis(acetyloxy)benzoic acid; [0260]
2-(benzyloxy)-5-hydroxybenzoic acid; [0261]
5-(benzyloxy)-2-hydroxybenzoic acid; [0262]
2,5-bis(benzyloxy)benzoic acid; [0263] 2,5-dihydroxyhomobenzoic
acid (homogentisic acid), [0264]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; [0265]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; [0266]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; [0267]
2-(acetyloxy)-5-hydroxyhomobenzoic acid; [0268]
5-(acetyloxy)-2-hydroxyhomobenzoic acid; [0269]
2,5-bis(acetyloxy)homobenzoic acid; [0270]
2-(benzyloxy)-5-hydroxyhomobenzoic acid; [0271]
5-(benzyloxy)-2-hydroxyhomobenzoic acid; [0272]
2,5-bis(benzyloxy)homobenzoic acid; [0273]
3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic
acid); [0274]
3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; [0275]
3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; [0276]
3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;
[0277] 3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenoic acid; [0278]
3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0279]
3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid; [0280]
3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid; [0281]
3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0282]
3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid;
[0283] and pharmaceutically acceptable salts and solvates thereof,
isomers, prodrugs and esters.
[0284] In another particular embodiment, the compounds of Formula
(I') are in the form of esters at position 1, in particular methyl
and ethyl esters.
[0285] Preferred compounds of formula (I') are those selected from
2-(acetyloxy)-5-hydroxybenzenesulfonic acid;
5-(acetyloxy)-2-hydroxybenzenesulfonic acid and
2,5-bis(acetyloxy)benzenesulfonic acid.
[0286] Other preferred compounds of Formula (I') are those selected
from the group consisting of: [0287] calcium
2,5-dihydroxybenzenesulfonate (calcium Dobesilate); [0288]
potassium 2,5-dihydroxybenzenesulfonate (potassium Dobesilate);
[0289] magnesium 2,5-dihydroxybenzenesulfonate (magnesium
Dobesilate); [0290] diethylamine 2,5-dihydroxybenzenesulfonate
(Ethamsylate).
[0291] The invention provides compositions comprising at least one
compound of Formula (I') and at least one additional therapeutic
agent, including but not limited to a chemotherapeutic agent, a
corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic
blocker, a beta-adrenergic agonist, an anticholinergic, an
inhibitor of 5-alpha-reductase, an antiandrogen, an oral
contraceptive, an immunomodulator, an immunosuppressant, an
anti-angiogenic, a bronchodilator, a leukotriene modifier, an
aminosalicylate, an anesthetic, a non-steroidal anti-inflammatory,
an antiparasitic, a proton pump inhibitor, an H2-receptor
antagonist, a therapy of the solubilized interleukin receptor,
intramuscular gold, a cytotoxic, an antioxidant and combinations of
two or more thereof.
[0292] The compounds of Formula (I') can optionally be used
together with one or more additional therapeutic agents, such as a
chemotherapeutic agent, a corticosteroid, an antibiotic, an
analgesic, an alpha-adrenergic blocker, a beta-adrenergic agonist,
an anticholinergic, an inhibitor of 5-alpha-reductase, an
antiandrogen, an oral contraceptive, an immunomodulator, an
immunosuppressant, an anti-angiogenic, a bronchodilator, a
leukotriene modifier, an aminosalicylate, an anesthetic, a
non-steroidal anti-inflammatory, an antiparasitic, a proton pump
inhibitor, an H2-receptor antagonist, a therapy of the solubilized
interleukin receptor, intramuscular gold, a cytotoxic, an
antioxidant and combinations of two or more thereof.
[0293] In a third aspect, the present invention relates to the use
of a compound of Formula (I''') or pharmaceutically acceptable salt
or solvate, isomer or prodrug thereof in the manufacturing of a
medicament for the treatment and/or prophylaxis of arthritis or
pain, wherein the compound of Formula (I'''):
##STR00014##
[0294] wherein: [0295] R.sub.1 is --(CH.sub.2).sub.aY or
--CH.dbd.CH--(CH.sub.2).sub.pZ; [0296] 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.+, --PO.sub.3R.sub.3;
[0297] 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;
[0298] X.sup.+ is an organic cation or an inorganic cation, such
that the general charge of the compound is neutral;
[0299] 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; [0300] 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;
[0301] R.sub.3 is a substituted or unsubstituted alkyl group or a
substituted or unsubstituted aryl group; [0302] a is number
selected from 0, 1, 2, 3, 4, 5 and 6; [0303] p is an integer
selected from 0, 1, 2, 3, 4, 5 and 6, [0304] 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.
[0305] 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 esters derivatives or pharmaceutically acceptable salts
or esters thereof for the treatment of arthritis or pain.
[0306] The X.sup.+ cation in the Compounds of Formula (I''') may be
any physiologically acceptable cation known by a skilled in the art
and includes, but is not limited to, those described in 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; the
disclosures of which are incorporated herein by reference in their
entirety. The X.sup.+ cation is selected in such a way that the
total charge of the compounds of Formula (I''') is neutral.
[0307] In a particular embodiment of the invention Y in the
compound of formula (I''') is selected from --SO.sub.3H,
--SO.sub.3.sup.-.X.sup.+ and --SO.sub.3R.sub.3.
[0308] In another particular embodiment, Z in the compound of
formula (I''') is selected from --CO.sub.2H,
--CO.sub.2.sup.-.X.sup.+ and --CO.sub.2R.sub.3.
[0309] In another particular embodiment, in the compound of formula
(I''') 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.
[0310] In another particular embodiment, R.sub.2 is selected from
methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl,
benzylsulfonyl, benzyl and phenyl
[0311] In another 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) and
p-chlorophenoxyisobutyryl
(--C(O)--C(CH.sub.3).sub.2--O--C.sub.6H.sub.4Cl).
[0312] In another embodiment, R.sub.3 is selected from methyl,
ethyl, isopropyl and C.sub.6H.sub.5--, more particularly from
methyl and ethyl.
[0313] In one embodiment of the invention, the inorganic cation is
sodium, potassium, lithium, calcium, or magnesium.
[0314] In another embodiment of the invention, the organic cation
is [NH.sub.4-pR.sub.p].sup.+: wherein p is in each case selected
independently from an integer number from 0 to 4, both included;
and R is an alkyl group of one to six carbon atoms such as, for
example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, or
n-pentyl.
[0315] In another embodiment of the invention, the organic cations
are a diethylamine [H.sub.2N.sup.+(C.sub.2H.sub.5).sub.2],
piperazine or pyridine group.
[0316] In other embodiments of the invention, the compounds of
Formula (I''') and pharmaceutically acceptable salts thereof
are:
##STR00015## ##STR00016## ##STR00017##
wherein: n is an integer selected from 1 and 2; m is an integer
selected from 1 and 2; and
X, R.sub.2 and R.sub.3 are as defined herein.
[0317] In one preferred embodiment, the compound of Formula (I''')
is selected from the group consisting of: [0318]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid;
[0319] 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0320] 2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic
acid; [0321] 2-(acetyloxy)-5-hydroxybenzenesulfonic acid; [0322]
5-(acetyloxy)-2-hydroxybenzenesulfonic acid; [0323]
2,5-bis(acetyloxy)benzenesulfonic acid; [0324]
5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0325]
2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic
acid; [0326]
2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid;
[0327] 2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid; [0328]
5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid; [0329]
2,5-bis(acetyloxy)benzenehomosulfonic acid; [0330]
3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic
acid); [0331]
3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; [0332]
3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic
acid; [0333]
3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid;
[0334] 3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenoic acid; [0335]
3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0336]
3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid; [0337]
3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid; [0338]
3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid; [0339]
3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; and pharmaceutically
acceptable salts, solvates and prodrugs thereof.
[0340] In another particular embodiment, the compounds of Formula
(I''') are in the form of esters at position 1, in particular
methyl and ethyl esters.
[0341] Preferred compounds of formula (I''') are those selected
from 2-(acetyloxy)-5-hydroxybenzenesulfonic acid;
5-(acetyloxy)-2-hydroxybenzenesulfonic acid and
2,5-bis(acetyloxy)benzenesulfonic acid.
[0342] In a particular embodiment, the arthritis is selected from
osteoarthritis, rheumatoid arthritis, polyarthritis, gouty
arthritis, lupus-related arthritis, psoriasis-related arthritis,
infectious arthritis, including viral, parasitic and bacterial
arthritis.
[0343] The invention provides compositions comprising at least one
compound of Formula (I''') and at least one additional therapeutic
agent, including but not limited to a chemotherapeutic agent, a
corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic
blocker, a beta-adrenergic agonist, an anticholinergic, an
inhibitor of 5-alpha-reductase, an antiandrogen, an
immunomodulator, an immunosuppressant, an anti-angiogenic such as
anti VEGF, anti FGF, anti HGF and anti EFG; a leukotriene modifier,
an aminosalicylate, an anesthetic, a non-steroidal
anti-inflammatory, an antiparasitic, a therapy of the solubilized
interleukin receptor, intramuscular gold, a cytotoxic, an
antioxidant, and combinations of two or more thereof.
[0344] The compounds of Formula (I''') can optionally be used
together with one or more additional therapeutic agents, such as a
chemotherapeutic agent, a corticosteroid, an antibiotic, an
analgesic, an alpha-adrenergic blocker, a beta-adrenergic agonist,
an anticholinergic, an inhibitor of 5-alpha-reductase, an
antiandrogen, an immunomodulator, an immunosuppressant, an
anti-angiogenic such as anti VEGF, anti FGF, anti HGF and anti EFG;
a leukotriene modifier, an aminosalicylate, an anesthetic, a
non-steroidal anti-inflammatory, an antiparasitic, a therapy of the
solubilized interleukin receptor, intramuscular gold, a cytotoxic,
an antioxidant, and combinations of two or more thereof.
[0345] The compounds of Formula (I), (I') and (I''') may be
synthesized by a skilled in the art using conventional or
commercially available methods. The synthesis of the compounds of
Formula (I), (I') and (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.
[0346] Compounds of Formula (I), (I') and (I''') also may be in the
form of solvates, particularly in the form of hydrates. The
preparation of the compounds of Formula (I), (I') and (I'''), as
well as the solvates thereof may be carried out by one skilled in
the art using conventional methods and commercially available
reagents.
[0347] Even if 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.
[0348] The term "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.
[0349] 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.
[0350] 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.
[0351] The pharmaceutically acceptable salts of Formula (I), (I')
and (I''') may be prepared from organic or inorganic acids or basis
by conventional methods by the reaction of the appropriate acid or
base with the compound.
[0352] In a particular embodiment of the invention, the
2,5-dihydroxybenzene derivatives of the invention may be optionally
used in combinations with each other. In this manner and as an
example, it is possible to combine the gentisic with the
homogentisic or an ester of dobesilate ester with the homogentisic,
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.
[0353] In some embodiments, the invention provides a composition
comprising an ester derivative from those of Formula (I), (I') and
(I'''), in particular a 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 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.
[0354] The compounds of Formulas (I), (I') and (I''') also may be
in the form of solvates, particularly in the form of hydrates. The
preparation of the compounds of Formulas (I), (I') and (I''') as
well as their solvates may be synthesized by one skilled in the art
using conventional methods and commercially available reagents.
[0355] The 2,5-dihydroxybenzene compounds of Formulas (I), (I') and
(I''') are preferably formulated in the form of potassium, calcium,
magnesium and ethylamine salts. The scope of the present invention
encompasses 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. The
pharmaceutically acceptable salts of 2,5-dihydroxybenzene compounds
of Formulas (I), (I') and (I''') may be prepared from organic or
inorganic acids or bases by conventional methods by the reaction of
the appropriate acid or base with the compound.
[0356] In the methods of the present invention, the compounds of
Formulas (I), (I') and (I''') may be used at a level from about 1
mg/kg of weight to about 200 mg/kg of weight without evidencing
toxicity.
[0357] Corticosteroids include, but are not limited to, both
topical (in creams, unguents, ointments, or gels) and systemic,
intra-articular and inhaled, topical corticoids, such as,
triamcinolone acetate, and the like, systemic corticoids, such as
for example, prednisone, and the like.
[0358] Immunosuppresants and chemotherapy agents include, but are
not limited to, topical or systemic, such as, cyclosporine,
methotrexate, azathioprine, leflunomide, and vincristine.
[0359] Immunomodulators including, but not limited to, Interferon
alpha.
[0360] Leukotriene modifiers include, but are not limited to, for
example, montelukast, zafirlukast, zileuton, cromolyn,
nedocromil.
[0361] Aminosalicylates including, but not limited to,
sulfasalazine, sulfapyridine, olsalazine, mesalamine, balsalazide;
antihistamines, such as, diphenhydramine, hydroxizine, and the
like.
[0362] Antiangiogenics such as bevacizumab.
[0363] Bismuth salts.
[0364] Proton pump inhibitors include, but are not limited to,
omeprazole, lansoprazole, pantoprazole.
[0365] H2-receptor antagonists include, but are not limited to,
cimetidine, ranitidine. Anti-parasitic, such as
hydrochloroquine.
[0366] Analgesics, such as, codeine, dihydrocodeine, morphine,
oxycodone.
[0367] Antimicrobial compounds include, but are not limited to,
macrolides, such as, for example, azithromycin, clarithromycin,
dirithromycin, erythromycin, milbemycin, troleandomycin, and the
like; monobactams, such as, for example, aztreonam, and the like;
tetracyclines, such as, for example, demeclocycline, doxycycline,
minocycline, oxytetracycline, tetracycline, and the like;
aminoglycosides, such as, for example, amikacin, gentamicin,
kanamycin, neomycin, netilmicin, paromomycin, streptomycin,
tobramycin, and the like; carbacephems, such as, for example,
loracarbef, and the like; carbapenems such as, for example,
ertapenem, imipenem, meropenem, and the like; penicillins, such as,
for example, amoxicillin, ampicillin, azlocillin, carbenicillin,
cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin,
penicillin, piperacillin, ticarcillin, and the like; polypeptides,
such as, for example, bacitracin, colistin, polymyxin B, and the
like; beta-lactamase inhibitors; cephalosporins, such as, for
example, cefaclor, cefamandol, cefoxitin, cefprozil, cefuroxime,
cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,
cefpodoxime, cefadroxil, ceftazidime, ceftibuten, ceftizoxime,
ceftriaxone, cefazolin, cefixime, cefalexin, cefepime, and the
like; quinolones, such as, for example, ciprofloxacin, enoxacin,
gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin,
norfloxacin, ofloxacin, trovafloxacin, and the like;
streptogramins; sulfonamides, such as, for example, mefanide,
prontosil, sulfacetamide, sulfamethizole, sulfanilamide,
sulfasalazine, sulfisoxazole, trimethoprim,
trimethoprim-sultamethoxazole, and the like; and the combination
drugs such as for example, sulfamethoxazole and trimethoprim, and
the like. Suitable antimicrobial compounds of the invention are
described more fully in the literature, such as in Goodman and
Gilman, The Pharmacological Basis of Therapeutics (9th Edition),
McGraw-Hill, (1996); Merck Index on CD-ROM, 13th Edition; STN
Express, file phar and file registry, the disclosures of each of
which are incorporated by reference herein in their entirety.
[0368] Suitable non-steroidal anti-inflammatory drugs (NSAIDs)
include, but are not limited to, acetaminophen, acemetacin,
aceclofenac, alminoprofen, amfenac, bendazac, benoxaprofen,
bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin,
clopirac, diclofenac, etodolac, felbinac, fenclozic acid, fenbufen,
fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, ibufenac,
ibuprofen, indomethacin, isofezolac, isoxepac, indoprofen,
ketoprofen, lonazolac, loxoprofen, metiazinic acid, mofezolac,
miroprofen, naproxen, oxaprozin, pirozolac, pirprofen, pranoprofen,
protizinic acid, salicylamide, sulindac, suprofen, suxibuzone,
tiaprofenic acid, tolmetin, xenbucin, ximoprofen, zaltoprofen,
zomepirac, aspirin, acemetcin, bumadizon, clidanac, diflunisal,
enfenamic acid, fendosal, flufenamic acid, flunixin, gentisic acid,
ketorolac, meclofenamic acid, mefenamic acid, mesalamine, prodrugs
thereof, and the like. Suitable NSAIDs are described more fully in
literature, such as in Goodman and Gilman, The Pharmacological
Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, pgs.
617-657; the Merck Index on CD-ROM, (13.sup.th Edition); and in
U.S. Pat. Nos. 6,057,347 and 6,297,260 assigned to NitroMed Inc.,
the disclosures of which are incorporated herein by reference in
their entirety.
[0369] In some embodiments the NSAIDs are acetaminophen,
diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
naproxen or aspirin.
[0370] Suitable topical anesthetics include, but are not limited to
lidocaine.
[0371] Thus, another aspect of the present invention refers to a
method for the treatment and/or prophylaxis of a disease selected
from hemangiomas and hemangioblastomas, 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 or solvate thereof, isomer or
prodrug thereof. For example, the patient may be administered with
an effective amount of, at least, one 2,5-dihydroxybenzene compound
of Formula (I).
[0372] In a particular embodiment, the patient may be administered
an effective amount of, at least, one 2,5-dihydroxybenzene compound
of Formula (I) and at least one additional therapeutic agent,
including, but not limited to, a chemotherapeutic agent, a
corticosteroid, an antibiotic, an analgesic, an antiandrogen, an
immunomodulator, an anti-angiogenic, including anti-VEGF, anti-FGF,
anti-EGF and anti-HGF; inhibitors of tyrosin-kinase receptors,
protein kinase C inhibitors, a non-steroidal anti-inflammatory, a
therapy of the solubilized interleukin receptor, a cytotoxic, an
antioxidant and combinations of two or more thereof.
2,5-dihydroxybenzene compounds and/or additional therapeutic agents
may be administered separately or as components of the same
composition in one or more pharmaceutically acceptable
vehicles.
[0373] In another embodiment, the invention refers to a method for
the treatment and/or prophylaxis of any of the diseases selected
from the group consisting of benign prostatic hyperplasia,
Barrett's disease, asthma, skeletal muscle and tendon repair,
Crohn's disease, ulcerative colitis and leishmaniasis, 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 or solvate thereof, isomer or
prodrug thereof.
[0374] In a particular embodiment, the patient may be administered
an effective amount of, at least, one 2,5-dihydroxybenzene compound
of Formula (I') and at least one additional therapeutic agent,
including, but not limited to, a chemotherapeutic agent, a
corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic
blocker, a beta-adrenergic agonist, an anticholinergic, an
inhibitor of 5-alpha-reductase, an antiandrogen, an oral
contraceptive, an immunomodulator, an immunosuppressant, an
anti-angiogenic, a bronchodilator, a leukotriene modifier, an
aminosalicylate, an anesthetic, a non-steroidal anti-inflammatory,
an antiparasitic, a proton pump inhibitor, an H2-receptor
antagonist, a therapy of the solubilized interleukin receptor,
intramuscular gold, a cytotoxic, an antioxidant and combinations of
two or more thereof. 2,5-dihydroxybenzene compounds and/or
additional therapeutic agents may be administered separately or as
components of the same composition in one or more pharmaceutically
acceptable vehicles.
[0375] In another embodiment, the invention refers to a method for
the treatment and/or prophylaxis of arthritis or pain, 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 or solvate thereof, isomer or
prodrug thereof.
[0376] In a particular embodiment, the patient may be administered
an effective amount of, at least, one 2,5-dihydroxybenzene compound
of Formula (I''') and at least one additional therapeutic agent,
including, but not limited to, a chemotherapeutic agent, a
corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic
blocker, a beta-adrenergic agonist, an anticholinergic, an
inhibitor of 5-alpha-reductase, an antiandrogen, an
immunomodulator, an immunosuppressant, an anti-angiogenic such as
anti VEGF, anti FGF, anti HGF and anti EFG; a leukotriene modifier,
an aminosalicylate, an anesthetic, a non-steroidal
anti-inflammatory, an antiparasitic, a therapy of the solubilized
interleukin receptor, intramuscular gold, a cytotoxic, an
antioxidant, and combinations of two or more thereof.
2,5-dihydroxybenzene compounds and/or additional therapeutic agents
may be administered separately or as components of the same
composition in one or more pharmaceutically acceptable
vehicles.
[0377] When administered separately, the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') may be administered
approximately at the same time as part of the whole treatment
regime, that is to say as a combination therapy. The expression
"approximately at the same time" includes the administration of the
2,5-dihydroxybenzene compound simultaneously, sequentially, at the
same moment, in different moments during the same day, on different
days, as long as it is administered as part of a whole treatment
regime, that is to say, a combination therapy or a therapeutic
cocktail.
[0378] When administered alone, the compounds and compositions of
the present invention may be administered in combination with
pharmaceutically accepted vehicles and in the dosages described
herein. When the compounds and compositions of the invention are
administered as a combination of, at least, one
2,5-dihydroxybenzene compound of Formulas (I), (I') and (I''')
and/or, at least, one additional therapeutic agent, a combination
with one or more additional compounds known to be effective for the
specific pathology established as an objective for the treatment
may be used. Different additional therapeutic agents and/or
compounds may be administered simultaneously with, after, or before
administering the 2,5-dihydroxybenzene compound.
[0379] The pharmaceutical compositions containing the formulas of
the invention may be presented in any suitable form of
administration, for example, for systemic, transdermal, oral,
buccal, parenteral, topical, rectal, intravaginal administration or
by inhalation; therefore, they shall include the acceptable
pharmaceutical excipients necessary to formulate the desired form
of administration.
[0380] The compositions comprise an effective amount of
2,5-dihydroxibenzene compounds of Formulas (I), (I') and (I'''),
from about 0.001 and about 30%. Furthermore, the composition
comprises a pharmaceutical acceptable vehicle. Generally, the
vehicle is organic and may contain the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') diluted or dispersed.
Lotions, creams, solutions, gels and solids are the usual physical
forms of the composition.
[0381] The subject treated with the drug of the invention is an
animal, preferably a mammal and more specifically a human. The main
object of the present invention is directed to the treatment or
prevention of the described diseases, mainly in humans.
Secondarily, the present invention may be used for the treatment or
prevention of said diseases in pets and farm animals, not limited
to, bovine, equine and porcine.
[0382] The medicament of the present invention may be administered
by any of the routes conventionally used to administer drugs. Such
routes include, but are not limited, to topical, oral, buccal,
parenteral, inhalatory, rectal intravaginal, intraocular and
transdermal administration for the treatment of hemangiomas or
hemangioblastomas; topical, oral, buccal, transdermal, parenteral
or rectal route for the treatment of diseases selected from the
group consisting of benign prostatic hyperplasia, Barrett's
disease, asthma, skeletal muscle and tendon repair, Crohn's
disease, ulcerative colitis and leishmaniasis; topical,
transdermal, oral, buccal, parenteral, by inhalation, rectal,
intravaginal, intraocular, otical or intraarticular route for the
treatment of arthritis or pain.
[0383] The parenteral route of administration may be
intraperitoneal, intravenous, intraarterial, perioral,
subcutaneous, intramuscular, etc.
[0384] The compositions of the invention may be administered in the
conventional dosage forms prepared by the combination of
pharmacologically standardized "carriers". These combinations
involve procedures such as mixing, granulation, compression, and
dissolution in suitable ingredients. The form and nature of the
pharmacologically acceptable carrier is related to the active
ingredient with which it is mixed and with the route of
administration.
[0385] The term "carrier", as used herein, refers to the diluents
and excipients used to prepare the pharmaceutical composition. The
term "pharmacologically acceptable" refers to the requirements
described in the Pharmacopoeia related to the manufacture and use
of drugs in animals, and especially in humans.
[0386] The pharmacologically acceptable carriers may be liquid or
solid. The compositions of the invention may be administered
orally. For this purpose, the pharmaceutical composition may be
prepared in liquid form, such as solutions, syrups or suspensions
or may be formulated as a product to be reconstituted with water or
other vehicles before administration. Liquid formulations may be
prepared using conventional means with pharmacologically acceptable
additives such as suspension agents (sorbitol), non-aqueous
vehicles (oil or ether), emulsifying agents (lecithin) and
preservatives (sorbic acid). The pharmaceutical composition may be
in the form of tablets, capsules or aggregates prepared using
conventional methods with pharmacologically acceptable excipients
such as binding agents (polyvinyl, pyrrolidone or hydroxypropyl
cellulose), extenders (lactose or microcrystalline cellulose),
lubricants (magnesium stearate or talc); disintegrators (potato
starch) or wetting agents (sodium lauryl sulfate). Tablets may be
coated using pharmaceutically acceptable methods.
[0387] Compositions for oral or bucal administration may be
formulated such that they have a controlled release of the active
compound. Said formulations may include one or several agents of
continuous release such as glycerol monostearate, glycerol
distearate and wax.
[0388] Pharmaceutical compositions containing the active principle
of the invention may be also applied topically on the epidermis, in
the oral cavity, in the eye, in the ear, in the nasal cavity or in
the urethral, vaginal or rectal mucosa. Compositions for use in
topical administration include liquid or gel preparations for
application on the skin, such as creams, ointments, liniments or
pastes and drops suitable for delivery to the eye, ear or nose.
According to the invention, creams, drops, liniments, lotions,
ointments and pastes are liquid or semi-solid compositions for
external application. These formulations may be prepared by mixing
the active principle in powdered form, alone or in solution or
suspension in an aqueous or non-aqueous fluid with a greasy or
non-greasy base. The base may comprise complex carbohydrates such
as glycerol, various forms of paraffin, beeswax; a mucilage, a
mineral or edible oil or fatty acids; or a macrogel. Formulations
may additionally comprise suitable emulsifying agents such as
surfactants, and suspending agents such as agar, vegetable gums,
cellulose derivatives, and other ingredients such as preservatives,
antioxidants, etc.
[0389] According to the invention, lotions and drops include those
suitable to be applied on the skin or delivered to the eye. Eye
lotions and drops may be formulated in sterile aqueous solution;
oily solutions or suspensions may be prepared by diluting the
active principle in a suitable aqueous solution. Such solutions may
optionally contain a suitable bactericide, fungicide, preservative
and surfactant. Lotions and liniments for application on the skin
may also contain dehydrating agents such as alcohol and/or wetting
agents such as glycerol, an oil or a fatty acid.
[0390] The formulations of the invention also can be administered
nasally or by inhalation. For nasal or inhalation administration,
the formulations are conveniently delivered in the form of an
aerosol spray in pressurized packs or a nebulizer, with the use of
a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to release a
specific amount. Capsules and cartridges of, for example, gelatin
for use in an inhaler may be formulated containing a powder mix of
the compound and a suitable powder base such as lactose or
starch.
[0391] The compounds of the invention may be also formulated for a
delayed release. Such long acting formulations may be administered
by implantation (for example, subcutaneously or intramuscularly) or
by an intramuscular injection. Thus, for example, the compounds may
be formulated with suitable polymeric or hydrophobic materials (for
example, as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
[0392] 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.
[0393] 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.
[0394] In a particular embodiment of the invention, a compound of
formula (I), (I') or (I''') is administered at least once per week.
In other embodiments, a compound of formula (I), (I') or (I''') is
administered at least once per day. In yet other embodiments, a
compound of formula (I), (I') or (I''') is administered twice per
day. In another particular embodiment, a compound of formula (I),
(I') or (I''') is administered over a period of at least about one
week. In other embodiments, a compound of formula (I), (I') or
(I''') is administered over a period of at least about four
weeks.
[0395] 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.
[0396] In a particular embodiment, a compound of formula (I), (I')
or (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), (I') or (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.
[0397] In one embodiment, the 2,5-dihydroxybenzene compounds of
Formulas (I), (I') and (I''') may be administered in an amount of
about 0.05 g per day to about 50 g per day. In particular
embodiments, the 2,5-dihydroxybenzene compounds of Formulas (I),
(I') and (I''') may be administered in an amount of about 0.10 g
per day to about 25 g per day. In more particular embodiments, the
2,5-dihydroxybenzene compounds of Formulas (I), (I') and (I''') may
be administered in an amount of about 0.25 g per day to about 10 g
per day. In a more particular embodiment, the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') may be administered in
an amount of about 0.5 g per day to about 5 g pr day. In an even
more particular embodiment, the 2,5-dihydroxybenzene compounds of
Formulas (I), (I') and (I''') may be administered in an amount of
about 0.75 g per day to about 2.5 g per day. In another particular
embodiment, the 2,5-dihydroxybenzene compounds of Formulas (I),
(I') and (I''') may be administered in an amount of about 1 g per
day to about 1.5 g per day. The particular amounts of the
2,5-dihydroxybenzene compounds of Formulas (I), (I') and (I''') may
be administered as a single dose once a day; or in multiple doses
several times a day; or as a sustained-release oral formulation. In
one embodiment of the invention, the 2,5-dihydroxybenzene compounds
of Formulas (I), (I') and (I''') are administered as about 50 g, 25
g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25 g or 0.1 g once per day
(q.d). In another embodiment of the invention, the
2,5-dihydroxybenzene compounds of Formulas (I), (I') and (I''') are
administered as about 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g,
0.25 g or 0.1 g twice per day (b.i.d.) In another embodiment of the
invention, the 2,5-dihydroxybenzene compounds of Formulas (I), (I')
and (I''') are administered as about 50 g, 25 g, 10 g, 5 g, 1 g,
0.75 g, 0.5 g, 0.25 g or 0.1 g three times per day (t.i.d.) In
another embodiment of the invention, the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') are administered as
about 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25 g or 0.1 g
four times per day.
[0398] In particular embodiments, the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') may be administered
topically in a formulation comprising an amount of about 0.001% to
about 30% (w/w) of the 2,5-dihydroxybenzene compounds of Formulas
(I), (I') and (I'''). In a more particular embodiment, the
2,5-dihydroxybenzene compounds of Formulas (I), (I') and (I''') may
be administered topically in a formulation comprising an amount of
about 0.01% to about 20% (w/w) of the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I'''). In an even more
particular embodiment, the 2,5-dihydroxybenzene compounds of
Formula (I), (I') and (I''') may be administered topically in a
formulation comprising an amount of about 0.1% to about 15% (w/w)
of the 2,5-dihydroxybenzene compounds of Formulas (I), (I') and
(I'''). In a more particular embodiment, the 2,5-dihydroxybenzene
compounds of Formula (I) may be administered topically in a
formulation comprising an amount of about 0.5% to about 10% (w/w)
of the 2,5-dihydroxybenzene compounds of Formulas (I), (I') and
(I'''). In another particular embodiment, the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') may be administered
topically in a formulation comprising an amount of about 1% to
about 5% (w/w) of the 2,5-dihydroxybenzene compounds of Formulas
(I), (I') and (I'''). In an even more particular embodiment, the
2,5-dihydroxybenzene compounds of Formula (I), (I') and (I''') may
be administered topically in a formulation comprising an amount of
about 2.5% to about 4% (w/w) of the 2,5-dihydroxybenzene compounds
of Formulas (I), (I') and (I'''). The topical formulation
comprising the 2,5-dihydroxybenzene compounds of Formula (I), (I')
and (I''') may be administered as a single dose once a day; or in
multiple doses several times throughout the day. In one embodiment
of the invention, the topical formulation comprises about 30%, 20%,
15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the
2,5-dihydroxybenzene compound of Formulas (I), (I') and (I''') is
administered four times per day. In another embodiment of the
invention, the topical formulation comprising about 30%, 20%, 15%,
10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') is administered three
times per day (t.i.d). In yet another embodiment of the invention,
the topical formulation comprising about 30%, 20%, 15%, 10%, 5%,
2.5%, 1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene
compounds of Formulas (I), (I') and (I''') is administered two
times per day (b.i.d). In another embodiment of the invention, the
topical formulation comprising about 30%, 20%, 15%, 10%, 5%, 2.5%,
1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene compounds of
Formulas (I), (I') and (I''') is administered once per day
(q.d.).
[0399] In yet other embodiments, the invention provides a kit or
package comprising a compound of formula (I), (I') or (I'''), in
packaged form, accompanied by instructions for use. The compound of
formula (I), (I') or (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), (I') or (I''') is to be
administered.
[0400] For example, a kit may comprise a compound of formula (I),
(I') or (I''') in unit dosage form, along with instructions for
use. For example, such instructions may indicate that
administration of a compound of formula (I), (I') or (I''') is
useful in the treatment of one or more of the diseases selected
from the group consisting of benign prostatic hyperplasia,
Barrett's disease, asthma, skeletal muscle and tendon repair,
Crohn's disease, ulcerative colitis and leishmaniasis. The compound
of formula (I), (I') or (I''') may be packaged in any manner
suitable for administration. For example, when the compound of
formula (I), (I') or (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.
[0401] 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.
[0402] The following non-limiting examples further describe and
enable one of ordinary skill in the art to make and use the present
invention.
EXAMPLES OF THE INVENTION
Example 1
Preparation of Lotions
[0403] Lotions comprise from about 0.001% to about 30% of the
compounds of Formula I, from 1% to 25% of an emollient and the
suitable amount of water. Examples of emollients are: [0404] I.
Hydrocarbon waxes and oils. Such as mineral oil, petrolatum,
paraffin, ceresin, microcrystalline wax, polyethylene and
perhydrosqualene. [0405] II. Silicone oils such as dimethyl
polysiloxanes, methylphenyl polysiloxanes and water-soluble and
alcohol-soluble silicone glycol copolymers. [0406] 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. [0407] IV. Acetoglyceride esters, such as
acetylated monoglycerides. [0408] V. Ethoxylated glycerides, such
as ethoxylated glycerol monostearate. [0409] VI. Alkyl esters of
fatty acids having 10 to 20 carbon atoms. Methyl, isopropyl and
butyl esters of fatty acids are useful herein. Examples include,
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. [0410] 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. [0411] 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. [0412] 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. [0413] 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. [0414] XI.
Ether-esters, such as fatty acid esters of ethoxylated fatty
alcohols. [0415] 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. [0416] 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. [0417]
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. [0418] XV. Waxes such as beeswax, spermaceti, myristoyl
myristate and stearyl stearate. [0419] 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. [0420] XVII.
Vegetable waxes, including, but not limited to, carnauba and
candelilla waxes. [0421] XVIII. Phospholipids such as lecithin and
derivatives. [0422] XIX. Sterols. Examples include, but are not
limited to, cholesterol and acyl esters of cholesterol. [0423] XX.
Amides, such as fatty acid amides, ethoxylated acyl amides and
solid fatty acid alkanolamides.
[0424] The lotions of the invention additionally comprise from 1%
to 10% of an emulsifier. The emulsifiers can be anionic, cationic
or non-ionic.
[0425] 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.
[0426] 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.
[0427] 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.
[0428] 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.
[0429] 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.
Example 2
Preparation of Creams
[0430] The compositions of the present invention may be also
formulated in the form of a cream. Creams contain from about 0.001%
to about 30% of the components of Formula (I), (I') or (I'''), from
5% to 50% of an emollient and the adequate amount of water. The
emollients described above in example 1 are also suitable for the
cream formulation. Optionally, the cream may contain an emulsifier
at a level from 3% to 50%. The emulsifiers described above in
example 1 would also be suitable in this case.
Example 3
Preparation of Solutions
[0431] The compositions of the present invention may also be
formulated in the form of a solution. Solutions contain from about
0.001% to about 30% of the compounds of Formula (I), (I') or (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.
[0432] 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.
Example 4
Preparation of Gels
[0433] The composition in the form of gel could be obtained by
simply adding a suitable thickening agent to the composition in the
form of the solution described in example 3. The suitable
thickening agents have already been described in example 1.
[0434] Gel formulations contain from about 0.001% to about 30% of
the compounds of Formula (I), (I') or (I'''), 5% to 75% of a
suitable organic solvent, 0.5% to 20% of a suitable thickening
agent and the required amount of water.
Example 5
Preparation of Solids
[0435] The compositions of 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 compounds of Formula (I), (I') or (I''') and from 50% to 98% of
an emollient such as the one described above. The composition may
also contain from 1% to 20% of a suitable thickening agent, as
those described in the previous examples, and, optionally,
emulsifiers and water.
[0436] 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 in
examples 1-5.
[0437] The effective amount of 2,5-hydroxybenzene sulfonic used in
topical form will vary according to the specific circumstances of
application, the duration of exposition and similar considerations.
In general, the amount will vary from 0.01 microgram to 50
micrograms of 2,5-dyhydroxybenzene sulfonic (Dobesilate) per square
centimeter of the epidermis area. The amount of topical composition
of 2,5-dihydroxybenzene sulfonic (Dobesitale) and the carrier
applied on the affected area is determined according to the amount
of 2,5-dihydroxybenzene sulfonic (Dobesilate) contained
therein.
Example 6
Systematically Administered Compositions
[0438] The 2,5-dihydroxybenzene sulfonic (Dobesilate) is also
useful when administered systemically, either orally or
parenterally. The safe and effective required dose of
2,5-dihydroxybenzene sulfonic (Dobesilate) will vary according to
the particular condition to be treated, the severity of the
condition, the duration of the treatment and like factors within
the specific knowledge and expertise of the pation or the attending
physician and commensurate with the reasonable benefit/risk ration
applicable to the use of any drug. The detailed systemic doses and
dose ranges are based on the administration of 2,5-dihydroxybenzene
sulfonic (Dobesilate) to a human 154 pound (70 kg) and may be
adjusted to provide equivalent doses to patients of different
weights. Oral doses may comprise from about 0.05 g to about 50 g
per day, usually and preferably in fractionated doses.
[0439] The parenteral administration may be combined with an
acceptable vehicle such as pyrogen-free sterile water, in doses
from 0.5 mg to 200 mg of 2,5-dihydroxybenzene sulfonic
(Dobesilate). Parenteral administration from 0.5 to 200 mg of
2,5-dihydroxybenzene sulfonic (Dobesilate) may be subcutaneous,
intradermic, intramuscular, intraarticular or intravenous.
[0440] For oral administration, the 2,5-dihydroxibenzene sulfonic
(Dobesilate) may be formulated in unit doses such as pills,
capsules, tablets, granules, solutions, elixirs, chewing gums,
chewable tablets, and the like. Suppositories manufactured by
conventional methods may comprise 2,5-dihydroxibenzene sulfonic
(Dobesilate). The forms of oral unit doses include
2,5-dihydroxibenzene sulfonic (Dobesilate) and a pharmaceutically
acceptable vehicle. Each unit form would contain from about 15 mg
up to about 2 g of 2,5-dihydroxybenzene sulfonic (Dobesilate) and a
pharmaceutical vehicle. A pharmaceutically acceptable vehicle
refers to a solid or liquid excipient, a diluent or an
encapsulating substance. Examples of substances that may be useful
as pharmaceutically vehicles of the 2,5-dihydroxybenzene sulfonic
(Dobesilate) include: sugars such as lactose, glucose and sucrose,
starches such as corn starch or potato starch, cellulose and
derivatives thereof, such as sodium carboxymethylcellulose,
ethylcellulose and cellulose acetate; powdered tragacanth; malt;
gelatin; talc; magnesium stearate, stearic acid, calcium sulphate,
vegetable oils such as peanut oil, cottonseed oil, sesame oil,
olive oil, corn oil and theobroma oil, polyols such as propylene
glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar;
alginic acid; pyrogen-free water; isotonic saline; phosphate buffer
solutions; cocoa butter, (suppository base) as well as other
non-toxic compatible substances typically used on pharmaceutical
formulations. Wetting agents and lubricants such as sodium lauryl
sulfate, as well as coloring agents, flavoring agents and
preservatives may also be present. Agents well known in the art for
the preparation of enteric coatings may also be used in the oral
formulation of the 2,5-dihydroxybenzene sulfonic (Dobesilate), so
that it is released by the acid media of the stomach and absorbed
through the intestinal wall.
[0441] The pharmaceutical vehicle used together with the
2,5-dihydroxybenzene sulfonic (Dobesilate) will be included at the
necessary concentration to provide an adequate size-dose rate
relation. Preferably, the vehicle shall comprise from 0.1% to 99%
of the total weight of the composition.
Example 7
Hemangioma
[0442] The cream comprising 2,5-dihydroxybenzene sulfonic (2.5%)
was topically applied twice a day for 3 months on the face of a
child suffering from infantile hemangioma. FIG. 1A shows the child
before the treatment and FIGS. 1B, 1C and 1D show the child after
the treatment with said cream during 1, 2 and 3 months,
respectively, evidencing a substantial recovery of the lesion.
Example 8
Hemangioblastoma
[0443] The cream comprising 2,5-dihydroxybenzene sulfonic (2.5%)
was topically applied twice a day during 1 month on the face of the
child suffering from Nakagawa angioblastoma. As shown in FIG. 2B,
there is a reduction in the intensity of the reddish coloration
caused by the lesion.
Example 9
Effect of 2,5-dicetoxybenzenesulfonic on the Treatment of the
Intestinal Inflammatory Disease Induced in the Mouse
[0444] The induction of the intestinal inflammatory disease
described below is a representative model for the evaluation of
therapeutic strategies to treat Crohn's disease and ulcerative
colitis. 7-8 week old female mice of strain C57BL/6J-664 were used.
The intestinal inflammatory disease (IID) was induced by feeding
the mice with 3% dextran sulfate sodium (DSS; MW 40,000) dissolved
in drinking water in 2 cycles. Each cycle consisted of 7 days with
3% DSS in the drinking water separated by 7 days with regular
water. A daily clinical evaluation of the animals was performed in
which the body weight, the consistency of the faeces and the
presence of blood in the faeces were determined. Thus, the
validated score of the clinical activity of the disease was
evaluated with a 0 to 6 scale, considering the following
parameters: consistency of the faeces, presence or absence of fecal
blood and loss of weight.
[0445] At the end of the first cycle of exposure to DSS, the mice
were divided into the following treatment groups: a first group was
administered intraperitoneal (i.p) injections of vehicle (0.9%
NaCl). Another group received intramuscular injections of
Solu-Medrol, a standard IID treatment, at a dose of 10 mg/kg/day. A
third group was administered i.p. injections of potassium
2,5-diacetroxybenzene sulfonate (DABS, 100 mg/kg/day). The last
group was treated orally with 125 mg/kg day of DABS.
[0446] As shown in FIG. 3, the loss of weight produced by the two
cycles of exposure to DSS is reduced by the treatment with DABS.
DABS treatment beneficially affects the IID clinical course, as
demonstrated by the determination of the disease clinical score
(FIG. 4) that is reduced due to the i.p. and the oral
administration of DABS in the first two DSS cycles. Furthermore, it
is shown that the efficacy of DABS is not lower (in some points it
is higher) than the one corresponding to the standard treatment
with Solu-Medrol (FIGS. 3 and 4).
Example 10
Effect of Potassium 2,5-Diacetoxybenzene Sulfonate on the Treatment
Experimentally Induced Asthma in Mice
[0447] 6-9 week old Balb/c mice were used. The ovoalbumin
(OVA)/aluminum complex was obtained after dissolving OVA (500
.mu.g/mL) in PBS, and mixing it with an equal volume of 10%
aluminum potassium sulfate at pH 6.5 for 1 hour. After centrifuging
the pellet (750.times.g for 5 minutes) the OVA/aluminum pellet was
resuspended in distilled water. On day 0, the mice were
intraperitoneally injected with 100 .mu.g of OVA/aluminum. Eight
days later, the mice were anesthetized and exposed to 250 .mu.g of
OVA. Later, they were administered 125 .mu.g of OVA on days 15, 18
and 21. Each rat received sublingual administration of OVA.
[0448] The following treatments were administered to the animals:
(i.p.) vehicle from day 2, potassium 2,5-diacetoxybencene sulfonate
(DABS; 100 mg/kg/day, i.p.) from day 2, DABS (100 mg/kg/day, i.p.)
from day 8 and Combivent (20 .mu.g/200 .mu.g in aerosol) on days
20, 21 and 22, the latter as a reference treatment.
[0449] In order to evaluate the pulmonary function, the response to
methacholine in conscious mice was determined, 24 hours after the
last exposure to OVA. The mice were exposed to increasing
methacholine concentrations (5 and 20 mg/mL) in the form of aerosol
using an ultrasonic nebulizer during 2 minutes. The degree of
bronchoconstriction was expressed as the enhanced pressure
(P.sub.enh) which correlates to the mouse air resistance, impedance
and pressure within the pleura. The P.sub.enh was calculated using
the formula P.sub.enh=[(T.sub.e/R.sub.t-1).times.(PEF/PIF)], where
Te is expiratory time, Rt is relaxation time, PEF is peak
expiratory flow and PIF is peak inspiratory flow.times.0.67
coefficient.
[0450] After measuring airway hyperreactivity, the mice were
sacrificed and bronchoalveolar lavage (BAL) of the right lung was
collected. The total number of cells in the BAL fluid was
determined.
[0451] The treatment with DABS, when it started on day 2 and when
it started on day 8, completely prevented the methacoline induced
bronchoconstriction in OVA-sensitized mice (FIG. 5). Likewise, the
DABS treatment significantly reduced the presence of BAL cells in
asthmatic mice, even more than the treatment with Combivent (FIG.
6).
Example 11
Use of 2,5-dihydroxybenzene Sulfonic Acid (DHBS) for the Treatment
of Skeletal Muscle Lesions
[0452] The capacity of a 2,5-dihydroxybenzene derivative, the
2,5-dihydroxybenzene sulfonic acid (DHBS) to effectively treat
skeletal muscle lesions is shown herein. The efficacy is evident,
not only in the images of conventional diagnosis that show the
recovery of the muscular damage, but also there is a clear
functional recovery of the affected limb.
[0453] This example supports the use of 2,5-dihydroxybenzene
derivatives in the treatment of skeletal muscle lesions as well as
muscle-tendinous and muscle-ligamentous injuries.
[0454] The first patient's left quadriceps was broken by practicing
sports. Two days after the muscle was broken, the magnetic
resonance imaging reveals a lesion with a considerably large
hematoma (FIGS. 7A and 7B). At that moment, the patient starts a
daily oral treatment with 500 mg of 2,5-dihydroxybenzene sulfonic
acid (DHBS) for two weeks. After this period, a new magnetic
resonance is performed and it reveals the recovery of the lesion in
the quadriceps, the hematoma can no longer be observed (FIGS. 7C
and 7D). Besides, at that moment, the patient is able to extend the
left leg almost completely (FIGS. 8A and 8B). This functional
recovery, as well as the diagnostic resolution of the lesion occur
within a shorter period than the one required in the case of
conventional treatments (antiinflammatories) after a lesion of this
magnitude. An observation that may be applied to the other cases
that support this example.
[0455] Other patient has a hematoma and muscular breaking of the
brachial biceps, as shown in the magnetic resonance image of FIG.
9A. The hematoma can be appreciated externally (FIG. 10A) and the
lesion, produced by professional practice (dancing) the day before
the consultation, limits the elbow flexion (FIG. 10B) and extension
(FIG. 10C). The treatment with DHBS (1500 mg/day, p.o.) during 20
days markedly reduces the size of the lesion and of the hematoma
(FIG. 9B) and recovers the functionality of the elbow flexion and
extension (FIGS. 10D and 10E).
[0456] The treatment with DHBS (1500 mg/day, p.o.) for 11 days
reduced the muscular lesion of another patient, produced in the
semitendinous muscle by practicing sports 9 days before starting
the treatment with DHBS. In FIG. 11, the magnetic resonance image
shows the upper part of the left leg of the patient before (A) and
after (B) the treatment with DHBS.
[0457] In another case, the magnetic resonance image of the
breaking produced in a patient's Achilles tendon (FIG. 12A) is
shown, as well as the marked reduction of said lesion after two
months of treatment with DHBS (1500 mg/day, p.o.) (FIG. 12B).
Example 12
Effect of the Treatment with Potassium 2,5-dihydroxybenzensulfonate
and Potassium 2,5-Diacetoxybenzenesulfonate on the Experimental
Infection with Leishmania major in a Mouse Model
[0458] This model is based in the massive inoculation of Leishmania
promatigotes in the mouse paw pad. Under these conditions, the
parasite induces a progressive inflammation correlated with the
multiplication of parasites at the site of inoculation. BALB/c
strain female mice that developed severe and uncontrolled injuries
were used (Foote S J, Handman E. Brief Funct Genomic Proteomic,
2005). This model has been used in pharmacology to monitor the
therapeutic capacity of new leishmanicide compounds and the
preventive capacity of potential vaccines against leishmaniasis
((Nelson K G et al. Antimicrob Agents Chemother. 2006).
[0459] The animals were inoculated with 5.times.10.sup.6 of L.
major promastigotes (strain Hervas) in 50 .mu.L of PBS into the
plantar pad of the right back paw. As negative control of the
infection, a group of mice inoculated with 50 .mu.L of PBS was
used. The sizes of the lesions were measured every 7 days until the
animals were sacrificed (week 9) using a Vernier caliper. The
thickness of the right back paw (infected) and the left back paw
(uninfected) of all the animals was measured at the base of the
fifth toe. The progression of the inflammation is represented as
the difference in thickness between the infected and the
non-infected paws.
[0460] In a first assay, the infected animals were daily injected
by the intraperitoneal (i.p.) route with 100 .mu.L of saline (0.9%
NaCl in H.sub.2O) (vehicle) or with 4 mg of potassium
2,5-dihydroxybenzene sulfonate (DHBS; 200 mg/kg of weight) in 100
.mu.L of saline during 14 days from the third week after the
infection. A significant reduction in the increase of paw thickness
was observed from the eighth week after the infection (FIG.
13).
In another assay, the infected animals were administered a daily
intraperitoneal (i.p.) injection of 100 .mu.L of saline (0.9% NaCl
in H.sub.2O) (vehicle) or of 4 mg of potassium 2,5-diacetoxybenzene
sulfonate (DABS; 200 mg/kg of weight) in 100 .mu.L of saline. Such
treatment started simultaneously with the infection (day 0) and
continued until the animals were sacrificed in the week 9
post-infection. As shown in FIG. 14, the treatment with DABS
produces a statistically significant reduction in the size of the
lesion as from the third week post-infection up to the end of the
assay. Said differences increase during the experiment.
[0461] In a third assay, the treatments used were the same as the
previous assay (vehicle and DABS 200 mg/kg/day i.p.), but were
administered as from the third week after the inoculation. The size
of the lesion was significantly smaller in the group treated with
DABS as from the eighth week after the infection (FIG. 15).
[0462] The following examples illustrate that, 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 13
Inhibition of Fibroblasts Mitogenesis Induced by the Fibroblast
Growth Factor-1 (FGF-1)
[0463] Inhibition of FGF-1 induced mitogenesis was observed in
quiescent cultures of Balb/c 3T3 fibroblasts by
2-acetoxy-5-hydroxybenzene sulfonate (FIG. 16),
5-acetoxy-2-hydroxybenzene sulfonate (FIG. 17) and
2,5-diacetoxybenzene sulfonate (FIG. 18). The evaluated compounds
were used in the form of potassium salt, except in the first case
in which calcium salt was used. The experiments were carried out as
described in Fernandez-Tornero C et al. J Biol Chem, 2003.
Example 14
Effect of Monoesters of 2,5-dihydrorxybenzene Sulfonate on the
Proliferation of Rat Glioma C6 Cells
[0464] The following example shows the efficacy of
2,5-dihydroxybenzene sulfonic, potassium 2-acetoxy-5-hydroxybenzene
sulfonate (2A-5HBS) and potassium 5-acetoxy-2-hydroxybenzene
sulfonate (5A-2HBS) monoesters to reduce the proliferative capacity
of glioma cells and supports the use of the compound in treating
gliomas.
[0465] The cell line used was the C6 cell line and the experiment
was carried out as described in examples 2 and 3. Once adhered, the
cells were treated or not (controls) with (5A-2HBS) (500 .mu.M) or
(2A-5HBS) (500 .mu.M) and they were allowed to proliferate for 48
h. After this time the glioma cell proliferation was evaluated by
means of staining the fixed cells with crystal violet. The number
of cells is proportional to the amount of retained dye, which was
determined spectrophotometrically by measuring the absorbance at
595 nm once the dye was extracted from the cells.
[0466] Both 2,5-dihydroxybenzene sulfonate, (5A-2HBS) and (2A-5HBS)
monoesters caused the inhibition of rat glioma cell proliferation
(FIG. 19).
Example 15
Analysis of the Structural Interaction of the Esters of
2,5-dihydroxybenzene Sulfonate with the Fibroblast Growth Factor-1
(FGF-1)
[0467] Based on the crystal diffraction of the
FGF-1:2-acetoxy-5-hydroxybenzene sulfonic acid,
FGF-1:5-acetoxy-2-hydroxybenzene sulfonic acid and
FGF-1:2,5-diacetoxybenzene sulfonic acid complexes, the structures
of the complexes were calculated and represented. FIGS. 20, 21 and
22, which show the surface of the dyed protein according to its
electrostatic potential (light grey: negative charge; dark grey:
positive charge; white: lack of charge), show the manner in which
2-acetoxy-5-hydroxybenzene sulfonic acid,
5-acetoxy-2-hydroxybenzene sulfonic acid and 2,5-diacetoxybenzene
sulfonic acid interact, respectively, with FGF-1. The electron
density of the compound, contoured at 1.sigma. (FIGS. 20-22, panels
C), allowed locating and determining the orientations of the
compounds with respect to the protein (FIGS. 20-22, panels A and
B), as well as confirming that the compounds conserve the acetoxyl
groups in positions 2, 5 and, 2 and 5, respectively, when they bind
to the protein. The compounds occupy a site that is very close to
the one that has been described occupied by 2,5-dihydroxybenzene
sulfonic acid, the aromatic ring of which forms a cation-.pi. bond
with the N.sup..epsilon. group of lysine 132, which is marked in
FIGS. 20-22, panels A, as a reference.
[0468] 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 incorporated by reference.
[0469] 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.
* * * * *