Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-08-03
2003-08-26
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06610742
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The present invention relates a method for using retinoid antagonists, such as retinoids with selective Retinbic Acid Receptor (“RAR”) antagonistic activity, Retinoid X Receptor (“RXR”) antagonistic activity or mixed RAR-RXR antagonistic activity, to treat T-helper cell type 2 (“Th2”)-mediated immune diseases. Th2-mediated immune diseases include immunoglobulin E (“IgE”)-mediated allergic diseases. The present invention also relates to using retinoid antagonists to prepare medicaments for treating Th2-mediated immune diseases.
2. Description
Retinoids are a class of compounds structurally related to vitamin A and include natural and synthetic compounds. Retinoids are clinically useful in the treating dermatological and oncological diseases.
Retinoid activity is thought to be mediated by the nuclear retinoid receptors RAR&agr;, &bgr;, &ggr; and RXR&agr;, &bgr;, &ggr;, belonging to the superfamily of steroid, thyroid hormone, vitamin D, peroxisome proliferator-activated receptors [Pfahl et al.,
Vitamins and Hormones
, 49: 327-382 (1994)]. Retinoids with receptor agonistic activity bind to and activate receptors, whereas retinoids with receptor antagonistic activity bind to receptors but do not activate them.
Experimentally, retinoids with retinoid receptor agonistic activity have been shown to be active in model systems for treating dermatological and oncological diseases and in models for treating immunological diseases. Retinoids with retinoid receptor agonistic activity have been shown active in treating adjuvant arthritis [Brinckerhoff et al.,
Science
, 221: 756-758 (1983)] and experimental allergic encephalomyelitis [Massacesi et al.,
J. Clin. Invest
., 88: 1331-1337 (1991); Racke et al.,
J. Immunol
., 154, 450-458 (1995)], animal models for rheumatoid arthritis and multiple sclerosis, respectively. Both diseases are considered to belong to Th1-mediated immune diseases.
Experimentally, retinoids!with retinoid receptor antagonistic activity (retinoid antagonists) have been shown effective in counteracting many properties of retinoids with retinoid receptor agonistic activity (retinoid agonists), such as inhibiting cell proliferation, inducing cell differentiation, inducing apoptosis and inhibiting angiogenesis [Bollag et al.,
Int. J. Cancer
, 70: 470-472 (1997)]. Retinoid antagonists also suppress toxic side effects of retinoid agonists, such as the signs and symptoms of the hypervitaminosis A syndrome and teratogenesis [Standeven et al.,
Toxicol. Appl. Pharmacol
., 138: 169-175 (1996); Eckhardt and Schmitt,
Toxicol. Letters
, 70: 299-308 (1994)]. Therefore, they may be useful clinically in preventing or treating adverse events caused by retinoid agonists.
Retinoid antagonists have been proposed for clinical use in the prevention and treatment of retinoid-induced toxicity and side effects, particularly of the so-called hypervitaminosis A syndrome. Retinoid antagonists have also been proposed to be used in combination with retinoid receptor agonists or other nuclear receptor agonists for preventing and treating preneoplastic or neoplastic lesions, vitreo-retinopathy, and retinal detachment. In addition, retinoid antagonists may be useful as single agents, based on their anti-proliferative effect, for treatment of certain neoplasms insensitive to retinoid receptor agonists [WO 97/09297].
The subject invention provides for the first time a method for using retinoid antagonists in the treatment of Th2-mediated immune diseases, such as IgE-mediated allergic diseases and diseases mediated by the Th2-related cytokines.
SUMMARY OF THE INVENTION
The subject invention provides a method of treating a T-helper cell type 2-mediated immune disease or a disease mediated by T-helper cell type 2-related cytokines. This method comprises administering to a subject having a T-helper cell type 2-mediated immune disease or a disease mediated by T-helper cell type 2-related cytokines an effective amount of a compound selected from the group consisting of retinoid antagonists, pharmaceutically acceptable salts of retinoid antagonists, and pharmaceutically acceptable hydrolyzable esters of such retinoid antagonists and their salts.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
In the scope of the present invention the term “retinoid antagonists” is used for retinoids or compounds with RAR, RXR or mixed RAR-RXR antagonistic activity. It includes compounds with receptor neutral antagonistic activity (neutral antagonists), receptor inverse agonistic activity (inverse agonists) and negative hormone activity (negative hormones) [Klein et al.,
J. biol. Chem
., 271: 22692-22696 (1996)].
In the scope of the present invention the term “retinoid antagonists” encompass compounds of formulas I-XVI depicted below:
a) RAR &agr;-antagonists of formulas:
wherein R
1
is C
5-10
-alkyl, and R
2
and R
3
independently of each other are hydrogen or fluorine;
such compounds are described in U.S. Pat. No. 5,391,766 and
J. Med. Chem
., 40: 2445 (1997);
b) RAR &agr;, &bgr; antagonists of formulas:
wherein R
4
is diamantyl, X is O or NH, R
5
is phenyl or benzyl, and
wherein optionally either ring A or ring B is present;
such compounds are described in
Med. Chem. Res
., 1: 220 (1991);
Biochem. Biophys. Res. Com
., 231: 243 (1997); and
J. Med. Chem
., 37: 1508 (1994);
c) RAR &bgr;, &ggr; antagonists of formula
wherein R
6
and R
7
independently of each other hydroxy, C
1-4
-alkoxy, optionally branched C
1-5
-alkyl or adamantyl;
such compounds are described in
J. Med. Chem
. 38: 4993 (1995);
d) RAR &ggr; antagonists of formulas:
such compounds are described in
Cancer Res
., 55: 4446 (1995);
e) RAR &agr;, &bgr;, &ggr; antagonists of formulas:
wherein Y is —CH
2
— or sulfur and Z is —CH═ or nitrogen, and R
8
is hydrogen or C
1-4
-alkyl;
such compounds are described in
J. Med. Chem
. 38: 3163 and 4764 (1995);
J. Biol. Chem
., 271: 11897 and 22692 (1996);
f) RXR antagonists of formulas:
wherein the dotted bond is optional; and, when the dotted bond is present, R
9
is methyl and R
10
is hydrogen; and, when the dotted bond is absent, R
9
and R
10
taken together are methylene to form a cis-substituted cyclopropyl ring; R
11
is C
1-4
-alkoxy;
such compounds are described in EP Patent Appl. No. 97 107 843.1
; J. Med. Chem
., 39: 3229 (1996); and
Nature
, 383: 450 (1996).
In accordance with this invention, it has thus been found that administration of retinoid antagonists, pharmaceutically acceptable salts, and pharmaceutically acceptable hydrolyzable esters thereof, are efficacious in treating patients with T-helper cell type 2 (Th2)-mediated diseases. It has also been found that the administration of retinoid antagonists is efficacious in treating patients with diseases mediated by Th2-related cytokines, such as interleukin-4 (IL4) and IL-5.
The invention, therefore, in one aspect, relates to the use of retinoid antagonists, their pharmaceutically acceptable salts or pharmaceutically acceptable hydrolyzable esters, for the manufacture of a medicament for the treatment of T-helper cell type 2 (Th2)-mediated immune diseases. In another aspect the invention relates to the use of retinoid antagonists, their pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof for the manufacture of a medicament for the treatment of disease mediated by Th2-related cytokines, such as IL4 and IL-5.
The invention also relates to a method for treating patients having T-helper cell type 2 (Th2)-mediated immune diseases comprising administering to said human patient a compound selected from the group of retinoid antagonists, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof, said compound being administered in an amount effective to treat said disease. The term
Bollag Werner
Klaus Michael
Panina-Bordignon Paola
Sinigaglia Francesco
Hoffman-La Roche Inc.
Johnston George W.
Parise John P.
Travers Russell
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