Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-05-07
2001-12-04
Killos, Paul J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S055000, C560S059000, C562S465000, C562S469000, C554S218000, C568S442000, C514S502000, C514S570000
Reexamination Certificate
active
06326397
ABSTRACT:
BACKGROUND OF THE INVENTION
Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Retinoids have been found to be clinically useful in the treatment of dermatological and oncological diseases.
Retinoids with retinoid receptor agonistic activity have been shown to be active not only in model systems for the treatment of dermatological and oncological diseases but also in models for the treatment of T-helper cell type 1 (Th1)-mediated immune diseases. Retinoids with retinoid receptor agonistic activity are active in the treatment of adjuvant arthritis [Brinckerhoffet 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) are effective in counteracting many properties of retinoids with retinoid receptor agonistic activity (retinoid agonists) such as inhibition of cell proliferation, induction of cell differentiation, induction of apoptosis and inhibition of angiogenesis [Bollag et al., Int. J. Cancer 70, 470-472 (1997)]. Retinoid antagonists are also suppressing 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 prevention and therapy 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 prevention and treatment of preneoplastic or neoplastic lesions, vitreo-retinopathy and retinal detachment. In addition, retinoid antagonists have been proposed for use as single agents, based on their anti-proliferative effect, for treatment of certain neoplasms insensitive to retinoid receptor agonists [WO 97/09297].
SUMMARY OF THE INVENTION
The present invention relates to the compounds of the formula I
wherein the dotted bond can be either hydrogenated or form a double bond; and, when the dotted bond forms a double bond, R
1
is lower alkyl and R
2
is hydrogen; and, when the dotted bond is hydrogenated, R
1
and R
2
taken together are methylene to form a cis-substituted cyclopropyl ring; R
3
is hydroxy or lower alkoxy; R
4
is alkyl or alkoxy; and R
5
and R
6
are, independently, a C
4-12
alkyl or a 5-12 cycloalkyl substituent containing from 1-3 rings which are either unsubstituted or substituted with from 1-3 lower alkyl groups, with the carbon atom of R
5
and R
6
being linked to the remainder of the molecule to form a quaternary carbon atom and pharmaceutically acceptable salts of carboxylic acids of formula I are effective in inducing IL-12 production and suppressing T-helper cell type 2 (Th2) activity and therefore are useful in treating diseases mediated by Th2 activity and Th2-related cytokines such as IL-4 and IL-5.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I are effective in inducing IL-12 production and suppressing T-helper cell type 2 activity as shown by the fact that all of these compounds are active in the in vitro assay of Example 4 and 5 hereinafter. Therefore, the compounds of formula I can be used to increase the production of IL-12 and to suppress T helper cell type 2 activity and are therefore useful for the treatment of T-helper cell type 2 (Th2)-mediated immune diseases.
As used herein the term “alkyl” means straight-chain, branched or cyclic alkyl residues, in particular those containing from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, t-butyl, decyl, dodecyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term “lower alkyl” means alkyl groups containing from 1 to 7, preferably 1-4 carbon atoms. Most preferred lower alkyl groups are methyl and ethyl. Alkyl and alkoxy groups denoted by R
4
preferably contain 1-8 carbon atoms, more preferably 1-4 carbon atoms. Particularly preferred group R
4
are ethoxy and butoxy. Examples of C
4-12
alkyl groups represented by R
5
or R
6
are tert.-butyl, 1,1-dimethylpropyl, 1-methyl-1-ethylpropyl, 1-methyl-1-ethylhexyl and 1,1-dimethyldecyl. Of these groups, tert.-butyl is preferred. When one of R
5
and R
6
is a 5 to 12 cycloalkyl hydrocarbon substituted, the substituent contains from 1 to 3 fused hydrocarbon rings which may be unsubstituted or substituted with from 1 to 3 lower alkyl groups. The substituents R5 and R
6
are attached to the remainder of the molecule of formula I by a carbon atom which, when so attached, forms a quaternary carbon atom. Among the preferred mono- or polycyclic hydrocarbon substituents represented by R
5
and R
6
are 1-adamantyl and. 1-methylcyclohexyl.
The compounds of formula I wherein R
3
is hydroxy form salts with pharmaceutically acceptable bases such as alkali salts, e.g. Na and K-salts, and ammonium or substituted ammonium salts such trimethylammonium salts which are within the scope of this invention.
In one embodiment, the invention comprises compounds of the formula I a
wherein R
1
is lower alkyl and R
3
to R
6
are as in formula I; and pharmaceutically acceptable salts of carboxylic acids of formula Ia.
In another embodiment the invention comprises compounds of the formula:
wherein R
3
to R
6
are as in formula I; and pharmaceutically acceptable salts of carboxylic acids of formula Ib.
The compounds of formula I wherein R
1
and R
2
taken together are methylene, may be present in pure enantiomeric form or as racemates. While formula Ib arbitrarily depicts a particular enantiomeric form it is to be understood that the invention also comprises the opposite enantiomers as well as the racemates.
Particularly preferred are compounds of the formula Ia wherein R
1
is methyl, R
4
is ethoxy or butoxy and R
5
and R
6
are tert.-butyl.
The compounds of formula I above bind specifically to Retinoid X Receptors (RXR), but do not activate them. Accordingly the compounds of this invention can be used to reduce or abolish adverse events induced by retinoids (retinoid agonists) in patients with dermatological or oncological diseases. Experimental investigations on this subject are described in Examples; 1-3.
In a second aspect, the present invention relates to the use of retinoid antagonists comprising retinoids with selective Retinoic Acid Receptor (RAR) antagonistic activity, Retinoid X Receptor (RXR) antagonistic activity or mixed RAR-RXR antagonistic activity, for the manufacture of a medicament for the treatment of T-helper cell type 2 (Th2)-mediated immupe diseases such as immunoglobulin E (IgE)-mediated allergic diseases, or diseases mediated by the Th2-related cytokines, as well as to the use of said active substances for the treatment of such diseases.
In accordance with that aspect of the 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)].
Thus, the term “retinoid antagonists” encompasses
a) RXR antagonists of the formula I given earlier herein, particularly those of the formula
wherein the dotted bond is optional; and, when the dotted bond is present, R
1
is methyl and R
2
is hydrogen; and, when the dotted bond is absent, R
1
and R
2
taken together are methyl
Bollag Werner
Klaus Michael
Mohr Peter
Panina-Bordignon Paola
Rosenberger Michael
Hoffman-La Roche Inc.
Johnston George W.
Killos Paul J.
Parise John P.
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