O- or S-substituted tetrahydronaphthalene derivatives having...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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Reexamination Certificate

active

06465663

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel compounds having retinoid and/or retinoid antagonist-like biological activity. More specifically, the present invention relates to O- or S-substituted tetrahydronaphthalene derivatives which bind to retinoid receptors and have retinoid-like or retinoid antagonist-like biological activity.
BACKGROUND ART
Compounds which have retinoidlike activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and recently issued patents which are assigned to the assignee of the present application, are directed to further compounds having retinoid-like activity.
Although pharmaceutical compositions containing retinoids have well established utility (as is demonstrated by the foregoing citation of patents and publications from the voluminous literature devoted to this subject) retinoids also cause a number of undesired side effects at therapeutic dose levels, including headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skin irritation, headache and hepatotoxicity. These side effects limit the acceptability and utility of retinoids for treating disease.
It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RAR
&agr;
, RAR
&bgr;
and RAR
&ggr;
, in RXR the subtypes are: RXR
&agr;
, RXB
&bgr;
and RXR
&ggr;
. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property. Some compounds bind to one or more RAR receptor subtypes, but do not trigger the response which is triggered by agonists of the same receptors. A compound that binds to a biological receptor but does not trigger an agonistlike response is usually termed an antagonist. Accordingly, the “effect” of compounds on retinoid receptors may fall in the range of having no effect at all, (inactive compound, neither agonist nor antagonist), the compound may elicit an agonist-like response on all receptor subtypes (pan-agonist), or a compound may be a partial agonist and/or partial antagonist of certain receptor subtypes if the compound binds to but does not activate certain receptor subtype or subtypes but elicits an agonist-like response in other receptor subtype or subtypes. A pan antagonist is a compound that binds to all known retinoid receptors but does not elicit an agonist-like response in any of the receptors.
It has been recently discovered and described in a pending application assigned to the same assignee as the present application that retinoid antagonist-like activity of a compound is also a useful property, in that such antagonist compounds can be utilized to block certain undesired side effects of retinoids, to serve as antidotes to retinoid overdose or poisoning, and may lend themselves to other pharmaceutical applications as well. More particularly, regarding the published scientific and patent literature in this field, published PCT application WO 94/14777 describes certain heterocyclic carboxylic acid derivatives which bind to RAR retinoid receptors and are said in the application to be useful for treatment of certain diseases or conditions, such as acne, psoriasis, rheumatoid arthritis and viral infections. A similar disclosure is made in the article by
Yoshimura et al. J Med. Chem.
1995, 38, 3163-3173. Kaneko et al. Med. Chem Res. (1991) 1:220-225; Apfel et al. Proc. Natl. Acad. Sci. USA Vol 89 pp 7129-7133 Augusty 1992 Cell Biology; Eckhardt et al. Toxicology Letters, 70 (1994) 299-308; Keidel et al. Molecular and Cellular Biology, Vol 14, No. 1, Jan. 1994, p 287-298; and Eyrolles et al. J. Med. Chem. 1994, 37, 1508-1517 describe compounds which have antagonist like activity at one or more of the RAR retinoid subtypes.
SUMMARY OF THE INVENTION
Among the compounds of Formulas 1 through 6, the present invention covers the compounds of Formula 1. Compounds of the remaining formulas are disclosed here inasmuch as the methods of their synthesis pertains to the best modes of the presently contemplated synthetic routes leading to the compounds of Formula 1. Thus the present invention pertains to compounds of Formula 1
wherein
X
1
is [C(R
1
)
2
]
n
where R
1
is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
X
2
is S or O;
Z is
—N═N—,
—N(O)═N—,
—N═N(O)—,
—N═CR
1
—,
—CR
1
═N,
—(CR
1
═CR
1
)
n
,— where n′ is an integer having the value 0-5,
—CO—NR
1
—,
—CS—NR
1
—,
—NR
1
—CO,
—NR
1
—CS,
—COO—,
—OCO—;
—CSO—;
—OCS—;
—CO—CR
1
═CR
1
—;
R
2
is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF
3
, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R
3
is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
R
4
is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C
1
-C
10
-alkylphenyl, naphthyl, C
1
-C
10
-alkyl-naphthyl, phenyl-C
1
-C
10
alkyl, napthyl-C
1
-C
10
alkyl; CN, or (CH
2
)
p
CO
2
R
8
where p is an integer between 0 to 10;
R
5
is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbo-cyclic aryl selected from the group consisting of phenyl, C
1
-C
10
-alkylphenyl, naphthyl, C
1
-C
10
-alkylnaphthyl, phenyl-C
1
-C
10
alkyl, napthyl-C
1
-C
10
alkyl; Si(C
1-6
alkyl)
3
, COR
14
, camphanoyl, C(R
15
)(R
16
)X
2
R
17
;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R
2
groups, or
when Z is —(CR
1
═CR
1
)
n
, — and n′ is 3, 4 or 5 then Y represents a direct valence bond between said (CR
2
═CR
2
)
n
, group and B;
A is (CH2)
q
where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1

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