Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-23
2001-05-01
Aulakh, C. S. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S285000, C546S290000, C546S322000, C514S345000, C514S357000
Reexamination Certificate
active
06225328
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to certain adamantyl compounds of retinoid type and to pharmaceutical/cosmetic compositions comprised thereof; the subject compounds are especially useful for the treatment of disorders and/or ailments manifesting an overregulation of RAR receptors and/or a hypervitaminosis A.
2. Description of the Prior Art
It is known to this art that retinoic acid and certain of its analogs (also deemed retinoids) are capable of inducing differentiation of embryonic teratocarcinoma cells (F9) in mice. Secretion of the plasminogen activator which accompanies this differentiation is an index of the biological response of F9 cells to retinoids. It is also known that the ability of these retinoids to induce the plasminogen activator directly correlates with the affinity which they have for RAR (retinoic acid receptors) receptors endogenous to F9 cells (
Skin Pharmacol
., 3, pp. 256-267 (1990)).
It is also known that dermatological, rheumatic, respiratory, cardiovascular, osseous or ophthalmological disorders or ailments are in particular related to an overregulation (overexpression or overactivity) of RAR receptors and/or to a hypervitaminosis A (presence in the body of an abnormal amount of vitamin A or of its metabolites). Thus, need continues to exist for compounds which will inhibit the biological effects of an overregulation of RAR receptors and/or of a hypervitaminosis A.
SUMMARY OF THE INVENTION
It has now surprisingly and unexpectedly been determined that certain adamantyl compounds of retinoid type do not induce differentiation of F9 cells but, however, become bound to RARs, this binding being of the antagonist type.
Thus, the present invention features the formulation of an effective amount of at least one compound of retinoid type of the following formula (I) into pharmaceutical/cosmetic compositions for the treatment of disorders or ailments related to an overregulation of RAR receptors and/or to a hypervitaminosis A.
The subject compounds have the following structural formula (I):
in which R
1
is (i) the —CH
3
radical, (ii) the —CH
2
OH radical, (iii) an —O—R
3
radical, or (iv) a —CO—R
4
radical, wherein R
3
and R
4
are as defined below; Ar is a radical selected from among those of the following formulae (a)-(d):
wherein R
5
is as defined below; R
2
is an —(X)
n
—(CH
2
)
p
—R
6
radical, an —(X)
n
—(CH
2
)
q
—R
7
radical, a —CH═CH—(C
2
)
s
—R
6
radical, or a —CH═CH—(CH
2
)
t
—R
7
radical, wherein R
6
, R
7
, X, R, p, q, s and t are as defined below; R
3
is a hydrogen atom, a lower alkyl radical, or a —(CH
2
)
m
—(CO)
n
—R
8
radical, wherein R
8
, m and n are as defined below; R
4
is a hydrogen atom, a lower alkyl radical, a radical of the formula:
or an —OR
9
radical, wherein R′, R″ and R
9
are as defined below; R
5
is a hydrogen or halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a hydroxyl radical or an —OR
10
or —OCOR
10
radical, wherein R
10
is as defined below; R
6
is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, or an alkynyl radical; R
7
is an aryl radical, a mono- or polyhydroxyalkyl radical in which the hydroxyl moieties are optionally protected in the methoxy or acetoxy or acetonide form, an aminoalkyl radical in which the amine functional group is optionally substituted by one or two lower alkyl radicals, a polyether radical, a —COR
4
radical, a saturated or unsaturated heterocycle, or an aminoaryl radical; R
8
is a lower alkyl radical or a saturated heterocycle; R
9
is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical, or a sugar residue or an amino acid or peptide residue; R
10
is a lower alkyl radical; X is an oxygen atom or an —S(O)
r
radical; R′ and R″, which may be identical or different, are each a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical, or an amino acid, peptide or sugar residue, or alternatively, taken together, form a saturated heterocycle, with the proviso that R′ and R″ may together form, with the nitrogen atom from which they depend, a saturated heterocycle; m is an integer ranging from 1 to 3, inclusive; n is an integer ranging from 0 to 1, inclusive; p is an integer ranging from 5 to 12, inclusive; g is an integer ranging from 0 to 12, inclusive; r is an integer ranging from 0 to 2, inclusive; s is an integer ranging from 3 to 10, inclusive; t is an integer ranging from 0 to 10 inclusive; and the salts and chiral and geometric isomers thereof.
The compounds of formula (I) can therefore also be salts, when R
1
or R
7
represents a carboxylic acid functional group or when R
7
represents an amine functional group, as well as the chiral (optical) and geometric isomers thereof. When the compounds according to the invention exist in the form of salts, they are preferably salts of an alkali metal or alkaline earth metal, or, alternatively, of zinc or of an organic amine.
DETAILED DESCRIPTION OF BEST MODE AND PREFERRED EMBODIMENTS OF THE INVENTION
More particularly according to the present invention, by “lower alkyl radical” is intended a radical having from 1 to 6 carbon atoms and preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
By “linear or branched alkyl radical having from 1 to 20 carbon atoms” is preferably intended methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
By “monohydroxyalkyl radical” is preferably intended a radical having from 1 to 6 carbon atoms, in particular a hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
By “polyhydroxyalkyl radical” is preferably intended to radical having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.
By “aryl radical” is preferably intended a phenyl radical optionally substituted by at least one halogen atom, or at least one hydroxyl or nitro functional group.
By “aminoaryl radical” is preferably intended an aminophenyl radical optionally substituted by at least one halogen atom, or at least one hydroxyl or nitro functional group.
By “aralkyl radical” is preferably intended a benzyl or phenethyl radical optionally substituted by at least one halogen atom, or at least one hydroxyl or nitro functional group.
By “alkenyl radical” is intended a radical preferably having from 2 to 5 carbon atoms and having one or more sties of ethylenic unsaturation, for example the allyl radical.
By “sugar residue” is intended a residue derived, in particular, from glucose, galactose or mannose, or from glucuronic acid.
By “amino acid residue” is intended, in particular, a residue derived from lysine, glycine or aspartic acid and by “peptide residue” is intended, mean more particularly, a dipeptide or tripeptide residue prepared via the combination of amino acids.
By “saturated heterocycle” is preferably intended a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4 position by a C
1
-C
6
alkyl or mono- or polyhydroxyalkyl radical as defined above.
By “unsaturated heterocycle” is preferably intended a pyridine, furan or thiophene radical.
The “halogen atoms” are preferably fluorine, chlorine or bromine atoms.
By “aminoalkyl radical is intended a radical preferably having from 1 to 6 carbon atoms, in particular the aminomethyl, 3-aminopropyl and 6-aminohexyl radicals.
By “polyether radical” is intended a radical preferably having from 1 to 6 carbon atoms, in particular the methoxymethoxy, methoxyethoxy, methoxyethoxymethoxy, methoxymethoxyethyl, methoxymethoxypropyl and methoxyhexyloxy radicals.
Lastly, by “alkynyl radical” is intended a radical preferably having from 2 to 6 carbon atoms, in particu
Aulakh C. S.
Burns Doane Swecker & Mathis L.L.P.
Centre International de Recherches Dermatologiques
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