Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-09-04
2000-05-02
Trinh, Ba K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514422, 514444, 514468, 546196, 5462841, 548525, 549 60, 549383, A61K 31455, A61K 3134, C07D30779, C07D31178, C07D40500
Patent
active
060573414
DESCRIPTION:
BRIEF SUMMARY
The present invention relates, as novel and useful industrial products, to biaromatic compounds simultaneously exhibiting a lipophilic unit derived from 1,2,3,4,4a,9b-hexahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran connected to a second aromatic nucleus via a linker containing 3 bonds, The compounds obtained exhibit pharmacological responses of retinoid agonist type, characterized by a marked effect in the fields of cell differentiation and proliferation.
The present invention also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine or else in cosmetic compositions.
As the compounds according to the invention exhibit an activity in cell proliferation and differentiation, they can consequently be used in the topical and systemic treatment of dermatological conditions linked to a disorder of keratinization, dermatological conditions (or others) having an inflammatory, viral and/or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant. These compounds can additionally be used in the treatment of degenerative diseases of the connective tissue, for controlling ageing of the skin, whether photoinduced or chronologic, and treating disorders of cicatrization. Finally, they find an application in the ophthalmological field, in particular in the treatment of corneopathies. Furthermore, the compounds according to the invention can find an application in the field of osteoporosis. Finally, they can generally find an application in the treatment of any disease which is associated with a modification in the expression of the receptors of the superfamily of the nuclear receptors for thyroid and steroid hormones.
They can also be used in cosmetic compositions for body or hair hygiene.
Antagonists of retinoic acid are known comprising a lipophilic part derived from 1,2,3,4,4a,9b-hexahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran and a linker comprising 4 free bonds or bonds included within a ring (EP 708,100 and EP 709,382).
It is also known, to date, that the change from an agonist retinoid structure to antagonist retinoid structure requires the introduction of well defined modifications into the lipophilic part (A. Nadzan, Annual report in medicinal chemistry, 1995, vol. 30, 119; M. Teng, T et al., J. Medicinal Chemistry, 1996, vol. 39, 3035; C. Apfel et al., Proceedings of National Academy of Sciences, USA, 1992, vol. 89, 7129).
The Applicant Company has now just found, surprisingly and contrary to what was established until now, that the modification alone of the linker (chemical unit comprising a sequence containing three bonds, in this case) makes it possible to change from an antagonist activity to an agonist activity, without, furthermore, other modifications.
The compounds according to the invention are represented by the following general formula (I): ##STR2## in which, Ar represents one of the following radicals: ##STR3## R.sub.7 and R.sub.8 being defined hereinbelow, X represents the following bonds of formula (a)-(g), which can be read in both directions: ##STR4##
W and R.sub.7 being defined hereinbelow, radical,
m and n as well as R.sub.3 to R.sub.6 being defined below, radical, R.sub.7 being defined hereinbelow, --CO--R.sub.9 radical, R.sub.9 being defined hereinbelow, radical, 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 r' and r", taken together, form a heterocycle, from 1 to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical, or a sugar or amino acid or peptide residue, being defined hereinabove, radical, mixtures in any proportion and their pharmaceutically acceptable salts.
The pharmaceutically acceptable salts are in particular addition salts with a standard acid or a standard base. When the compounds according to the invention are provided in the form of salts by addition of a base, it concerns sa
REFERENCES:
patent: 5702710 (1997-12-01), Charpentier et al.
patent: 5747530 (1998-05-01), Charpentier et al.
Centre International de Recherches Dermatologiques Galderma
Trinh Ba K.
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