| 摘要 |
<p>#CMT# #/CMT# Biaromatic compounds (I) and their salts, solvates and/or hydrates, are new. #CMT# : #/CMT# Biaromatic compounds of formula (I) and their salts, solvates and/or hydrates, are new. R1 : -OR6, -NR6-OR6 or -NR6R6; R2 : halo, 1-12C alkyl, -OR7, -NHR7 or aralkyl; R3 : 1-12C alkyl, 3-12C cycloalkyl or -(CH 2) mR8; X : -(CH 2) z-NR9-C(Y1)-(NR10) w-; m : 0-4; Y1 : S or O; z, w : 0-1; Ar1, Ar2 : aromatic radical (optionally substituted by R4 or R5) such as Ar1 is 1,3-diphenyl, pyridin-2,6-diyl, pyridin-2,4-diyl, pyridin-3,5-diyl, pyrimidin-2,4-diyl, pyrazin-2,6-diyl or pyrimidin-4,6-diyl and Ar2 may also be 1,4-diphenyl, pyridin-2,5-diyl, pyrimidin-2,5-diyl or pyrazin-2,5-diyl; R4, R5 : H, halo, 1-12C alkyl, OH, alkoxy, polyether, aralkyl, aryl or amino (optionally substituted by 1-2 radicals of 1-12C alkyl or aralkyl); R6 : H, 1-7C alkyl, aryl or aralkyl; R7 : H, 1-7C alkyl, aryl or aralkyl; R8 : 1-7C alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl, -OR11 or optionally substituted amino; R9, R10 : H or1-4C alkyl; and R11 : H, 1-7C alkyl, aryl or aralkyl. Independent claims are included for (1) a composition comprising (I) and an excipient; (2) a cosmetic composition comprising (I) in a support; and (3) the preparation of (I). #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Antiinflammatory; Dermatological; Antiseborrheic; Antipsoriatic; Antirheumatic; Antiallergic; Respiratory-Gen; Cytostatic; Virucide; Immunosuppressive; Nootropic; Anorectic; Metabolic; Cardiovascular-Gen.; Antiarthritic; Endocrine-Gen; Antiasthmatic; Immunostimulant; Immunomodulator; Antidiabetic; Neuroprotective; Antiarteriosclerotic; Hypotensive. #CMT#MECHANISM OF ACTION : #/CMT# Peroxisome proliferator-activated receptor (PPAR) modulator. The potency of (I) in modulating PPAR receptor was tested in HeLN cells and was determined using the luminescence produced. The result showed that (Z)-2-ethoxy-3-{3'-[(methyl-octanoyl-amino)-methyl] -biphenyl-4-yl}-acrylic acid exhibited an apparent binding constant of 2000 nM. #CMT#USE : #/CMT# (I) are useful for personal or capillary hygiene to control and/or restore the cutaneous lipids metabolism. (I) are useful to treat: dermatological diseases related to a disorder of keratinization relating differentiation and proliferation, particularly in acnes like vulgaris, comedonian, polymorphic, rosacea, nodulocystic, senile, conglobata, secondary acnes such as the solar, medicamentous or professional acne; ichtyosis, ichtyosiform states, Darrier's disease, Palmoplantar keratodermas, leucoplasias and leucoplasiform state, cutaneous or mucous lichen (oral); dermatological diseases with an inflammatory immuno-allergic component, with or without cellular proliferation disorder, in particular cutaneous, mucous or ungual psoriasis, psoriatic rheumatism, cutaneous atopy e.g. eczema, respiratory atopy or gingival hypertrophy; dermic/epidermic (viral) benign or malignant proliferations, particularly verruca vulgaris, plane warts, epidermodysplasia verruciform or oral papillomatous or floridous T-cells lymphoma; proliferations susceptible to be induced by UV e.g. basal and spinocellulars Epithelioma; cutaneous precancerous lesions e.g. keratoacanthoma; immune dermatoses e.g. lupus erythematosus; bullous immune diseases; collagen diseases e.g. scleroderma; dermatological or general diseases with immunological component; cutaneous disorders due to UV exposure, skin aging, chronological or photo-induced or pigmentations and actinic keratosis or pathologies associated to chronological or actinic aging e.g. xerosis; sebaceous function disorders hyperseborrhea, simple seborrhea or seborrheic dermatitis; cicatrization or stretch marks disorders; pigmentation disorders e.g. hyperpigmentation, melasma, hypopigmentation or vitiligo; lipid metabolism diseases e.g. obesity, hyperlipidemia non-insulino-dependent diabetes or syndrome X; inflammatory diseases e.g. arthritis; cancerous or precancerous states; alopecia of different origin e.g. alopecia due to chemotherapy or radiations; immune system disorders e.g. asthma, type I sugar diabetes, multiple sclerosis and immune system dysfunctioning; and cardiovascular system diseases e.g. arteriosclerosis or hypertension (all claimed). #CMT#ADVANTAGE : #/CMT# (I) exhibit good activity and pharmaceutical properties. (I) can be easily synthesized. The measurement of bioconversion and toxicity of the enantiomer, are not necessary. The measurement of the enantiomeric purity on the synthesis intermediates and the finished product, is also not necessary. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of (I) comprises: (a) deprotection of a biaryl compound of formula (II), (b) reaction with an isocyanate (when Y1 is O) or a thioisocyanate (when Y1 is S), or alternatively a reaction with nitrophenylchloroformate followed by a reaction with an amine for the compounds in which R12 is -NR9G, (c) an addition by a carboxylic acid halide (when Y1 is O) or a thiocarboxylic acid halide (when Y1 is S) for the compounds for which R12 is -CH 2NR9G; (d) optionally, a saponification reaction of the obtained compounds in the presence of sodium hydroxide e.g. in a mixture of tetrahydrofuran, methanol and water; (e) optionally, a treatment of the obtained compounds with oxalyl chloride followed by a reaction with hydroxylamine or O-substituted hydroxylamine. R16 : -NR9G or -CH 2NR9G; and G : amino or hydrogen protective group. Preferred Components: The amount of is 0.001-10 wt.% in pharmaceutical composition and 0.001-3 wt.% in cosmetic composition. #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Preferred Definitions: R1 : -OH; R2 : 1-4C alkyl, -OR7- or F; R7 : 1-4C alkyl; R3 : 3-8C (cyclo)alkyl, cycloalkyl, -(CH 2) m-R8; R8 : phenyl optionally substituted by CH 3 or CF 3; m : 0-2; X : -NR9-C(Y1)-NR10- or -CH 2-NR9-C(Y1)-; R9 : CH 3; R10 : H; Y1 : O; R4 : H, 1-7C alkoxy or polyether; and R5 : H. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 0.0001-100 mg/kg/day, enterally, parenterally, topically or ocularly. #CMT#SPECIFIC COMPOUNDS : #/CMT# 81 Compounds (I) are specifically claimed e.g. (Z)-2-ethoxy-3-{3'-[(methyl-octanoyl-amino)-methyl] -biphenyl-4-yl}-acrylic acid of formula (Ia), (Z)-2-ethoxy-3-{4[6(3-heptyl-1-methyl-ureido)-pyridin-2-yl]-phenyl}-acrylic acid, (Z)-2-ethoxy-3-{4[6(1-methyl-3-pentyl-ureido)-pyridin-2-yl]-phenyl}-acrylic acid, (Z)-2-ethoxy-3- {6[3(3-heptyl-1-methyl-ureido)-phenyl]-pyridin-3-yl}-acrylic acid hydrochloride and (E)-S-3-[3'-(3-heptyl-1-methyl-ureido)-biphenyl-4-yl]-2-methyl-acrylic acid. #CMT#EXAMPLE : #/CMT# Aqueous solution of lithium hydroxide (2.1 ml) was added to a solution of 2-ethoxy-3-{3'-[(methyl-octanoyl-amino)-methyl]-biphenyl-4-yl}-ethyl acrylate (0.64 g) in tetrahydrofuran (15 ml). The reaction mixture was agitated at 68[deg]C for 24 hours. The reaction mixture was further worked up to obtain (Z)-2-ethoxy-3-{3'-[(methyl-octanoyl-amino)-methyl]-biphenyl-4-yl}-acrylic acid (0.48 g; 80%).</p> |
