COMPOSITIONS CONTAINING COMPOUNDS HAVING RETINOID-LIKE ACTIVITY AND REDUCED SKIN TOXICITY EFFECTS AND SOME SUCH NOVEL COMPOUNDS

摘要

A pharmaceutical composition for treating or preventing one or more of the diseases and conditions selected from the group consisting of dermatoses, malignant hyperproliferative diseases, atherosclerosis and restenosis resulting from neointimal hyperproliferation, non-malignant hyperproliferative diseases, autoimmune diseases, immunological disorders, chronic inflammatory diseases, diseases associated with lipid metabolism and transport such as dyslipidemias, dry eye syndrome, for promoting wound healing, and for reversing and preventing the effect of sun damage to skin, containing an effective dose of a compound of the formula 11 ז' באייר התשס" א - April 30, 2001 where the symbols are defined as follows: R1 is lower alkyl, Cl, Br, or I; R2 is H, lower alkyl, Cl, Br, or I; R3 is lower alkyl, Cl, Br, I, OR11, SR11, OCOR11, SCOR11, NH2, NHR11, N(R11)2, NHCOR11, or NR11- COR11; R5 and R6 independently are H, lower alkyl, Cl, Br, I, lower alkoxy or lower alkyltho of 1 to 6 carbons; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7 (OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R11 is alkyl of 1 to 10 carbons, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2 - 5 carbons; X1 is CR5 or N, and in case X1 is N it can be located in any unsubstituted position of the 6-membered aromatic ring; Y is phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, imidazolyl and oxazolyl, with the proviso that when the compound has formula (I) then Y is not phenyl, A and Z are as defined in the specification, X1 is O, S, or NR15 and R15 is H or lower alkyl; the dashed circle in the 6 membered ring of formula (II) indicates the presence of two double bonds in the 5 membered ring, and X3 is O, S, NH or N-lower alkyl, and the X3 group can be located in any unsubstituted position of the 5-membered aromatic ring. Claimed as novel are the compounds of the formula: 12 ז' באייר התשס" א - April 30, 2001 where Y2 is thienyl, furyl or pyridyl; L1 and L2 are H or lower alkyl with the proviso that both are not H; or L1 and L2 jointly comprise -C(R20R20) - CH2-C (R20R20)-X4- and thereby form a heterocyclic ring condensed with the aromatic ring, or L1 and L2 jointly comprise - C(R20R20) - CH2-CH2-C(R20R20)- and thereby form a ring condensed with the aromatic ring; X4 is S, O, NH or N-lower alkyl, and R20 is independently H or lower alkyl, with the proviso that when L1 and L2 jointly comprise -C(R20R30) -CH2-CH2-C(R20R20) then Y2 is not phenyl.