Retinoid antagonists and uses thereof
AssigneeBristol-Myers Squibb Company
InventorsKenneth M. Tramposch, Xina Nair, Anne Marinier, Fred Christopher Zusi
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Abstract
Retinoid antagonist compounds have been found to be useful in the prevention and/or minimization of surgical adhesion formation. Also provided by the invention are certain novel substituted (5,6)-dihydronaphthalenyl compounds which are retinoid antagonists and possess the above-mentioned property in addition to their use as antiinflammatory agents for chronic skin inflammatory diseases, as agents for the treatment of rheumatic diseases and as agents for the treatment of various tumors as well as non-malignant proliferative skin conditions.
Claims8
A method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering to an animal host an effective amount of a retinoic acid antagonist for a period of time sufficient to permit tissue repair, wherein the retinoic acid antagonist is a compound of the formula
- or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which
- X is —O—CO—, —NH—CO—, —CS—NH, —CO—O—, —CO—NH—, —COS—, —SCO—, —SCH2—, —CH2—CH2—, —C(C—, —CH2—NH—, —COCH2—, —NHCS—, —CH2S—, —CH2O—, —OCH2—, —NHCH2— or —CR5═CR6—;
- Rm and Rk are independently hydrogen, halogen, C1-6 alkyl, hydroxy, C1-6 alkyloxy or nitro;
- n is zero or one;
- A is —NH(CH2)m—, —S—, —SO—, —SO2—, —O—, —C(C—, —CR8R9, —CR8═CR9—, phenyl, phenyl substituted by a C1-6 alkyl, C1-6 alkoxy, halogen, CO2R8, —(CH2)mOR8, —(CH2)mNR9R8, or —COR10 group, naphthyl, naphthyl substituted by a C1-6 alkyl, C1-6 alkoxy, halogen, CO2R8, —(CH2)mOR8, —(CH2)mNR8R9 or —COR10, or heteroaryl;
- Q is phenyl, naphthyl or heteroaryl, said phenyl, naphthyl or heteroaryl group being optionally substituted by one to three same or different C1-6 alkyl, C1-6 fluoroalkyl, C1-6 alkoxy, halogen, CO2R11, —(CH2)qOR11, —(CH2)qNR11R12, —NHCOR13 or —COR13 with the proviso that when A is —S—, —SO—, —SO2— or —O—, then Q is a phenyl, naphthyl or heteroaryl group substituted by one to three halogen, C1-6 fluoroalkyl, CO2R11, —(CH2)qOR11, —(CH2)qNR11R12, —NHCOR13 or —COR13;
- R5 and R6 are each independently hydrogen or C1-6 alkyl;
- R8 and R9 are each independently hydrogen or C1-6 alkyl;
- R10 and R13 are each independently hydrogen, C1-6 alkyl or C1-6 fluoroalkyl;
- R11 and R12 are each independently hydrogen or C1-6 alkyl;
- Ra and Rb are independently hydrogen or C1-6 alkyl;
- but when n is one, Ra and Rb together can form a radical of the formula
- Z is hydrogen, C1-6 alkyl, benzyl, p-methoxybenzyl, allyl or trimethylsilylethyl;
- m and q are independently 0 to 2;
- p is 0 or 1 with the proviso that when p is 0 then Q is phenyl, naphthyl or heteroaryl substituted by one to three —(CH2)qOR11, —(CH2)qNR11R12, or —COR13;
- R2 and R3 are each independently hydrogen or C1-6 alkyl;
- R1 is —CO2Z, C1-6 alkyl, —CH2OH, —CONHR7 or CHO;
- R7 is hydrogen or C1-6 alkyl;
- provided that when X is —C≡C—, A is not —CR8═CR9— or —C≡C—.
A method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering to an animal host an effective amount of a retinoic acid antagonist for a period of time sufficient to permit tissue repair, wherein the retinoic acid antagonist is a compound of the formula
- wherein (a) R is and X is (b) R is and X is (c) R is and X is (d) R is and X is (e) R is and X is (f) R is and X is (g) R is and X is (h) R is and X is (i) R is and X is (j) R is and X is (k) R is and X is (l) R is and X is (m) R is and X is (n) R is and X is (o) R is and X is (p) R is and X is (q) R is and X is (r) R is and X is or (s) R is and X is
A method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering to an animal host an effective amount of a retinoic acid antagonist for a period of time sufficient to permit tissue repair, said retinoic acid antagonist having the formula
- or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which
- X is —O—CO—, —NH—CO—, —CS—NH, —CO—O—, —CO—NH—, —COS—, —SCO—, —SCH2—, —CH2—CH2—, —C—C, —CH2—NH—, —COCH2—, —NHCS—, —CH2S—, —CH2O—, —OCH2—, —NHCH2— or —CR5═CR6—;
- Rm and Rk are independently hydrogen, halogen, C1-6 alkyl, hydroxy, C1-6alkyloxy or nitro;
- n is zero or one;
- R4 is —(CH2)t—Y;
- R1 is —CO2Z, —C1-6 alkyl, CH2OH, —CONHRy or CHO;
- R2 and R3 are independently hydrogen or C1-6 alkyl;
- Ra and Rb are independently hydrogen or C1-6 alkyl;
- but when n is one, Ra and Rb together can form a radical of the formula
- Y is phenyl or naphthyl and both radicals can be optionally substituted with one to three same or different C1-6 alkyl or halogen groups;
- Z is hydrogen or C1-6 alkyl;
- R5, R6 and Ry are independently hydrogen or C1-6 alkyl;
- and
- t is zero to six.
Dependencies are inferred from the claim text.