Antagonist or reverse RAR agonist for use in the treatment of side effects of chemotherapy and / or radiation therapy

摘要

A retinoic acid receptor (RAR) antagonist or an inverse RAR agonist that binds to receptors of the RARα, RARß and RARγ subtypes, to be used in the treatment of chemotherapy side effects and / or radiation therapy in a mammal undergoing chemotherapy and / or radiation therapy, in which the side effects are neutropenia, leukopenia or thrombocytopenia, in which the RAR antagonist or inverse RAR agonist has the chemical structure according to formula (I): ** Formula ** or a pharmaceutically acceptable salt thereof; in which X is S, O, NR in which R is H or alkyl of 1 to 6 carbon atoms, or X is [C (R1) 2] n in which R1 is independently H or an alkyl of 1 to 6 atoms of carbon and n is an integer between 0 and 2, both included; R2 are independently hydrogen, an alkyl of 1 to 6 carbon atoms, F, Cl, Br, I, CF3, fluorosubstituted alkyl of 1 to 6 carbon atoms, OH, SH, alkoxy of 1 to 6 carbon atoms or alkylthio of 1 to 6 carbon atoms; R3 are independently hydrogen, alkyl of 1 to 6 carbon atoms or F; m is an indicator that has the value of 0-3; n is an integer that has the value of 0-4; or is an integer that has the value of 0-3; Z is -CONR1-, -CSNR1-, -NR1CO-, -NR1-CS-, -C≡C-, -C = C-, -N = N-, -N = CR1-, -CR1 = N-, -COO-, -OCO-; -BEAR-; -OCS- or - (CR1 = CR1) n'-, in which n 'is an integer from 0 to 5; Y is a phenyl or naphthyl group, or a heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, the phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or when Z is - (CR1 = CR1) n'- and n 'is 3, 4 or 5, then Y represents a direct valence link between said group (CR2 = CR2) n' and B; A is (CH2) q in which q is 0-5, a branched chain alkyl having 3 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms and 1 or 2 double bonds, alkynyl having 2-6 carbon atoms and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, CH2OH, CH2OR11, CH2OCOR11, CHO, CH (OR12) 2, CHOR13O, -COR7, CR7 (OR12) 2, CR7OR13O, or a tri-alkylsilyl in that the alkyl groups have 1 to 6 carbon atoms; R7 is an alkyl, cycloalkyl or alkenyl group containing from 1 to 5 carbon atoms; R8 is an alkyl group of 1 to 10 carbon atoms or time-silylalkyl in which the alkyl group has 1 to 10 carbon atoms, a cycloalkyl group of 3 to 10 carbon atoms, phenyl or a lower alkylphenyl; in which the alkyl group has 1 to 6 carbon atoms; R9 and R10 are independently hydrogen, an alkyl group of 1 to 10 carbon atoms, a cycloalkyl group of 3 to 10 carbon atoms, phenyl or a lower alkylphenyl in which the alkyl group has 1 to 6 carbon atoms; R11 is an alkyl of 1 to 6 carbon atoms, phenyl or alkylphenyl in which the alkyl group has 1 to 6 carbon atoms; R12 is an alkyl of 1 to 6 carbon atoms; R13 is a divalent alkyl radical of 2 to 5 carbon atoms; R14 is (R15) r-phenyl, (R15) r-naphthyl or (R15) r-heteroaryl in which the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N and r is a number integer that has the values of 0-5; and R15 is independently H, F, Cl, Br, I, NO2, N (R8) 2, N (R8) COR8, NR8CON (R8) 2, OH, OCOR8, OR8, CN, an alkyl group having from 1 to 10 carbon atoms, a fluorosubstituted alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms and 1 to 3 double bonds, an alkynyl group having 2 to 10 atoms of carbon and 1 to 3 triple bonds or a trialkylsilyl or trialkylsilyloxy group in which the alkyl groups independently have 1 to 6 carbon atoms.