Propionamide derivatives useful as androgen receptor modulators
Compounds of formula (I) wherein R1 to R4, X and A are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are useful in hormonal therapy, e.g., in the treatment or prevention of male hypogonadism and age-related conditions such as andropause.
1. A compound of formula (I)
wherein
R1 is (C 1 -C 7 )alkyl, hydroxy(C 1 -C 7 )alkyl or —(CH 2 ) n —CHO, wherein n is 0-6;
R2 is nitro, cyano or halogen;
R3 is hydrogen, (C 1 -C 7 )alkyl or halo(C 1 -C 7 )alkyl;
R4 is hydrogen, (C 1 -C 7 )alkyl, COR 10 or SO 2 R 13 ;
X is O or NH;
A is a group selected from:
wherein R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from hydrogen, halogen, nitro, cyano, (C 1 -C 7 )alkyl, halo(C 1 -C 7 )alkyl, cyano(C 1 -C 7 )alkyl, amino, mono- or di(C 1 -C 7 )alkylamino, amino(C 1 -C 7 )alkyl, hydroxy(C 1 -C 7 )alkyl, (C 1 -C 7 )alkoxy(C 1 -C 7 )alkyl, —NHCOR 10 , —N(COR 10 ) 2 , —COR 11 , —OR 12 , —OSO 2 R 13 , —SO 2 R 14 , —NHSO 2 R 13 , SR 15 and an imide ring; or
R 5 and R 6 , R 6 and R 7 , R 7 and R 8 , or R 8 and R 9 form, together with any of the ring atom(s) to which they are attached, a condensed 5 to 7 membered aliphatic or aromatic carbocyclic ring or a condensed 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from N, O and S;
R 10 and R 11 are independently selected from (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl, amino(C 1 -C 7 )alkyl, mono- or di(C 1 -C 7 )alkylamino(C 1 -C 7 )alkyl, (C 6 -C 10 )aryl, —N(R 16 ) 2 and —OR 17 ;
R 12 and R 15 are independently selected from hydrogen, (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl, amino(C 1 -C 7 )alkyl, mono- or di(C 1 -C 7 )alkylamino(C 1 -C 7 )alkyl, (C 6 -C 10 )aryl, and —COR 18 ;
R 13 and R 14 are independently selected from (C 1 -C 7 )alkyl or (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl and (C 6 -C 10 )aryl;
R 16 and R 17 are independently selected from hydrogen, (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl, amino(C 1 -C 7 )alkyl and (C 6 -C 10 )aryl;
R 18 is (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl or (C 6 -C 10 )aryl;
R 19 and R 20 are independently selected from hydrogen, halogen, (C 1 -C 7 )alkyl and (C 2 -C 7 )alkenyl;
and wherein each aryl or ring residue defined above may be substituted;
or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1 , wherein R 4 is hydrogen and R 3 is methyl.
3. A compound according to claim 1 , wherein X is O.
4. A compound according to claim 1 , wherein R 1 is methyl or hydroxymethyl and R 2 is nitro or cyano.
5. A compound according to claim 1 , wherein R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from hydrogen, halogen, nitro, cyano, (C 1 -C 7 )alkyl, (C 1 -C 7 )alkoxy, halo(C 1 -C 7 )alkyl, hydroxy(C 1 -C 7 )alkyl and —NHCOR 10 , wherein R 10 is (C 1 -C 7 )alkyl, halo(C 1 -C 7 )alkyl, hydroxy or (C 1 -C 7 )alkoxy.
6. A compound according to claim 5 , wherein at least one of R 5 , R 6 , R 7 , R 8 and R 9 is a halogen.
7. A compound according to claim 6 , wherein at least two of R 5 , R 6 , R 7 , R 8 and R 9 are selected from halogen, cyano and acetamido.
8. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.
9. A method of hormonal therapy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in claim 1 .
10. A method for the treatment of an androgen receptor dependent condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in claim 1 .
11. A method according to claim 9 , comprising administering a therapeutically effective amount of the compound orally.