Steroids having 7-oxgen and 17-heteroaryl substitution
View Patent ↗The invention relates to the use of compounds to ameliorate or treat an condition such as a cystic fibrosis, neutropenia or other exemplified conditions. Exemplary compounds that can be used include 3β-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene, 1α,3β-dihydroxy-4α-fluoroandrost-5-ene-17-one, 1α,3β,17β-trihydroxy-4α-fluoroandrost-5-ene, 1β,3β-dihydroxy-6α-bromoandrost-5-ene, 1α-fluoro-3β,12α-dihydroxyandrost-5-ene-17-one, 1α-fluoro-3β,4α-dihydroxyandrost-5-ene and 4α-fluoro-3β,6α,17β-trihydroxyandrostane.
1. A compound having the structure
or a salt thereof, wherein the dotted line is an optional double bond;
R 1 is —OH, ═O, —SH, amide, ester or ether;
R 2 is —OH, ═O, halogen, alkyl, ester or ether;
R 3 is —H, —OH, halogen, alkyl, ester or ether;
R 4 is a heterocycle;
R 5 and R 6 independently are —H, —CH 3 , —C 2 H 5 , —C 3 H 7 , alkyl, —OH, —F, —Cl, —Br or —I;
R 7 is —CH 2 —, —C(halogen) 2 —, CH(α-alkyl), —CH(β-alkyl), —CH(α-OH), —CH(β-OH) or —C(alkyl) 2 ;
R 9 is —CH 2 —, —CH(α-OH), —CH(β-OH) or —C(alkyl) 2 — or R 9 is ═CH— when the optional double bond is present,
R 10A , R 10B , R 10C and R 10D independently are —H, alkyl, —CH 3 , halogen, —SR PR or —OR PR and each R 10A , R 10B , R 10C and R 10D is independently in the α-configuration or the β-configuration; and
R PR independently are —H or a protecting group.
2. The compound of claim 1 wherein the compound has the structure
wherein R 1 is —OH;
R 2 is —OH or —OCH 3 ;
R 3 is —H, a halogen, —O—C(O)CH 3 or —O—C(O)CH 2 CH 3 ;
R 4 is a heterocycle wherein the heterocycle is 1-aziridyl, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-isoindole, 2-isoindoline, 4- morpholine, 9-carbazole or β-carboline.
3. The compound of claim 1 wherein the compound has the structure
wherein R 1 is —OH;
R 2 is —OH or —OCH 3 ;
R 3 is —H, a halogen, —O—C(O)CH 3 or —O—C(O)CH 2 CH 3 ;
R 4 is a heterocycle, wherein the heterocycle is a C-linked heterocycle; and
R 10A , R 10B , R 10C or R 10D is —H, a halogen or —OR PR .
4. The compound of claim 3 wherein the C-linked heterocycle is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl.
5. The compound of claim 4 wherein the compound has the structure
wherein R 1 and R 2 are —OH;
R 3 is —H or —O—C(O)CH 3 ;
R 4 is 3-pyridyl; and
R 10A or R 10B is —H, —OR PR or —F.
6. The compound of claim 1 wherein the compound has the structure
wherein R 1 is —OH;
R 2 is —OH or —OCH 3 ;
R 3 is —H, —O—C(O)CH 3 or —O—C(O)CH 2 CH 3 ;
R 4 is a heterocycle, wherein the heterocycle is an N linked heterocycle;
R 10A , R 10B , R 10C or R 10D independently dependently are −H, a halogen or —OR PR .
7. The compound of claim 6 wherein R 4 is an N-linked heterocycle wherein the N-linked heterocycle is —N-pyrrolidine, —N1-pyrazolone, —N 2 -pyrazolone, —N-imidazolidin-2-one, —N1-imidazole, —N1-4,5-dihydroimidazole, —N-morpholine, —N-piperidine, —N-indole, —N-indoline, —N-quinolidine or —N-1-piperazine, optionally substituted at N4 with optionally substituted alkyl, aryl or heteroaryl.
8. The compound of claim 1 wherein the compound has the structure
9. The compound of claim 8 wherein
R 1 is —OH, ═O or —NH—C(O)CH 3 ;
R 2 is —OH or —OCH 3 ; and
R 3 is —H, —OH, —O—C(O)CH 3 or —O—C(O)CH 2 CH 3 ; and
R 4 is an N-linked heterocycle.
10. The compound of claim 9 , wherein the N-linked heterocycle is —N-pyrrolidine, —N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N-1-imidazole, —N-1-4,5-dihydroimidazole, —N-morpholine, —N-1-pyridine, —N-piperidine or —N-piperazine.
11. The compound of claim 8 wherein
R 1 is —OH, ═O or —NH—C(O)CH 3 ;
R 2 is —OH or —OCH 3 ; and
R 3 is —H, —OH, —O—C(O)CH 3 or —O—C(O)CH 2 CH 3 ; and
R 4 is a C-linked heterocycle.
12. The compound of claim 11 wherein the C-linked heterocycle is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
13. The compound of claim 1 wherein the compound is 3β,7β-dihydroxy-17-(3-pyridyl)-5α-androst-16-ene.
14. A pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients and a compound according to claim 1 .