US 10,377,791 B2 · Therapeutically active estratrienthiazole derivatives as inhibitors of 17 B-hydroxysteroid dehydrogenase, type 1

Abstract

The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof wherein R1 to R6 are as defined in the claims. The invention further relates to their use as inhibitors of 17β-HSD and in treatment or prevention of steroid hormone de-pendent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of the 17β-HSD1 enzyme and/or requiring the lowering of the endogenous estradiol concentration. The present invention also relates to the preparation of the aforementioned compounds and to pharmaceutical compositions comprising as an active ingredient(s) one or more of the aforementioned compounds or pharmaceutically acceptable salts thereof.

Claims16

Dependent claims

A compound of formula (Ih)

wherein
(i) R1 is selected from the group consisting of H, NO2, OH, and N(R′)2;
(ii) R2 and R4 are each independently selected from the group consisting of H, halogen, C1-6-alkyl, C1-3-haloalkyl, C1-3-perhaloalkyl, CN, NO2, N3, N(R′)2, (CH2)nN(R′)2, OR′, (CH2)nOR′, CO2R′, CONHR′, NHCOR″, C(═NH)R″, C(═N—OH)R″ and COR″;
R′ is H or C1-6-alkyl, C1-3-haloalkyl, or C1-3-perhaloalkyl, or when part of any N(R′)2 both R's together with the nitrogen they are attached to may form an 5 to 6 membered aliphatic or aromatic heterocyclic ring comprising 1 or 2 heteroatoms each independently selected from N and 0;
R″ is C1-6-alkyl, C1-3-haloalkyl, or C1-3-perhaloalkyl;
and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.

5 more elements

A compound selected from the group consisting of:

Compound 46 3-((7aS,10R)-7a-methyl-8-oxo-6,7,7a,8,9,10,10a,10b,11,12-decahydro-5bH-cyclopenta[7,8]phenanthro[1,2-d]oxazol-10-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 47 3-((3R,12aS)-12a-methyl-1-oxo-2,3,3a,3b,4,5,10b,11,12,12a-decahydro-1H-cyclopenta[7,8]phenanthro[3,2-d]oxazol-3-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 48 3-((3R,12aS)-8,12a-dimethyl-1-oxo-2,3,3a,3b,4,5, 10b,11, 12,12a-decahydro-1H-cyclopenta[7, 8]phenanthro[3,2-d]oxazol-3-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 49 3-((7aS,10R)-2,7a-dimethyl-8-oxo-6,7,7a,8,9,10,10a,10b,11,12-decahydro-5bH-cyclopenta[7,8]phenanthro[1,2-d]oxazol-10-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 50 3-((3R,12aS)-12a-methyl-1,8-dioxo-2,3,3a,3b,4,5,8,9,10b,11,12,12a-dodecahydro-1H-cyclopenta[7,8]phenanthro[3,2-d]oxazol-3-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 51 3-((7aS,10R)-7a-methyl-2,8-dioxo-2,5b,6,7,7a,8,9,10,10a,10b,11,12-dodecahydro-1H-cyclopenta[7,8]phenanthro[1,2-d]oxazol-10-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 77 3-((3R,12aS)-6-chloro-12a-methyl-1-oxo-2,3,3a,3b,4,5,10b,11,12,12a-decahydro-1H-cyclopenta[7,8]phenanthro[3,2-d]oxazol-3-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 78 3-((3R,12aS)-6-fluoro-12a-methyl-1-oxo-2,3,3a,3b,4,5,10b,11,12,12a-decahydro-1H-cyclopenta[7,8]phenanthro[3,2-d]oxazol-3-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 83 3-((13S,15R)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 84 3-((13S,15R)-13-methyl-2-nitro-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl) propanamide;
Compound 85 3-((13S,15R)-13-methyl-4-nitro-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl) propanamide;
Compound 86 3-((13S,15R)-2-fluoro-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 87 3-((13S,15R)-2-amino-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 88 3-((13S,15R)-2-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 89 3-((13S,15R)-4-amino-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 90 3-((13S,15R)-4-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
Compound 94 3-((13S,15R)-4-hydroxy-13-methyl-1-nitro-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
and
Compound 105 3-((13S,15R)-4-(tert-butyl)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide;
or a pharmaceutically acceptable salt thereof.

17 more elements

Dependencies are inferred from the claim text.

Therapeutically active estratrienthiazole derivatives as inhibitors of 17 B-hydroxysteroid dehydrogenase, type 1

Life of this patent

Therapeutically active estratrienthiazole derivatives as inhibitors of 17 B-hydroxysteroid dehydrogenase, type 1

Life of this patent

Abstract

Claims16