IP Library › Granted Patent US 12,503,484
Granted Patent B2
US 12,503,484 · App. 17/640,294 · Granted Dec 23, 2025

Androstane derivatives with activity as pure or predominantly pure stimulators of SERCA2a for the treatment of heart failure

Inventors: Alberto Cerri (Milan, IT); Patrizia Ferrari (Varese, IT); Mara Ferrandi (Milan, IT); Paolo Barassi (Castelvaccana, IT); Giusseppe Bianchi (Milan, IT); Shih-Che Hsu (Taipai, TW); Francesco Peri (Milan, IT); Antonio Zaza (Milan, IT); Marcella Rocchetti (Brugherio, IT); Andrea Luraghi (Cerrro Maggiore, IT); Eleonora Torre (Desio, IT); Carlotta Ronchi (Milan, IT)
Assignee: Seismic Pharmaceuticals
C07J1/0011A61K45/06
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Quick Facts
Patent No.
US 12,503,484
App. No.
17/640,294
Granted
Dec 23, 2025
Kind
B2
Abstract

Compounds and compositions for the activation of SERCA2a are disclosed. In particular, provided are compounds that act as predominantly pure or pure SERCA2a activators while only moderately inhibiting the Na + /K + ATPase. In general, the disclosed compounds are derivatives of androstane having the formula (I). Also disclosed herein are pharmaceutical compositions comprising one or more of the compounds of formula (I) for use for the treatment of heart failure.

Claims (115)

1 . A compound having a formula (I)

wherein:

X is selected from the group consisting of a carboxylic acid, carboxylic ester or a bioisoster thereof, primary alcohol, ester, and an amine group, wherein the bioisoster consists of a sulfate, sulfonic acid, phosphate, phosphonate, or a nitrogen-containing heterocyclic ring;

n is 1, 2, 3, 4, or 5;

a C3-C1′ dashed line represents an optional exocyclic double bond C═C at position C3-C1′;

a C2-C3 dashed line represents an optional endocyclic double bond C═C;

Y at C6 is a hydroxyl (OH) in the alpha- or beta-configuration or a hydroxymethyl (CH 2 OH) in the alpha-configuration;

Z at C7 is a —H or —OH in an alpha-configuration or a ketone, wherein a dashed line represents an optional carbonyl group (C═O) at Z; or

a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2 . The compound of claim 1 , wherein X is selected from the group consisting of a carboxylic acid, carboxylic ester, primary amine, secondary amine, and cyclic amine.

3 . The compound of claim 1 , wherein X is a carboxylic acid or a carboxylic ester.

4 . The compound of claim 1 , which is selected from the group consisting of:

(E)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(E)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(E)-3-[2-(azetidin-3-yl) ethyliden]-6alpha-hydroxyandrostane-17-one;

(Z)-3-[2-(azetidin-3-yl) ethyliden]-6alpha-hydroxyandrostane-17-one;

(E)-3-(4-aminobutyl)-6alpha-hydroxyandrost-2-ene-17-one hydroiodide;

3-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxyandrost-2-ene-17-one hydroiodide;

(E,Z)-3-(4-aminobutyliden)6alpha-hydroxyandrostane-17-one;

(E)-3-[2-(piperidin-4-yl)ethyliden]-6alpha-hydroxyandrostane-17-one;

(Z)-3-[2-(piperidin-4-yl)ethyliden]-6alpha-hydroxyandrostane-17-one;

3beta-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxyandrostane-17-one;

Ethyl (6alpha-hydroxy-17-ketoandrostane-3beta-yl) acetate;

4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyric acid;

4-(6beta-hydroxy-17-oxoandrostane-3-yl) butyric acid;

2-(6beta-hydroxy-17-oxoandrostane-3-yl) acetic acid;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyrate;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) caproate;

6-(6beta-hydroxy-17-oxoandrostane-3-yl) caproic acid;

(E,Z)-3-(5-N-methylaminopentyliden)-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-[2-(pyrrolidine-3yl) ethyliden]-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-[2-(azetidine-3-yl) ethyliden]-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-[2-(piperidin-4-yl)ethyliden]-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-(5-N-methylaminopentyliden)-6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one;

3beta-[2-(azetidine-3-yl)ethyl]-6alpha-hydroxymethylandrostane-7,17-dione;

3beta-[2-(azetidine-3-yl)ethyl]-6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one;

3beta-[2-(pyrrolidine-3yl)ethyl]-6alpha-hydroxymethylandrostane-7,17-dione;

3beta-[2-(pyrrolidine-3yl)ethyl]6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one;

3beta-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxymethylandrostane-7,17-dione; and

3beta-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one.

5 . The compound of claim 1 , which is selected from the group consisting of:

(E)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(E)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

Ethyl (6alpha-hydroxy-17-ketoandrostane-3beta-yl) acetate;

4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyric acid;

4-(6beta-hydroxy-17-oxoandrostane-3-yl) butyric acid;

2-(6beta-hydroxy-17-oxoandrostane-3-yl) acetic acid;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyrate;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) caproate; and

6-(6beta-hydroxy-17-oxoandrostane-3-yl) caproic acid.

6 . The compound of claim 1 , selected from the group consisting of 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyric acid and 2-(6beta-hydroxy-17-oxoandrostane-3-yl) acetic acid.

7 . The compound of claim 1 , wherein the pharmaceutically acceptable salt is selected from chloride, bromide, sulfate, phosphate, nitrate, fumarate, succinate, oxalate, malate, tartrate, maleate, citrate, methanesulfate, and benzoate.

8 . A pharmaceutical composition comprising the compound of claim 1 , in combination with at least one pharmaceutically acceptable vehicle and/or excipient.

9 . The pharmaceutical composition of claim 8 , formulated for intravenous injection, intramuscular injection, enteral administration, parenteral administration, or inhalation.

10 . The pharmaceutical composition of claim 8 , formulated for oral administration.

11 . The pharmaceutical composition of claim 8 , administered at a dose of between about 1 mg/kg and about 20 mg/kg, or between about 1 mg/kg and about 10 mg/kg.

12 . The pharmaceutical composition of claim 8 , further comprising one or more additional therapeutically active ingredients selected from the group consisting of CE inhibitors, AIRBs, diuretics, Ca 2+ channel blockers, β-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, activators of the soluble guanylate cyclase (sGC), and beta-arrestin ligand of angiotensin II receptor.

13 . A method of treating an individual having heart failure, the method comprising the steps of:

(1) providing an individual having heart failure;

(2) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) the compound of claim 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and

(3) measuring one or more parameters of heart function;

wherein the administering of the pharmaceutical composition results in an improvement in heart function.

14 . The method of claim 13 , wherein the compound is selected from the group consisting of:

(E)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(E)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(E)-3-[2-(azetidin-3-yl) ethyliden]-6alpha-hydroxyandrostane-17-one;

(Z)-3-[2-(azetidin-3-yl) ethyliden]-6alpha-hydroxyandrostane-17-one;

(E)-3-(4-aminobutyl)-6alpha-hydroxyandrost-2-ene-17-one hydroiodide;

3-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxyandrost-2-ene-17-one hydroiodide;

(E,Z)-3-(4-aminobutyliden)-6alpha-hydroxyandrostane-17-one;

(E)-3-[2-(piperidin-4-yl)ethyliden]-6alpha-hydroxyandrostane-17-one;

(Z)-3-[2-(piperidin-4-yl)ethyliden]-6alpha-hydroxyandrostane-17-one;

3beta-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxyandrostane-17-one;

Ethyl (6alpha-hydroxy-17-ketoandrostane-3beta-yl) acetate;

4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyric acid;

4-(6beta-hydroxy-17-oxoandrostane-3-yl) butyric acid;

2-(6beta-hydroxy-17-oxoandrostane-3-yl) acetic acid;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyrate;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) caproate;

6-(6beta-hydroxy-17-oxoandrostane-3-yl) caproic acid;

(E,Z)-3-(5-N-methylaminopentyliden)-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-[2-(pyrrolidine-3yl) ethyliden]-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-[2-(azetidine-3-yl) ethyliden]-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-[2-(piperidin-4-yl)ethyliden]-6alpha-hydroxymethylandrostane-7,17-dione;

(E,Z)-3-(5-N-methylaminopentyliden)-6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one;

3beta-[2-(azetidine-3-yl)ethyl]-6alpha-hydroxymethylandrostane-7,17-dione;

3beta-[2-(azetidine-3-yl)ethyl]-6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one;

3beta-[2-(pyrrolidine-3yl)ethyl]-6alpha-hydroxymethylandrostane-7,17-dione;

3beta-[2-(pyrrolidine-3yl)ethyl]6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one;

3beta-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxymethylandrostane-7,17-dione; and

3beta-[2-(piperidin-4-yl)ethyl]-6alpha-hydroxymethyl-7alpha-hydroxyandrostane-17-one.

15 . The method of claim 14 wherein the compound is selected from the group consisting of:

(E)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6alpha-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(E)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

(Z)-4-(6beta-hydroxy-17-oxoandrostane-3-yliden) butyric acid;

Ethyl (6alpha-hydroxy-17-ketoandrostane-3beta-yl) acetate;

4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyric acid;

4-(6beta-hydroxy-17-oxoandrostane-3-yl) butyric acid;

2-(6beta-hydroxy-17-oxoandrostane-3-yl) acetic acid;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) butyrate;

Ethyl 4-(6alpha-hydroxy-17-oxoandrostane-3-yl) caproate; and

6-(6beta-hydroxy-17-oxoandrostane-3-yl) caproic acid.

16 . The method of claim 13 , wherein the pharmaceutical composition is administered orally.

17 . The method of claim 16 , wherein the pharmaceutical composition is administered at a dose of between about 1 mg/kg and about 20 mg/kg, or between about 1 mg/kg and about 10 mg/kg.

18 . The method of claim 13 , wherein the pharmaceutical composition is administered intravenously.

19 . The method of claim 18 , wherein the pharmaceutical composition is administered at a dose of between about 0.125 mg/kg and about 10 mg/kg.

20 . The method of claim 13 , wherein the pharmaceutical composition comprises one or more additionally therapeutically active ingredients selected from the group consisting of ACE inhibitors, AIRBs, diuretics, Ca 2+ channel blockers, β blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, activators of the soluble guanylate cyclase (sGC), and beta-arrestin ligand of angiotensin II receptor.

21 . The method of claim 13 , wherein the individual is human.

Assignments (9)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 28, 2026
From: SEISMIC PHARMACEUTICALS INC.
To: SEISMIC PHARMACEUTICALS OPERATIONS LLC
Reel/Frame 073612/0268 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 28, 2026
From: WINDTREE THERAPEUTICS INC.
To: SEISMIC PHARMACEUTICALS
Reel/Frame 073612/0195 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 24, 2025
From: WINDTREE THERAPEUTICS INC.
To: SEISMIC PHARMACEUTICALS
Reel/Frame 073017/0704 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 12, 2022
From: UNIVERSITY OF MILANO-BICOCCA
To: WINDTREE THERAPEUTICS, INC.
Reel/Frame 060484/0734 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2022
From: CERRI, ALBERTO
To: CVIE THERAPEUTICS COMPANY LIMITED
Reel/Frame 060474/0276 →
CHANGE OF NAME Recorded Jul 11, 2022
From: CVIE INTERNATIONAL LIMITED
To: CVIE THERAPEUTICS LIMITED
Reel/Frame 060625/0192 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2022
From: GIUSEPPE BIANCHI; FERRARI, PATRIZIA; FERRANDI, MARA; BARASSI, PAOLO; ZAZA, ANTONIO; ROCCHETTI, MARCELLA; RONCHI, CARLOTTA; HSU, SHIH-CHE; PERI, FRANCESCO; LURAGHI, ANDREA; TORRE, ELEANORA
To: WINDTREE THERAPEUTICS, INC
Reel/Frame 060478/0141 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2022
From: CVIE THERAPEUTICS LIMITED
To: WINDTREE THERAPEUTICS, INC.
Reel/Frame 060474/0634 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2022
From: CVIE THERAPEUTICS COMPANY LIMITED
To: CVIE INTERNATIONAL LIMITED
Reel/Frame 060474/0398 →
Priority Claims (1)
EP 19202257 · Oct 9, 2019 · regional
Continuity (1)
Related Publication 20230009312A1 · Jan 12, 2023
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