Modulators of liver receptor homologue 1 (LRH-1) and uses

Patent metadata

Field	Value
Publication number	US-10843996-B2
Application number	US-201816495092-A
Country	US
Kind code	B2
Filing date	Mar 16, 2018
Priority date	Mar 17, 2017
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

This disclosure relates to modulators of liver receptor homologue 1 (LRH-1) and methods of managing disease and conditions related thereto. In certain embodiments, modulators are derivatives of hexahydropentalene. In certain embodiments, this disclosure relates to methods of treating or preventing cancer, diabetes, or cardiovascular disease by administering an effective amount of a hexahydropentalene derivative disclosed herein.

First claim

What is claimed is:

1. A compound having the following formula:

prodrugs or salts thereof wherein,
R 1 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 10 ;
R 2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 10 ;
R 3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 10 ;
R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 10 ;
R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 10 ;
R 6 is lipid or alkyl, wherein R 6 is optionally terminally substituted with a hydroxy, carboxy, or phosphate, wherein the hydroxy, carboxy, or phosphate are optionally further substituted with R 10 ;
R 7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 7 is optionally substituted with one or more, the same or different, R 10 ; or
R 1 and R 7 together are an oxo or oxime, wherein the oxime is optionally substituted with one or more, the same or different, R 10 ;
R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 11 ; and
R 11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydoxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benozyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

2. The compound of claim 1 , wherein R 2 and R 3 are hydrogen, R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl.

3. The compound of claim 1 wherein R 6 is alkyl terminally substituted with a hydroxy, carboxy, or phosphate, wherein the hydroxy, carboxy, or phosphate are optionally further substituted with R 10 .

4. The compound of claim 1 , having one of the following formula:

wherein R 6 is hydrogen, alkyl, or alkanoyl optionally substituted with R 10 .

5. The compound of claim 1 , wherein R 1 is hydroxyl, alkyl, amino, aminoalkyl, carbamoyl, sulphate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl, wherein R 1 is optionally substituted with R 10 .

6. The compound of claim 1 having one of the following formula:

wherein,
X is —CH 2 —, —C(OH)(OH)—, —C(OH)H, —C(Hal)(Hal)-, —C(Hal)H—, —O—, —S—, —(S═O)—, —SO 2 —, —NH—, —(C═O)—, —(C═NH)—, or —(C═S)—;
Y is —CH 2 —, —C(OH)(OH)—, —C(OH)H, —C(Hal)(Hal)-, —C(Hal)H—, —O—, —S—, —(S═O)—, —SO 2 —, —NH—, —(C═O)—, —(C═NH)—, or —(C═S)—;
Z is —CH 2 —, —C(OH)(OH)—, —C(OH)H, —C(Hal)(Hal)-, —C(Hal)H—, —O—, —S—, —(S═O)—, —SO 2 —, —NH—, —(C═O)—, —(C═NH)—, or —(C═S)—; and
R 1 is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl.

7. The compound of claim 6 , wherein
a) X is O, and R 1 is alkanoyl;
b) X is —NH—, and R 1 is alkanoyl;
c) X is O, and R 1 is aminosulfonyl;
d) X is —NH—, and R 1 is aminosulfonyl;
e) X is —(C═O)—, R 1 is amino;
f) X is O, Y is —(C═O)—, R 1 is amino;
g) X is O, Y is —(C═O)—, Z is —NH—, and R 1 is sulfonate; and
h) X is O, Y is —(C═O)—, Z is —NH—, and R 1 is aminosulfonyl.

8. The compound of claim 1 , wherein the compound is 5-hexyl-4-phenyl-3a-(1-phenylvinyl)-1,2,3,3a,6,6a-hexahydropentalen-1-yl sulfamide or salt thereof.

9. The compound of claim 1 , wherein the compound is 5-hexyl-4-phenyl-3a-(1-phenylvinyl)-1,2,3,3a,6,6a-hexahydropentalen-1-yl)acetamide or salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

11. A compound 10-(3-phenyl-3a-(1-phenylvinyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)decanoic acid or salt thereof.

12. A pharmaceutical composition comprising a compound 10-(3-phenyl-3a-(1-phenylvinyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)decanoic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Assignees

• Univ Emory

Inventors

• Ortlund Eric
• Mays Suzanne
• Jui Nathan
• Flynn Autumn
• Dugan Michael

Classifications

• C07C49/683

  having unsaturation outside the aromatic rings · CPC title

• C07D303/04

  containing only hydrogen and carbon atoms in addition to the ring oxygen atoms · CPC title

• C07C2602/22

  the ring system containing eight carbon atoms, e.g. pentalene · CPC title

• C07C59/86

  containing six-membered aromatic rings and other rings · CPC title

• C07F9/091

  with hydroxyalkyl compounds with further substituents on alkyl · CPC title