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

Patent metadata

Field	Value
Publication number	US-12065402-B2
Application number	US-202318200431-A
Country	US
Kind code	B2
Filing date	May 22, 2023
Priority date	Mar 17, 2017
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

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

The invention claimed is:

1. A method of treating inflammatory bowel diseases (IBD) comprising administering to a subject in need thereof an effective amount of 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, benzoyl, 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, benzoyl, 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, benzoyl, 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, benzoyl, 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, benzoyl, 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, benzoyl, 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, benzoyl, 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, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

2. The method of claim 1 , the compound has one of the following formula:

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

3. The method of claim 1 , the compound has 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.

4. The method of claim 1 , 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.

5. The method 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.

6. The method 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.

Assignees

• Univ Emory

Inventors

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

Classifications

• C07F9/572

  Five-membered rings · CPC title

• C07F9/091

  with hydroxyalkyl compounds with further substituents on alkyl · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• C07C309/66

  Methanesulfonates · CPC title

• C07C307/02

  Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids · CPC title