Progesterone phosphate analogs and uses related thereto

Patent metadata

Field	Value
Publication number	US-10487109-B2
Application number	US-201715728459-A
Country	US
Kind code	B2
Filing date	Oct 9, 2017
Priority date	Aug 12, 2013
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

Abstract

This disclosure relates to progesterone phophate derivatives and uses related thereto. In certain embodiments, the disclosure relates to compounds disclosed herein and uses for managing inflammation such as those resulting from traumatic brain injury or stroke.

First claim

What is claimed is:

1. A method of reducing the symptoms or delaying the progression of stroke or traumatic brain injury, comprising administering an effective amount of a pharmaceutical composition comprising a compound of Formula I

or esters, or salts thereof wherein
X is O, N—OR 10 , or N—OCR 1 R 2 OPZ(OR 3 ) 2 ;
Y is O, N—OR 10 , or N—OCR 1 R 2 OPZ(OR 3 ) 2 ; provided at least one X or Y is N—OCR 1 R 2 OPZ(OR 3 ) 2 ;
Z is ═O or ═S;
R 1 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 4 ;
R 2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 4 ; or
R 1 and R 2 form a carbocyclic ring;
R 3 is phosphate ion, hydrogen, —CH 2 O(C═O)alkyl, or a group selected from alkyl, alkanoyl, and formyl further substituted with one or more, the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 4 ;
R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
R 5 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, tertbutyl, methoxy, ethoxy, 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, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R 10 is hydrogen or a group selected from alkyl and formyl further substituted with one or more, the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;
R 20 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 20 is optionally substituted with one or more, the same or different, R 30 ;
R 30 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 30 is optionally substituted with one or more, the same or different, R 40 ; and

R 40 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethyl amino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl
to a subject in need thereof.

2. The method of claim 1 , wherein X is N—OCR 1 R 2 OPZ(OR 3 ) 2 and Y is O.

3. The method of claim 1 , wherein Y is N—OCR 1 R 2 OPZ(OR 3 ) 2 and X is O.

4. The method of claim 1 , wherein R 1 and R 2 are hydrogen or alkyl.

5. The method of claim 1 , wherein R 1 and R 2 form a cyclopropyl ring.

6. The method of claim 1 , wherein R 3 is phosphate ion, hydrogen, alkanoyl, or alkyl.

7. A method of reducing the symptoms or delaying the progression of stroke or traumatic brain injury, comprising administering an effective amount of a pharmaceutical composition comprising a compound of Formula IA

or esters, or salts thereof wherein
Z is ═O or ═S;
R 1 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 4 ;
R 2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 4 ; or
R 1 and R 2 form a carbocyclic ring;
R 3 is phosphate ion, hydrogen, —CH 2 O(C═O)alkyl, or a group selected from alkyl, alkanoyl, and formyl further substituted with one or more, the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 4 ;
R 3′ is phosphate ion, hydrogen, —CH 2 O(C═O)alkyl, or a group selected from alkyl, alkanoyl, and formyl further substituted with one or more, the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, wherein R 3′ is optionally substituted with one or more, the same or different, R 4 ;
R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
R 5 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, tertbutyl, methoxy, ethoxy, 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, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl
to a subject in need thereof.

8. A method of reducing the symptoms or delaying the progression of stroke or traumatic brain injury, comprising administering an effective amount of a pharmaceutical composition comprising a compound of Formula IG

or esters, or salts thereof wherein
Z

Assignees

• Univ Emory

Inventors

• Guthrie David Brian
• Lockwood Mark Andrew
• Natchus Michael G
• Liotta Dennis C
• Stein Donald G
• Sayeed Iqbal

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/57

  substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone · CPC title

• C07J43/003

  not condensed · CPC title

• C07J41/0016 Primary

  Oximes · CPC title