Water-soluble derivatives and prodrugs of acacetin and methods of making and using thereof

Patent metadata

Field	Value
Publication number	US-9260461-B2
Application number	US-201414171228-A
Country	US
Kind code	B2
Filing date	Feb 3, 2014
Priority date	Feb 3, 2014
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

Water-soluble derivatives and/or prodrugs of acacetin are described herein. The compounds can be used as cardioprotection agents against myocardial infarction induced by ischemia-reperfusion. In one embodiment the compounds are used to treat ischemic cardiac diseases. In the preferred embodiment, the compounds are used to treat and/or prevent myocardial infarction in humans.

First claim

We claim:

1. A compound of Formula I:

wherein:
m and n are independently an integer from 0 to 3;
X is O or N or S;
R 1 is selected from the group consisting of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, alkaryl, arylalkyl, carboxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxyalkyl, alkoxyalkyl, PO 3 H 2 , PO 3 2− M, where M is one or more ammonium ions, alkali metal ions, or alkaline earth metal ions, phosphate ester, SO 3 H, SO 3 − M, where M is an ammonium ion, alkali metal ion, or alkaline earth metal ion, sulfonic ester, sulfonic ester, sulfonamide, —C(═O)-A 1 , and —C(═O)-L-A 2 ; wherein A 1 and A 2 are independently halo, hydroxy, thiol, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkaryl, arylalkyl, carbamate, amino, alkylamino, arylamino, dialkylamino, alkylarylamino, diarylamino, sulfonamide, heteroalkyl; wherein L is alkylene, alkenylene, alkynylene, aralkylene or alkarylene; and
R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, alkaryl, arylalkyl, carboxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxyalkyl, alkoxyalkyl, PO 3 H 2 , PO 3 2− M, where M is one or more ammonium ions, alkali metal ions, or alkaline earth metal ions, phosphate ester, SO 3 H, SO 3 − M, where M is an ammonium ion, alkali metal ion, or alkaline earth metal ion, sulfonic ester, sulfonic ester, sulfonamide, —C(═O)-A 1 , and —C(═O)-L-A 2 ; wherein A 1 and A 2 are independently hydrogen, halo, alkoxy, hydroxy, thiol, alkyl, alkenyl, alkynyl cycloalkyl, cycloalkenyl, cycloalkynyl, alkaryl, arylalkyl, carbamate, amino, alkylamino, arylamino, dialkylamino, alkylarylamino, diarylamino, sulfonamide, heteroalkyl; wherein L is alkylene, alkenylene, alkynylene, arylene, aralkylene or alkarylene;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , having formula IIA:

wherein:
X=O; m=0; n=0;
R 1 is selected from the group consisting of PO 3 H 2 , PO 3 2− M, wherein M is one or more ammonium ions, alkali metal ions, or alkaline earth metal ions, phosphate ester, sulfonic ester and sulfonamide; and
R 2 is selected from the group consisting of hydrogen, PO 3 H 2 , PO 3 2− M, wherein M is one or more ammonium ions, alkali metal ions, or alkaline earth metal ions, phosphate ester, sulfonic ester and sulfonamide;
wherein if R 2 is H, R 1 is not sulfonate.

3. The compound of claim 1 , having formula IIB:

wherein:
X=O; m=1; n=0;
R 1 is selected from the group consisting of PO 3 H 2 , PO 3 2− M, wherein M is one or more ammonium ions, alkali metal ions, or alkaline earth metal ions, phosphate ester, sulfonate with ammonium or alkali or alkaline earth metal ions, sulfonic ester and sulfonamide; and
R 2 is selected from the group consisting of hydrogen, PO 3 H 2 , PO 3 2− M, wherein M is one or more ammonium ions, alkali metal ions, or alkaline earth metal ions, phosphate ester, sulfonate with ammonium or alkali or alkaline earth metal ions, sulfonic ester and sulfonamide.

4. The compound of claim 1 having the structure:

5. The compound of claim 1 having the structure:

6. The compound of claim 1 having the structure:

7. The compound of claim 1 having the structure:

8. The compound of claim 1 having the structure:

9. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers.

10. A pharmaceutical composition comprising the compound of claim 2 and one or more pharmaceutically acceptable carriers.

11. A pharmaceutical composition comprising the compound of claim 3 and one or more pharmaceutically acceptable carriers.

12. The composition of claim 9 , wherein the compound is selected from the group consisting of:

13. A method for treating myocardial infarction, comprising administrating to a patient in need thereof an effective amount of a water soluble compound of Formula I of claim 1 , alone or in combination with acacetin.

14. The method of claim 13 , wherein the compound is a compound of Formula IIA of claim 2 .

15. The method of claim 13 , wherein the compound is a compound of Formula IIB of claim 3 .

16. The method of claim 13 , wherein the compound has the following structure:

Compound
X
m
R 1
n
R 2

A
O
0
P(O)(OH) 2 • x (NEt 3 )
0
H

B
O
0
P(O)(ONa) 2
0
H

C
O
1
P(O)(ONa) 2
0
 H.

17. The method of claim 13 , wherein the effective amount is from about 0.001 to about 100 mg/kg of the body weight of the patient per day.

18. The method of claim 13 , wherein the patient is a human.

19. A method for treating ventricular arrhythmia, comprising administrating to a patient in need thereof an effective amount of a water soluble compound of Formula I of claim 1 , alone or in combination with acacetin.

20. A method for inhibiting ventricular arrhythmia, comprising administrating to a patient in need thereof an effective amount of a water soluble compound of Formula I of claim 1 , alone or in combination with acacetin.

Assignees

• Versitech Ltd
• Shanghai Inst Pharm Industry

Inventors

• Li Gui-Rong
• Lin Feng

Classifications

• C07F9/65522 Primary

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P9/06

  Antiarrhythmics · CPC title