US2012142781A1PendingUtilityA1
Antagonists of the Magnesium Binding Defect as Therapeutic Agents and Methods for Treatment of Abnormal Physiological States
Est. expiryAug 9, 2020(expired)· nominal 20-yr term from priority
Inventors:Ibert Clifton Wells
A61P 9/12A61P 43/00A61P 9/00A61P 5/50A61P 3/10A61P 25/08A61P 3/00A61P 15/00G01N 2800/042C07C 237/20C07C 237/22A61K 31/165C07C 237/12G01N 2800/321A61K 31/16
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Claims
Abstract
This invention provides a class of therapeutic compounds and methods for the treatment of mammals with physiological disorders, such as for example a frequently occurring type of essential hypertension, which are critically associated with the decreased binding of magnesium to the plasma membranes of their cells. These methods consist of administering to a mammal in need of such treatment a compound selected from a series of disubstituted trans, trans 1,3-butadienes, 1,3-disubstituted perhydrobutadienes, 1,2-disubstituted trans ethylenes and 1,2 disubstituted ethanes and disubstituted propanes, each of which embodies, in common, the unique structural feature essential for the biological activity of these compounds. This invention also provides for pharmaceutical formulations that employ these novel compounds.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
wherein:
R 1 , R 2 and R 5 are independently selected from the group consisting of H and C 1 -C 2 alkyl;
R 3 and R 4 are selected from C 2 -C 8 alkyl;
R 6 is the L-isomer (amino acid convention) of R 7 —(CH 2 ) n HC(NH 2 )—CO—;
wherein
n is an integer from 0 to 3;
R 7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyrazinyl, and said substituent is hydroxy, halo, amino, nitro, methyl or acetoxy;
X is independently selected in each instance from the group consisting of trans, trans >C══CH—HC══C<, trans >C══C<, and >C*H—(CH 2 ) m —HC*<, where “*” indicates a chiral carbon atom and R 3 and R 4 are oriented L- and D-(amino acid convention) at these respective chiral centers; and
m=0, 1 or 2,
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
2 . The compound of claim 1 wherein R 1 , R 2 and R 5 are hydrogen.
3 . The compound of claim 1 wherein R 1 is methyl and R 2 and R 5 are hydrogen.
4 . The compound of claim 1 wherein R 1 and R 2 are methyl and R 5 is hydrogen.
5 . The compound of claim 1 wherein R 1 and R 2 are hydrogen and R 5 is methyl.
6 . The compound of claim 1 wherein R 1 , R 2 and R 5 are methyl.
7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula
wherein:
R 1 , R 2 and R 5 are independently selected from the group consisting of H and C 1 —C 2 alkyl;
R 3 and R 4 are selected from C 2 -C 8 alkyl;
R 6 is the L-isomer (amino acid convention) of R 7 —(CH 2 ) n —HC(NH 2 )—CO—;
wherein
n is an integer from 0 to 3;
R 7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyrazinyl, and said substituent is hydroxy, halo, amino, nitro, methyl or acetoxy;
X is independently selected in each instance from the group consisting of trans, trans >C══CH—HC══C<, trans >C══C<, and >C*H—(CH 2 ) m —HC*< where “*” indicates a chiral center and R 3 and R 4 are oriented L- and D-(amino acid convention) at these respective chiral centers; and
m=0, 1 or 2, or
a pharmaceutically acceptable salt, solvate or prodrug thereof.
8 . The pharmaceutical composition of claim 7 wherein R 1 , R 2 and R 5 are hydrogen.
9 . The pharmaceutical composition of claim 7 wherein R 1 is methyl and R 2 and R 5 are hydrogen.
10 . The pharmaceutical composition of claim 7 wherein R 1 and R 2 are methyl and R 5 is hydrogen.
11 . The pharmaceutical composition of claim 7 wherein R 1 and R 2 are hydrogen and R 5 is methyl.
12 . The pharmaceutical composition of claim 7 wherein R 1 , R 2 and R 5 are methyl.
13 . A method of treating a mammal affected with the magnesium-binding defect, comprising administering to the mammal a pharmaceutically effective amount of a compound of the formula
wherein:
R 1 , R 2 and R 5 are independently selected from the group consisting of H and C 1 -C 2 alkyl;
R 3 and R 4 are selected from C 2 -C 8 alkyl;
R 6 is the L-isomer (amino acid convention) of R 7 —(CH 2 ) n —HC(NH 2 )—CO—;
wherein
n is an integer from 0 to 3;
R 7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyrazinyl, and said substituent is hydroxy, halo, amino, nitro, methyl or acetoxy;
X is independently selected from the group consisting of trans, trans >C══CH—HC══C<, trans >C══C<, and >C*H—(CH 2 ) m —HC*< where “*” indicates a chiral carbon atom and R 3 and R 4 are oriented L- and D-(amino acid convention) at these respective chiral centers; and
m=0, 1 or 2, or
a pharmaceutically acceptable salt, solvate or prodrug thereof.
14 . The method of claim 13 wherein R 1 , R 2 and R 5 are hydrogen.
15 . The method of claim 13 wherein R 1 is methyl and R 2 and R 5 are hydrogen.
16 . The method of claim 13 wherein R 1 and R 2 are methyl and R 5 is hydrogen.
17 . The method of claim 13 wherein R 1 and R 2 are hydrogen and R 5 is methyl.
18 . The method of claim 13 wherein R 1 , R 2 and R 5 are methyl.
19 . A method of treating a mammal with salt-sensitive, essential hypertension, comprising administering to the mammal a pharmaceutically effective amount of a compound of the formula:
wherein:
R 1 , R 2 and R 5 are independently selected from the group consisting of H and C 1 -C 2 alkyl;
R 3 and R 4 are selected C 2 -C 8 alkyl;
R 6 is the L-isomer (amino acid convention) of R 7 —(CH 2 ) n HC(NH 2 )—CO—;
wherein
n is an integer from 0 to 3;
R 7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyrazinyl and said substitute is hydroxy, halo, amino, nitro, methyl or acetoxy;
X is independently selected from the group consisting to trans, trans >C══CH—HC══C<, trans >C══C<, and >C*H—(CH 2 ) m —HC*< where “*” indicates a chiral carbon atom and R 3 and R4 are oriented L- and D-(amino acid convention) at these respective chiral centers; and
m=0, 1 or 2, or
a pharmaceutically acceptable salt, solvate or prodrug thereof.
20 . The method of claim 19 wherein R 1 , R 2 and R 5 are hydrogen.
21 . The method of claim 19 wherein R 1 is methyl and R 2 and R 5 are hydrogen.
22 . The method of claim 19 wherein R 1 and R 2 are methyl and R 5 is hydrogen.
23 . The method of claim 19 wherein R 1 and R 2 are hydrogen and R 5 is methyl.
24 . The method of claim 19 wherein R 1 , R 2 and R 5 are methyl.
25 . A method of treating a mammal with insulin resistance of Type 2 diabetes mellitus, comprising administering to the mammal a pharmaceutically effective amount of a compound of the formula:
wherein:
R 1 , R 2 and R 5 are independently selected from the group consisting of H and C 1 -C 2 alkyl;
R 3 and R 4 are selected from C 2 -C 8 alkyl;
R 6 is the L-isomer (amino acid convention) of R 7 —(CH 2 ) n HC(NH 2 )—CO—;
wherein
n is an integer from 0 to 3;
R 7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyrazinyl and said substitute is hydroxy, halo, amino, nitro, methyl or acetoxy;
X is independently selected from the group consisting of trans, trans >C══CH—HC══C<, trans >C══C<, and >C*H—(CH 2 ) m —HC*< where “*” is a chiral carbon atom and R 3 and R 4 are oriented L- and D-(amino acid convention) at these respective chiral centers; and
m=0, 1 or 2, or
a pharmaceutically acceptable salt, solvate or prodrug thereof.
26 . The method of claim 25 wherein R 1 , R 2 and R 5 are hydrogen.
27 . The method of claim 25 wherein R 1 is methyl and R 2 and R 5 are hydrogen.
28 . The method of claim 25 wherein R 1 and R 2 are methyl and R 5 is hydrogen.
29 . The method of claim 25 wherein R 1 and R 2 are hydrogen and R 5 is methyl.
30 . The method of claim 25 wherein R 1 , R 2 and R 5 are methyl.Join the waitlist — get patent alerts
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