Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula:

• wherein:
• R1, R2 and R5 are independently selected from the group consisting of H and C1-C2 alkyl;
• R3 and R4 are selected from C2-C8 alkyl;
• R6 is selected from H and the L-isomer (amino acid convention) of R7—(CH2)n—HC(NH2)—CO—;
• wherein
• n is an integer from 0 to 3;
• R7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyridinyl, 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—(CH2)m—HC*< where “*” indicates a chiral center and R3 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.

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:
• R1, R2 and R5 are independently selected from the group consisting of H and C1-C2 alkyl;
• R3 and R4 are selected from C2-C8 alkyl;
• R6 is selected from the group consisting of H and the L-isomer (amino acid convention) of R7—(CH2)n—HC(NH2)—CO—;
• wherein
• n is an integer from 0 to 3;
• R7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyridinyl, 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—(CH2)m—HC*< where “*” indicates a chiral carbon atom and R3 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.

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:
• R1, R2 and R5 are independently selected from the group consisting of H and C1-C2 alkyl;
• R3 and R4 are selected C2-C8 alkyl;
• R6 is selected from the group consisting of H and the L-isomer (amino acid convention) of R7—(CH2)n—HC(NH2)—CO—;
• wherein
• n is an integer from 0 to 3;
• R7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyridinyl, and said substituent 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—(CH2)m—HC*< where “*” indicates a chiral carbon atom and R3 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.

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:
• R1, R2 and R5 are independently selected from the group consisting of H and C1-C2 alkyl;
• R3 and R4 are selected from C2-C8 alkyl;
• R6 is selected from the group consisting of H and the L- isomer (amino acid convention) of R7—(CH2)n—HC(NH2)—CO—;
• wherein
• n is an integer from 0 to 3;
• R7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyridinyl, 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—(CH2)m—HC*< where “*” is a chiral carbon atom and R3 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.

A method of treating a mammal affected with pre-eclampsia/eclampsia, comprising administering to the mammal a pharmaceutically effective amount of a compound of the formula:

• wherein:
• R1, R2 and R5 are independently selected from the group consisting of H and C1-C2 alkyl;
• R3 and R4 are selected from C2-C8 alkyl;
• R6 is selected from the group consisting of H and the L-isomer (amino acid convention) of R7—(CH2)n—HC(NH2)—CO—;
• wherein
• n is an integer from 0 to 3;
• R7 is selected from the group consisting of unsubstituted heteroaryl and monosubstituted heteroaryl, wherein said heteroaryl is pyridinyl, 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—(CH2)m—HC*< where “*” indicates a chiral carbon atom and R3 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.