Method for preventing tissue injury from hypoxia

A method for treating or preventing a disease caused by hypoxic tissue injury, comprising administering to a patient in need of such treatment a clinically achievable, effective amount of a compound that inhibits signal transduction by inhibiting cellular accumulation of linoleate-containing phosphatidic acid (PA) through inhibition of the enzyme LPAAT (lysophosphatidic acyltransferase), wherein said compound is a diastereomer, hydrate, salt, solvate or mixtures thereof, and has a straight or branched aliphatic hydrocarbon structure of formula I:

• ##STR79## wherein n is an integer from one to four and m is an integer from four to twenty, R.sub.1 and R.sub.2 are independently hydrogen, a straight or branched chain alkyl, alkenyl or alkynyl of up to twenty carbon atoms in length or --(CH.sub.2).sub.w R.sub.5,
• wherein if R.sub.1 or R.sub.2 is --(CH.sub.2).sub.w R.sub.5, w is an integer from one to twenty and R.sub.5 is a hydroxyl, halo, C.sub.1-8 alkoxyl group or a substituted or unsubstituted carbocycle or heterocycle having from four to eight carbon atoms, N being a hetero atom of the resulting heterocycle,
• wherein R.sub.3 is hydrogen, a hydroxy group, a C.sub.1-3 straight or branched alkyl, or a C.sub.1-3 alkoxy, wherein a total sum of carbon atoms comprising R.sub.1 or R.sub.2, (CH.sub.2).sub.n and (CH.sub.2).sub.m does not exceed forty,
• wherein R.sub.4 is a terminal moiety comprising a substituted or unsubstituted heterocyclic moiety, wherein the heterocyclic moiety consists essentially of one to three ring structures having 5-7 members each, a hetero atom, and a predominantly planar structure or is essentially aromatic;
• or the compounds include resolved enantiomers, diastereomers, hydrates, salts, solvates and mixtures thereof that have a straight or branched aliphatic hydrocarbon structure of formula II:
• ##STR80## wherein n, m, R.sub.3 and R.sub.4 are defined as provided in formula I above, R.sub.6 and R.sub.7 are hydrogen, a straight or branched chain alkane, alkene or alkyne of up to twenty carbon atoms in length, or --(CH.sub.2).sub.x R.sub.8, wherein x is an integer from zero to fourteen and R.sub.8 is a moiety having a general structure as provided in formula III:
• ##STR81## wherein m, R.sub.3 and R.sub.4 are defined as provided in formula I above, Z is N or CH and p is an integer from zero to four, wherein R.sub.9 is H or a straight or branched chain alkane, alkene or alkyne of up to twenty carbon atoms in length.

A method for treating cystic fibrosis, comprising administering to a patient in need of such treatment an effective amount of a compound that inhibits signal transduction by inhibiting cellular accumulation of non-arachidonyl, linoleate- or myristylate-containing PA through an inhibition of the enzyme LPAAT, wherein said compound is a diastereomer, hydrate, salt, solvate or mixtures thereof, and has a straight or branched aliphatic hydrocarbon structure of formula I:

• ##STR83## wherein n is an integer from one to four and m is an integer from four to twenty, R.sub.1 and R.sub.2 are independently hydrogen, a straight or branched chain alkyl, alkenyl or alkynyl of up to twenty carbon atoms in length or --(CH.sub.2).sub.w R.sub.5,
• wherein if R.sub.1 or R.sub.2 is --(CH.sub.2).sub.w R.sub.5, w is an integer from one to twenty and R.sub.5 is a hydroxyl, halo, C.sub.1-8 alkoxyl group or a substituted or unsubstituted carbocycle or heterocycle having from four to eight carbon atoms, N being a hetero atom of the resulting heterocycle,
• wherein R.sub.3 is hydrogen, a hydroxy group, a C.sub.1-3 straight or branched alkyl, or a C.sub.1-3 alkoxy, wherein a total sum of carbon atoms comprising R.sub.1 or R.sub.2, (CH.sub.2).sub.n and (CH.sub.2).sub.m does not exceed forty,
• wherein R.sub.4 is a terminal moiety comprising a substituted or unsubstituted heterocyclic moiety, wherein the heterocyclic moiety consists essentially of one to three ring structures having 5-7 members each, a hetero atom, and a predominantly planar structure or is essentially aromatic;
• or the compounds include resolved enantiomers, diastereomers, hydrates, salts, solvates and mixtures thereof that have a straight or branched aliphatic hydrocarbon structure of formula II:
• ##STR84## wherein n, m, R.sub.3 and R.sub.4 are defined as provided in formula I above, R.sub.6 and R.sub.7 are hydrogen, a straight or branched chain alkane, alkene or alkyne of up to twenty carbon atoms in length, or --(CH.sub.2).sub.x R.sub.8, wherein x is an integer from zero to fourteen and R.sub.8 is a moiety having a general structure as provided in formula III:
• ##STR85## wherein m, R.sub.3 and R.sub.4 are defined as provided in formula I above, Z is N or CH and p is an integer from zero to four, wherein R.sub.9 is H or a straight or branched chain alkane, alkene or alkyne of up to twenty carbon atoms in length.