Quaternary amine containing ether or ester lipid derivatives and therapeutic compositions

A pharmaceutical composition comprising a pharmaceutical carrier in combination with an amount of a compound of the formula:

• ##STR8## wherein:
• X is S or NHC(O);
• R.sub.1 is linear or branched, saturated or unsaturated C14-C20 alkyl containing not more than four double bonds, phenyl, or naphthyl;
• R.sub.2 is hydroxyl, phenyl, C1-C5 alkoxy, or C1-C5 alkylthio;
• R.sub.3 is linear or branched, saturated or unsaturated C1-C20 alkyl containing not more than four double bonds, and is unsubstituted or substituted with one to three hydroxy groups;
• R.sub.4 is C1-C5 alkyl;
• or R.sub.3 and R.sub.4 are covalently joined and together with N.sup.+ form a five or six membered monocyclic ring or with N.sup.+ form a monocyclic ring which contains one further hetero atom selected form oxygen, nitrogen or sulfur and is unsubstituted or substituted from one to three times by hydroxy or C1-C4 alkylhydroxy;
• R.sub.5 is C1-C5 alkyl;
• and
• Z.sup.- is a pharmaceutically acceptable anion;
• wherein the amount is effective to treat tumors, HIV infection or a condition associated with protein kinase C activity in a mammal.

A method of treating tumors in a subject in need of such treatment which comprises administering to the subject an effective amount of a compound of the formula:

• R.sub.1 --X--R.sub.2 --N.sup.+ (R.sub.3)(R.sub.4)(R.sub.5) Z.sup.-
• wherein
• R.sub.1 is a linear C10-C20 alkyl containing not more than four double bonds, or C10-C20 alkylcarbonyl containing not more than four double bonds;
• X is O or S;
• R.sub.2 is ethylene or n-propylene which is unsubstituted or is 2-substituted by hydroxyl, C1-C5 alkoxy, or C1-C5 alkylthio;
• R.sub.3 is linear or branched, saturated or unsaturated C1-C20 alkyl containing not more than four double bonds, and is unsubstituted or substituted from one to three times by hydroxy groups;
• R.sub.4 is C1-C5 alkyl;
• or R.sub.3 and R.sub.4 are covalently joined and together with N.sup.+ form a five or six membered monocyclic ring or with N.sup.+ form a monocyclic ring which contains one further hetero atom selected from oxygen, nitrogen or sulfur and is unsubstituted or substituted from one to three times by hydroxy or C1-C4 alkylhydroxy;
• R.sub.5 is C1-C5 alkyl, except that when either R.sub.3 or R.sub.4 is joined to N.sup.+ with a double bond, then R.sub.5 is absent;
• and
• Z.sup.- is a pharmaceutically acceptable anion.

A method of treating a condition associated with protein kinase C activity in a subject in need of such treatment, which comprises administering to the subject an effective amount of a compound of the formula:

• ##STR9## wherein:
• X is S or O;
• R.sub.1 is linear or branched, saturated or unsaturated C3-C20 alkyl containing not more than four double bonds;
• linear or branched, saturated or unsaturated C3-C20 alkylcarbonyl containing not more than four double bonds;
• phenyl or naphthyl;
• R.sub.2 is H, hydroxyl, phenyl, C1-C5 alkylcarbonyloxy, C1-C5 alkylthio, C1-C5 alkylcarboximido, or C1-C5 alkoxy which is unsubstituted or is substituted by phenyl or C1-C5 alkoxy;
• or wherein R.sub.1, R.sub.2 and X together are ##STR10## forming a five-membered monocyclic ring where R.sub.6 is H or C1-C5 alkyl, R.sub.7 is C1-C20 alkyl and Y is O or S;
• R.sub.3 is linear or branched, saturated or unsaturated C1-C20 alkyl containing not more than four double bonds, and is unsubstituted or substituted from one to three times by hydroxy groups;
• R.sub.4 is C1-C5 alkyl;
• R.sub.5 is C1-C5 alkyl;
• Z.sup.- is a pharmaceutically acceptable anion;
• wherein said amount is effective to inhibit protein kinase C activity in the subject.

A method of treating an HIV-1 infection in a subject in need of such treatment, comprising administering said subject an amount effective to treat said infection of a compound of the formula:

• R.sub.1 --X--R.sub.2 --N.sup.+ (R.sub.3)(R.sub.4)(R.sub.5) Z.sup.-
• wherein:
• X is S or O;
• R.sub.1 is linear or branched, saturated or unsaturated C10-C20 alkyl containing not more than four double bonds, linear or branched, saturated or unsaturated C10-C20 alkylcarbonyl containing not more than four double bonds, phenyl, or naphthyl;
• R.sub.2 is C5 to C6 cycloalkylene or a straight-chained or branched, saturated or unsaturated aliphatic hydrocarbon chain containing 2-8 carbon atoms, which is unsubstituted or substituted one or more times by hydroxyl, phenyl, C1-C5 alkylcarbonyloxy, C1-C5 alkylthio, C1-C5 alkylcarboxamido or by C1-C5 alkoxy which is unsubstituted or is substituted by phenyl or C1-C5 alkoxy;
• or R.sub.2 is joined to X with ##STR11## wherein Y is O or S and is joined to R.sub.2 and R.sub.1 is absent, to form a five-membered monocyclic ring where R.sub.6 is H or C1-C5 alkyl, and R.sub.7 is C1-C20 alkyl;
• R.sub.3 is a linear or branched, saturated or unsaturated C1-C20 alkyl containing not more than four double bonds, which is unsubstituted or substituted with one to three hydroxy groups;
• R.sub.4 is hydrogen or C1-C5 alkyl;
• or R.sub.3 and R.sub.4 are covalently joined and together with N.sup.+ form a five or six membered monocyclic ring selected from the group consisting of piperidine, pyridine, morpholine, pyrrolidine, piperazine, thiazole, and imidazole, and which is unsubstituted or substituted from one to three times by hydroxy or C1-C4 alkylhydroxy;
• R.sub.5 is hydrogen or C1-C5 alkyl;
• and
• Z.sup.- is a pharmaceutically acceptable anion.

A method of treating an HIV-1 infection in a subject in need of such treatment, comprising administering to said subject in an amount effective to treat said infection a compound of the formula:

• ##STR12## wherein:
• n is 2-4;
• X is S, O, or NHC(O);
• R.sub.21 is C14-C20 linear saturated or unsaturated alkyl containing not more than three double bonds;
• R.sub.22 is hydrogen, methyl, or ethyl;
• R.sub.23, R.sub.24 and R.sub.25 are independently either hydrogen or methyl;
• and
• Z.sup.- is a pharmaceutically acceptable anion.

A method of treating tumors, HIV-1 infection, or a condition associated with protein kinase C activity in a subject in need of such treatment which comprises administering to the subject an effective amount of a compound of the formula:

• ##STR13## wherein:
• X is S or NHC(O);
• R.sub.1 is linear or branched, saturated or unsaturated C14-C20 alkyl containing not more than four double bonds, phenyl, or naphthyl;
• R.sub.2 is hydrogen, hydroxyl, phenyl, C1-C5 alkoxy, or C1-C5 alkylthio;
• R.sub.3 is linear or branched, saturated or unsaturated C1-C20 alkyl containing not more than four double bonds, and is unsubstituted or substituted with one to three hydroxy groups;
• R.sub.4 is C1-C5 alkyl;
• or R.sub.3 and R.sub.4 are covalently joined and together with N.sup.+ form a five or six membered monocyclic ring or with N.sup.+ form a monocyclic ring which contains one further hetero atom selected form oxygen, nitrogen or sulfur and is unsubstituted or substituted from one to three times by hydroxy or C1-C4 alkylhydroxy;
• R.sub.5 is C1-C5 alkyl;
• and
• Z.sup.- is a pharmaceutically acceptable anion.

A method of treating tumors, HIV-1 infection, or a condition associated with protein kinase C activity in a subject in need of such treatment which comprises administering to the subject an effective amount of a compound of the formula:

• ##STR14## wherein:
• R.sub.1 is linear or branched, saturated or unsaturated C14-C20 alkyl containing not more than four double bonds, linear or branched, saturated or unsaturated C10-C20 alkylcarbonyl containing not more than four double bonds, phenyl, or naphthyl;
• R.sub.3 is linear or branched, saturated or unsaturated C2-C20 alkyl containing not more than four double bonds, is hydroxy substituted at the terminal carbon and is substituted with zero to two additional hydroxy groups;
• R.sub.4 is hydrogen or C1-C5 alkyl;
• R.sub.5 is hydrogen or C1-C5 alkyl;
• R.sub.10 is hydrogen or methyl;
• and
• Z.sup.- is a pharmaceutically acceptable anion.

A method of treating tumors, HIV-1 infection, or a condition associated with protein kinase C activity in a subject in need of such treatment which comprises administering to the subject an effective amount of a compound of the formula:

• ##STR15## wherein:
• R.sub.7 is hydrogen, phenyl, or linear or branched, saturated or unsaturated C1-C16 alkyl containing not more than four double bonds or one triple bond;
• R.sub.8 is hydrogen or saturated or unsaturated, linear or branched C1-C5 alkyl;
• R.sub.9 is saturated or unsaturated, linear or branched C1-C19 alkyl containing not more than four double bonds;
• R.sub.3 is linear or branched, saturated or unsaturated C1-C20 alkyl containing not more than four double bonds, is hydroxy substituted at the terminal carbon and is substituted with zero to three additional hydroxy groups;
• R.sub.4 is C1-C5 alkyl;
• R.sub.5 is C1-C5 alkyl;
• and
• Z.sup.- is a pharmaceutically acceptable anion.

A method of treating tumors, HIV-1 infection, or a condition associated with protein kinase C activity in a subject in need of such treatment which comprises administering to the subject an effective amount of a compound of the formula ##STR16## wherein:

• R.sub.1 is C10-C20 linear saturated or unsaturated alkyl containing not more than one double bond;
• R.sub.2 is H or C1-C5 alkoxy;
• X is S or O;
• R.sub.3 and R.sub.4 are covalently joined and together with N.sup.+ form a five or six membered monocyclic ring selected from the class consisting of piperidine, pyridine, morpholine, pyrrolidine, piperazine, thiazole, and imidazole, which ring is substituted with zero to three hydroxy groups or and substituted with zero to three C1-C4 alkylhydroxy groups;
• R.sub.5 is H or C1-C5 alkyl;
• and
• Z.sup.- is a pharmaceutically acceptable anion.