Lipoxin A4 analogs

A method of treating pulmonary or respiratory tract inflammation in a mammal, wherein the method comprises adminstering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I):

• wherein:
• each R1, R2 and R3 are independently halo, —OR6, —SR6, —S(O)tR7 (where t is 1 or 2) or —N(R7)R8;
• or R1 and R2 together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
• or R1 and R2 together with the carbons to which they are attached form the following bicyclic heterocyclic structure:
• (where q is 0 to 3, p is 1 to 4 and each R1 is hydrogen, alkyl, aralkyl or aryl);
• each R4 is —R9—R12, —R9—R13—R11, —R9—O—R10—R11, —R9—O—R12, —R9—C(O)—R10—R11, —R9—N(R7)—R10—R11, —R9—S(O)t—R10—R11 (where t is 0 to 2), or —R9—C(F)2—R9—R11;
• each R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• each R6 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(S)R7, —C(O)OR14, —C(S)OR14, C(O)N(R7)R8, or —C(S)N(R7)R8;
• each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl;
• R8 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(O)OR14, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, —N(R7)2, and —C(O)OR7);
• each R9 is independently a direct bond or a straight or branched alkylene chain;
• each R10 is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene;
• each R11 is independently —C(O)OR7, —C(O)N(R7)2, —P(O)(OR7)2, —S(O)2OR7, —S(O)2N(H)R7 or tetrazole;
• R12 is aryl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• R13 is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene;
• and
• R14 is alkyl, aryl or aralkyl;
• as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers;
• or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.

A compound of formula (I):

• wherein:
• each R1, R2 and R3 are independently halo, —OR6, —SR6, —S(O)tR7 (where t is 1 or 2) or —N(R7)R8;
• or R1 and R2 together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
• or R1 and R2 together with the carbons to which they are attached form the following bicyclic heterocyclic structure:
• (where q is 0 to 3, p is 1 to 4 and each R15 is hydrogen, alkyl, aralkyl or aryl);
• each R4 is —R9—R12, —R9—R13—R11, —R9—O—R10—R11, —R9—O—R12, —R9—C(O)—R10—R11, —R9—N(R7)—R10—R11, —R9—S(O)t—R10—R11 (where t is 0 to 2), or —R9—C(F)2—R9—R11;
• each R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• each R6 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(S)R7, —C(O)OR14, —C(S)OR14—C(O)N(R7)R8, or —C(S)N(R7)R8;
• each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl;
• R8 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(O)OR14, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, —N(R7)2, and —C(O)OR7);
• each R9 is independently a direct bond or a straight or branched alkylene chain;
• each R10 is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene;
• each R11 is independently —C(O)OR7, —C(O)N(R7)2, —P(O)(OR7)2, —S(O)2OR7, —S(O)2N(H)R7 or tetrazole;
• R12 is aryl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• R13 is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene;
• and
• R14 is alkyl, aryl or aralkyl;
• as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers;
• or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.

A pharmaceutical composition useful in treating an inflammatory or autoimmune disorder in a mammal, which composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I):

• wherein:
• each R1, R2 and R3 are independently halo, —OR6, —SR6, —S(O)tR7 (where t is 1 or 2) or —N(R7)R8;
• or R1 and R2 together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
• or R1 and R2 together with the carbons to which they are attached form the following bicyclic heterocyclic structure:
• (where q is 0 to 3, p is 1 to 4 and each R15 is hydrogen, alkyl, aralkyl or aryl);
• each R4 is —R9—R12, —R9—R13—R11, —R9—O—R10—R11, —R9—O—R12, —R9—C(O)—R10—R11, —R9—N(R7)—R10—R11, —R9—S(O)t—R10—R11 (where t is 0 to 2), or —R9—C(F)2—R9—R11;
• each R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• each R6 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(S)R7, —C(O)OR14, —C(S)OR14, —C(O)N(R7)R8, or —C(S)N(R7)R8;
• each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl;
• R8 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(O)OR14, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, —N(R7)2, and —C(O)OR7);
• each R9 is independently a direct bond or a straight or branched alkylene chain;
• each R10 is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene;
• each R11 is independently —C(O)OR7, —C(O)N(R7)2, —P(O)(OR7)2, —S(O)2OR7, —S(O)2N(H)R7 or tetrazole;
• R12 is aryl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• R13 is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene;
• and
• R14 is alkyl, aryl or aralkyl;
• as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers;
• or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.

A pharmaceutical composition useful in treating pulmonary or respiratory tract inflammation in a mammal, wherein the composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I):

• wherein:
• each R1, R2 and R3 are independently halo, —OR6, —SR6, —S(O)tR7 (where t is 1 or 2) or —N(R7)R8;
• or R1 and R2 together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
• or R1 and R2 together with the carbons to which they are attached form the following bicyclic heterocyclic structure:
• (where q is 0 to 3, p is 1 to 4 and each R15 is hydrogen, alkyl, aralkyl or aryl);
• each R4 is —R9—R12, —R9—R13—R11, —R9—O—R10—R11, —R9—O—R12, —R9—C(O)—R10—R11, —R9—N(R7)—R10—R11, —R9—S(O)t—R10—R11 (where t is 0 to 2), or —R9—C(F)2—R9—R11;
• each R5 is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• each R6 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(S)R7, —C(O)OR14, —C(S)OR14, —C(O)N(R7)R8, or —C(S)N(R7)R8;
• each R7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl;
• R8 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R7, —C(O)OR14, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, —N(R7)2, and —C(O)OR7);
• each R9 is independently a direct bond or a straight or branched alkylene chain;
• each R10 is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene;
• each R11 is independently —C(O)OR7, —C(O)N(R7)2, —P(O)(OR7)2, —S(O)2OR7, —S(O)2N(H)R7 or tetrazole;
• R12 is aryl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by —C(O)OR7 or —C(O)N(R7)2 and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
• R13 is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene;
• and
• R14 is alkyl, aryl or aralkyl;
• as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers;
• or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.