Lipoxin analogs as novel inhibitors of angiogenesis
The present invention is generally drawn to novel isolated therapeutic agents, termed lipoxins, generated from the interaction between a dietary omega-6 polyunsaturated fatty acid (PUFA) such as arachidonic acid (AA), oxygenases and the analgesic aspirin (ASA). Surprisingly, careful isolation of compounds generated from the combination of components in an appropriate environment provide di- and tri-hydroxy containing derivatives of AA containing compounds having unique structural and physiological properties. The present invention therefore provides for many new useful therapeutic di- and tri-hydroxy derivatives of AA (lipoxins, aspirin-triggered epi-lipoxins) that diminish, prevent, or eliminate NV, hemangiogenesis and/or angiogenic condition(s) of corneal tissue. The present invention also provides methods of use, methods of preparation, and packaged pharmaceuticals for use as medicaments for the compounds disclosed throughout the specification.
1. A method to treat corneal neovascularization comprising administering a composition comprising a lipoxin compound to the corneal tissue of a subject in need thereof, wherein the lipoxin compound comprises the formula
wherein X is R1, OR.1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which can be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms, inclusive;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
wherein Zi, Zii, Ziii, Ziv and Zv are each independently selected from —NO2, —CN, —C(═O)—R1, —SO3H, a hydrogen atom, halogen, methyl, —ORx, wherein Rx is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
or
(vii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN);
wherein Q3 is O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) a hydrogen atom;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which can be straight chain or branched;
(c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;
(d) an alkenyl of 2 to 8 carbon atoms, inclusive, which can be straight chain or branched; or
(e) Ra Q2Rb
wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein R4 is
(a) a hydrogen atom;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y1 or Y2 is —OH, methyl, or —SH and wherein the other is
(a) a hydrogen atom
(b) CHaZb
where a+b=3, a=0 to 3, b=0 to 3; and
each Z, independently, is a cyano, a nitro, or a halogen atom;
(c) an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched; or
(d) an alkoxy of 1 to 4 carbon atoms, inclusive;
or Y1 and Y2 taken together are
(a) ═NH; or
(b) ═O;
wherein R5 is
(a) an alkyl of 1 to 9 carbon atoms which can be straight chain or branched;
(b) —(CH2)n-Ri
wherein n=0 to 4 and Ri is
(i) a cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) a phenyl; or
(iii) substituted phenyl
wherein Zi, Zii, Ziii, Ziv and Zv are each independently selected from —NO2, —CN, —C(═O)—R1, —SO3H, a hydrogen atom, halogen, methyl, —ORx, wherein Rx is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(c) RaQaRb
wherein Qa is O or S;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched;
wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
(d) —C(Riii)(Riv)-Ri
wherein Riii and Riv are each, independently:
(i) a hydrogen atom;
(ii) CHaZb where a+b=3, a=0 to 3, b=0+3, and wherein each Z, independently, is a cyano, a nitro, or a halogen atom;
(e) a haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched; and
wherein R6 is
(a) a hydrogen atom;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) a halogen.
2. The method of claim 1 , wherein the lipoxin compound comprises the formula
wherein Q 1 is a carbonyl;
X is a hydroxyl, an —OR, or a pharmaceutically acceptable salt of a carboxylic acid;
R, if present, is an alkyl group; and
R 4 is a hydrogen atom.