US 2003/0191332 A1Published application

Prevention of neutrophil recruitment

AssigneeThe Brigham and Women's Hospital, Inc.

InventorCharles N. Serhan

Life of this patent

Estimating the term…

Abstract

Aspirin (ASA) triggers a switch in the biosynthesis of lipid mediators, inhibiting prostanoid production and initiating 15-epi-lipoxin generation, through the acetylation of cyclooxygenase II.

Drawings

Claims13

Dependent claims

A compound having the formula:

24
wherein X is R1, ORx, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(Vi) substituted phenyl
25
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Rb is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
26
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4.

32 more elements

A compound having the formula

27
wherein X is R1, ORx, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
28
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Ra is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
29
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=O to 3, b=O to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4.

31 more elements

A compound having the formula

30
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
31
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
32
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4.

30 more elements

An in vivo method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation in a subject, comprising;

administering to the subject an effective anti-inflammatory amount of a pharmaceutical composition comprising a compound having the formula
36
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
37
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
38
wherein Zi, Zii, Zii, 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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4;
and
a pharmaceutically acceptable in vivo carrier.

35 more elements

A method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation in a subject, comprising:

administering to the subject an effective anti-inflammatory amount of a pharmaceutical composition comprising a compound having the formula
39
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
40
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Ra is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
41
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a 0 to 3, b 0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4;
and
a pharmaceutically acceptable carrier.

35 more elements

A pharmaceutical composition comprising a compound having the formula

42
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
43
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C=0), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
44
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof;
and
a pharmaceutically acceptable carrier, provided 16phenoxy-LXA4 is excluded and provided when said compound is 15-epi-16-(para-fluoro)-phenoxy-LXA4, said pharmaceutically acceptable carrier is not a ketone.

34 more elements

A packaged pharmaceutical composition for treating a PMN responsive state in a subject, comprising:

a container holding a therapeutically effective amount of at least one lipoxin compound having the formula
45
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
46
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C=0), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
47
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof;
and
instructions for using said lipoxin compound for treating an PMN responsive state in the subject.

35 more elements

Dependencies are inferred from the claim text.

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Abstract

Aspirin (ASA) triggers a switch in the biosynthesis of lipid mediators, inhibiting prostanoid production and initiating 15-epi-lipoxin generation, through the acetylation of cyclooxygenase II.

Drawings

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Drawings

Claims13

Dependent claims

A compound having the formula:

24
wherein X is R1, ORx, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(Vi) substituted phenyl
25
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Rb is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
26
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4.

32 more elements

A compound having the formula

27
wherein X is R1, ORx, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
28
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Ra is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
29
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=O to 3, b=O to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4.

31 more elements

A compound having the formula

30
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
31
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
32
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4.

30 more elements

An in vivo method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation in a subject, comprising;

administering to the subject an effective anti-inflammatory amount of a pharmaceutical composition comprising a compound having the formula
36
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
37
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
38
wherein Zi, Zii, Zii, 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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4;
and
a pharmaceutically acceptable in vivo carrier.

35 more elements

A method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation in a subject, comprising:

administering to the subject an effective anti-inflammatory amount of a pharmaceutical composition comprising a compound having the formula
39
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
40
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C═O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Ra is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
41
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a 0 to 3, b 0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof, excluding 16-phenoxy-LXA4 and 15-epi-16-(para-fluoro)-phenoxy-LXA4;
and
a pharmaceutically acceptable carrier.

35 more elements

A pharmaceutical composition comprising a compound having the formula

42
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
43
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C=0), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
44
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof;
and
a pharmaceutically acceptable carrier, provided 16phenoxy-LXA4 is excluded and provided when said compound is 15-epi-16-(para-fluoro)-phenoxy-LXA4, said pharmaceutically acceptable carrier is not a ketone.

34 more elements

A packaged pharmaceutical composition for treating a PMN responsive state in a subject, comprising:

a container holding a therapeutically effective amount of at least one lipoxin compound having the formula
45
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
46
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 may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule;
or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (C=0), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a 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 may be straight chain or branched;
or
(e) RaQ2Rb wherein Q2 is —O— or —S—;
wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is
47
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 may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof;
and
instructions for using said lipoxin compound for treating an PMN responsive state in the subject.

35 more elements

Dependencies are inferred from the claim text.

Description13,467 words

Summary1,326 words

#Aspirin (acetylsalicylic acid, ASA) has been available for use as an analgesic-antipyretic for almost a century and novel therapeutic applications for this drug, for example in lowering the risk of myocardial infarction or as a prophylaxis against colorectal cancer, continue to be uncovered (Weissmann, G. (1991) Sci. Am. 264, 84-90; Ridker, P. M., Cushman, M., Stampfer, M. J., Tracy, R. P. & Hennekens, C. H. (1997) N. Engl. J. Med. 336, 973-979; Marcus, A. J. (1995) N. Engl. J. Med. 333, 656-658). The acetylation of cyclooxygenases I and II (COX I and II) and the subsequent irreversible inhibition of prostaglandin (PG) and thromboxane biosyntheses are well understood mechanisms of some of ASA's pharmacological actions (Marcus, A. J. (1995) N. Engl. J. Med. 333, 656-658; Herschman, H. R. (1998) Trends Cardiovasc. Med. 8, 145-150). More recently, ASA was found to cause a switch in eicosanoid biosynthesis as the acetylation of COX II changes the enzyme's activity to produce 15R-hydroxyeicosatetraenoic acid from agonist-released arachidonic acid Herschman, H. R. (1998) Trends Cardiovasc. Med. 8, 145-150). Human neutrophils, and other cells possessing 5-lipoxygenase, utilize this substrate via transcellular biosynthetic routes to produce 15-epi-lipoxin A4 (15-epi-LXA4) and 15-epi-lipoxin B4 (15-epi-LXB4) (Serhan, C. N. (1997) Prostaglandins 53, 107-137; Chiang, N., Takano, T., Clish, C. B., Petasis, N. A., Tai, H. -H. & Serhan, C. N. (1998) J. Pharmacol. Exp. Ther. 287, 779-790). These aspirin-triggered lipoxins (ATL) are the endogenous 15R enantiomeric counterparts of lipoxin A4 (LXA4) and lipoxin B4 (LXB4), respectively, and share their bioactivities (Serhan, C. N. (1997) Prostaglandins 53, 107-137(5)).

#Unlike other cicosanoids (e.g., leukotrienes, PGs, etc.), which are generally considered local pro-inflammatory mediators, lipoxins (LX) display potent inhibitory actions in several key events in inflammation, such as polymorphonuclear cell (PMN) chemotaxis, transmigration across endothelial and epithelial cells, and diapedesis from post-capillary venules (Serhan, C. N. (1997) Prostaglandins 53, 107-137(5)). LX are generated in several pathogenic scenarios in vivo, for example: in lung tissue of patients with severe pulmonary disease; and by PMN from patients with asthma or rheumatoid arthritis, where their presence is proposed to be linked to long-term clinical improvement (Lee, T. H., Crea, A. E., Gant, V., Spur, B. W., Marron, B. E., Nicolaou, K. C., Reardon, E., Brezinski, M. & Serhan, C. N. (1990) Am. Rev. Respir. Dis. 141, 1453-1458; Chavis, C., Chanez, P., Vachier, I., Bousquet, J., Michel, F. B. & Godard, P. (1995) Biochem. Biophys. Res. Commun. 207,273-279; Chavis, C., Vachier, I., Chanez, P., Bousquet, J. & Godard, P. (1996) J. Exp. Med. 183, 1633-1643; Thomas, E., Leroux, J. L., Blotman, F. & Chavis, C. (1995) Inflamm. Res. 44, 121-124). Interestingly, ATL show an even greater level of inhibition than native LX in preventing neutrophil adhesion, where they are twice as potent (Serhan, C. N. (1997) Prostaglandins 53, 107-137). ATL are also more potent inhibitors of microbial induction of cytokine release. Specifically, 15-epi-LXA4 showed greater inhibition than LXA4 of S. typhimurium-induced secretion and gene regulation of the potent leukocyte chemoattractant IL-8, generated by intestinal epithelial cells (Gewirtz, A. T., McCormick, B., Neish, A. S., Petasis, N. A., Gronert, K., Serhan, C. N. & Madara, J. L. (1998) J. Clin. Invest. 101, 1860-1869). It is therefore likely that, in addition to the inhibition of prostaglandin formation, the benefits of ASA therapy also result from the triggering of novel anti-inflammatory lipid mediators that act locally to down regulate leukocytes.

#In one aspect, the present invention is directed to compounds having the formulae (I-V): 1

Brief description of the drawings8 figures

#The invention will be more filly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

#FIG. 1 depicts (A) Initial metabolic step of LXA4 inactivation in mouse whole blood and 15-oxo-LXA4 MS/MS spectrum. LXA4 (21 μM) was incubated ex vivo in mouse whole blood for 3 h. The MS/MS spectrum of the major oxo-product is indicative of 15-oxo-LXA4, with diagnostic product ions at m/z: 349 (a=[M−H]−), 331 (a-H2O), 313 (a-2H2O), 305 (b=[M−H]−-CO2), 287 (b-H2O), 269 (b-2H2O), 233 (c), and 217 (c-0). (B) Biostability of LXA4 and stable analogs in mouse whole blood. LXA4, 15(R/S)-methyl-LXA4 (ATLa1, which carries a racemic methyl group at C-15), and 15-epi-16-(para-fluoro)-phenoxy-LXA4 (ATLa2, in which a bulky (para-fluoro)-phenoxy group replaces the ω-chain at C-16) were added (see Methods) to heparinized mouse whole blood and incubated at 37° C. for 0 and 3 h. Following centrifugation at 800×g and 0° C., the plasma supernatants were drawn off and stopped in two volumes of ice cold methanol. The lipoxins were extracted by solid phase methodology and quantitated by LC/MS/MS. Values represent means±SEM (n=3-4).

#FIG. 2 demonstrates that ATLa2 inhibits TNF-α-induced PMN infiltration by both local air pouch and i.v. delivery. When injected locally into the air pouch, following injection of vehicle (900 μl PBS), murine TNF-α (20 ng/100 μl PBS) induced the infiltration of 4.8±1.1×106 PMN by 4 h. Dexamethasone (10 μg/air pouch), ASA (1 mg/air pouch), and ATLa2 (10 μg/air pouch) were locally administered in 900 μl PBS and prior to TNF-α. Systemic delivery of ATLa2 was by i.v. injection into the mouse tail vein (10 μg/mouse). 2.1±0.7×105 PMN were found in the air pouch 4 h after injection of vehicle (1 ml sterile PBS) alone. Values represent mean±SEM (n=3-5). *P<0.05, P<0.15 Student's two-tailed t-test

Detailed description11,278 words

#The features and other details of the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.

#Aspirin (ASA) triggers a switch in the biosynthesis of lipid mediators, inhibiting prostanoid production and initiating 15-epi-lipoxin generation, through the acetylation of cyclooxygenase II. These aspirin-triggered lipoxins (ATL) may mediate some of ASA's beneficial actions and therefore are of interest in the search for novel anti-inflammatories that could manifest fewer unwanted side-effects. Design modifications to native ATL structure prolong its biostability in vivo. In mouse whole blood, ATL analogs protected at carbon 15 (ATLa1) and the omega end (ATLa2) were recoverable to ˜90 and 100% at 3 hours, respectively, compared to a ˜40% loss of native lipoxin A4 (LXA4). ATLa2 retains bioactivity and, at levels as low as ˜24 mmol/mouse, potently inhibited TNF-α-induced leukocyte recruitment into the dorsal air pouch. Inhibition was evident by either local intra-air pouch delivery (˜77% inhibition) or via systemic delivery by intravenous injection (˜85% inhibition) and proved more potent than local delivery of either ASA or dexamethasone. Rank order for inhibiting PMN infiltration was: ATLa2 (10 μg, i.v.)≈ATLa2 (10 μg, local)>ASA (1.0 mg, local)≈dexamethasone (10 μg, local). Applied topically to mouse ear skin, ATLa2 also inhibited PMN infiltration induced by leukotriene B4 (˜78% inhibition) or phorbol ester, which initiates endogenous chemokine production (˜49% inhibition). These results indicate that this fluorinated analog of natural aspirin-triggered LXA4 is bioavailable by either local or systemic delivery routes and is a more potent and precise inhibitor of neutrophil accumulation than ASA.

#Abbreviations: ASA, Aspirin, acetylsalicylic acid; ATL, aspirin-triggered lipoxins; ATLa1, 15(R/S)-methyl-lipoxin A4; ATLa2, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4; COX I and II, cyclooxygenases I and II; 15-epi-LXA4, 15-epi-lipoxin A4, 5S,6R,15R-trihydroxyeicosa-7E,9E,11Z,13E-tetraenoic acid; 15-epi-LXB4, 15-epi-lipoxin B4, 5S,14R,5R-trihydroxyeicosa-6E,8Z,10E,12E-tetraenoic acid; i.v., intravenous; LC/MS/MS, liquid chromatography-tandem mass spectrometry; LTB4, leukotriene B4, 5S,12R-dihydroxyeicosa-6E,8Z,10Z,14E-eicosatetraenoic acid; LX, lipoxins; LXA4, lipoxin A4, 5S,6R,15S-trihydroxyeicosa-7E,9E,11Z,13E-tetraenoic acid; LXB4, lipoxin B4, 5S,14R,15S-trihydroxyeicosa-6E,8Z,10E,12E-tetraenoic acid; PG, prostaglandin; PMA, phorbol 12-myristate 13-acetate; PMN, polymorphonuclear leukocyte; TNF-α, tumor necrosis factor α.

Abstract

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Claims13

Abstract

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Claims13

Description13,467 words

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Classification11 codes

Life of this patent

Description13,467 words