US2003195248A1PendingUtilityA1
Novel approach to anti-microbial host defense with molecular shields with lipoxin compounds
Priority: Dec 18, 2001Filed: Dec 18, 2002Published: Oct 16, 2003
Est. expiryDec 18, 2021(expired)· nominal 20-yr term from priority
A61P 43/00A61K 31/232A61P 31/04A61K 31/202A61P 31/00
48
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Claims
Abstract
Methods to cause tissue, such as mucosal cells, to express increased amounts of bactericidal permeability increasing protein (BPI) are described. The BPI inducing agents include, for example, lipoxin compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for the stimulation of bactericidal permeability increasing protein (BPI) in a subject's tissue, comprising the step of administering a therapeutically effective amount of lipoxin or a lipoxin analog, such that the subject's tissues express increased levels of BPI to treat infection.
2 . The method of claim 1 , wherein the lipoxin analog has the formula:
wherein R 1 if present can be
and R 2 if present can be
wherein X is R 1 , OR. 1 , or SR 1 ;
wherein R 1 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 Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can 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 Q 1 is (C═O), SO 2 or (CN);
wherein Q 3 is O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b 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 Y 1 or Y 2 is —OH, methyl, or —SH and wherein the other is
(a) a hydrogen atom
(b) CH a Z b
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 Y 1 and Y 2 taken together are
(a) ═NH; or
(b) ═O;
wherein R 5 is
(a) an alkyl of 1 to 9 carbon atoms which can be straight chain or branched;
(b) —(CH 2 ) n —R i
wherein n=0 to 4 and R i is
(i) a cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) a phenyl; or
(iii) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(c) R a Q a R b
wherein Q a is O or S;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched;
wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
(d) —C(R iii )(R iv )—R i
wherein R iii and R iv are each, independently:
(i) a hydrogen atom;
(ii) CH a Z b 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 R 6 is
(a) a hydrogen atom;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) a halogen;
wherein R 3a , and R 3b are each independently:
(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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y 3 or Y 4 is —OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
wherein a+b=3, a=0 to 3, b=0 to 3,
and wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 3 and Y 4 taken together are
(a) ═NH; or
(b) ═O;
wherein Y 5 or Y 6 is —OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
where a+b=3, a=0 to 3, b=0 to 3
wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 5 and Y 6 taken together are
(a) ═NH; or
(b) ═O;
wherein R a is
(a) a hydrogen atom; or
(b) alkyl of 1 to 8 carbon atoms;
wherein R x is
(a) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(b) a substituted phenoxy
wherein Z i through Z v are as defined above; or
wherein Z i through Z v are as defined above.
wherein R b and R c are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or a thiol;
(c) a methyl or a halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms;
wherein R d and R e are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or thiol;
(c) a methyl or halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms; or
(f) an alkyl or haloalkyl of 2 to 4 carbon atoms, inclusive, which can be straight chain or branched.
3 . The method of claim 1 , wherein the lipoxin analog has the formula:
wherein X is R 1 , OR 1 , or SR 1 ;
wherein R 1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbon 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
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Q 1 is (C═O), SO 2 or (CN), provided when Q 1 is CN, then X is absent;
wherein Q 3 and Q 4 are each independently O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b wherein Q 2 is —O— or —S—; wherein R a is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b is a hydrogen atom;
wherein R 4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R 5 is
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Y 1 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 CH a Z b where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R 6 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.
4 . The method of claim 1 , wherein the lipoxin analog has the formula:
5 . A method for the stimulation of bactericidal permeability increasing protein (BPI) in a mucosal cell, comprising the step of administering a therapeutically effective amount of lipoxin or a lipoxin analog, such that the mucosal cell expresses increased levels of BPI to treat infection.
6 . The method of claim 5 , wherein the mucosal cells are epithelial cells.
7 . The method of claim 5 , wherein the mucosal cells are oral epithelial cells.
8 . The method of claim 5 , wherein the epithelial cells are intestinal cells.
9 . The method of claim 5 , wherein the lipoxin analog has the formula:
wherein R 1 if present can be
and R 2 if present can be
wherein X is R 1 , OR. 1 , or SR 1 ;
wherein R 1 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 Z i , Z ii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can 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 Q 1 is (C═O), SO 2 or (CN);
wherein Q 3 is O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein R 4 is
(a) a hydrogen atom;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y 1 or Y 2 is —OH, methyl, or —SH and wherein the other is
(a) a hydrogen atom
(b) CH a Z b
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 Y 1 and Y 2 taken together are
(a) ═NH; or
(b) ═O;
wherein R 5 is
(a) an alkyl of 1 to 9 carbon atoms which can be straight chain or branched;
(b) —(CH 2 ) n —R i
wherein n=0 to 4 and R i is
(i) a cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) a phenyl; or
(iii) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(c) R a Q a R b
wherein Q a is O or S;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched;
wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
(d) —C(R iii )(R iv )—R i
wherein R iii and R iv are each, independently:
(i) a hydrogen atom;
(ii) CH a Z b 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 R 6 is
(a) a hydrogen atom;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) a halogen;
wherein R 3a , and R 3b are each independently:
(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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y 3 or Y 4 is —OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
wherein a+b=3, a=0 to 3, b=0 to 3,
and wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 3 and Y 4 taken together are
(a) ═NH; or
(b) ═O;
wherein Y 5 or Y 6 is —OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
where a+b=3, a=0 to 3, b=0 to 3
wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 5 and Y 6 taken together are
(a) ═NH; or
(b) ═O;
wherein R a is
(a) a hydrogen atom; or
(b) alkyl of 1 to 8 carbon atoms;
wherein R x is
(a) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(b) a substituted phenoxy
wherein Z i through Z v are as defined above; or
wherein Z i through Z v are as defined above.
wherein R b and R c are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or a thiol;
(c) a methyl or a halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms;
wherein R d and R e are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or thiol;
(c) a methyl or halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms; or
(f) an alkyl or haloalkyl of 2 to 4 carbon atoms, inclusive, which can be straight chain or branched.
10 . The method of claim 5 , wherein the lipoxin analog has the formula:
wherein X is R 1 , OR 1 , or SR 1 ;
wherein R 1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbon 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
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Q 1 is (C═O), SO 2 or (CN), provided when Q 1 is CN, then X is absent;
wherein Q 3 and Q 4 are each independently O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b wherein Q 2 is —O— or —S—; wherein R a is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b 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 R 5 is
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Y 1 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 CH a Z b where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R 6 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.
11 . The method of claim 5 , wherein the lipoxin analog has the formula:
12 . A method for inhibition or prevention of infection by bacteria in a subject, comprising the step of administering a therapeutically effective amount of a-lipoxin or lipoxin analog to the subject suitable to cause mucosal cells in the subject to express increased levels of BPI, such that infection by bacteria in the subject is prevented or inhibited.
13 . The method of claim 12 , wherein the mucosal cells are epithelial cells.
14 . The method of claim 12 , wherein the mucosal cells are oral epithelial cells.
15 . The method of claim 12 , wherein the epithelial cells are intestinal cells.
16 . The method of claim 12 , wherein the lipoxin analog has the formula:
wherein R 1 if present can be
and R 2 if present can be
wherein X is R 1 , OR. 1 , or SR 1 ;
wherein R 1 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 Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can 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 Q 1 is (C═O), SO 2 or (CN);
wherein Q 3 is O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein R 4 is
(a) a hydrogen atom;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y 1 or Y 2 is —OH, methyl, or —SH and wherein the other is
(a) a hydrogen atom
(b) CH a Z b
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 Y 1 and Y 2 taken together are
(a) ═NH; or
(b) ═O;
wherein R 5 is
(a) an alkyl of 1 to 9 carbon atoms which can be straight chain or branched;
(b) —(CH 2 ) n —R i
wherein n=0 to 4 and R i is
(i) a cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) a phenyl; or
(iii) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(c) R a Q a R b
wherein Q a is O or S;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched;
wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
(d) —C(R iii )(R iv )—R i
wherein R iii and R iv are each, independently:
(i) a hydrogen atom;
(ii) CH a Z b 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 R 6 is
(a) a hydrogen atom;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) a halogen;
wherein R 3a , and R 3b are each independently:
(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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y 3 or Y 4 is —OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
wherein a+b=3, a=0 to 3, b=0 to 3,
and wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 3 and Y 4 taken together are
(a) ═NH; or
(b) ═O;
wherein Y 5 or Y 6 is OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
where a+b=3, a=0 to 3, b=0 to 3
wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 5 and Y 6 taken together are
(a) ═NH; or
(b) ═O;
wherein R a is
(a) a hydrogen atom; or
(b) alkyl of 1 to 8 carbon atoms;
wherein R x is
(a) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(b) a substituted phenoxy
wherein Z i through Z v are as defined above; or
wherein Z i through Z v are as defined above.
wherein R b and R c are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or a thiol;
(c) a methyl or a halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms;
wherein R d and R c are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or thiol;
(c) a methyl or halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms; or
(f) an alkyl or haloalkyl of 2 to 4 carbon atoms, inclusive, which can be straight chain or branched.
17 . The method of claim 12 , wherein the lipoxin analog has the formula:
wherein X is R 1 , OR 1 , or SR 1 ;
wherein R 1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbon 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
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Q 1 is (C═O), SO 2 or (CN), provided when Q 1 is CN, then X is absent;
wherein Q 3 and Q 4 are each independently O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b wherein Q 2 is —O— or —S—; wherein R a is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b is a hydrogen atom;
wherein R 4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R 5 is
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(—O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Y 1 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 CH a Z b where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R 6 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.
18 . The method of claim 12 , wherein the lipoxin analog has the formula:
19 . A method for inhibition or prevention of invasion by bacteria in a subject, comprising the step of administering a therapeutically effective amount of a lipoxin or lipoxin analog to the subject suitable to cause mucosal cells in the subject to express increased levels of BPI, such that invasion by bacteria in the subject is prevented or inhibited.
20 . The method of claim 19 , wherein the mucosal cells are epithelial cells.
21 . The method of claim 19 , wherein the mucosal cells are oral epithelial cells.
22 . The method of claim 19 , wherein the epithelial cells are intestinal cells.
23 . The method of claim 19 , wherein the lipoxin analog has the formula:
wherein R 1 if present can be
and R 2 if present can be
wherein X is R 1 , OR. 1 , or SR 1 ;
wherein R 1 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 Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can 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 Q 1 is (C═O), SO 2 or (CN);
wherein Q 3 is O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein R 4 is
(a) a hydrogen atom;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y 1 or Y 2 is —OH, methyl, or —SH and wherein the other is
(a) a hydrogen atom
(b) CH a Z b
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 Y 1 and Y 2 taken together are
(a) —NH; or
(b) ═O;
wherein R 5 is
(a) an alkyl of 1 to 9 carbon atoms which can be straight chain or branched;
(b) —(CH 2 ) n —R i
wherein n=0 to 4 and R i is
(i) a cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) a phenyl; or
(iii) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(c) R a Q a R b
wherein Q a is O or S;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched;
wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
(d) —C(R iii )(R iv )—R i
wherein R iii and R iv are each, independently:
(i) a hydrogen atom;
(ii) CH a Z b 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 R 6 is
(a) a hydrogen atom;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) a halogen;
wherein R 3a , and R 3b are each independently:
(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) R a Q 2 R b
wherein Q 2 is —O— or —S—;
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched; and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;
wherein Y 3 or Y 4 is —OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
wherein a+b=3, a=0 to 3, b=0 to 3, and wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 3 and Y 4 taken together are
(a) ═NH; or
(b) ═O;
wherein Y 5 or Y6 is —OH, methyl, hydrogen, or —SH and
wherein the other is
(a) a hydrogen atom;
(b) CH a Z b
where a+b=3, a=0 to 3, b=0 to 3
wherein 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;
(d) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched;
or Y 5 and Y 6 taken together are
(a) ═NH; or
(b) ═O;
wherein R a is
(a) a hydrogen atom; or
(b) alkyl of 1 to 8 carbon atoms;
wherein R x is
(a) substituted phenyl
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which can be a straight chain or branched, and hydroxyl;
(b) a substituted phenoxy
wherein Z i through Z v are as defined above; or
wherein Z i through Z v are as defined above.
wherein R b and R c are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or a thiol;
(c) a methyl or a halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms;
wherein R d and R e are each independently:
(a) a hydrogen atom;
(b) a hydroxyl, or thiol;
(c) a methyl or halomethyl;
(d) a halogen;
(e) an alkoxy of 1 to 3 carbon atoms; or
(f) an alkyl or haloalkyl of 2 to 4 carbon atoms, inclusive, which can be straight chain or branched.
24 . The method of claim 19 , wherein the lipoxin analog has the formula:
wherein X is R 1 , OR 1 , or SR 1 ;
wherein R 1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbon 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
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Q 1 is (C═O), SO 2 or (CN), provided when Q 1 is CN, then X is absent;
wherein Q 3 and Q 4 are each independently O, S or NH;
wherein one of R 2 and R 3 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) R a Q 2 R b wherein Q 2 is —O— or —S—; wherein R a is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b is a hydrogen atom;
wherein R 4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R 5 is
wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x 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 Y 1 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 CH a Z b where a+b=3, a=0 to 3, b=O to 3 and Z is cyano, nitro or a halogen;
wherein R 6 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.
25 . The method of claim 19 , wherein the lipoxin analog has the formula:Join the waitlist — get patent alerts
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