IP Library › Granted Patent US 7,915,311
Granted Patent B2
US 7,915,311 · App. 11/837,693 · Granted Mar 29, 2011

Approach to anti-microbial host defense with molecular shields with lipoxin compounds

Assignee: The Brigham and Women's Hospital, Inc.
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Quick Facts
Patent No.
US 7,915,311
App. No.
11/837,693
Granted
Mar 29, 2011
Kind
B2
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 (144)

1. A method to treat sepsis in a subject, comprising the step of administering to a subject infected with sepsis a therapeutically effective amount of a lipoxin analog according to formula I or II,

wherein formula I is:

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 3 , 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; and

wherein formula II is:

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, such that the subject with sepsis is treated.

2. The method of claim 1 , wherein the lipoxin analog has the formula:

3. The method of claim 1 , further comprising a pharmaceutically acceptable carrier.

4. The method of claim 2 , further comprising a pharmaceutically acceptable carrier, wherein said pharmaceutically acceptable carrier is not a ketone.

Assignments (1)
CONFIRMATORY LICENSE Recorded Oct 1, 2020
From: BRIGHAM AND WOMEN'S HOSPITAL
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 053948/0696 →
Continuity (3)
Continuation 10323591 · Dec 18, 2002
Provisional Application 60342138 · Dec 18, 2001
Related Publication 20080214665A1 · Sep 4, 2008