US 5,441,951 A · Lipoxin compounds

Abstract

Compounds having the active site of natural lipoxins, but a longer tissue half-life are disclosed. These small molecules are useful for treating vasoconstrictive, inflammatory, myeloid suppressive, cardiovascular, and gastrointestinal diseases.

Claims20

Dependent claims

A lipoxin compound having an active region of a natural lipoxin and a metabolic transformation region resistant to in vivo metabolism.

A lipoxin compound of the structural formula:

##STR64## wherein X is R.sub.1, OR.sub.1, or SR.sub.1 ;
wherein R.sub.1 is
(i) hydrogen;
(ii) alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;
(iv) aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl ##STR65## wherein Z.sub.i, Z.sub.iii,, and Z.sub.v are each independently selected from the group consisting of --NO.sub.2, --CN, --C(.dbd.O)--R.sub.1, --SO.sub.3 H, and hydrogen;
wherein Z.sub.ii and Z.sub.iv are each independently selected from the group consisting of halogen, methyl, hydrogen, and hydroxyl;
(vii) detectable label molecule;
or
(viii) straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q.sub.1 is (C.dbd.O), SO.sub.2 or (CN);
wherein Q.sub.3 is O, S or NH;
wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is
(a) H;
(b) alkyl of 1 to 8 carbon atoms, inclusive, which may be straight chain or branched;
(c) cycloalkyl of 3 to 6 carbon atoms, inclusive;
(d) alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched;
or
(e) R.sub.a Q.sub.2 R.sub.b wherein Q.sub.2 is --O-- or --S--;
wherein R.sub.a is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched;
and wherein R.sub.b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched;
wherein R.sub.4 is
(a) H;
(b) alkyl of 1 to 6 carbon atoms, inclusive, which may be straight chain or branched;
wherein Y.sub.1 or Y.sub.2 is --OH, methyl, or --SH and wherein the other is
(a) H
(b) CH.sub.a Z.sub.b where a+b=3, a=0 to 3, b=0 to 3;
and Z is cyano, nitro, or halogen;
(c) alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched;
or
(d) alkoxy of 1 to 4 carbon atoms, inclusive;
or Y.sub.1 and Y.sub.2 taken together are
(a) .dbd.N;
or
(b) .dbd.O;
wherein R.sub.5 is
(a) alkyl of 1 to 9 carbon atoms which may be straight chain or branched;
(b) --(CH.sub.2).sub.n --R.sub.i wherein n=0 to 4 and R.sub.i is
(i) cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) phenyl;
or
(iii) substituted phenyl ##STR66## wherein Z.sub.i, Z.sub.iii,, and Z.sub.v are each independently selected from the group consisting of hydrogen, --NO.sub.2, --CN, --C(.dbd.O)--R.sub.1, methoxy, and --SO.sub.3 H;
and wherein Z.sub.ii and Z.sub.iv are each independently selected from the group consisting of halogen, methyl, hydrogen, and hydroxyl;
(c) --R.sub.a Q.sub.a R.sub.b wherein Q.sub.a =--O-- or --S--;
wherein R.sub.a is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched;
wherein R.sub.b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched;
(d) --C(R.sub.iii)(R.sub.iv)--R.sub.i wherein R.sub.iii and R.sub.iv are selected independently from the group consisting of
(i) H;
(ii) CH.sub.a Z.sub.b where a+b=3, a=0 to 3, b=0+3, and wherein any Z is independently selected from the group consisting of halogen;
(e) haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched;
and
wherein R.sub.6 is
(a) H;
(b) alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) halogen;
but excluding the C-1 position amides, C-1 position alkanoates, and pharmaceutically acceptable C-1 position salts of (5S, 6R, 15S)-trihydroxy-7E, 9E, 11Z, 13E-eicosatetraenoic acid (LXA.sub.4);
and excluding C-5, C-6, and C-15 position alkanoates of LXA.sub.4.

56 more elements

Dependencies are inferred from the claim text.

Abstract

Claims20

Dependent claims

A lipoxin compound having an active region of a natural lipoxin and a metabolic transformation region resistant to in vivo metabolism.

A lipoxin compound of the structural formula:

##STR64## wherein X is R.sub.1, OR.sub.1, or SR.sub.1 ;
wherein R.sub.1 is
(i) hydrogen;
(ii) alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;
(iv) aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl ##STR65## wherein Z.sub.i, Z.sub.iii,, and Z.sub.v are each independently selected from the group consisting of --NO.sub.2, --CN, --C(.dbd.O)--R.sub.1, --SO.sub.3 H, and hydrogen;
wherein Z.sub.ii and Z.sub.iv are each independently selected from the group consisting of halogen, methyl, hydrogen, and hydroxyl;
(vii) detectable label molecule;
or
(viii) straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q.sub.1 is (C.dbd.O), SO.sub.2 or (CN);
wherein Q.sub.3 is O, S or NH;
wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is
(a) H;
(b) alkyl of 1 to 8 carbon atoms, inclusive, which may be straight chain or branched;
(c) cycloalkyl of 3 to 6 carbon atoms, inclusive;
(d) alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched;
or
(e) R.sub.a Q.sub.2 R.sub.b wherein Q.sub.2 is --O-- or --S--;
wherein R.sub.a is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched;
and wherein R.sub.b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched;
wherein R.sub.4 is
(a) H;
(b) alkyl of 1 to 6 carbon atoms, inclusive, which may be straight chain or branched;
wherein Y.sub.1 or Y.sub.2 is --OH, methyl, or --SH and wherein the other is
(a) H
(b) CH.sub.a Z.sub.b where a+b=3, a=0 to 3, b=0 to 3;
and Z is cyano, nitro, or halogen;
(c) alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched;
or
(d) alkoxy of 1 to 4 carbon atoms, inclusive;
or Y.sub.1 and Y.sub.2 taken together are
(a) .dbd.N;
or
(b) .dbd.O;
wherein R.sub.5 is
(a) alkyl of 1 to 9 carbon atoms which may be straight chain or branched;
(b) --(CH.sub.2).sub.n --R.sub.i wherein n=0 to 4 and R.sub.i is
(i) cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) phenyl;
or
(iii) substituted phenyl ##STR66## wherein Z.sub.i, Z.sub.iii,, and Z.sub.v are each independently selected from the group consisting of hydrogen, --NO.sub.2, --CN, --C(.dbd.O)--R.sub.1, methoxy, and --SO.sub.3 H;
and wherein Z.sub.ii and Z.sub.iv are each independently selected from the group consisting of halogen, methyl, hydrogen, and hydroxyl;
(c) --R.sub.a Q.sub.a R.sub.b wherein Q.sub.a =--O-- or --S--;
wherein R.sub.a is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched;
wherein R.sub.b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched;
(d) --C(R.sub.iii)(R.sub.iv)--R.sub.i wherein R.sub.iii and R.sub.iv are selected independently from the group consisting of
(i) H;
(ii) CH.sub.a Z.sub.b where a+b=3, a=0 to 3, b=0+3, and wherein any Z is independently selected from the group consisting of halogen;
(e) haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched;
and
wherein R.sub.6 is
(a) H;
(b) alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) halogen;
but excluding the C-1 position amides, C-1 position alkanoates, and pharmaceutically acceptable C-1 position salts of (5S, 6R, 15S)-trihydroxy-7E, 9E, 11Z, 13E-eicosatetraenoic acid (LXA.sub.4);
and excluding C-5, C-6, and C-15 position alkanoates of LXA.sub.4.

56 more elements

Dependencies are inferred from the claim text.

Lipoxin compounds

Life of this patent

Abstract

Claims20

Lipoxin compounds

Life of this patent

Abstract

Claims20