US2008064749A1PendingUtilityA1
Lipoxin Analogs as Novel Inhibitors of Angiogenesis
Est. expiryMar 2, 2021(expired)· nominal 20-yr term from priority
A61P 35/00A61P 9/08A61P 43/00A61P 9/10A61P 9/00A61P 27/02A61K 31/202A61K 31/203A61P 17/02A61K 31/20
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Claims
Abstract
The present invention is directed to methods for the prevention or inhibition of angiogenesis. The method is accomplished by the administration of an effective amount of 15-epi-16-(para-fluoro)-phenoxy-lipoxin A 4 , LXA 4 , 15-epi-LXA 4 or 15-R/S-methyl, LXA 4 and pharmaceutically acceptable salts, esters, amides, carboxylic acids, or prodrugs thereof, to a subject in need thereof. As a consequence of the action of the therapeutic agent, angiogenesis is prevented or inhibited in the subject.
Claims
exact text as granted — not AI-modified1 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a formula:
wherein X is R 1 , OR x , 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 , if present, is
(a) a hydrogen atom;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
(c) a halogen; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
2 . The method of claim 1 , further comprising a pharmaceutically acceptable carrier.
3 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a formula:
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) an alkenyl of 2 to 8 carbon atoms, inclusive, straight chain or branched;
wherein n=1 to 10, inclusive;
wherein R 2 , 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 1 or Y 2 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, 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 1 and Y 2 taken together are
(a) ═NH; or
(b) ═O;
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 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) 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—; and
wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched;
wherein R b is either alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched or substituted phenyl;
(d) —C(R iii )(R iv )—R i
wherein R iii and R iv are each independently:
(i) a hydrogen atom; or
(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; or
(e) haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
4 . The method of claim 3 , further comprising a pharmaceutically acceptable carrier.
5 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a formula:
wherein R a is
(a) a hydrogen atom; or
(b) alkyl of 1 to 8 carbon atoms;
wherein R b and R c , if present, 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 , if present, 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 alkyls or haloalkyl of 2 to 4 carbon atoms, inclusive, which can be straight chain or branched
wherein R x , if present, 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; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
6 . The method of claim 5 , further comprising a pharmaceutically acceptable carrier.
7 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a formula:
wherein R a is
(a) a hydrogen atom; or
(b) an alkyl of 1 to 8 carbon atoms;
wherein R b and R c are each independently:
(a) a hydrogen atom;
(b) a hydroxyl or a thiol;
(c) a halomethyl;
(d) a halogen;
(e) an alkyl of 1 to 3 carbon atoms, inclusive, straight chain or branched; or
(f) an alkoxy of 1 to 3 carbon atoms, inclusive;
wherein R d and R e , if present, 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, inclusive; or
(f) an alkyl or haloalkyl of 2 to 4 carbon atoms, inclusive, which can be straight chain or branched;
wherein R 5 , if present, 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) 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 either alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched or substituted phenyl;
(d) —C(R iii )(R iv ) 13 R i
wherein R iii and R iv are each, independently:
(i) a hydrogen atom; or
(ii) CH a Z b where a+b=3, a=0 to 3, b=0+3
wherein each Z, independently, is a cyano, a nitro, or a halogen atom; or
(e) haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
8 . The method of claim 7 , further comprising a pharmaceutically acceptable carrier.
9 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a formula:
wherein R a is
(a) a hydrogen atom; or
(b) alkyl of 1 to 8 carbon atoms, inclusive, straight chain or branched; and
wherein R b and R c are each, independently:
(a) a hydrogen atom;
(b) a hydroxyl or a thiol;
(c) a halomethyl;
(d) a halogen;
(e) an alkyl of 1 to 3 carbon atoms, inclusive, straight chain or branched;
(f) an alkoxy of 1 to 3 carbon atoms, inclusive; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
10 . The method of claim 9 , further comprising a pharmaceutically acceptable carrier.
11 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a formula:
wherein R a is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which can be straight chain or branched; or
(iii) a detectable label molecule;
wherein n=1 to 10, inclusive;
wherein Y 2 , 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 1 is —OH, methyl, or —SH;
wherein Y 2 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; or
(c) an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched;
wherein Y 3 and Y 5 are each independently:
(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; or
(c) an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched;
wherein Y 4 and Y 6 are each, independently
(a) a hydrogen atom;
(b) an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched;
(c) an alkoxy of 1 to 4 carbon atoms, inclusive, straight chain or branched; or
(d) a hydroxyl or thiol; and
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 3 and R i is
(i) a cycloalkyl of 3 to 10 carbon atoms, inclusive;
(ii) phenyl;
(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
(a) 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;
(d) a haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
12 . The method of claim 11 , further comprising a pharmaceutically acceptable carrier.
13 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a 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 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
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, if present, are each independently O, S or NH;
wherein one of R 2 and R 3 , if present, 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 carbons 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 , if present, 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, if present, is O or S; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
14 . The method of claim 13 , further comprising a pharmaceutically acceptable carrier.
15 . A method to prevent, reduce or inhibit angiogenesis comprising the step of administering to a subject an effective amount of a 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 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
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 R 4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched; and
pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, such that angiogenesis is prevented, reduced or inhibited in the subject.
16 . The method of claim 15 , further comprising a pharmaceutically acceptable carrier, wherein said pharmaceutical carrier is not a ketone.Join the waitlist — get patent alerts
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