Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism

Patent metadata

Field	Value
Publication number	US-9120744-B2
Application number	US-62412609-A
Country	US
Kind code	B2
Filing date	Nov 23, 2009
Priority date	Apr 16, 2007
Publication date	Sep 1, 2015
Grant date	Sep 1, 2015

Abstract

The invention relates to plasminogen activator-1 (PAI-1) inhibitor compounds and uses thereof in the treatment of any disease or condition associated with elevated PAI-1. The invention includes, but is not limited to, the use of such compounds to modulate lipid metabolism and treat conditions associated with elevated PAI-1, cholesterol, or lipid levels.

First claim

What is claimed is:

1. A compound of formula CLVII or a salt, ester, or prodrug thereof:

wherein
k, l, and o are independently 0, 1, 2, 3, 4, 5, or 6;
W is C or N;
X 1 , X 2 , X 3 , X 4 , and X 5 are independently selected from the group consisting of —H, —OH, —OR, —F, —Cl, —Br, —I, —NO 2 , —NO, —N(R) 2 , —N(R) 3 + , —C(O)R,—C(O)OR, —CHO, —C(O)NH 2 , —C(O)SR, —CN, —S(O) 2 R, —SO 3 R, —SO 3 H, —SO 2 N(R) 2 , —S═O, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
Y 1 is selected from the group consisting of O, NH, NR a , S, and CH 2 ;
Y 2 is selected from the group consisting of O, NH, NR b , S, and CH 2 ;
R, R a , and R b are independently selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, CH 2 —C 3 -C 6 cycloalkyl, phenyl, tolyl, and benzyl;
Z 1 and Z 2 are independently selected from the group consisting of C, P—OH, S, and S═O;
U is selected from the group consisting of —NR c C(O)OR e , —NR c C(O)NR f R e , —NR c C(O)SR e , —NR c P(O)(OH)R e , —NR c P(O)(OH)OR e , —NR c P(O)(OH)NR f R e , —NR c P(O)(OH)SR e , —NR c S(O)R e , —NR c S(O)OR e , —NR c S(O)NR f R e , NR c S(O)SR e , —NR c S(O) 2 R e , —NR c S(O) 2 OR e , NR c S(O) 2 NR f R e , —NR c S(O) 2 SR e , —OC(O)OR e , —OC(O)NR f R e , —OC(O)SR e , —OP(O)(OH)R e , —OP(O)(OH)OR e , —OP(O)(OH)NR d R e , —OP(O)(OH)SR e , —OS(O)R e , —OS(O)OR e , —OS(O)NR d R e , —OS(O)SR e , —OS(O) 2 R e , —OS(O) 2 OR e , —OS(O) 2 NR d R e , —OS(O) 2 SR, and —C(O)R c ;
R c and R d are independently selected from the group consisting of H, C 1 to C 12 alkyl, C 1 to C 12 haloalkyl, C 3 to C 6 cycloalkyl, (CH 2 ) m —C 3 -C 6 cycloalkyl, C 2 to C 6 heterocycloalkyl, (CH 2 ) m —C 2 -C 6 heterocycloalkyl, benzyl, aryl, (CH 2 ) m -aryl, heteroaryl, (CH 2 ) m -heteroaryl, and substituted derivatives thereof, or R c and R d taken together with the N atom to which they are bonded form a 3- to 8-membered heterocyclic ring;
m is 1, 2, 3, 4, 5, or 6;
R f is selected from the group consisting of H, C 1 to C 12 alkyl, C 1 to C 12 haloalkyl, C 3 to C 6 cycloalkyl, (CH 2 ) m —C 3 -C 6 cycloalkyl, C 2 to C 6 heterocycloalkyl, (CH 2 ) m —C 2 -C 6 heterocycloalkyl, benzyl, aryl, (CH 2 ) m -aryl, heteroaryl, (CH 2 ) m -heteroaryl, and substituted derivatives thereof; and
R e is selected from the group consisting of H, C 1 to C 12 alkyl, C 1 to C 12 haloalkyl, C 3 to C 6 cycloalkyl, (CH 2 ) m —C 3 -C 6 cycloalkyl, C 2 to C 6 heterocycloalkyl, (CH 2 ) m —C 2 -C 6 heterocycloalkyl, benzyl, aryl, (CH 2 ) m -aryl, heteroaryl, (CH 2 ) m -heteroaryl,

 and substituted derivatives thereof.

2. The compound of claim 1 having a formula LXIII, or a salt, ester, or prodrug thereof:

wherein k, l, o, W, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Z 1 , Z 2 , and U are as defined in claim 1 .

3. The compound of claim 1 or a salt, ester, or prodrug thereof, wherein R e is substituted aryl having a formula:

X 5 and X 6 are independently selected from the group consisting of —H, —OH, —OR, —F, —Cl, —Br, —I, —NO 2 , —NO, —N(R) 2 , —N(R) 3 ± , —C(O)R, —C(O)OR, —CHO, —C(O)NH 2 , —C(O)SR, —CN, —S(O) 2 R, —SO 3 R, —SO 3 H, —SO 2 N(R) 2 , —S═O, aryl, substituted aryl, and heteroaryl; and
R is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, CH 2 —C 3 -C 6 cycloalkyl, phenyl, tolyl, and benzyl.

4. The compound of claim 1 or a salt, ester, or prodrug thereof, wherein R e is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 2,5-dihydroxyphenyl, 2,5-dimethoxyphenyl, 3-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 2,4-dihydroxyphenyl, 2,4-dimethoxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 3,5-difluoro-4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-difluoro-4-methoxyphenyl, 4-methylphenyl, phenyl, naphthyl, biphenyl, indolyl, methyl, 2-chlorophenyl, (1-trichloromethyl-1-methyl)ethyl, 1,1-dimethylethyl, 2,2-dimethylpropyl, benzyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl, (4-pyridinyl)methyl, and

5. The compound of claim 1 having a formula XCI or a salt, ester, or prodrug thereof:

wherein R e is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 2,5-dihydroxyphenyl, 2,5-dimethoxyphenyl, 3-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl, 2,4-dihydroxyphenyl, 2,4-dimethoxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 3,5-difluoro-4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-difluoro-4-methoxyphenyl, 4-methylphenyl, phenyl, and methyl.

6. The compound of claim 1 having a formula XCII or a salt, ester, or prodrug thereof:

wherein R e is selected from the group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, (1-trichloromethyl-l-methyl)ethyl, 3-(trifluoromethyl)phenyl, 2,2-dimethylpropyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3-iodobenzyl, 4-iodobenzyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl, (4-pyridinyl) methyl, C 1 to C 6 alkyl, and

7. The compound of claim 1 , wherein R c , R d , and R f are independently selected from the group consisting of phenyl, tolyl, naphthyl, biphenyl, and indolyl.

8. The compound of claim 1 having a formula CL or a salt, ester, or prodrug thereof:

wherein X 1 and X 3 are independently selected from the group consisting of —H and —OH; U is selected from the group consisting of —NHC(O)OR e and —NHC(O)NHR e ; and R e is selected from the group consisting of 1-naphthyl, 2-naphthyl, 4-biphenyl-1-yl, and substituted derivatives thereof.

9. A compound having a formula selected from the group consisting of LXIV, LXXXI, LXXXVI, LXXXIX, XC, C, CIII, CIV, CXII, CXIII, CXIV, CXIX, CXX, CXXI, CXXXV, CXXXVI, CXXXVII, CXXXVIII, CXXXIX, CLX, CLXI, and salts, esters, or prodrugs thereof:

10. The compound of claim 1 or a salt, ester, or prodrug thereof, wherein U is —NR c C(O)OR e .

Assignees

• Lawrence Daniel A
• Emal Cory
• Cale Jacqueline
• Su Enming J
• Warnock Mark
• Li Shih-Hon
• Cupp Jeanne A
• Univ Michigan
• Eastern Michigan University

Inventors

• Lawrence Daniel A
• Emal Cory
• Cale Jacqueline
• Su Enming J
• Warnock Mark
• Li Shih-Hon
• Cupp Jeanne A

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title