# US 2008/0188543 A1 · Pharmaceutical compositions containing substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)

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- Number: US 2008/0188543 A1
- Document ID: US20080188543A1
- Status: Published application
- Kind: A1
- Application number: 12/026,268
- Filed: 2008-02-05
- Published: 2008-08-07
- Earliest claimed: 2007-02-05
- Assignees: Wyeth
- Inventors: Arun A. THAKUR; Mannching Sherry Ku; Hsueh-Ling Wu
- Web page: https://patentgrep.com/patent/US20080188543A1

## CPC

- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/4816: {Wall or shell material}
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Pharmaceutical compositions containing compounds of formula I are provided: wherein the constituent variables are as defined herein. The compounds are inhibitors of plasminogen activator inhibitor-1 (PAI-1) and the compositions are useful for treating conditions resulting from fibrinolytic disorders, such as deep vein thrombosis and coronary heart disease, Alzheimer's disease and pulmonary fibrosis.

## Claims

### Claim 1

A composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate or ester thereof:
wherein:
R1 is selected from C1-C8 alkyl, (—CH2)n—C3-C6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH2-pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups independently selected from halogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, —O—C1-C3 perfluoroalkyl, C1-C3 alkoxy, —OH, —NH2, and —NO2;
R2 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, —CH2—C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl, —CH2OH or CH2OAc;
R3 is selected from H, halogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, —CH2—C3-C6 cycloalkyl, C3-C6 cycloalkenyl, —CH2—C3-C6 cycloalkenyl, —NH2, or —NO2;
R4 is phenyl substituted by from 1 to 3 groups independently selected from halogen, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 perfluoroalkyl, and —O—C1-C3 perfluoroalkyl; and
from 1% to 25% w/w of one or more surfactants.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the compound of formula (I) is a compound of formula (II) or (III), or a pharmaceutically acceptable salt, solvate or ester thereof:

### Claim 3 (depends on 2)

The composition of claim 2, wherein the compound of formula (I) is a compound of formula (IV) or formula (V), or a pharmaceutically acceptable salt, solvate or ester thereof:
wherein:
R1 is selected from C1-C8 alkyl, C3-C6 cycloalkyl, —CH2—C3-C6 cycloalkyl, or benzyl, the rings of the cycloalkyl and benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, —O—C1-C3 perfluoroalkyl, C1-C3 alkoxy, —OH, —NH2, or —NO2;
R2 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, —CH2—C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl;
R3 is selected from H, halogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, —CH2—C3-C6 cycloalkyl, —NH2, or —NO2; and
R5, R6 and R7 are independently selected from H, halogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, —O—C1-C3 perfluoroalkyl, and C1-C3 alkoxy, provided that at least one of R5, R6 and R7 is not H.

### Claim 4 (depends on 3)

The composition of claim 3, wherein the compound of formula (I) is a compound of formula (VI), or a pharmaceutically acceptable salt, solvate or ester thereof:
wherein:
R1 is selected from benzyl, the benzyl group being optionally substituted by from 1 to 3 groups independently selected from halogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, —O—C1-C3 perfluoroalkyl, and C1-C3 alkoxy;
R2 is H;
R3 is H; and
R5, R6 and R7 are independently selected from H, halogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, —O—C1-C3 perfluoroalkyl and C1-C3 alkoxy, provided that at least one of R5, R6 and R7 is not H.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the compound of formula (I) is:
a) {1-Methyl-6-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
b) {1-Methyl-6-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
c) {1-Ethyl-6-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
d) {1-Ethyl-6-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
e) {1-Benzyl-6-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
f) {1-Benzyl-6-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
g) {1-[4-(tert-Butyl)benzyl]-6-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
h) {1-[4-(tert-Butyl)benzyl]-6-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
i) {1-Benzyl-5-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
j) {6-[4-(tert-Butyl)phenyl]-1-methyl-1H-indol-3-yl}(oxo)acetic acid;
k) [5-(4-Acetylphenyl)-1-benzyl-1H-indol-3-yl](oxo)acetic acid;
l) {1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
m) {1-Benzyl-4-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
n) {1-Benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
o) [1-Benzyl-5-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetic acid;
p) {1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
q) {1-Benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
r) [1-Benzyl-7-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetic acid;
s) {1-(4-tert-Butylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
t) {1-Benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
u) [1-Benzyl-6-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid;
v) {1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
w) {1-(4-Methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
x) {1-(4-Fluorobenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
y) [1-Butyl-5-(4-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid;
z) [1-Butyl-5-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid;
aa) [1-Butyl-5-(3-methoxyphenyl)-1H-indol-3-yl](oxo)acetic acid;
bb) [1-Butyl-5-(4-methoxyphenyl)-1H-indol-3-yl](oxo)acetic acid;
cc) {1-Butyl-5-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
dd) [1-(4-tert-Butylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid;
ee) [1-(4-tert-Butylbenzyl)-5-(3-methoxyphenyl)-1H-indol-3-yl](oxo)acetic acid;
ff) [1-(4-tert-Butylbenzyl)-5-(4-tert-butylphenyl)-1H-indol-3-yl](oxo)acetic acid;
gg) [1-(4-tert-Butylbenzyl)-5-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid;
hh) [1-(4-tert-Butylbenzyl)-5-(4-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid;
ii) [1-(4-tert-Butylbenzyl)-5-(2-methylphenyl)-1H-indol-3-yl](oxo)acetic acid;
jj) {1-(2-Ethylbutyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
kk) {2-[(Acetyloxy)methyl]-1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
ll) {2-(Hydroxymethyl)-1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
mm) {2-[(Acetyloxy)methyl]-1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
nn) {1-Benzyl-2-(hydroxymethyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
oo) [5-(3-Chlorophenyl)-1-cyclopentyl-1H-indol-3-yl]-oxo-acetic acid;
pp) [5-(3-chlorophenyl)-1-(cyclobutylmethyl)-1H-indol-3-yl](oxo)acetic acid;
qq) [5-(3-chlorophenyl)-1-(3-methylcyclopropyl)-1H-indol-3-yl](oxo)acetic acid;
rr) [5-(3-chlorophenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid;
ss) 5-(4-trifluoromethylphenyl)-1-(cyclopentyl)-1H-indol-3-yl](oxo)acetic acid;
tt) [5-(4-trifluoromethylphenyl)-1-(cyclobutylmethyl)-1H-indol-3-yl](oxo)acetic acid;
uu) [5-(4-trifluoromethylphenyl)-1-(3-methylcyclopentyl)-1H-indol-3-yl](oxo)acetic acid;
vv) [5-(4-trifluoromethylphenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid;
ww) [5-(4-trifluoromethylphenyl)-1-(cyclopentylpropyl)-1H-indol-3-yl](oxo)acetic acid;
xx) [5-(3-trifluoromethylphenyl)-1-(cyclopentyl)-1H-indol-3-yl](oxo)acetic acid;
yy) [5-(3-trifluoromethylphenyl)-1-(cyclobutylmethyl)-1H-indol-3-yl](oxo)acetic acid;
zz) [5-(3-trifluoromethylphenyl)-1-(3-methylcyclopentyl)-1H-indol-3-yl](oxo)acetic acid;
aaa) [5-(3-trifluoromethylphenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid;
bbb) [5-(3-trifluoromethylphenyl)-1-(cyclopentylpropyl)-1H-indol-3-yl](oxo)acetic acid; or
ccc) [5-(4-methoxyphenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid;
or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the compound is micronized [1-(4-tert-Butylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid, or a micronized pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 7 (depends on 6)

The composition of claim 6, wherein the composition comprises from 1% to 50% w/w of the compound.

### Claim 8 (depends on 6)

The composition of claim 6, wherein the composition comprises from 3.33% to 33% w/w of the compound.

### Claim 9 (depends on 6)

The composition of claim 6, wherein the composition comprises from 5% to 20% w/w of one or more surfactants.

### Claim 10 (depends on 6)

The composition according to claim 6, wherein the composition comprises from 5% to 15% w/w of one or more surfactants.

### Claim 11 (depends on 6)

The composition according to claim 6, wherein the composition comprises from 7% to 12.5% w/w of one or more surfactants.

### Claim 12 (depends on 6)

The composition according to claim 6, wherein the composition comprises about 20% w/w of one or more surfactants.

### Claim 13 (depends on 6)

The composition according to claim 6, wherein the composition comprises about 15% w/w of one or more surfactants.

### Claim 14 (depends on 6)

The composition according to claim 6, wherein the composition comprises about 10% w/w of one or more surfactants.

### Claim 15 (depends on 6)

The composition according to claim 6, wherein the composition comprises about 5% w/w of one or more surfactants.

### Claim 16 (depends on 9)

The composition according to claim 9, wherein at least one of the surfactants of the invention is a sodium docusate, a cyclodextrin, a polysorbate, a centrimide, a d-alpha-tocopheryl polyethylene glycol, a sodium lauryl sulfate, or a poloxamer.

### Claim 17 (depends on 16)

The composition according to claim 16, wherein at least one of the surfactants is d-alpha-tocopheryl polyethylene glycol 1000 succinate or sodium lauryl sulfate.

### Claim 18 (depends on 6)

The composition according to claim 6, comprising from 1% to 35% w/w of one or more binders.

### Claim 19 (depends on 6)

The composition according to claim 6, comprising from 3% to 30% w/w of one or more binders.

### Claim 20 (depends on 6)

The composition according to claim 6, comprising from 5% to 25% w/w of one or more binders.

### Claim 21 (depends on 6)

The composition according to claim 6, comprising from 10% to 20% w/w of one or more binders.

### Claim 22 (depends on 6)

The composition according to claim 6, comprising about 15% w/w of one or more binders.

### Claim 23 (depends on 18)

The composition according to claim 18, comprising at least one binder selected from the group consisting of microcrystalline cellulose, povidone, carbomers, polyoxamers, starch, methyl cellulose, chitosan, sodium alginate, sucrose, maltose, and gelatin.

### Claim 24 (depends on 6)

The composition according to claim 6, comprising 1% to 15% w/w of one or more disintegrants.

### Claim 25 (depends on 6)

The composition according to claim 6, comprising 2% to 12% w/w of one or more disintegrants.

### Claim 26 (depends on 6)

The composition according to claim 6, comprising 2% to 10% w/w of one or more disintegrants.

### Claim 27 (depends on 6)

The composition according to claim 6, comprising 2% to 8% w/w of one or more disintegrants.

### Claim 28 (depends on 6)

The composition according to claim 6, comprising about 5% w/w of one or more disintegrants.

### Claim 29 (depends on 24)

The composition according to claim 24, comprising at least one disintegrant selected from croscarmellose sodium, sodium starch glycolate, povidone and starch.

### Claim 30 (depends on 6)

The composition according to claim 6, comprising from 0.01% to 5% w/w of one or more glidants.

### Claim 31 (depends on 6)

The composition according to claim 6, comprising about 0.5% w/w of one or more glidants.

### Claim 32 (depends on 30)

The composition according to claim 30, comprising glidants selected from colloidal silicon dioxide, talc, magnesium silicate or calcium silicate.

### Claim 33 (depends on 6)

The composition according to claim 6, comprising from 0.01% to 5% w/w of one or more lubricants.

### Claim 34 (depends on 6)

The composition according to claim 6, comprising about 0.5% w/w of one or more lubricants.

### Claim 35 (depends on 33)

The composition according to claim 33, comprising lubricants selected from magnesium stearate, sodium stearyl fumarate or stearic acid.

### Claim 36 (depends on 6)

The composition according to claim 6, comprising from 10% to 85% w/w of one or more fillers.

### Claim 37 (depends on 6)

The composition according to claim 6, wherein the composition comprises from 1% to 50% w/w of the compound; and 5% to 20% w/w of one or more surfactants.

### Claim 38 (depends on 6)

The composition according to claim 6, wherein the composition comprises from 1% to 50% w/w of the compound; 5% to 20% w/w of one or more surfactants; and from 1% to 35% w/w of binders.

### Claim 39 (depends on 38)

The composition according to claim 38, further comprising from 1% to 15% w/w of one or more disintegrants.

### Claim 40 (depends on 39)

The composition according to claim 39, further comprising from 0.01% to 5% w/w of one or more glidants; from 0.01% to 1% w/w of one or more lubricants; and from 50% to 80% w/w of one or more fillers.

### Claim 41 (depends on 6)

The composition according to claim 6, wherein the composition comprises from 3.33% to 33% w/w of the compound; and from 5% to 15% w/w of one or more surfactants.

### Claim 42 (depends on 6)

The composition according to claim 6, wherein the composition comprises from 3.33% to 33% w/w of a compound of formula (I); and from 5% to 15% w/w of one or more surfactants; and from 3% to 30% w/w of binders.

### Claim 43 (depends on 42)

The composition according to claim 42, further comprising from 2% to 12% w/w of one or more disintegrants.

### Claim 44 (depends on 43)

The composition according to claim 43, further comprising from 0.01% to 5% w/w of one or more glidants; from 0.01% to 1% w/w of one or more lubricants; and from 50% to 80% w/w of one or more fillers.

### Claim 45 (depends on 1)

A method of treating Alzheimer's disease comprising the administration of a composition according to claim 1 to a mammal in need thereof.

### Claim 46 (depends on 1)

A method of increasing or normalizing levels of plasmin concentration comprising the administration of a composition according to claim 1 to a mammal in need thereof.