6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic...

Details 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic... 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic...

2002-06-13

2003-07-08

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S374000, C514S378000, C514S381000, C514S406000, C514S419000, C514S470000, C514S471000, C514S569000, C548S252000, C548S374100, C548S492000, C548S236000, C549S467000, C549S488000, C560S021000, C560S022000

Reexamination Certificate

active

06589970

ABSTRACT:

This invention relates to the composition and utility of 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis.
BACKGROUND OF THE INVENTION
Plasminogen activator inhibitor-1 (PAI-1) is a major regulatory component of the plasminogen-plasmin system. PAI-1 is the principal physiologic inhibitor of both tissue type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA). Elevated plasma levels of PAI-1 have been associated with thrombotic events as indicated by animal experiments (Krishnamurti,
Blood,
69, 798 (1987); Reilly,
Arteriosclerosis and Thrombosis,
11, 1276 (1991); Carmeliet,
Journal of Clinical Investigation,
92, 2756 (1993)) and clinical studies (Rocha,
Fibrinolysis,
8, 294,1994; Aznar,
Haemostasis
24, 243 (1994)). Antibody neutralization of PAI-1 activity resulted in promotion of endogenous thrombolysis and reperfusion (Biemond,
Circulation,
91, 1175 (1995); Levi,
Circulation
85, 305, (1992)). Elevated levels of PAI-1 have also been implicated in diseases of women such as polycystic ovary syndrome (Nordt,
Journal of clinical Endocrinology and Metabolism,
85, 4, 1563 (2000)) and bone loss induced by estrogen deficiency (Daci,
Journal of Bone and Mineral Research,
15, 8, 1510 (2000)). Accordingly, agents that inhibit PAI-1 would be of utility in treating conditions originating from fibrinolytic disorder such as deep vein thrombosis, coronary heart disease, pulmonary embolism, polycystic ovary syndrome, etc.
U.S. Pat. No. 5,530,019 describes compounds of the general formula:
wherein R
1
is optionally protected carboxy(lower)alkyl, R
2
is H, optionally substituted aryl or carboxy; X is a bond, —O—, —NH— or a cycloalkylene, and Y is an alkylene which may be interrupted by an oxygen atom, an alkenylene or an alkadienylene, which are described as useful as testosterone 5&agr;-reductase inhibitors useful in treating such diseases as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism, androgenic alopecia, acne, and other hyperandrogenisms.
DESCRIPTION OF THE INVENTION
This invention comprises compounds of the formula:
Wherein:
Ar is phenyl, naphthyl, furanyl, benzofuranyl, indolyl, pyrazolyl, oxazolyl, fluorenyl, phenylcycloalkane where the cycloalkane can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and Ar can be optionally substituted by from 1 to 3 groups selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, phenyl-(CH
2
)
0-6
—, phenyl-(CH
2
)
0-6
O—, C
3
-C
6
cycloalkyl, —(CH
2
)—C
3
-C
6
cycloalkyl, halogen, C
1
-C
3
perflouroalkyl and C
1
-C
3
perfluoroalkoxy where phenyl can be substituted with from 1 to 3 groups selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;
R
1
is hydrogen, C
1
-C
6
alkyl or phenyl-(CH
2
)
1-6
— where phenyl can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy;
R
2
and R
3
are independently hydrogen, C
1
-C
6
alkyl, phenyl-(CH
2
)
0-3
—, halogen and C
1
-C
3
perfluoroalkyl where phenyl can be substitute with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy;
R
4
is —CHR
5
CO
2
H, —CH
2
-tetrazole or an acid mimic or mimetic; where R
5
is hydrogen or optionally substituted benzyl; and
n=0 or 1;
or a pharmaceutically acceptable salt or ester form thereof.
One group of compounds of this invention includes those of the formulae 1 or
R
1
is hydrogen, C
1
-C
6
alkyl or phenyl-(CH
2
)
1-6
— where phenyl can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
2
and R
3
are independently hydrogen, C
1
-C
6
alkyl, phenyl-(CH
2
)
0-3
—, halogen and C
1
-C
3
perfluoroalkyl where phenyl can be substitute with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
4
is —CHR
5
CO
2
H or an acid mimic such as tetrazole, —CH
2
-tetrazole, SO
3
H, PO
3
H
2
, tetronic acid, etc.;
R
5
is hydrogen or benzyl;
R
6
is selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, phenyl-(CH
2
)
0-6
—, phenyl-(CH
2
)
0-6
O—, C
3
-C
6
, cycloalkyl, halogen, C
1
-C
3
perflouroalkyl and C
1
-C
3
perfluoroalkoxy; where the phenyl ring in these R
6
groups can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenyl-(CH
2
)
0-3
—, halogen, trifluoromethyl or trifluoromethoxy;
or a pharmaceutically acceptable salt or ester form thereof.
A second group of compounds of this invention includes those of the formula:
wherein:
Ar is a moiety selected from the group of:
 R
1
is hydrogen, C
1
-C
6
alkyl or phenyl-(CH
2
)
1-6
— where phenyl can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
2
and R
3
are independently hydrogen, C
1
-C
6
alkyl, phenyl-(CH
2
)
0-3
—, halogen and C
1
-C
3
perfluoroalkyl where phenyl can be substitute with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
4
is —CHR
5
CO
2
H or an acid mimic such as tetrazole, —CH
2
-tetrazole, SO
3
H, PO
3
H
2
, tetronic acid, etc.;
R
5
is hydrogen or benzyl;
R
7
is selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, phenyl-(CH
2
)
0-6
—, phenyl-(CH
2
)
0-6
O—, C
3
-C
6
cycloalkyl, halogen, C
1
-C
3
perflouroalkyl and C
1
-C
3
perfluoroalkoxy; where the phenyl ring in these R
7
groups can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;
R
8
and R
9
are each independently selected from H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenyl-(CH
2
)
0-3
—, halogen, trifluoromethyl or trifluoromethoxy;
or a pharmaceutically acceptable salt or ester form thereof.
A third subgroup of compounds of this invention comprises those of the formula:
wherein:
R
1
is hydrogen, C
1
-C
6
alkyl or phenyl-(CH
2
)
1-6
— where phenyl can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
2
and R
3
are independently hydrogen, C
1
-C
6
alkyl, phenyl-(CH
2
)
0-3
—, halogen and C
1
-C
3
perfluoroalkyl where phenyl can be substitute with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
4
is —CHR
5
CO
2
H or an acid mimic such as tetrazole, —CH
2
-tetrazole, SO
3
H, PO
3
H
2
, tetronic acid, etc.;
R
5
is hydrogen or benzyl;
R
7
is selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, phenyl-(CH
2
)
0-6
—, phenyl-(CH
2
)
0-6
O—, C
3
-C
6
, cycloalkyl, halogen, C
1
-C
3
perflouroalkyl and C
1
-C
3
perfluoroalkoxy; where the phenyl ring in these R
7
groups can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenyl-(CH
2
)
0-3
—, halogen, trifluoromethyl or trifluoromethoxy;
R
8
and R
9
are each independently selected from H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;
or a pharmaceutically acceptable salt or ester form thereof.
A fourth subgroup of compounds of this invention comprises those of the formula:
wherein:
R
1
is hydrogen, C
1
-C
6
alkyl or phenyl-(CH
2
)
1-6
— where phenyl can be substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
2
and R
3
are independently hydrogen, C
1
-C
6
alkyl, phenyl-(CH
2
)
0-3
—, halogen and C
1
-C
3
perfluoroalkyl where phenyl can be substitute with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, trifluoromethyl or trifluoromethoxy.
R
4
is —CHR
5
CO
2
H or an acid mimic such as tetrazole, —CH
2
-tetrazole, SO
3
H, PO
3
H
2
, tetronic acid, etc.;
R
5
is hydrogen or benzyl;
R
10
is selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, C
3
-C
6
, cycloalkyl, halogen, C
1
-C
3
perflouroalkyl and C
1
-C
3
perfluoroalkoxy;
R
11
is selected from C
1
-C
6
alkyl, phenyl-(CH
2
)
0-6
—, C
3
-C
6
cycloalkyl, or —(CH
2
)— C
3
-C
6
cycloalkyl; where the phenyl ring in these R
7
groups ca

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