Substituted naphthyl benzofuran derivatives as inhibitors of...

Details Substituted naphthyl benzofuran derivatives as inhibitors of... Substituted naphthyl benzofuran derivatives as inhibitors of...

2002-06-18

2003-07-29

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S382000, C514S469000, C548S243000, C548S250000, C549S414000, C549S469000, C549S471000

Reexamination Certificate

active

06599925

ABSTRACT:

This invention relates to the composition and the utility of substituted naphthyl benzofuran 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 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 (t-PA) and urokinase type plasminogen activator (u-PA). 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 fibrosis, polycystic ovary syndrome, etc.
U.S. Pat. No. 6,110,963 claims benzofuran derivatives useful in the treatment of hyperglycemia.
WO 95/10513 (Pfizer Inc.) discloses benzothiophenes and related compounds of formula I as estrogen agonists.
wherein: X=S, O, etc.; Y=alkyl, cycloalkyl, cycloalkenyl, phenyl, a 5- or 6-membered heterocycle, or a bicyclic ring system consisting of a 5- or 6-membered heterocyclic ring fused to a phenyl ring, all optionally substituted.
U.S. Pat. Nos. 5,948,795 and 5,962,698 (Eli Lilly and Company) describe benzothiophene derivatives of formula I and their use as PAI-1 inhibitors.
wherein: R
1
, R
2
, and R
3
are independently —OH, —OCO(C
1
-C
6
)alkyl, —O(CO)O(C
1
-C
6
)alkyl, —OCO-phenyl, —OCO-substituted phenyl, or O(CO)O-phenyl; and R
4
is N-pyrrolidinyl, N-piperidinyl, or N-hexamethyleneimino.
EP 0 655 439 (Eli Lilly and Company) teaches 5,6 fused ring bicyclic compounds inclusive of indoles, benzofurans, and benzothiophenes corresponding to the general formula I as platelet aggregation inhibitors:
wherein: A is an acidic group linked to the 5-membered ring by linking group L
a
, where L
a
is either a bond or a divalent chain of 1-15 carbon atoms; B is a basic group linked to the 6-membered ring by linking group L
b
, where L
b
is either a bond or a divalent chain of 1-15 carbon atoms.
DESCRIPTION OF THE INVENTION
This invention comprises compounds of formula 1:
wherein:
R, R
1
, R
2
, and R
3
are independently selected from hydrogen, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, —CH
2
-C
3
-C
6
cycloalkyl), C
1
-C
6
alkanoyl, halo, hydroxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, amino, —NH(alkyl of 1-6 carbon atoms), —N(alkyl of 1-6 carbon atoms)
2
, and perfluoroalkoxy of 1-6 carbon atoms;
R
4
is hydrogen, alkyl of 1-6 carbon atoms, branched alkyl of 1-6 carbon atoms, perflouroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, alkenyl-aryl, —CH
2
R
5
, —CH(OH)R
5
, —C(O)R
5
, —CH(SH)R
5
, or —C(S)R
5
or —(CH
2
)
n
—C
3
to C
6
cycloalkyl wherein n is an integer of from 0 to 2;
R
5
is hydrogen, alkyl of 1-6 carbon atoms, branched alkyl of 1-6 carbon atoms, perflouroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, alkenyl-aryl or —(CH
2
)
n
—C
3
to C
6
cycloalkyl wherein n is an integer of from 0 to 2;
R
6
is selected from hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, —CH
2
-cycloalkyl of 3 to 6 carbon atoms, alkylaryl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
n is an integer of 0-6;
A is COOH, or an acid mimic or mimetic; or a pharmaceutically acceptable salt or ester form thereof.
Acid mimic or mimetics which are included in the acidic groups of this invention, as noted in the definition of A, above, particularly include the pharmaceutically useful carboxylic acid mimics or mimetics known in the art, such as those described in R. Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press (1992), the contents of which are incorporated herein by reference. Non-limiting examples of these acid mimics include such as tetrazole, SO
3
H, PO
3
H
2
, tetronic acid, etc., or groups having the formulae:
wherein R
7
is C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
3
-C
6
cycloalkyl, —CH
2
—(C
3
-C
6
cycloalkyl), C
3
-C
6
cycloalkenyl, —CH
2
—(C
3
-C
6
cycloalkenyl), optionally substituted aryl or heteroaryl groups or optionally substituted —C
1
-C
6
alkyl-aryl or —C
1
-C
6
alkyl-heteroaryl, with the aryl and heteroaryl groups and their optional substitution as defined herein.
A subset of the compounds of this invention are those of the formula 2:
wherein R, R
1
, R
2
, R
3
, R
4
, R
6
, A, and n are as defined above, or a pharmaceutically acceptable salt or ester form thereof.
A further subset of the compounds of this invention comprises those having the formula 3:
wherein R, R
1
, R
2
, and R
3
, are as defined above,
n=0
A
1
is a carboxylic acid or a tetrazole group
2
R
6
is a hydrogens, C
1
-C
6
alkyl or a benzyl group optionally substituted by from 1 to 3 groups selected from the list of substituents for the aryl or heteroaryl groups described below;
Y represents two single bonded H atoms; one H and one OH; or a double bonded oxygen atom; and
R
5
is selected from C
1
-C
8
alkyl, preferably C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, —CH
2
—C
3
-C
6
cycloalkyl, or benzyl, the rings of the cycloalkyl and benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, C
1
-C
3
alkyl, C
1
-C
3
perfluoroalkyl, preferably —CF
3
, —O—C
1
-C
3
perfluoroalkyl, preferably —O—CF
3
, C
1
-C
3
alkoxy, —OH, —NH
2
, or —NO
2
;
or a pharmaceutically acceptable salt or ester form thereof.
As used herein, “aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryl groups include phenyl, naphthyl and the like. As used herein, “heteroaryl” refers to a monocyclic or bicyclic aromatic group of from 1 to carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). Such heteroaryl groups can have a single ring, such as pyridyl, pyrrolyl or furyl groups, or multiple condensed rings, such as indolyl, indolizinyl, benzofuranyl or benzothienyl groups. Preferred heteroaryls include pyridyl, pyrrolyl and furyl. It will be understood that the definitions of aryl and heteroaryl also refer to those portions of any aroyl or heteroaroyl groups described herein.
Unless otherwise limited by the definition for the aryl or heteroaryl groups herein, such groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, amino substituted by one or two alkyl groups of from 1 to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro, thioalkoxy of from 1 to 6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbon atoms, and trihalomethyl. Substituents on the alkyl, alkenyl, alkynyl, thioalkoxy and

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