Bicyclic fibrinogen antagonists

Details Bicyclic fibrinogen antagonists Bicyclic fibrinogen antagonists

1995-08-04

2002-06-11

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S221000, C514S215000, C514S213010, C540S490000, C540S500000, C540S506000, C540S512000, C540S513000, C540S504000, C540S514000, C540S523000

Reexamination Certificate

active

06403578

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel bicyclic compounds which inhibit platelet aggregation, pharmaceutical compositions containing the compounds and methods of using the compounds.
BACKGROUND OF THE INVENTION
Platelet aggregation is believed to be mediated primarily through the fibrinogen receptor, or GPIIb-IIIa platelet receptor complex, which is a member of a family of adhesion receptors referred to as integrins. It has been found that frequently the natural ligands of integrin receptors are proteins which contain an Arg-Gly-Asp sequence. Von Willebrand factor and fibrinogen, which are considered to be natural ligands for the GPIIb-IIIa receptor, possess an Arg-Gly-Asp (RGD in single letter amino acid code) sequence in their primary structure. Functionally, these proteins are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets.
Fibronectin, vitronecfin and thromospondin are RGD-containing proteins which have also been demonstrated to bind to GPIIb-IIIa Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls.
Linear and cyclic peptides which bind to vitronectin and contain an RGD sequence are disclosed in WO 89/05150 (PCT US88/04403). EP 0 275 748 discloses linear tetra- to hexapeptides and cyclic hexa- to octapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation. Other linear and cyclic peptides, the disclosure of which are incorporated herein by reference, are reported in EP-A 0 341 915. However, the peptide like structures of such inhibitors often pose problems, such as in drug delivery, metabolic stability and selectivity. Inhibitors of the fibrinogen receptor which are not constructed of natural amino acid sequences are disclosed in EP-A 0 372,486, EP-A 0 381 033 and EP-A 0 478 363. WO 92/07568 (PCT/US91/08166) discloses fibrinogen receptor antagonists which mimic a conformational &ggr;-turn in the RGD sequence by forming a monocyclic seven-membered ring structure. There remains a need, however, for novel fibrinogen receptor antagonists (e.g. inhibitors of the GPIIb-IIIa protein) which have potent in vivo and in vitro effects and lack the peptide backbone structure of amino acid sequences.
The present invention discloses novel bicyclic compounds including benzazepines and benzodiazepines, which are inhibitors of the GPIIb-IIIa receptor and inhibit platelet aggregation. Certain 5-phenyl-1,4-benzodiazepines are known as a class of drugs which affect the central nervous system, and have been used as anxiolytics. See Sternbach, L. H.,
J. Med. Chem.,
22, 2 (1979). It has also been disclosed that certain 5-phenyl-1,4-benzodiazepines antagonize the effects of cholecystokinin. See Friedinger,
Med. Res. Rev.,
9, 271 (1989). Certain bicyclic compounds which have fibrinogen antagonist activity are disclosed in WO 93/08174 (PCT/US92/08788) and WO 93/00095 (PCT/US/92/05463).
SUMMARY OF THE INVENTION
In one aspect this invention is a bicyclic compound comprising a substituted six-membered ring fused to a substituted seven-membered ring as described hereinafter in formula (I).
This invention is also a pharmaceutical composition for inhibiting platelet aggregation or clot formation, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
This invention further comprises the use of a compound of formula (I) in the manufacture of a medicament for inhibiting platelet aggregation.
In another aspect, this invention provides a method for inhibiting reocclusion of an artery or vein in a mammal following fibrinolytic therapy, which comprises internally administering an effective amount of a fibrinolytic agent and a compound of formula (I). This invention is also a method for treating stroke, transient ischemia attacks, or myocardial infarction.
DETAILED DESCRIPTION OF THE INVENTION
This invention discloses novel bicyclic compounds which inhibit platelet aggregation. The novel bicyclic compounds comprise a seven-membered ring fused to an aromatic six membered ring and having a nitrogen-containing substituent on the six membered ring and an aliphatic substituent, preferably containing an acidic moiety, on the seven membered ring. The fused 6-7 ring system is believed to interact favorably with the GPIIb-IIIa receptor and to orient the substituent sidechains on the six and seven membered rings so that they may also interact favorably with the receptor.
Although not intending to be bound to any specific mechanism of action, these compounds are believed to inhibit the binding of fibrinogen to the platelet-bound fibrinogen receptor GPIIb-IIIa, and may interact with other adhesion proteins via antagonism of a putative RGD binding site.
The compounds of this invention are compounds of formula (I):
wherein
A
1
is O, S, N—R
1
or CHR
1
;
A
4
is N—R
4
or CHR
4
;
R
2
is R
7
or Q—C
1-4
alkyl, Q—C
2-4
alkenyl or Q—C
2-4
alkynyl substituted by R
7
;
R
1
, R
4
and R
5
are H, Q—C
1-6
alkyl, Q—C
1-6
oxoalkyl, Q—C
2-6
alkenyl, Q—C
3-4
oxoalkenyl, Q—C
3-4
oxoalkynyl, Q—C
2-4
alkynyl, C
3-6
cycloalkyl, Ar or Het, optionally substituted by one or more of R
11
;
Q is H, C
3-6
cycloalkyl, Het or Ar;
R
6
is W—(CR′
2
)
q
—Z—(CR′R
10
)
r
—U—(CR′
2
)
s
—V—;
R
7
is —COR
8
, —COCR′
2
R
9
, —C(S)R
8
, —S(O)
m
OR′, —S(O)
m
NR′R″, —PO(OR′), —PO(OR′)
2
, —B(OR′)
2
, —NO
2
and Tet;
R
8
is —OR′, —NR′R″, —NR′SO
2
R′, —NR′OR′, —OCR′
2
C(O)OR′, —OCR′
2
OC(O)—R′, —OCR′
2
C(O)NR′
2
, CH
3
or AA;
R
9
is —OR′, —CN, —S(O)
r
R′, S(O)
m
NR′
2
, —C(O)R′C(O)NR′
2
or —CO
2
R′;
R
10
is H, C
1-4
alkyl or —NR′R″;
R
11
is H, halo, —OR
12
, —CN, —NR′R
12
, —NO
2
, —CF
3
, CF
3
S(O)
r
—, —CO
2
R′, —CONR′
2
, Q—C
0-6
alkyl-, Q—C
1-6
oxoalkyl-, Q—C
2-6
alkenyl-, Q—C
2-6
alkynyl-, Q—C
0-6
alkyloxy-, Q—C
0-6
alkylamino- or Q—C
0-6
alkyl-S(O)
r
—;
R
12
is R′, —C(O)R′, —C(O)NR′
2
, —C(O)OR
15
, —S(O)
m
R′ or S(O)
m
NR′
2
;
R
15
is H, C
1-6
alkyl or Ar—C
0-4
alkyl;
R′ is H, C
1-6
alkyl, C
3-7
cycloalkyl-C
0-4
alkyl or Ar—C
0-4
alkyl;
R″ is R′, —C(O)R′ or —C(O)OR
15
;
R′″ is R″ or AA2;
AA1 is an amino acid attached through its amino group and having its carboxyl group optionally protected, and AA2 is an amino acid attached through its carboxyl group, and having its amino group optionally protected;
U and V are absent or CO, CR′
2
, C(═CR′2), S(O)
n
, O, NR′, CR′OR′, CR′(OR″)CR′
2
, CR′
2
CR′(OR″), C(O)CR′
2
, CR′
2
C(O), CONR′, NR′CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR′, NR′C(S), S(O)
n
NR′, NR′S(O)
n
, N═N, NR′NR′, NR′CR′
2
, CR′
2
NR′, CR′
2
O, OCR′
2
, C≡C or CR′═CR′, provided that U and V are not simultaneously absent;
W is R′R′″N— or
;
Z is (CH
2
)
t
or Het;
m is 1 or 2;
n is 0 to
3
;
q is 0 to
3
;
r is 0 to 2;
s is 0 to 2; and
t is 0 to 2; or
pharmaceutically acceptable salts thereof.
In another embodiment, this invention is a compound of formula (II):
wherein R
1
, R
2
, R
4
, R
5
and R
11
are as defined in for formula (I) and R
6
is W—(CR′
2
)
q
—Z—(CR′R
10
)
r
—U—(CR′
2
)
s
—V—, where U, V and R′ are as defined for formula (I), R
10
is H, C
1-4
alkyl or —NR′R″, W is R′
2
N, H
2
NC(═NH), H
2
NC(═NH)NH or
; and Z is Ar, C
3-7
cycloalkyl, (CH
2
)
t
or Het. In particular, compounds of formula (II) where R
1
is H, C
1-4
alkyl or C(O)R′; R
2
is CH
2
CO
2
H or CH
2
CH
2
CO
2
H, R
4
is H, C
1-6
alkyl, C
3-6
cycloalkylC
0-4
alkyl or Ar—C
0-4
alkyl; and Z is phenyl, a six-membered Het or (CH
2
)
t
, a

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