Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-09
2002-07-09
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S379000, C514S416000, C514S616000, C514S620000, C546S234000, C548S241000, C548S482000, C564S155000, C564S157000, C564S164000, C564S244000, C564S246000
Reexamination Certificate
active
06417200
ABSTRACT:
This invention relates to antithrombotic carboximidamide derivatives which demonstrate activity as inhibitors of factor Xa and, accordingly, which are useful anticoagulants in mammals. In particular it relates to carboximidamide derivatives having high anticoagulant activity, and antithrombotic activity. Thus, this invention relates to new inhibitors of factor Xa, pharmaceutical compositions containing the compounds as active ingredients, and the use of the compounds as anticoagulants for prophylaxis and treatment of thromboembolic disorders such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, myocardial infarction and cerebral thrombosis, general hypercoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, and generalized tissue injury as it relates to the inflammatory process. In addition, the antithrombotic agents are useful as anticoagulants in in vitro applications.
The process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade leading to the formation of thrombin. Thrombin proteolytically removes activation peptides from the A&agr;-chains and the B&bgr;-chains of fibrinogen, which is soluble in blood plasma, initiating insoluble fibrin formation. The formation of thrombin from prothrombin is catalyzed by factor Xa.
Anticoagulation currently is achieved by the administration of heparins and coumarins. Parenteral pharmacological control of coagulation and thrombosis is based on inhibition of thrombin through the use of heparins. Heparins act indirectly on thrombin by accelerating the inhibitory effect of endogenous antithrombin III (the main physiological inhibitor of thrombin). Because antithrombin III levels vary in plasma and because clot-bound thrombin seems resistant to this indirect mechanism, heparins can be an ineffective treatment. Because coagulation assays are believed to be associated with efficacy and with safety, heparin levels must be monitored with coagulation assays (particularly the activated partial thromboplastin time (APTT) assay). Coumarins impede the generation of thrombin by blocking the posttranslational gamma-carboxylation in the synthesis of prothrombin and other proteins of this type. Because of their mechanism of action, the effect of coumarins can only develop slowly, 6-24 hours after administration. Further, they are not selective anticoagulants. Coumarins also require monitoring with coagulation assays (particularly the prothrombin time (PT) assay).
Recently, interest has grown in small synthetic molecules which demonstrate potent direct inhibition of thrombin and factor Xa. See, Jeremy J. Edmunds and Stephen T. Rapundalo (Annette M. Doherty, Section Editor),
Annual Reports in Medicinal Chemistry,
(1996), 31, 51-60.
Although the heparins and coumarins are effective anticoagulants, no commercial drug has yet emerged from the small synthetic molecules; and despite the continuing promise for this class of compounds, there still exists a need for anticoagulants which act selectively on factor Xa or thrombin, and which, independent of antithrombin III, exert inhibitory action shortly after administration, preferably by an oral route, and do not interfere with lysis of blood clots, as required to maintain hemostasis.
The present invention is directed to the discovery that the compounds of the present invention, as defined below, are potent inhibitors of factor Xa which may have high bioavailability following oral administration.
According to the invention there is provided a method of inhibiting factor Xa comprising using an effective amount of a factor Xa inhibiting compound of formula I
wherein
A
3
, A
4
, A
5
and A
6
, together with the two carbons to which-they are attached, complete a substituted benzene in which A
3
is CR
3
, A
4
is CR
4
, A
5
is CR
5
, and A
6
is CR
6
;
wherein
R
3
is hydrogen, hydroxy, [(1-2C)alkyl]carbonyloxy (which may bear an &ohgr;-carboxy substituent), benzoyloxy (which may bear one or more halo, hydroxy methoxy or methyl substitutents), methyl or methoxy;
one of R
4
and R
5
is hydrogen, methyl, halo, trifluoro-methyl, nitro, amino(imino)methyl, amino(hydroxyimino)methyl, R
f
O—, R
f
O
2
C—, R
f
O
2
C—CH
2
—, R
f
O
2
C—CH
2
—O—, 3-methoxycarbonyl-1-oxopropyl, R
g
NH— or bis(methylsulfonyl)amino;
the other of R
4
and R
5
is hydrogen, halo or methyl; and
R
6
is hydrogen, hydroxy, [(1-2C)alkyl]carbonyloxy (which may bear an (&ohgr;-carboxy substituent), benzoyloxy (which may bear one or more halo, hydroxy methoxy or methyl substitutents), methyl or methoxy;
in which R
f
is hydrogen, (1-4C)alkyl or benzyl; R
g
is hydrogen, acetyl, trifluoroacetyl, phenylalanyl, 2-(t-butoxycarbonylamino)-4-methylsulfinyl-1-oxobutyl or R
h
SO
2
—; and R
h
is (1-4C)alkyl, trifluoromethyl, phenyl, 3,5-dimethylisoxazol-4-yl or dimethylamino; or
two adjacent residues selected from R
3
, R
4
, R
5
and R
6
together form a benz ring; and the other two are each hydrogen; or
A
3
, A
4
, A
5
and A
6
, together with the two carbons to which they are attached, complete a substituted heteroaromatic ring in which
(a) one of A
3
, A
4
, A
5
and A
6
is N, and each of the others is CR
3
, CR
4
, CR
5
or CR
6
, respectively;
(b) two adjacent residues of A
3
, A
4
1
, A
5
and A
6
together form S, and each of the others is CR
3
, CR
4
, CR
5
or CR
6
, respectively;
(c) two non-adjacent residues of A
3
, A
4
, A
5
and A
6
are each N, and each of the others is CR
3
, CR
4
, CR
5
or CR
6
, respectively; or
(d) A
3
and A
4
together form a fused benz ring, and A
5
and A
6
together form —NH—;
wherein
each of R
3
, R
4
, R
5
and R
6
is hydrogen, or one or two of R
3
, R
4
, R
5
and R
6
is independently chloro, bromo or methyl and the others are hydrogen;
L
1
is —NH—CO—, —CO—NH—or —O—CH
2
— such that —L
1
—Q
1
is —NH—CO—Q
1
, —CO—NH—Q
1
or —O—CH
2
—Q
1
(provided that when —L
1
—Q
1
is —CO—NH—Q
1
, then R
2
is not —CO—NH—Q
1
or —CO—NH—Q
2B
);
Q
1
is Q
1A
, Q
1B
or Q
1C
wherein
Q
1A
is
in which R
a
is hydrogen, R
b
is hydrogen and R
c
is hydrogen or hydroxy; or R
a
is hydroxy, R
b
is hydrogen and R
c
is hydrogen; or R
a
and R
b
together form a methylene or oxo group and R
c
is hydrogen;
Q
1B
is
in which R
d
is hydrogen or hydroxy and R
e
is hydrogen or fluoro; and
Q
1C
is
R
2
is a residue defined for —NH—CO—Q
1
or —CO—NH—Q
1
; or
R
2
is —L
2A
—Q
2A
, —L
2B
—Q
2B
, —L
2C
—Q
2C
or —L
2D
—Q
2D
wherein
L
2A
is a direct bond; and
Q
2A
is
in which D is carbonyl or —CHR
k
in which R
k
is hydrogen, hydroxy, (1-6C)alkoxy or —CH
2
—R
j
in which R
j
is carboxy, [(1-4C)alkoxylcarbonyl or carbamoyl which may bear one or two (1-2C)alkyl substituents on the nitrogen; and one of R
m
and R
n
is hydrogen and the other is amino, bromo, (1-4C)alkyl or (1-4C)alkoxy, or R
m
and R
n
together form a benz ring;
L
2B
is —NH—CO—, —CO—NH—, —O—CO—, —CH
2
—O— or —O—CH
2
— such that —L
2B
—Q
2B
is —NH—CO—Q
2B
, —CO—NH—Q
2B
, —O—CO—Q
2B
, —CH
2
—O—Q
2B
or —O—CH
2
—Q
2B
; and
Q
2B
is
in which R
o
is hydrogen, halo, (1-6C)alkyl, (1-4C)alkoxy, benzyloxy or (1-4C)alkylthio; and R
p
is 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl, 4-pyridinyl, dimethylaminosulfonyl or —J—R
q
in which J is a single bond, methylene, carbonyl, oxo, —S(O)
q
— (wherein q is 0, 1 or 2), or —NR
r
— (wherein R
r
is hydrogen or methyl); and R
q
is (1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl;
L
2C
is —NR
v
—CO—X—, —NR
v
—CS—Y—, —CH
2
—CO—NR
w
—CH
2
—, —O—CO—, —O—CH
2
—, —S—CH
2
— or —CH
2
—NR
x
—CH
2
— such that —L
2C
—Q
2C
is —NR
v
—CO—X—Q
2C
, —NR
v
—CS—Y—Q
2C
, —CH
2
—CO—NR
w
—CH
2
—Q
2C
, —O—CO—Q
2C
, —O—CH
2
—Q
2C
, —S—CH
2
—Q
2C
or —CH
2
—NR
x
—CH
2
—Q
2C
in which X is —(CH
2
)x— (wherein x is 0, 1 or 2), —NR
w
—CH
2
—, —O—CH
2
— or —S—CH
2
—; Y is —NR
w
—CH
2
— or —O—CH
2
—; each of R
v
and R
w
is independently hydrogen, benzyl or (1-6C)alkyl which is not branched at the &agr;-position; and R
x
is hydrogen, benzyloxycarbonyl or [(
Beight Douglas Wade
Craft Trelia Joyce
Franciskovich Jeffry Bernard
Goodson Jr. Theodore
Hall Steven Edward
Eli Lilly and Company
Huang Evelyn Mei
Jackson Thomas E.
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