Anticoagulant agents

Details Anticoagulant agents Anticoagulant agents

1998-12-17

2001-03-13

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C215S300000, C215S400000, C215S400000, C215S325000, C215S325000, C215S325000, C540S480000, C540S521000, C546S113000, C548S452000, C548S453000, C548S480000, C564S091000, C564S098000, C564S099000

Reexamination Certificate

active

06200967

ABSTRACT:

This invention relates to thrombin inhibitors which are useful anticoagulants in mammals. In particular it relates to ortho-hydroxybenzamidine derivatives having high anticoagulant activity. Thus, this invention relates to new inhibitors of thrombin, 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 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.
Anticoagulation is currently 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 surface-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. See, for example Robert M. Scarborough,
Annual Resorts in Medicinal Chemistry,
(1995), 30, 71-80, where inhibitors which lack a polarizable functionality to interact with the active site Ser-195 hydroxy group of thrombin are termed active site inhibitors. Active site inhibitors in which the C-terminal moiety comprises an unsubstituted or certain substituted amidinophenyl (benzamidine) moiety are exemplified in EP 623596, WO 94/29336, WO 95/23609 and WO 95/35309. The amidinophenyl moiety is strongly basic, a property which militates against good oral bioavailability. See, for example R. J. Misra, et al.,
Bioorganic & Medicinal Chemistry Letters,
(1994), 4, 2165-2170, where less basic argatroban analogs were shown to retain useful thrombin inhibitory potency while exhibiting better distribution properties as shown by enhanced Caco-2 cell permeability. As discussed below, the compounds disclosed herein retain useful thrombin inhibitory potency while exhibiting improved distribution coefficients as a result of their particularly substituted amidinophenyl moieties. Subsequent to the priority date for the instant application, there were published international patent applications WO 96/24609 and WO 96/25426 disclosing certain substituted amidinophenyl compounds, including D-cyclohexylglycyl-N-[[4-(aminoimino-methyl)-3-hydroxyphenyl]methyl-L-prolinamide dihydrochloride at Example 53 of WO 96/25426.
Although the heparins and coumarins are effective anticoagulants, no generally accepted 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 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 thrombin inhibitors that may have high bioavailability following oral administration.
According to the invention there is provided a compound having the Formula I
X—C(O)—Y—G—R  I
wherein
X—C(O)— is D-prolinyl, D-homoprolinyl, R
m
—(CH
2
)
g
—NH—CH
2
—C(O)—,
in which
R
d
is carboxy or methylsulfonyl;
R
e
is NHR
c
, NHCOR
c
or NHCOOR
c
; in which
R
c
is (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl or a (C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alkyl radical of 4-10 carbons;
T is (C
3
-C
8
)cycloalkyl, (C
1
-C
8
)alkyl,
a is 0, 1 or 2; and
Q is —OH, (C
1
-C
4
)alkoxy, or —NH—A;
A is hydrogen, (C
1
-C
4
)alkyl, R″SO
2
—, R″OC(O)—, R″C(O)—, R
n
C(O)— or —(CH
2
)
g
—R
m
;
g is 1, 2, or 3;
B is hydrogen or (C
1
-C
4
)alkyl;
R′ is hydrogen or (C
1
-C
4
)alkyl;
R″ is (C
1
-C
4
)alkyl, (C
1
-C
4
)fluoroalkyl bearing one to five fluoros, —(CH
2
)
d
—R
m
, or unsubstituted or substituted aryl, where aryl is phenyl, naphthyl, a 5- or 6-membered unsubstituted or substituted aromatic heterocyclic ring, having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen, or a 9- or 10-membered unsubstituted or substituted fused bicyclic aromatic heterocyclic group having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
R
m
is —COOR
b
, —SO
2
(C
1
-C
4
alkyl), —SO
3
H, —P(O)(OR
b
)
2
or tetrazol-5-yl;
R
n
is —COOR
b
or tetrazol-5-yl;
each R
b
is independently hydrogen or (C
1
-C
4
)alkyl;
d is 1, 2, or 3;
m is 0, 1, or 2;
n is 0, 1, or 2; and
Z is hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, hydroxy, halo or (C
1
-C
4
)alkylsulfonylamino;
—V—G— is
in which
r is 0, 1 or 2;
R
g
is (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, or —(CH
2
)
p
—L—(CH
2
)
q
—T′;
R
p
is (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, or —(CH
2
)
p
—L—(CH
2
)
q
—T′;
where p is 0, 1, 2, 3, or 4; L is a bond, —O—, —S—, or —NH—; q is 0, 1, 2 or 3; and T′ is (C
1
-C
4
)alkyl, (C
3
-C
8
)cycloalkyl, —COOH, —CONH
2
, or Ar, where Ar is unsubstituted or substituted aryl, where aryl is phenyl, naphthyl, a 5- or 6-membered unsubstituted or substituted aromatic heterocyclic ring, having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen, or a 9- or 10-membered unsubstituted or substituted fused bicyclic aromatic heterocyclic group having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
R
y
is —CH
2
—, —O—, —S—, or —NH—; and
R
z
is a bond or, when taken with R
y
and the three adjoining carbon atoms, forms a saturated carbocyclic ring of 5-8 atoms, one atom of which may be —O—, —S—, or —NH—;
—G—R is —C(O)—NH—(CH
2
)
s
—R, —CH
2
—NH—(CH
2
)
s
—R, —CH
2
—NH—C(O)—R or —(CH
2
)
t
—O—R in which s is 1 or 2 and t is 1, 2 or 3; and
R is a 4-amidino-3-hydroxyphenyl group bearing 0, 1, 2 or 3 fluoro substituents;
or a pharmaceutically acceptable salt thereof.
In addition to a compound of Formula I, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient.
The present invention further provides a method of inhibiting thrombin comprising administering to a mammal in need of treatment, a thrombin inhibiting dose of a compound of Formula I.
The present invention also provides a method of inhibiting thrombosis in a mammal comprising ad

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