Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-21
2003-04-01
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...
C514S228200, C514S235800, C514S322000, C514S394000, C514S406000, C544S062000, C544S139000, C546S199000, C548S262800, C548S266400, C548S306100, C548S310700, C548S364700
Reexamination Certificate
active
06541499
ABSTRACT:
This invention relates to thrombin inhibitors which are useful anticoagulants in mammals. In particular it relates to heterocyclic derivatives having high anticoagulant activity, and antithrombotic 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 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.
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. See, for example Robert M. Scarborough,
Annual Reports in Medicinal Chemistry,
(1995), 30, 71-80.
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 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 and favorable pharmacokinetics following oral administration.
According to the invention there is provided a method of inhibiting thrombin comprising using an effective amount of a thrombin inhibiting compound of formula I (or a pharmaceutically acceptable salt thereof)
wherein
E is CH or CR
e
in which R
e
is methyl, methoxy or halo;
R denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
R
1
is R
1a
, R
1b
, or R
1c
in which
R
1a
is —CH
2
—R
r
, in which R
r
is 5-tetrazolyl, 2-carboxypyrrolidin-1-yl or 2-[[(1-4C)alkoxy]carbonyl]-pyrrolidin-1-yl; 2-carboxy-5-oxopyrrolidin-1-yl or 2-[[(1-4C)alkoxy]carbonyl]-5-oxopyrrolidin-1-yl;
R
1b
is —X
1
—(CH
2
)
s
—NR
s
R
t
in which X
1
is a direct bond, methylene or O; s is 1 or 2; provided that when s is 1, then X
1
is a direct bond, and further provided that the chain —(CH
2
)
s
— may bear one or two methyl or ethyl substituents or may be part of a trans-1,2-cyclohexanediyl; and R
s
and R
t
are independently hydrogen or (1-3C)alkyl or the group NR
s
R
t
is pyrrolidino, piperidino, morpholino, 1-imidazolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl, or benzylamino; and
R
1c
is —X
1
—(CH
2
)
s
—NR
s
R
t
in which X
1
is a direct bond, methylene or O; s is 1 or 2; provided that when s is 1, then X
1
is a direct bond, and further provided that the chain —(CH
2
)
s
— may bear one or two methyl or ethyl substituents or may be part of a trans-1,2-cyclohexanediyl; and the group NR
s
R
t
is 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 2-oxoimidazolidin-1-yl, 3-methyl-2-oxoimidazolidin-1-yl, 2-oxopyrrolidin-3-yl, 1-methyl-2-oxopyrrolidin-3-yl, 1-tetrazolyl, methylsulfonylamino or phenylsulfonylamino; and
R
2
is R
2a
, R
2b
, or R
2c
in which
R
2a
is —X
2
—(CH
2
)
n
—R
f
in which X
2
is a direct bond, methylene or O; n is 1, 2 or 3; and R
f
is 5-tetrazolyl, carboxy, [(1-4C)alkoxy]carbonyl or hydroxymethyl; or (provided that when n is 1, X
2
is a direct bond) R
f
is 2-carboxypyrrolidin-1-yl, 2-[[(1-4C)alkoxy]carbonyl]pyrrolidin-1-yl, (carboxymethyl)amino, [[(1-4C)alkoxy]carbonylmethyl]amino, (4-carboxymethylimidazol-1-yl)amino, [4-[[(1-4C)alkoxy]carbonylmethyl]imidazol-1-yl]amino, (4-carboxybenzyl)amino, [4-[[(1-4C)alkoxy]carbonyl]benzyl]amino, (3-amino-1,4-dioxo-4-hydroxybutyl)amino or [3-amino-1,4-dioxo-[(1-4C)alkoxy]butyl]amino;
R
2b
is —X
2
—(CH
2
)
m
—NR
a
R
b
in which X
2
is a direct bond, methylene, O or S; m is 1, 2, 3, 4 or 5; provided that when m is 1, then X
2
is a direct bond; and R
a
and R
b
are independently hydrogen, or (1-3C)alkyl, or one of R
a
and R
b
is hydrogen or methyl and the other is t-butyl, benzyl, or pyridylmethyl; or the group NR
a
R
b
is pyrrolidino, piperidino, morpholino, 1-imidazolyl, 1-pyrazolyl, or 1,2,4-triazol-4-yl; or
R
2b
is —[X
2
—(CH
2
)
n
]
p
—N(R
a
)—CO—A in which X
2
is a direct bond, methylene or O; n is 1, 2, 3 or 4; p is 0 or 1, R
a
is hydrogen or methyl; and —CO—A is a natural or unnatural &agr;-amino acyl group, which may bear one or more pharmaceutically acceptable protecting groups and may be further substituted on the &agr;-nitrogen; and
R
2c
is hydrogen, or
R
2c
is —NR
a
—CO—(CH
2
)
m
—R
b
or —O—CH
2
—R
b
in which m is 0 or 1, R
a
is hydrogen or methyl, and R
b
is a ring of formula XII or formula XIII
in which G is O, S, NH or CH
2
and R
c
is hydrogen or methyl, and L is NR
f
or CH
2
and R
f
is hydrogen or methyl; or
R
2c
is —NHCOR
g
in which R
g
is a five-membered heteroaromatic ring having 2 heteroatoms selected from O, S and N and in which the carbonyl group is bonded to a ring carbon situated between a ring heteroatom and another ring carbon; or
R
2c
is —(CH
2
)
n
—R
h
, —O—(CH
2
)
n
—R
h
or —NH—(CH
2
)
n
—R
h
in which n is 0, 1 or 2 and R
h
is cyclopentyl, cyano, or —CONR
i
R
j
in which R
i
and R
j
are independently hydrogen or methyl or the group NR
i
R
j
is pyrrolidino, piperidino, or morpholino; or
R
2c
is —X
2
—(CH
2
)
p
—R
k
, or —O—CH
2
—CH(CH
3
)—R
k
in which X
2
is a direct bond, methylene or O and p is 1, 2 or 3, provided that when p is 1, then X
2
is a direct bond, and R
k
is 2-oxopyrrolidin-1-yl or NHCOR
m
in which R
m
is (1-3C)alkyl, phenyl or pyridyl; or
R
2c
is —NH—CO—NR
i
R
j
in which R
i
and R
j
are independently hydrogen or methyl or the group NR
i
R
j
is pyrrolidino, piperidino, or morpholino; or
R
2c
is —O—CO—NR
p
R
q
in which R
p
and R
q
are independently hydrogen, methyl or ethyl or the group NR
p
R
q
is pyrrolidino, piperidino, or morpholino; or
R
2c
is —NH—SO
2
—R
r
in which
Bastian Jolie A
Chirgadze Nickolay Y
Denney Michael L
Fisher Matthew J
Foglesong Robert J
Anderson Arvie J.
Eli Lilly and Company
Jackson Thomas E.
Wright Sonya N.
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