Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-03
2001-09-11
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...
C514S233500, C514S324000, C514S337000, C514S385000, C514S443000, C544S146000, C546S202000, C546S256000, C546S281100, C548S311400, C548S525000, C549S051000, C549S058000
Reexamination Certificate
active
06288105
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 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
D is CH, CR
d
or N in which R
d
is methyl or methoxy;
E is CH, CR
e
or N in which R
e
is methyl, methoxy or halo;
R
2
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 a-nitrogen, provided that p is 1 when —CO—A is a glycyl or N-substituted glycyl group; or —CO—A is 3-amino-4-hydroxy-1-oxobutyl;
R
3
is is —X
3
—(CH
2
)
s
—NR
s
R
t
or —CH
2
—R
k
, in which X
3
is a direct bond, methylene or O; s is 1 or 2; provided that when s is 1, then X
3
is a direct bond; and R
s
and R
t
are independently hydrogen or (1-3C)alkyl or the group NR
s
R
t
is pyrrolidino, piperidino, or morpholino; and R
k
is 2-oxopyrrolidin-1-yl or 3-(1-oxoethyl)imidazolidin-1-yl; and
R
6
is hydrogen, hydroxy or methoxy.
A particular thrombin inhibiting compound of formula I (or a pharmaceutically acceptable salt thereof) is one wherein
D is CH, CR
d
or N in which R
d
is methyl or methoxy;
E is CH, CR
e
or N in which R
e
is methyl, methoxy or halo;
R
2
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, provided that p is 1 when —CO—A is a glycyl or N-substituted glycyl group;
R
3
is is —X
3
—(CH
2
)
s
—NR
s
R
t
or —CH
2
—R
k
, in which X
3
is a direct bond, methylene or O; s is 1 or 2; provided that when s is 1, then X
3
is a direct bond; and R
s
and R
t
are independently hydrogen or (1-3C)alkyl or the group NR
s
R
t
is pyrrolidino, piperidino, or morpholino; and R
k
is 2-oxopyrrolidin-1-yl or 3-(1-oxoethyl)imidazolidin-1-yl; and
R
6
is hydrogen, hydroxy or methoxy.
The &agr;-amino acyl group —CO—A conveniently may be represented as —CO—CH(R
b
)—NR
f
R
g
, or may be denoted by standard amino acid nomenclature. Thus, —CO—A may be an &agr;-amino acyl group derived from an &agr;-amino acid selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, serine, threonine, methionine, cysteine, proline, azetidine-2-carboxylic acid, pipecolic acid, aspartic acid, asparginine, glutamic acid, glutamine, lysine, arginine, histidine, etc. in which an amino group may bear, for example, a t-butoxycarbonyl protecting group; a carboxy group may be protected as its (1-4C)alkyl ester; a hydroxy group may bear, for example, a benzyl protecting group; and a thiol group may bear, for example a t-butyl protecting group. In addition, when —CO—A is represented as —CO—CH(R
b
)—NR
f
R
g
, each of R
f
and R
g
may be hydrogen or methyl, or —NR
f
R
g
may be a pyrrolidino, piperidino, morpholino or 1,1-dioxothiomorpholin-4-yl group (and R
b
denotes the side chain or protected side chain of an &agr;-amino acyl group as defined above).
A particular value for D is CH.
A particular value for E is CH or CR
e
in which R
e
is methoxy.
A particular value for R
3
is pyrrolidinomethyl or 2-pyrrolidinoethoxy.
A particular value for —CO—A is O-benzyl-serinyl, L-serinyl, N-(t-butoxycarbonyl)-L-serinyl, L-aspartyl, L-phenylalanyl, L-alanyl, L-tyrosinyl, L-asparaginyl, N-(t-butoxycarbonyl)-&ggr;-methyl-L-glutamyl or N-(t-butoxycarbonyl)-L-prolinyl.
Another particular value for —CO—A is (R)-3-amino-4-hydroxy-1-oxobutyl.
A particular value for R
6
is hydroxy.
When p is 1, a particular set of values is: X
2
is O and n is 2, 3 or 4.
A preferred value for p is 0.
One particular compound of formula I is the one described below as Example 2.
Another particular compound of formula I is the one described below as Example 17.
The present invention also provides a method of inhibiting coagulation in a mammal comprising administering to a mammal in need of treatment, a coagulation inhibiting dose of a thrombin inhibiting compound of formula I having any of the above definitions.
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 thrombin inhibiting compound of formula I having any of the above definitions.
Further, the present invention provides a method of treating a thromboembolic disorder comprising administering to a mammal in need of treatment, an effective dose of a thrombin
Chirgadze Nickolay Y
Fisher Matthew J
Harper Richard W
Lin Ho-Shen
McCowan Jefferson R
Anderson Arvie J.
Eli Lilly and Company
Huang Evelyn Mei
Jackson Thomas E.
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