Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-23
2003-09-16
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S525000, C548S517000
Reexamination Certificate
active
06620837
ABSTRACT:
This invention relates to thrombin inhibitors which are useful anticoagulants in mammals. In particular it relates to substituted benzo[b]thiophene 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 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).
Antithrombotic diamines are disclosed in International Patent Application Publication Number WO 97/25033, WO 98/48798 and WO 98/49161. Compounds of this invention have lower volumes of distribution and, therefore, improved pharmacokinetic properties over those of WO 97/25033, WO 98/48798 and WO 98/49161.
Although the heparins and coumarins are effective anticoagulants, no widely used drug has yet emerged from the 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.
According to the invention there is provided a compound of formula I (or a pharmaceutically acceptable salt thereof)
wherein
A is carbonyl or methylene;
R
d
is —[O—(CH
2
)
d
]
c
—R
c
in which c is 0 or 1; d is 1, 2, or 3; and R
c
is carboxy, [(1-4C)alkoxy]carbonyl, hydroxymethyl or carbamoyl; provided that if c is 0, R
c
is carboxy, [(1-4C)alkoxy]carbonyl or carbamoyl;
R
e
is hydrogen, methyl, methoxy or halo;
R
2
is R
2a
or R
2b
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;
R
2b
is —X
2
—(CH
2
)
m
—NR
a
R
b
in which X
2
is a direct bond, methylene or O; m is 1, 2 or 3; 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 the group NR
a
R
b
is pyrrolidino, piperidino or morpholino;
R
3
is R
3a
or R
3b
in which
R
3a
is 2-(2-oxopyrolidin-1-yl)ethoxy;
provided that R
2
is R
2b
when R
3
is R
3a
;
R
3b
is —X
3
—(CH
2
)
s
—NR
s
R
t
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
6
is hydrogen, hydroxy or methoxy.
As a further aspect of the invention, there is provided a prodrug (or a pharmaceutically acceptable salt thereof) of any of the above described thrombin inhibiting compounds of formula I which will form a prodrug.
In this specification, the following definitions are used, unless otherwise described: Halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain (“normal”) radical, a branched chain isomer such as “isopropyl” being specifically denoted.
It will be appreciated that certain compounds of formula I (or salts or prodrugs, etc.) may exist in, and be isolated in, isomeric forms, including cis- or trans-isomers, as well as optically active, racemic, or diastereomeric forms. It is to be understood that the present invention encompasses a compound of formula I as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer, any of which mixtures or form possesses inhibitory properties against thrombin, it being well known in the art how to prepare or isolate particular forms and how to determine inhibitory properties against thrombin by standard tests including those described below.
In addition, a compound of formula I (or salt of prodrug, etc.) may exhibit polymorphism or may form a solvate with water or an organic solvent. The present invention also encompasses any such polymorphic form, any solvate or any mixture thereof.
Particular values are listed below for radicals, substituents, and ranges, for illustration only, and they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
A particular value for a (1-3C)alkyl group is, for example, methyl, ethyl, propyl or isopropyl, and for a (1-4C)alkoxy group is, for example, methoxy, ethoxy, isopropoxy or t-butoxy.
A particular value, independently, for A is carbonyl or methylene;
for R
d
is carboxy, methoxycarbonyl, carbamoyl, 3-(ethoxycarbonyl)propoxy, 3-carboxypropoxy, 4-amino-4-oxobutoxy, 4-hydroxybutoxy, (t-butoxycarbonyl)methoxy, or carboxymethoxy;
for R
e
is hydrogen or methoxy;
for R
2
is 2-(1-pyrrolidinyl)ethoxy, 3-carboxypropoxy, or 3-(methoxycarbonyl)propoxy;
for R
3
is 2-(1-pyrrolidinyl)ethoxy, 1-pyrrolidinyl)methyl or 2-(2-oxopyrrolidin-1-yl)ethoxy; and
for R
6
is hydrogen or hydroxy.
A particular value for R
2
is R
2a
. A further particular value for R
2
is R
2b
.
A particular value for R
3
is R
3a
. A further particular value for R
3
is R
3b
and R
2
is R
2b
.
A particular compound of formula I is one in which R
d
is methoxycarbonyl, R
e
is hydrogen and R
3
is 2-(2-oxopyrrolidin-1-yl)ethoxy.
A further particular compound of formula I is 2-[3-methoxycarbonyl-4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]-3-[4-[2-(2-oxopyrrolidin-1-yl)ethoxy]benzyl]benzo[b]-thiophene.
Specific compounds of formula I are described in the accompanying Examples. The compound described as Example 13, 2-[3-carboxymethoxy-4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]-3-[4-[2-(2-oxopyrrolidin-1-yl)ethoxy]benzyl]-benzo[b]thiophene, (or a pharmaceutically acceptable salt thereof) is a preferred species.
A pharmaceutically acceptable salt of an antithrombotic agent of the instant invention includes one which is an acid-addition salt made with an acid which provides a pharmaceutically accepta
Bastian Jolie Anne
Kohn Todd Johnathan
Sall Daniel Jon
Takeuchi Kumiko
Toth John Eldon
Anderson Arvie J.
Eli Lilly and Company
Jackson Thomas E.
Lambkin Deborah C.
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