Antithrombotic compound

Details Antithrombotic compound Antithrombotic compound

1999-11-08

2001-04-10

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S210180, C546S146000, C540S354000

Reexamination Certificate

active

06214841

ABSTRACT:

This invention relates to a heterocyclic ketone compound having surprisingly potent antithrombotic efficacy. Thus, the invention relates to the new antithrombotic compound, pharmaceutical compositions containing the compound as an active ingredient, and the use of the compound for prophylaxis or treatment of a thromboembolic disorder such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, myocardial infarction or cerebral thrombosis, general hypercoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, or generalized tissue injury as it relates to the inflammatory process. In addition, the new compound is useful as an anticoagulant in in vitro and ex vivo applications.
Certain peptidyl heterocycles are disclosed in U.S. Pat. No. 5,523,308 as inhibitors of thrombin useful in the treatment of thrombin-related disorders. Surprisingly, the compound of the instant invention exhibits high potency in inhibition of both thrombin and factor Xa, as well as highly potent antithrombotic efficacy.
According to the invention, there is provided a compound of formula I
Y—CO—X—CO—Arg—R  I
wherein
Arg is L-arginyl;
R is 2-benzothiazolyl;
X—CO— is L-prolyl or (S)-azetidin-2-carbonyl; and
Y—CO— is a group of formula IIa, IIb, IIc or IId;
or a pharmaceutically acceptable salt thereof.
A particular compound of formula I is one in which X—CO— is L-prolyl (Pro).
A more particular compound of formula I is one in which X—CO— is Pro and Y—CO— is a group of formula IIa or IIb.
One preferred compound of formula I is one in which X—CO— is Pro and Y—CO— is a group of formula IIa, which compound may be denoted as a compound of formula Ia.
The preferred species is described hereinbelow as Example 1, where it is isolated as the acid addition salt with sulfuric acid.
Another particular compound of formula I is one in which X—CO— is Pro and Y—CO— is a group of formula IIb, which compound may be denoted as a compound of formula Ib.
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 also provides a method of inhibiting thrombosis in a mammal comprising administering to a mammal in need of treatment, an antithrombotic dose of a compound of formula I.
As is further discussed below, a compound of the instant invention is a potent, direct inhibitor of one or both of the enzymes thrombin and factor Xa of the coagulation cascade. Accordingly, 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, as well as a method of inhibiting thrombin in an in vitro or ex vivo application. Similarly, the present invention further provides a method of inhibiting factor Xa comprising administering to a mammal in need thereof, a factor Xa inhibiting dose of a compound of formula I, as well as a method of inhibiting factor Xa in an in vitro or ex vivo application.
It is preferred that the chiral center indicated by the asterisk in the group Y be of (R)-stereochemistry, corresponding to that of a D-amino acid.
However, 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 antithrombotic properties, it being well known in the art how to prepare or isolate particular forms and how to determine antithrombotic properties by standard tests including those described below. Owing to the facile epimerization of the &agr;-proton of the Arg moiety, adjacent to the benzoxazolyl keto group, it may be preferred to use the compound of formula I as a mixture of epimers at that center.
In addition, a compound of formula I (or a pharmaceutically acceptable salt thereof) may form a solvate with water or an organic solvent. Further, the compound, salt or solvate thereof may exhibit polymorphism. The present invention also encompasses any such solvate, polymorphic form, or mixture thereof.
A compound of formula I may be made by processes which include processes known in the chemical art for the production of structurally analogous compounds or by a novel process described herein. Novel processes and intermediates for the manufacture of a compound of formula I as defined above provide further feature of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as defined above, unless otherwise specified. It will be recognized that it may be preferred or necessary to prepare a compound of formula I in which a functional group is protected using a conventional protecting group, then to remove the protecting group to provide the compound of formula I.
Thus, there is provided a process for preparing a compound of formula I (or a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions which includes
oxidation of the alcohol of a corresponding compound of formula III
Y—CO—X—CO—Arg(OH)—R  III
in which Arg(OH) indicates that the carbonyl portion of the L-arginyl group is replaced by a hydroxymethylene group;
whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group; and
whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I is required, it is obtained by reacting the basic form of the compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure, such as, for example, exchanging the counterion of a salt.
Conveniently, the oxidation is carried out in an inert solvent, using oxalyl chloride, dimethyl sulfoxide and a tertiary amine, for example as described below in Example 1. It generally is preferred that the amino groups of Y—CO— and the Arg side chain be protected during the oxidation.
A compound corresponding to compound of formula I in which one or more functional groups is protected provides another aspect of the invention. Such a compound may be represented as a compound of Formula Ip
(PY)Y—CO—X—CO—Arg(p
A
)—R  Ip
which bears one or more of the protecting groups p
A
and P
Y
wherein p
A
is an optional protecting group(s) for the guanidino moiety of the Arg side chain and P
Y
is an optional protecting group for the amino nitrogen of the perhydroisoquinoline moiety. A typical value for p
A
is tosyl and for P
Y
is benzyloxycarbonyl.
Conveniently, an alcohol of formula III is prepared in a protected form by coupling a protected form of an acid of formula IV
Y—CO—X—CO—OH  IV
with a protected form of the alcohol of formula V
H—Arg(OH)—R  V
using a conventional coupling method, for example the mixed anhydride method described in Example 1.
The (optionally protected) acid of formula IV may be made by a conventional method. For example, when Y—CO— is of formula IIa and X—CO— is prolyl, the protected acid of formula IV may be prepared as described below in Example 1 or as described in EP 670310 at Example 85. Similarly, when Y—CO— is of formula IId or IIb and X—CO— is prolyl, the protected acid of formula IV is disclosed at Example 80 or 82 of EP 670310 or U.S. Pat. No. 5,436,229. The preparation of the amino alcohol of formula V in which the guanidino group bears an N-tosyl protecting group is described below in Example 1.
As mentioned above, the invention includes a pharmaceutically acceptable salt of a compound of formula I, which possesses sufficiently basic functional groups to react with any of a number of inorganic and organic acids which afford a nontoxic anion to for

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