Prodrugs of thrombin inhibitors

Details Prodrugs of thrombin inhibitors Prodrugs of thrombin inhibitors

1999-07-15

2001-07-17

Davenport, Avis M. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C530S300000, C530S331000

Reexamination Certificate

active

06262028

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically useful prodrugs of pharmaceutically active compounds, which active compounds are, in particular, competitive inhibitors of trypsin-like serine proteases, especially thrombin, the use of the prodrugs as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.
BACKGROUND
Blood coagulation is the key process involved in both haemostatis (ie the prevention of blood loss from a damaged vessel) and thrombosis (ie the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).
Coagulation is the result of a complex series of enzymatic reactions. One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin.
Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore, thrombin activates factor V and factor VIII leading to a “positive feedback” generation of thrombin from prothrombin.
By inhibiting the aggregation of platelets and the formation and crosslinking of fibrin, effective inhibitors of thrombin would therefore be expected to exhibit antithrombotic activity. In addition, antithrombotic activity would be expected to be enhanced by effective inhibition of the positive feedback mechanism.
PRIOR ART
The development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrin. (1994) 5, 411.
Blombäck et al (in J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)) reported thrombin inhibitors based on the amino acid sequences situated around the cleavage site for the fibrinogen A&agr; chain. Of the amino acid sequences discussed, these authors suggested the tripeptide sequence Phe—Val—Arg would be the most effective inhibitor.
Low molecular weight peptide-based thrombin inhibitors have subsequently been disclosed in, for example, U.S. Pat. No. 4,346,078; International Patent Applications WO 93/11152, WO 94/29336, WO 93/18060 and WO 95/01168; and European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642 and 601 459.
More recently, thrombin inhibitors based on peptide derivatives have been disclosed in European Patent Application 0 669 317 and International Patent Applications WO 95/23609, WO 95/35309, WO 96/25426 and WO 94/29336.
In particular, the latter application discloses the peptide derivatives R
a
OOC—CH
2
—(R)Cgl—Aze—Pab—H, wherein R
a
represents H, benzyl or C
1-6
alkyl.
Although these active compounds are known to exhibit significant antithrombin activity, it would be beneficial to improve their pharmacokinetic properties both after oral and parenteral administration. Examples of pharmacokinetic properties which it is desirable to improve include:
(a) providing an improved absorption from the gastro-intestinal tract, with a view to reducing intra- and/or inter-individual variability in relation to the bioavailability of the active compounds;
(b) flattening the plasma concentration time profit (ie reducing the peak/trough ratio in the plasma concentration over the dosing interval), with a view to reducing the risk of falling outside the therapeutic interval and the side effects caused by a concentration peak which is too high (eg bleeding), and those caused by one which is too low (eg thrombus formation); and
(c) increasing the duration of action of the active compounds.
Moreover, oral and parenteral administration of active thrombin inhibitors may lead to undesirable local bleeding (eg in the intestinal lumen or subcutaneously) as a result of a high local concentrations.
Finally, orally administered active thrombin inhibitors which also inhibit trypsin and other serine proteases in the gastrointestinal tract may exhibit additional side effects, including indigestion (eg if trypsin is inhibited in the intestinal lumen).
Although certain N-benzyloxycarbonyl derivatives of the aforementioned active compounds are also disclosed as thrombin inhibitors in International Patent Application WO 94/29336, that these derivatives may be useful as prodrugs is not mentioned. In fact, WO 94/29336 makes no mention of suitable prodrugs of the active compounds.
We have found that the above problems may be solved by administering compounds according to the present invention which, whilst inactive per se, upon oral and/or parenteral administration are metabolised in the body to form active thrombin inhibitors, including those mentioned above.
DISCLOSURE OF THE INVENTION
According to the present invention there is provided a compound of formula I,
R
1
O(O)C—CH
2
—(R)Cgl—Aze—Pab—RTm I
wherein
R
1
represents —R
3
or —A
1
C(O)N(R
4
)R
5
or —A
1
C(O)OR
4
;
A
1
represents C
1-5
alkylene;
R
2
(which replaces one of the hydrogen atoms in the amidino unit of Pab—H) represents OH, OC(O)R
6
, C(O)OR
7
or C(O)OCH(R
8
) OC(O)R
9
;
R
3
represents H, C
1-10
alkyl, or C
1-3
alkylphenyl (which latter group is optionally substituted by C
1-6
alkyl, C
1-6
alkoxy, nitro or halogen);
R
4
and R
5
independently represent H, C
1-6
alkyl, phenyl, 2-naphthyl or, when R
1
represents —A
1
C(O)N(R
4
) R
5
, together with the nitrogen atom to which they are attached represent pyrrolidinyl or piperidinyl;
R
6
represents C
1-17
alkyl, phenyl or 2-naphthyl (all of which are optionally substituted by C
1-6
alkyl or halogen);
R
7
represents 2-naphthyl, phenyl, C
1-3
alkylphenyl (which latter three groups are optionally substituted by C
1-6
alkyl, C
1-6
alkoxy, nitro or halogen), or C
1-12
alkyl (which latter group is optionally substituted by C
1-6
alkoxy, C
1-6
acyloxy or halogen);
R
8
represents H or C
1-4
alkyl; and
R
9
represents2-naphthyl, phenyl, C
1-6
alkoxy or C
1-8
alkyl (which latter group is optionally substituted by halogen, C
1-6
alkoxy or C
1-6
acyloxy); provided that when R
1
represents R
3
, R
3
represents benzyl, methyl, ethyl, n-butyl or n-hexyl and R
2
represents C(O)OR
7
, then R
7
does not represent benzyl;
or a pharmaceutically-acceptable salt thereof (hereinafter referred to as “the compounds of the invention”).
The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, eg chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, eg fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (eg HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
According to a further aspect of the invention there is provided the use of a compound of formula I, as hereinbefore defined but without the proviso, as a prodrug.
Alkyl groups which R
3
, R
4
, R
5
, R
6
, R
7
and R
9
may represent may be linear or, when there are a sufficient number of carbon atoms, be branched, be cyclic or partially cyclic, be saturated or unsaturated, be interrupted by oxygen and/or be substituted or terminated by OH, provided that the OH group is not attached to an sp
2
carbon atom or a carbon atom which is adjacent to an oxygen atom.
By “partially cyclic alkyl groups” we mean groups such as CH
2
Ch.
Alkyl groups which R
8
may represent, and R
3
, R
6
and R
7
may be

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