Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-05-31
1999-07-06
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514557, 514558, 530324, 530333, 530345, A61K 3858, C07K 14815
Patent
active
059197625
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel hirudin conjugates formed from a hirudin and lipophilic compounds, to the preparation thereof and to the use thereof as drugs.
Hirudin is a naturally occurring protein which has been known for a long time and has anticoagulant properties. It is the strongest and most selective thrombin inhibitor known to date (Naturwissenschaften, 42, (1955), 537; Hoppe-Seylers Z. fur Biol. Chemie 366, (1985), 379). Natural hirudin is a mixture of chemically related peptides with a molecular weight of 6,900-7,000 daltons and 64-66 amino acids. To date about 20 naturally occurring hirudin variants have been described (Scharf et al., FEBS-Letters 255, (1989), 105-110).
EP 345616 describes products composed of hirudin coupled to polymeric carriers. Carriers which are mentioned are soluble and insoluble polymers such as dextran, Sepharose, heparin, levan and gelatin partial hydrolysate. The carrier-modified hirudins are said to have improved pharmacological properties such as a longer half-life.
DE 40 14 260 describes hirudin/polyalkylene glycol conjugates which, compared with natural hirudin, have a more favorable pharmacological profile of action, for example a prolonged biological activity and a better bioavailability.
Both the abovementioned patent applications describe hirudin derivatives with prolonged activity achieved by modifying the hirudin with a high molecular weight polymer. The molecular weight of the polymer in these cases amounts to several kilodaltons so that there is a considerable increase in the molecular weight of the polypeptide hirudin. However, high molecular weight polymers of these types are not exactly defined chemically; on the contrary they comprise a population of various molecules distributed over a molecular weight range. Accordingly, the hirudin coupling products prepared therewith are not composed of a single chemical compound either, on the contrary they are composed of populations of molecules which differ from one another in their molecular weight.
However, it is desirable that active substances which are used as drugs be chemically defined as exactly as possible in order to allow their behavior in the body to be controlled better.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1: Anti-FIIa activity in rats after intravenous administration of 1 mg/kg of Sunyldiketene.sub.3 -hirudin, Octyldiketene.sub.2 hirudin, Octyldiketene.sub.3 -hirudin, Hexyldiketene.sub.3 -hirudin, and r-Hirudin.
FIG. 2: Anti-FIIa activity in dogs after intravenous administration of 5000 ATU/kg of Octyldiketene.sub.3 -hirudin and r-Hirudin.
FIG. 3: Anti-FIIa activity after i.v. administration of 1 mg/kg farnesylhirudin.
FIG. 4: Thrombin-induced aggregation of washed platelets after pretreatment with r-Hirudin, palmitoyl-hirudin, cholesterylhirudin, lutensol-hirudin, famesyl-hirudin, and Lutrol-succ-hirudin.
FIG. 5: Delay in thrombotic occlusion of an arteriovenous shunt in a rat after intravenous administration of r-Hirudin, Oct.sub.2 - hirudin, and Oct.sub.2 -hirudin.
It is an object of the present invention to provide hirudin derivatives which have pharmacological properties which are better than those of normal hirudin and which do not have the abovementioned disadvantages of the hirudins modified with high molecular weight polymers.
We have found that this object is achieved by hirudin conjugates formed from a hirudin and one or more lipophilic compounds, where the lipophilic compound has an octanol/water partition coefficient of more than 1.8 and is covalently linked to the hirudin.
Suitable for the hirudin conjugates according to the invention are all naturally occurring hirudins as well as variants derived from them, called hirudin muteins, and fragments with a thrombin-inhibiting effect.
Hirudins of these types and their preparation are disclosed, for example, in EP 171 024, EP 158 986, DE 38 055 406, WO 92/1712, GB 2 247 239, EP 557 199, WO 92/5748, DE 40 14 260.
Also very suitable for preparing the hirudin conjugates according to the invention are peptides or peptide derivatives
REFERENCES:
patent: 4767742 (1988-08-01), Dodt et al.
patent: 4810697 (1989-03-01), Speiser et al.
patent: 5359030 (1994-10-01), Ekwuribe
Eckes Peter
Hornberger Wilfried
Schweden Jurgen
Subkowski Thomas
BASF - Aktiengesellschaft
Gupta Anish
Robinson Douglas W.
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