Carbohydrate derivatives

Details Carbohydrate derivatives Carbohydrate derivatives

1998-11-18

2001-01-16

Fonda, Kathleen K. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S054000, C514S056000, C536S004100, C536S018200, C536S021000, C536S118000, C536S122000, C536S123100

Reexamination Certificate

active

06174863

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a carbohydrate derivative, a pharmaceutical composition containing the same, as well as the use of said carbohydrate derivative for the manufacture of a medicament.
BACKGROUND OF THE INVENTION
Heparin is a commonly used anticoagulant from biological sources such as intestinal mucosa. In the presence of heparin, the inactivation of thrombin by anti-thrombin III (AT-III) is greatly accelerated, involving changes in both the conformation of heparin and AT-III on complexation. Thrombin regulates the last step in the blood coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which form an insoluble gel, a fibrin clot, by cross-linking.
The structural features of heparin that are required for interacting AT-III have been subject to various investigations. There are parts in the heparin polymer which show only low affinity for AT-III, whereas other parts were found to be more important for binding to AT-III. Studies of fragmented heparin have finally resulted in the identification of a pentasaccharide fragment accounting for the minimal high-affinity structure that binds to AT-III (see e.g. Physiological Reviews, 71 (2), 488/9, 1991). In this high-affinity fragment eight sulfate groups are present. Four of the sulfate groups were found to be essential for binding to AT-III (Advances in Carbohydrate Chemistry and Biochemistry; Vol. 43; Eds. R. S. Tipson, D. Horton; Publ. Harcourt Brace Jovanovich; B. Casu (pages 51-127), paragraph 6), whereas the other further attribute to higher affinity. This finding was confirmed in synthetic analogues of the pentasaccharide fragment (see e.g. Agnew. Chem. 32 (12), 1671-1818, 1993).
The identification of the high-affinity pentasaccharide fragment inspired the preparation of synthetic analogues thereof. Small synthetic carbohydrate molecules of the glycosaminoglycan type were found to be potent and selective anti-Xa inhibitors. See for instance European patent 84,999. Later filed patents/patent applications showed that many variants of these molecules have similar and even higher activities and further improved pharmacological properties, such as the glycosaminoglycan-related carbohydrate derivatives disclosed in EP 529,715 and EP 454,220. These carbohydrate derivatives are devoid of the characteristic functional groups of glycosaminoglycans: free hydroxyl groups, N-sulfate and N-acetyl groups. Further, all of the pentasaccharides disclosed in these latter patent applications carry at least seven sulfate groups. In the field of antithrombotic oligosaccharide derivatives it was thus generally assumed that at least seven sulfate groups are required in pentasaccharide compounds in order to obtain clinically acceptable levels of antithrombotic activity.
Unexpectedly, however, a class of glycosaminoglycan-related carbohydrate derivatives has now been found having only four to six sulfate groups and which still display significant clinically effective antithrombotic activity. In addition, the compounds of this invention show fewer side effects. For example, bleeding risks are reduced and the low sulfate content of the compounds does not give rise to heparin-induced thrombocytopenia (HIT) [HIT is a severe side effect, which may be the cause of the death of a patient]. Further, compounds of this invention have a biological half-life which allows once-a-day-treatment. Once-a-day-treatment may be considered to be more favourable than, for example, once-a-week-treatment, allowing quick adaptation of the medical treatment is the condition of a patient requires so. Also hospital logistics are easier with one-a-day-treatment, as no complex dosing schemes are required for the treatment of the patients.
Thus, the compounds of the invention display an unexpected and delicately balanced pharmacological profiles.
SUMMARY OF THE INVENTION
The invention therefore relates to a carbohydrate derivative having formula I
wherein R
1
is (1-4C)alkoxy; R
2
, R
3
and R
4
are independently (1-4C)alkoxy or OSO
3
−
; the total number of sulfate groups is 4, 5 or 6; and the twisted lines represent bonds either above or below the plane of the six-membered ring to which they are attached; or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are useful for treating and preventing thrombin-mediated and thrombin-associated diseases. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, and neurodegenerative diseases. The carbohydrate derivatives of the invention may also be used as inhibitors of smooth muscle cell proliferation and for the treatment of angiogenesis, cancer and retrovirus infections, like HIV.
Further, the compounds of the invention may be used as anticoagulants and anticoagulant coatings in extracorporeal blood circuits, as necessary in dialysis and surgery.
The compounds of the invention may also be used as in vitro or ex vivo anticoagulants.
DETAILED DESCRIPTION OF THE INVENTION
Preferred carbohydrate derivatives according to the invention have the D-unit has the structure
R
1
is methoxy; and R
2
, R
3
and R
4
are independently methoxy or OSO
3
−
.
More preferred carbohydrate derivatives are those wherein R
2
is methoxy. In particularly preferred carbohydrate derivatives R
3
is methoxy. The most preferred carbohydrate derivative is the one wherein R
4
is methoxy.
In the term (1-4C)alkoxy the (1-4C)alkyl group is a branched or unbranched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl, t-butyl, and the like. The most preferred alkyl group is methyl.
The counter-ions which compensate the charged moieties are pharmaceutically acceptable counter-ions, like hydrogen, or more preferably alkali or earth-alkali metal ions, like sodium, calcium, or magnesium.
The carbohydrate derivatives according to this invention may be prepared according to well known methods described and used for the synthesis of oligosaccharides. In this respect, in particular reference is made to the previously mentioned European patent EP 529,715. A suitable process for the preparation of the carbohydrate derivatives of formula I is characterized by a process wherein protected monosaccharides having different structures are coupled to give protected disaccharides, after which:
(a) protected disaccharides of one type are coupled to protected disaccharides of another type to give protected tetrasaccharides, which tetrasaccharides are coupled to a protected monosaccharide to give protected pentasaccharides; or
(b) protected monosaccharides are coupled to protected disaccharides to give protected trisaccharides, which are further coupled to protected disaccharides to give protected pentasaccharides;
after which the protective groups are cleaved and free hydroxy groups are sulfated, after which the compound obtained is optionally converted into a pharmaceutically acceptable salt.
The monosaccharides are D-glucose, D-mannose, L-idose, D-glucuronic acid or L-iduronic acid, suitably functionalized with the required alkyl groups or by temporarily protective groups. Suitable protective groups are well known in the art. Preferred protective groups include benzyl and acetyl for hydroxy groups, and benzyl for the carboxylate groups of uronic acids. Other protective groups, such as benzoyl, levulinyl, alkoxyphenyl, chloroacetyl, trityl, and the like may be used with equal success. Coupling of the saccharide is performed in a manner known in the art, e.g. deprotection of the 1-position of the glycosyl-donor, and/or activation of this position (e.g. by making

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