Chemical compound, the preparation thereof and its use in pharma

Details Chemical compound, the preparation thereof and its use in pharma Chemical compound, the preparation thereof and its use in pharma

1997-03-28

1997-11-11

O'Sullivan, Peter

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

514825, 514826, 514863, 514903, 514908, 564247, A61K 31155, C07C25718

Patent

active

056864965

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/02113 filed Jun. 3, 1995.
The invention relates to the compound of formula ##STR2## Related compounds are known from WO 93/16036. They are described as LTB.sub.4 -antagonists and are suitable for therapeutic use in the corresponding indications.
It has been found that the compound of Formula 1 is characterised by its versatility in the therapeutic field. Particular mention should be made of those possible applications for which the LTB.sub.4 -receptor-antagonistic properties come into play. Example include, in particular: arthritis, asthma, chronic obstructive lung diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastro or enteropathy induced by non-steroidal antilogistics, Alzheimers disease, shock, reperfusion damage/ischaemia, atherosclerosis and multiple sclerosis.
The new compounds may also be used to treat diseases or conditions in which the passage of cells from the blood through the vascular endothelium into tissue is of importance (such as metastasis) or diseases and conditions in which the combination of LTB.sub.4 or another molecule (for example 12-HETE) with the LTB.sub.4 -receptor influences cell proliferation (such as chronic myelocytic leukaemia).
The new compounds may also be used in conjunction with other active substances, e.g. those which are used for the same indications or, for example, with antiallergics, secretolytics, .beta..sub.2 -adrenergics, steroids administered by inhalation, antihistamines and/or PAF-antagonists. The substances may be administered topically, orally, transdermally, nasally, parenterally or by inhalation.
The therapeutic or prophylactic dose depends not only on the potency on the individual compounds and the body weight of the patient, but also on the nature and gravity of the condition. For oral use the dose is between 10 and 500 mg, preferably between 20 and 250 mg. For inhalation a dosage of between 0.5 and 25, preferably between 2 and 20 mg of active substance is delivered to the patient.
The new compounds may be administered, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments or suppositories.
The Examples which follow illustrate some possible formulations for the preparations.


EXAMPLES OF FORMULATIONS

1. Tablets


______________________________________ Composition: ______________________________________ Active substance according 20 parts by weight to the invention Stearic acid 6 parts by weight Glucose 474 parts by weight ______________________________________
The ingredients are processed in the usual way to form tablets weighing 500 mg. If desired, the content of active substance increased or reduced and the quantity of glucose increased or reduced accordingly.
2. Suppositories


______________________________________ Compositions: ______________________________________ Active substance according 100 parts by weight to the invention Powdered lactose 45 parts by weight Cocoa butter 1555 parts by weight ______________________________________
The ingredients are processed in the usual way to form suppositories weighing 1.7 g.
3. Inhalation powder
Micronised powdered active substance (Compound of formula 1; particle size of about 0.5 to 7 .mu.m) is packed into hard gelatine capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled from conventional inhalers, e.g. according to DE-A 33 45 722.
The new compound exhibits a surprisingly superior effect, compared with the known LTB.sub.4 -antagonists. This is illustrated, for example, in the test results on the LTB.sub.4 -induced accumulation of neutrophiles in the mouse's ear. The ED.sub.50 value of 0.05 mg/kg obtained is far lower than the values found for structurally similar compounds.
The new compound may be prepared by conventional methods:
Method 1
The amidoxime ##STR3## is catalytically hydrogenated.
The reaction is conveniently carried out in a polar solvent such as ethanol, glacial ac

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