Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-09-15
2001-09-18
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S244000
Reexamination Certificate
active
06291531
ABSTRACT:
The present invention relates to a new LTB
4
antagonist, processes for preparing it and its use as a pharmaceutical composition.
LTB
4
antagonists are known from the prior art. Thus, International Patent Application WO 98/11062 discloses benzamidine derivatives having the abovementioned pharmacological activity.
Surprisingly, it has been found that the new LTB
4
antagonist according to the invention has superior properties to the compounds known from the prior art. In this context the exceptionally high in vitro and in vivo activity as well as the surprisingly high metabolic stability of the new LTB
4
antagonist according to the invention should be mentioned.
The LTB
4
antagonist according to the invention is the compound of formula (I)
optionally in the form of the pharmacologically acceptable acid addition salts thereof. As mentioned above, the compound of formula (I) can be converted into the salts thereof, particularly for pharmaceutical use into the physiologically and pharmacologically acceptable salts thereof with an inorganic or organic acid. Suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. In addition, mixtures of the abovementioned acids can be used.
As has been found, the compound of formula I is characterised by its versatility of use in the therapeutic field. Particular emphasis should be laid on those applications for which the LTB
4
-receptor-antagonistic properties play a part.
The following should be mentioned in particular: arthritis, asthma, chronic obstructive lung diseases such as chronic bronchitis, psoriasis, ulcerative colitis, gastro- or enteropathy induced by nonsteroidal antiphlogistics, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis, multiple sclerosis.
The new compounds may also be used to treat illnesses or conditions in which the passage of cells from the blood through the vascular endothelium into the tissues is of importance (such as metastasis) or illness and conditions in which the combination of LTB
4
or another molecule (such as 12-HETE) with the LTB
4
receptor has an influence on cell proliferation (e.g. chronic myeloid leukaemia).
The new compound may also be used in conjunction with other active substances, e.g. those which are used for the same indications, or e.g. with antiallergic agents, secretolytics, &bgr;
2
-adrenergics, steroids taken by inhalation, antihistamines and/or PAF antagonists. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation.
The activity can be investigated pharmacologically and biochemically using tests as disclosed for example in WO 93/16036, pp. 15 to 17; reference is hereby made to the contents of this publication.
The therapeutic or prophylactic dose depends—apart from the potency of the individual compounds and the patient's body weight—on the nature and gravity of the condition. For oral administration the dosage is between 10 and 500 mg, preferably between 20 and 250 mg. By inhalation the amount of active substance delivered to the patient is between about 0.5 and 25, preferably between about 2 and 20 mg.
Solutions for inhalation generally contain between about 0.5 and 5% of active substance. The new compounds may be administered in conventional preparations, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments and suppositories.
The following Examples show some possible ways of formulating the preparations:
Tablets
Composition:
Active substance according to the invention
20 parts by weight
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 active substance content may be increased or reduced and the quantity of glucose reduced or increased accordingly.
Suppositories
Composition:
Active substance according to the invention
100 parts by weight
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. Powder for Inhalation
Micronised powdered active substance (compound of formula I; particle size about 0.5 to 7 &mgr;m) are packed into hard gelatine capsules in quantities 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, to which reference is hereby made.
The new compound may be obtained analogously to methods of synthesis known from the prior art for preparing structurally comparable benzamidine derivatives. At this point reference is made particularly to the methods of preparation disclosed by International Patent Application WO 98/11062, which describe, inter alia, the method of synthesising benzamidine derivatives by reducing the corresponding amidoximes, by aminolysis of the corresponding imino ester and by reacting suitably substituted phenols with aryloxyalkyls substituted by a nucleofugic leaving group in the manner of a Williamson ether synthesis.
Alternatively, the compound of formula (I) according to the invention may be obtained, for example, by reacting the nitrile of formula (II)
with Li-hexamethyldisilazane. For the reaction it is appropriate to use non-polar and polar aprotic solvents such as toluene, ether, tetrahydrofuran at temperatures from −80° C. to 120° C. To cleave the silyl groups, inorganic and organic acids are used such as HCl, HBr, H
2
SO
4
, sulphonic acids such as p-toluenesulphonic acid, benzenesulphonic acid or methanesulphonic acid and carboxylic acids such as formic acid, acetic acid or trifluoroacetic acid at temperatures from 0° C. to 100° C.
The compound according to the invention may be prepared, starting from compounds known from the prior art, inter alia using the process described in the following synthesis example. Various other embodiments of the process will be apparent to anyone skilled in the art from the present specification and from the abovementioned International Patent Application WO 98/11062; reference is hereby made to the contents of this publcation. It is specifically pointed out that the following synthesis example is provided solely as an illustration and not as a restriction to the invention.
REFERENCES:
patent: 5731332 (1998-03-01), Anderskewitz et al.
patent: 6197824 (2001-03-01), Schromm et al.
Barts Samuel
Boehringer Ingelheim Pharma KG
Devlin M-E. M.
Raymond R. P.
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