Heteroaromatic pentadienoic acid derivatives useful as inhibitor

Details Heteroaromatic pentadienoic acid derivatives useful as inhibitor Heteroaromatic pentadienoic acid derivatives useful as inhibitor

1999-06-23

2000-02-15

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514443, 514320, 514324, 514311, 549471, 549467, 549 58, 546196, 546202, 546165, 546174, 546175, A61K 3134, A61K 3138, A61K 31445, C07D21500, C07D40100

Patent

active

060253908

DESCRIPTION:

BRIEF SUMMARY
This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
Co-pending International Application, application number PCT/EP96/00157 discloses certain indole derivatives which are indicated to reduce bone resorption by inhibiting osteoclast H.sup.+ -ATPase.
Diseases associated with loss of bone mass are known to be caused by over activity of osteoclast cells. It is also known that certain compounds, usually related to bafilomycin, are useful for treating such diseases: For example International Patent Application, publication number WO 91/06296 discloses certain bafilomycin macrolides for the treatment of bone affecting diseases.
However, bafilomycin derivatives are not selective for osteoclasts in humans. The use of these compounds is therefore associated with unacceptable toxicity due to generalised blockade of other essential v-ATPases. Indeed, to date there is no known treatment which is selective for the human osteoclasts.
The search for a successful treatment for diseases associated with loss of bone mass in humans is further complicated in that the nature of the therapeutic target for the selective inhibition of the osteoclasts is controversial. Thus Baron et al (International Patent Application publication number WO 93/01280) indicate that a specific vacuolar ATPase (V-ATPase) has been identified in osteoclasts as a potential therapeutic target. However, the Baron work was carried out in chickens and Hall et al (Bone and Mineral 27, 1994, 159-166), in a study relating to mammals, conclude that in contrast to avian osteoclast V-ATPase, mammalian osteoclast V-ATPase is pharmacologically similar to the v-ATPase in other cells and, therefore, it is unlikely to be a good therapeutic target.
We have now found a group of compounds which are selective for mammalian osteoclasts, acting to selectively inhibit their bone resorbing activity. These compounds are therefore considered to be particularly useful for the treatment and/or phophylaxis of diseases associated with loss of bone mass, such as osteoporosis and related osteopenic diseases, Paget's disease, hyperparathyroidism and related and related diseases. These compounds are also considered to possess anti-tumour activity, antiviral activity (for example against Semliki Forest, Vesicular Stomatitis, New castle Disease, Influenza A and B, HIV viruses), antiulcer activity (for example the compounds may be useful for the treatment of chronic gastritis and peptic ulcer induced by Helicobacter pylori), immunosupressant activity, antilipidemic activity, antiatheroselerotic activity and to be useful for the treatment of AIDs and Alzheimer's disease. In a further aspect, these compounds are also considered useful in inhibiting angiogenesis, i.e. the formation of new blood vessels which is observed in various types of pathological conditions (angiogenic diseases) such a rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours.
Accordingly, the present invention provides a compound of formula (I): ##STR2## or a salt thereof, or a solvate thereof, wherein:
R.sub.1 represents an alkyl group or a substituted or unsubstituted aryl group;
R.sub.2, R.sub.3 and R.sub.4 each independently represent hydrogen, alkyl, aryl or substituted aryl;
R.sub.5 and R.sub.6 each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R.sub.5 and R.sub.6 together represent methylenedioxy, carbonyldioxy or carbonyldiamino;
X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NR.sub.S R.sub.t wherein R.sub.S and R.sub.t each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally

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Popa, et al., "Synthesis of abscisic acid analogs with antitranspirant properties", Chemical Abstracts, 108 No. 25, p. 201, column 2 (1988).

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