Indole derivatives for the treatment of osteoporosis

Details Indole derivatives for the treatment of osteoporosis Indole derivatives for the treatment of osteoporosis

1999-05-05

1999-11-16

McKane, Joseph K.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514414, 548183, 548468, A61K 31405, A61K 31425, C07D40306, C07D41706

Patent

active

059859059

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 WO93/01280) 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 prophylaxis of diseases associated with loss of bone mass, such as osteoporosis and related osteopenic diseases, Paget's disease, hyperparathyroidism and related diseases. These compounds are also considered to possess anti-tumour activity, antiviral activity (for example against Semliki Forest, Vesicular Stomatitis, Newcastle 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, antiatherosclerotic 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 as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours.
Accordingly, the present invention provides a compound of formula (I): ##STR1## or a salt thereof, or a solvate thereof, wherein: R.sub.2, R.sub.3 and R.sub.4 each independently represent hydrogen, alkyl, aryl or substituted aryl; alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R.sub.6 and R.sub.7 together represent methylenedioxy, carbonyldioxy or carbonyldiamino; hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; and attached represent a heterocyclic group.
Suitably, Z.sub.1 and Z.sub.2 together with the carbon atom to which they are attached represent a moiety of formula (a): ##STR2## wherein the asterisked (*) carbon is attached to the double bond, R.sub.1 represents hydrogen or a thioxo group; X represents O or NR.sub.9 wherein R.sub.9 is C.sub.1-6 alkyl or an optionally substituted heterocyclic group or

REFERENCES:
patent: 5296499 (1994-03-01), Sohda et al.

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