Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-12
2004-09-07
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S295000, C544S373000, C546S201000, C548S467000, C548S506000, C548S511000, C514S414000, C514S323000
Reexamination Certificate
active
06787550
ABSTRACT:
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.
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 Application Publication Number WO 91/06296 (Aktiebolaget Astra) 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 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, 159-166, (1994)), 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.
It has now surprisingly been found that particular indole compounds 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 antitumour 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, antiatheroscierotic activity and to be useful for the treatment of AIDS and Alzheimer's disease. Furthermore, 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 invention provides a compound of formula (I)
or a salt thereof, or a solvate thereof,
wherein;
R
1
and R
2
each independently represents C
1-6
alkoxy or halo;
R
3
and R
4
each independently represents hydrogen, C
1-6
alkoxy, arylC
1-6
alkoxy, hydroxy, carboxyC
1-6
alkoxy, hydroxyC
1-6
alkoxy, dihydroxyC
1-6
alkoxy, mono-and di-(C
1-6
alkyl)aminoC
1-6
alkoxy or aminoC
1-6
alkoxy, and;
R
5
represents —NR
s
R
t
wherein R
s
and R
t
each independently represent hydrogen, unsubstituted or substituted C
1-6
alkyl, or unsubstituted or substituted heterocyclyl.
Suitably, R
1
and R
2
each independently represents methoxy or chloro.
Suitable positions for substitution for R
1
or R
2
are the 4, 5, 6 or 7 position.
Favourably R
1
or R
2
are at the 5 or 6 position.
Preferably, R
1
is 5-chloro and R
2
is 6-chloro.
Suitably, R
3
is hydroxy, methoxy, ethoxy, propoxy, benzyloxy, carboxyethoxy, hydroxyethoxy, dihydroxypropoxy, dimethylaminoethoxy or aminopropoxy.
Suitably, R
3
is located ortho or meta to the —COR
5
moiety.
Suitably, R
4
is hydrogen or methoxy.
Suitably, R
4
is located meta to the —COR
5
moiety.
Suitably, R
s
or R
t
represent unsubstituted or substituted C
1-6
alkyl, or unsubstituted or substituted heterocyclyl.
When R
s
or R
t
represent unsubstituted or substituted C
1-6
alkyl, suitable C
1-6
alkyl groups are ethyl, propyl and butyl.
When R
s
or R
t
represent substituted alkyl, favoured groups are 3-[4(3-methoxyphenyl)piperzin-1-yl]propyl and 3-[4-(2-pyrimidinyl)piperazin-1-yl]propyl.
Suitably, R
s
or R
t
represent an unsubstituted or substituted piperidinyl group.
Favourably, R
s
or R
t
represent an unsubstituted or substituted 4-piperidinyl group.
When R
s
or R
t
represent a substituted piperidinyl group, suitable substituents include C
1-6
alkyl, fused C
3-8
cycloalkyl, arylC
1-6
alkyl, hydroxyC
1-6
alkyl, polyhydroxyC
1-6
alkyl, C
1-6
alkoxycarbonylC
1-6
alkyl, carboxyC
1-6
alkyl, and aminoC
1-6
alkyl.
Favoured substituents for piperidinyl groups are C
1-6
alcyl groups, especially methyl groups.
When R
s
or R
t
represent a substituted piperidinyl group, it is preferred that the substituents are attached to one or both of the carbon atoms alpha to the nitrogen atom.
Examples of substituted piperidinyl groups are 1,2,2,6,6-pentamethylpiperidin-4-yl and 2,2,6,6-tetramethylpiperidin-4-yl groups.
Favourably, R
t
is hydrogen.
There is a subgroup of compounds falling wholly within formula (I), being of formula (I′)
wherein;
R
1
, R
2
, R
3
, R
4
, and R
5
are as defined in formula (I), with the proviso that formula (I′) does not include;
4-(5,6-dichloro-1H-indol-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzamide;
4-(5,6-dichloro-1H-indol-2-yl)-3-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzamide;
4-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzamide;
4-(5,6-dichloro-1H-indol-2-yl)-3-methoxy-N-(3-diethylaminopropyl)benzamide;
4-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-(3-diethylaminopropyl)benzamide;
4-(5,6-dichloro-1H-indol-2-yl)-3-methoxy-N-[3-[4-(3-chlorophenyl)piperazinyl]propyl]benzamide;
4-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-[3-[4-(3-chlorophenyl)piperazinyl]propyl]benzamide;
4-(5,6-dichloro-1H-indol-2-yl)-3-methoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)-N-methylbenzamide, or;
4-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)-N-methylbenzamide.
It is considered that compounds of formula (I′) are novel. Accordingly, the present invention provides a compound of formula (I′) or a salt thereof or a solvate thereof.
There is a subgroup of compounds falling wholly within formula (I) of formula (IA)
wherein;
R
1
, R
2
, R
3
, R
4
, and R
5
are as defined in formula (I), R
s
is 3-[4-(3-methoxyphenyl)piperazin-1-yl]propyl or 3-[4-(2-pyrimidinyl)piperazin-1-yl]propyl, and R
t
is hydrogen. It is considered that compounds of formula (IA) are novel.
Accordingly, the present invention provides a compound of formula (IA) or a salt thereof or a solvate thereof.
There is a subgroup of compounds falling wholly within formula (I) of formula (IB)
wherein;
R
1
, R
2
, R
3
, R
4
, and R
5
are as defined in formula (I), R
s
is 3-pyridyl or 3-(6-methoxy)pyridyl, and R
t
is hydrogen. It is considered that compounds of formula (IB) are novel.
Accordingly, the present invention provides a compound of formula (IB) or a salt thereof or a solvate thereof.
There is a subgroup of compounds falling wholly within formula (I) of formula (IC)
wherein;
R
2
, R
4
, and R
5
are as defined in formula (I), R
s
is 2,2,6,6-tetramethylpiperidin-4-yl, R
t
is hydrogen, R
3
is 3-ethoxy, and R
1
is 5-chloro or 5-methoxy. It is considered that compounds of formula (IC) are novel.
Accordingly, the present invention provides a compound of formula (IC) or a salt thereof or a solvate thereof.
There is a subgroup of compounds falling wholly within formula (I) of formula (ID)
wherein;
R
1
, R
2
, R
4
, and R
5
are as defined in formula (I), R
s
is 2,2,6,6-tetramethylpiperidin-4-yl, R
t
is hydrogen, R
3
is 2-methox
Farina Carlo
Gagliardi Stefania
Novella Pietro A.
Berch Mark L.
Habte Kahsay
Nikem Research S.r.l.
Wolf Greenfield & Sacks P.C.
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