Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-16
2002-05-07
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S397000
Reexamination Certificate
active
06384042
ABSTRACT:
The present invention relates to a new use, in particular a new pharmaceutical use for compounds having 5-HT
3
(serotonin M) receptor, in particular specific 5-HT
3
receptor, antagonist activity, especially in the manufacture of a pharmaceutical composition.
The 5-HT
3
-receptor antagonists comprise a defined and recognised class of pharmaceutically active compounds well known in the art and characterised, as their name implies, by their pharmacological activity. Various 5-HT
3
receptor antagonist compounds are commercially available and clinically applied, e.g. in the treatment of emesis.
In accordance with the present invention it has now surprisingly been found that 5-HT
3
receptor antagonists are useful for the systemic treatment of inflammatory rheumatic or rheumatoid diseases other than crystal induced arthritis, especially gout, and from living pathogen induced inflammatory diseases as long as the living pathogen is still present, especially of inflammation, e.g. of inflammatory processes, conditions, events and disease as well as their sequelae or symptoms, associated with rheumatic or rheumatoid diseases.
Hence, the present invention relates to the use of a 5-HT
3
receptor antagonist or of a pharmaceutically acceptable salt of such an antagonist for the manufacture of a pharmaceutical composition for the systemic treatment of an inflammatory rheumatic or rheumatoid disease other than crystal induced arthritis and other than living pathogen induced inflammatory diseases as long as the living pathogen is still present, for example the treatment of any process, condition, event, or disease as hereinafter described. In particular, the present invention provides the use as mentioned before where, in addition to pain, at least one further sequela or symptom in addition to pain that is associated with the inflammatory rheumatoid or rheumatic disease is alleviated, ameliorated or controlled.
Any 5-HT
3
receptor antagonist can be used in accordance with the invention. Preferred 5-HT
3
receptor antagonists which may be employed in accordance with the present invention are:
A) Ondansetron [1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-IH-imidazol-1-yl]methyl]-4H-carbazol-4-one (cf. Merck Index, twelfth edition, item 6979);
B) Granisetron [endo-1-methyl-N-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-IH-imidazole-3-carboxamide: (cf. loc. cit., item 4557); and
C) Dolasetron [IH-indole-3-carboxylic acid (2&agr;, 6&agr;, 8&agr;, 9&agr;&bgr;)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester] (cf. loc. cit., item 3471).
Particular 5-HT
3
receptor antagonists which may be employed in accordance with the present invention are those of the formula 1 as defined in European Patent Publication 189002 B1, the contents of which are incorporated herein by reference, in particular the compound:
D) Indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclo[3,2,1]-oct-3-yl-ester, also known as tropisetron. (cf. loc.cit., item 9914).
Further 5-HT
3
receptor antagonists which may be used preferably in accordance with the present invention are:
E) 4,5,6,7-tetrahydro-5-[(1-methyl-indol-3-yl)carbonyl]benzimidazole (see also ramosetron, see U.S. Pat. No. 5,344,927);
F) (+)-10-methyl-7-(5-methyl-1H-imidazol-4-ylmethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (see also fabesetron, EP 0 361 317); and
G) [N-(1-ethyl-2-imidazolin-2-yl-methyl)-2-methoxy-4-amino-5-chlorobenzamide (see also lintopride-Chem.- Abstr.-No. 107429-63-0).
A further 5-HT
3
receptor antagonists which may be used preferably in accordance with the present invention is
H) 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (see also alosetron, EP 0 306 323).
Each of these compounds, alone or in combination with one or more other 5-HT
3
inhibitor, may be used for the treatment according to the invention.
For use in accordance with the present invention tropisteron (especially in the formulation called NAVOBAN®) is most preferred.
5-HT
3
-receptor antagonists may be employed in accordance with the invention in free or in pharmaceutically acceptable salt form, e.g. as known in the art, for example, in the case of compounds A) to D) above in pharmaceutically acceptable acid addition salt form, for example, in the case of: compound A) the hydrochloride dihydrate; compound B) the hydrochloride; compound C) the mesylate; and compound D) the monohydrochloride. References to 5-HT
3
receptor antagonists collectively or individually throughout the present specification and claims are accordingly to be understood as embracing both free compounds and such pharmaceutically acceptable salt forms, e.g. as clinically employed, and further also solvates, e.g. hydrates, or specific crystal forms of any of these compounds or salts.
Thus, the invention relates to the use of a 5-HT
3
receptor antagonist or of a pharmaceutically acceptable salt of such an antagonist for the manufacture of a pharmaceutical composition for the systemic treatment of an inflammatory rheumatic or rheumatoid disease other than crystal induced arthritis and other than living pathogen induced inflammatory diseases as long as the living pathogen is still present, where the 5-HT
3
receptor antagonist is selected from the group consisting of ondansetron, granisetron, dolasetron, tropisetron, ramosetron, fabesetron, lintopride and alosetron, which may be used in free form, that is, not as a salt, or as a pharmaceutically acceptable salt.
In accordance with the present invention it has now surprisingly been found that 5-HT
3
receptor antagonists are useful for the treatment of inflammation. They are useful for the treatment of inflammatory rheumatic or rheumatoid processes, conditions or events, for example, consequential to disease (including infection, for example viral infection, with the proviso that in case of an acute infection or parasite infestation, e.g. bacterial, fungal or, in a broader sense, viral or protozoal infection, or infestation by a parasite, first treatment of the infection or infestation itself, e.g. with antibiotics or other treatment, is indicated to remove the living pathogen before the 5-HT
3
antagonist is used), as well for the treatment of inflammatory disease as such.
“Treatment” as used herein includes systemic use for the alleviation, amelioration or control of inflammation, e.g. of inflammatory rheumatic or rheumatoid disease, process, condition or event. It also includes intervention for the alleviation, amelioration or control of the sequelae or symptoms of inflammation, for example degeneration (e.g. of cells, epithelia or tissues), or especially swelling, exudation or effusion, or pain. In this context the term “treatment” is further to be understood as embracing use to reverse, restrict or control progression of any specified disease, process, condition, event or the like, including use for disease modifying effect. If any of the mentioned diseases, processes, conditions or events is associated with pain, the term “treatment” preferably encompasses the alleviation, amelioration or control (including temporal or permanent removal) of at least one further sequela or symptom in addition to pain, such as swelling, effusion, exsudation, stiffness, lack of flexibility of joints, or degeneration, more preferably of all symptoms and most preferably of the total clinical picture of the respective disease, irritation or manifestation.
The present invention is in particular applicable to the systemic treatment of an inflammatory disease other than crystal induced arthritis (gout) or preferably other than living pathogen induced inflammation as long as the living pathogen is still present, especially of manifestations at the locomotor apparatus, such as various inflammatory rheumatoid diseases (except for crystal induced arthritis (e.g. gout) and living pathogen induced diseases as long as the pathogen (e.g. a virus, bacterium, fungus, protozoon or parasite) is still present, so that causal treatment against th
Färber Lothar
Möller Wolfgang
Stratz Thomas
Jarvis William R. A.
Kim Vicki
Loeschorn Carol A.
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