Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-14
2002-10-08
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S299000, C514S394000, C514S396000, C514S214020, C514S216000, C514S412000, C514S413000
Reexamination Certificate
active
06462065
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.
Specifically, the present invention relates to the treatments defined below.
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 treatment of local non-inflammatory, local irritation-related and local inflammatory disease conditions. This is surprising in that (a) the 5-HT
3
receptor antagonists are effective alone; (b) do not only bring pain relief, but also are effective in the treatment of other symptoms, such as effusion, swelling, stiffness and the like, and (c) are locally effective, thus not having to rely on systemic administration that may show effects e.g. by working via effects on nerves and/or synapses at the spinal cord. It is also astonishing that relatively high local doses are both tolerated and effective when local administration is employed.
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 treatment of a non-inflammatory local disease of the musculo-sceletal system, of a local irritation condition of a joint or tendon sheath, or for the local treatment a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition 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 of the local disease, local irritation condition or local manifestation 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-1H-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)-1H-imidazole-3-carboxamide: (cf. loc. cit., item 4557); and
C) Dolasetron [1H-indole-3-carboxylic acid (2&agr;, 6&agr;, 8&agr;, 9&agr;&bgr;)-octahydro-3-oxo-2,6methano-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).
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.
For use in accordance with the present invention tropisetron (especially in the formulation called NAVOBAN®) is most preferred.
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 treatment of a non-inflammatory local disease of the musculo-sceletal system, of a local irritation condition of a joint or tendon sheath, or for the local treatment a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition 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 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 certain diseases, processes, conditions or events, namely non-inflammatory local diseases of the musculo-sceletal system; local irritation conditions of the joints or tendon sheaths; or the local treatment also of local manifestations at the locomotor apparatus of inflammatory diseases; such as conditions, processes or events that are due to trauma (including surgery or preferably accident); overload; posture fault; degenerative processes; conditions subsequent to another disease (including infection, for example viral infection, or tumor diseases); or other conditions that result in irritation of the locomotor apparatus of the body; meaning especially therapy of the respective non-inflammatory disease, irritation or manifestation as such, its sequelae or its symptoms, or any combinations of these.
“Treatment” as used herein includes use for the alleviation, amelioration or control of said diseases, processes, conditions or events. It also includes intervention for the alleviation, amelioration or control of the sequelae or symptoms of any one or more of these diseases, for example degeneration (e.g. of cells, epithelia or tissues), swelling, exudation, effusion or pain, stiffness or inflexibility of joints. 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, manifestations or events, especially an inflammatory disease, process, condition, manifestation or event, 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, lack of flexibility (e.g. due to stiffness and/or lack of flexib
Färber Lothar
Möller Wolfgang
Stratz Thomas
Fay Zohreh
Ferraro Gregory D.
Kwon Brian-Yong S.
Novartis AG
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