Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-22
2002-04-30
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S465000, C548S504000, C549S013000
Reexamination Certificate
active
06380242
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the use of certain indole and indazole derivatives in the treatment of migraine. Further, the invention relates to certain N-alkylamino indole and indazole compounds, to pharmaceutical and diagnostic compositions containing them and to their medical use, particularly in the treatment or diagnosis of CNS conditions.
BACKGROUND OF THE INVENTION
Through its interaction with receptors found on neuronal and other cells, 5-hydroxytryptamine (5-HT or serotonin) mediates a variety of physiological effects. Imbalances in this interaction are believed to be responsible for such conditions as anxiety, hallucination, migraine, chemotherapy-induced nausea and for disorders in sexual activity, cardiovascular activity and thermoregulation, amongst others. From an improved understanding of the 5-HT receptor population it is apparent that these effects are mediated selectively through individual types and subtypes of the 5-HT receptors. Migraine, for example, has been treated with ergotamine, dihydroergotamine, methylsergide and, most recently, sumatriptan, all of which presumably act at the 5-HT
1D
receptor subtype.
Current treatments for migraine, including sumatriptan, continue to have unwanted side effects. These include coronary vasospasm, hypertension and angina. Recent evidence suggests that the observed sumatriptan-mediated contraction of coronary arteries may be due to the stimulation of the 5-HT
1B
(formerly 5-HT
1D&bgr;
) subtype of the 5-HT receptors (Kaumann, A. J. Circulation, 1994, 90:1141-1153).
Given the physiological and clinical significance of the 5-HT
1D
receptor, and the potential side effect liability of stimulation of the 5-HT
1B
receptor, it would be desirable to provide compounds that bind with high affinity to the 5-HT
1D
receptor. Such compounds would be medically useful, for example, to treat indications for which administration of a 5-HT
1D
ligand is indicated, such as migraine. Such compounds could also be used diagnostically, for example, to identify these receptors and to screen drug candidates.
SUMMARY OF THE INVENTION
It has been found that compounds of Formula I,
wherein:
X is selected from the group consisting of N, CH and C-lower alkyl;
R
1
represents a 5 to 7-membered monocyclic or benzo-fused heterocyclic ring, which may be unsaturated, and which may contain one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino and mono- or di-lower alkyl amino;
Ak represents a C
1-3
alkylene chain which may be substituted with R
2
, where R
2
represents lower alkyl;
R
3
and R
4
are independently selected from the group consisting of H, lower alkyl, lower alkenyl, cycloalkyl and optionally-substituted benzyl; or one pair of R
2
and
R
3
or R
3
and R
4
together may form an alkylene or alkenylene bridge which, with the nitrogen atom, form a 3- to 7-membered ring which may contain one or more substituents selected from the group consisting of lower alkyl, hydroxy, hydroxymethyl, alkoxymethyl, amino and substituted amino;
R
5
is selected from the group consisting of H, lower alkyl and a 4- to 7-membered carbocyclic or heterocyclic group, which may be unsaturated
and salts and solvates thereof, bind to the Serotonin 5-HT
1D
receptor and are, therefore, useful, in accordance with one aspect of the invention, for the treatment of diseases such as migraine.
In another aspect of the invention, compounds of Formula I, and radio-labeled forms thereof, are also useful as a pharmacological tool for the identification of other compounds, including potential drug candidates, which bind to the 5-HT
1D
receptor.
Radio-labeled forms of compounds of Formula I are also useful as diagnostic tools for the identification of 5-HT
1D
binding sites in vitro.
According to another aspect of the present invention there are provided compounds of Formula II and a salt, solvate or hydrate thereof:
wherein:
X is selected from the group consisting of N, CH and C-lower alkyl;
R
6
represents a 5 to 7-membered monocyclic or benzo-fused heterocyclic ring, which may be unsaturated, and which may contain one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino and mono- or di-lower alkyl amino;
Ak represents a C
1-3
alkylene chain which may be substituted with R
7
, where R
7
represents lower alkyl;
R
8
and R
9
are independently selected from the group consisting of H, lower alkyl, lower alkenyl, cycloalkyl and optionally-substituted benzyl;
R
10
is selected from the group consisting of H, lower alkyl and a 4- to 7-membered carbocyclic or heterocyclic group, which may be unsaturated.
It is another aspect of the present invention to provide compounds which bind selectively to the 5-HT
1D
receptor, relative particularly to the 5-HT
1B
receptor.
According to another aspect of the invention there are provided compositions comprising a compound of Formula I and a carrier, either for use as reagents, for example in the identification of 5-HT
1D
receptors or 5-HT
1D
receptor ligands, or for pharmaceutical use to treat conditions where stimulation of the 5-HT
1D
receptor is indicated.
According to another aspect of the invention there are provided compositions comprising a compound of Formula II and a carrier.
It is another aspect of the present invention to provide a method effective to treat medical conditions for which stimulation of the 5-HT
1D
receptor is indicated, such as migraine.
These and other aspects of the present invention are described in greater detail hereinbelow.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The term “lower alkyl” as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term “cycloalkyl” as used herein means a 3- to 7-membered carbocyclic ring and includes cyclopropyl, cyclohexyl and the like.
The term “lower alkoxy” as used herein means straight and branched chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term “optionally substituted benzyl” as used herein means an unsubstituted benzyl radical or a benzyl radical substituted on the phenyl ring with 1-3 substituents independently selected from halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O.
The term “pharmaceutically acceptable salt” means an acid addition salt which is compatible with the treatment of patients.
A “pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of their intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluenesulfonic and methanesulfonic acids. Either the mono- or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts e.g. oxalates may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
The term “solvate” means a compound of Formula I, or a pharmaceutically acceptable salt of a compound of For
Arora Jalaj
Edwards Louise
Isaac Methvin
O'Brien Anne
Slassi Abdelmalik
Arent Fox Kintner & Plotkin & Kahn, PLLC
Desai Rita
NPS Allelix Corp.
Rotman Alan L.
LandOfFree
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