Heterocyclic compounds for the treatment of migraine

Details Heterocyclic compounds for the treatment of migraine Heterocyclic compounds for the treatment of migraine

2000-11-13

2004-04-06

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S234500, C514S235200, C514S252190, C514S255050, C514S322000, C514S323000, C514S338000, C514S339000, C514S403000, C514S414000, C514S415000, C544S062000, C544S140000, C544S143000, C544S371000, C544S373000, C546S121000, C546S208000, C546S211000, C546S275700, C546S277400, C548S361100, C548S468000, C548S503000

Reexamination Certificate

active

06716837

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain 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 such as migraine.
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:
W is a CH group or a N atom;
Z is N or C-R4;
B and D are selected independently from CH and N, with the proviso that at least one of B and D is CH and with the further proviso that one of B and D can represent N only when W and Z are both other than N;
A is a group of Formula II, III or IV, such that group A contains at least 1 N atom;
NR7 is either —NH— or —N═
is a single or double bond;
X is a N atom, a CH group or a C(OH) group when
is a single bond; or, when is a double bond, a C atom;
Y is an NH, N-alkyl, N-benzyl or CH
2
group;
U and V each represent a N atom or a CH group, with the proviso that both cannot be N;
a and b are, independently, 0 or 1 ; c is an integer from 0 to 3 ; d is an integer from 1 to 3 ; e is an integer from 1 to 2 ; f is an integer from 0 to 3 ; g is an integer from 3 to 6 and h is an integer from 2 to 3 ; such that the sum of c and d is at least 2 and the sum of e and f is at least 2;
R
1
is selected from the group consisting of H, alkyl, alkyloxy, alkanoyl, aminoalkylenyl, alkylaminoalkylenyl, a hydroxyalkylenyl group, an alkyloxyalkylenyl group, a cycloalkyl group, a cycloalkylalkylenyl group, a heterocycloalkyl group, a heterocycloalkylalkylenyl group, an aryl group, a heterocycloaryl group, an amido group, a thioamido group, an arylcarbonyl group and an arylsulfonyl group;
R
2
and R
3
are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl and optionally-substituted benzyl ; or R
2
and R
3
, together with the nitrogen atom to which they are attached, may form a mono- or bi-cyclic group containing up to 10 carbon atoms and which, in addition, may contain a second heteroatom selected from the group consisting of N, S and O, and which may contain one or more substituents selected from the group consisting of alkyl, hydroxy, hydroxymethyl, alkyloxymethyl, amino and substituted amino;
R
4
is selected from the group consisting of H, alkyl and cycloalkyl
CR
5
represents a group selected from —CH2—, CH(OH)—, —C(O)—, —CH(alkyl)— and —CH(alkyloxy)—;
R6 is selected from the group consisting of H, alkyl, aryl, halogen, hydroxy, alkyloxy, amino, monoalkylamino and di-substitutedalkylamino;
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-labelled 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-labelled forms of compounds of Formula I are also useful as diagnostic tools for the identification of 5-HT
1D
binding sites in vitro.
In another aspect, the present invention provides 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.
In another aspect of the present invention, there is provided 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 AND PREFERRED EMBODIMENTS
The term “alkyl” as used herein means, unless otherwise stated, 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 terms “alkylene” and “alkylenyl” as used herein means straight or branched chain divalent, i.e., bridging, alkyl chains containing from one to six carbon atoms and includes methylene, e.g., —CH2—, ethylene, propylene, butylene and the like. The term “alkenyl” as used herein means straight and branched chain unsaturated radicals containing from one to six carbon atoms and includes allyl, propenyl, isopropenyl, pentenyl and the like.
The term “cycloalkyl” as used herein means a monocyclic ring system containing up to 8 atoms or a bicyclic ring system containing up to 12 atoms, including “heterocycloalkyl” ring systems which may contain up to two heteroatoms selected from the group consisting of N, S and O, and includes cyclopropyl, cyclohexyl, bicyclo[3.2.1]octyl, bicyclo[4.3.2]undecyl, aziridinyl, pyrrolidinyl, piperidinyl, troponyl, azabicyclo[2.2.2]octyl, tetrahydropyranyl, pyranyl, thiopyranyl, tetrahydrothiopyranyl, morpholinyl and the like, which ring system may be unsaturated and/or substituted. The terms “cycloalkyl-alkylenyl” and heterocyclo-alkylenyl” refer to rings systems of the type just described that are further substituted by a bridging alkylenyl group such as methylenyl and ethylenyl, and includes such groups as cyclohexyl-1-methylenyl, tetrahydropyranyl-4-ethylenyl, and the like. In the context of these definitions, the term “group” refers to a substituent as noted, which may be further substituted by one or two substituents selected from halo, hydroxy, alkyl, alkoxy, thioalkyl and trifluoroalkyl. For instance, a heterocycloalkyl such as pyrrolidinyl is a referred to as a heterocycloalkyl group when substituted by methyl, e.g. to yield N-methyl-pyrrolidinyl.
The term “alkyloxy” as used herein means straight and branched chain alkyloxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term “alkanoyl” as used herein means straight and branched chain alkanoyl radicals containing from one to six carbon atoms and includes acetyl, propionyl, pivaloyl and the like.
The term “aminoalkylenyl” as used herein means straight and branched chain amino-substituted alkyl or

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