Arylsulfonyl derivatives with 5-HT6 receptor affinity

Details Arylsulfonyl derivatives with 5-HT6 receptor affinity Arylsulfonyl derivatives with 5-HT6 receptor affinity

2002-08-09

2004-11-30

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S255030, C514S317000, C514S326000, C544S376000, C544S377000, C544S395000, C546S196000, C546S197000, C546S206000, C546S236000

Reexamination Certificate

active

06825202

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to new 1-(5-arylsulfonyl-phenyl)piperazine and 4-(5-arylsulfonyl-phenyl)piperidine derivatives with 5-HT6 receptor affinity, and associated pharmaceutical compositions, methods for use as therapeutic agents, and methods of preparation thereof.
BACKGROUND OF THE INVENTION
The actions of the neurotransmitter 5-hydroxytryptamine (5-HT) as a major modulatory neurotransmitter in the brain, are mediated through a number of receptor families termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Based on a high level of 5-HT6 receptor mRNA in the brain, it has been stated that the 5-HT6 receptor may play a role in the pathology and treatment of central nerve system disorders. In particular, 5-HT6 selective ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder. (See for ex. B. L. Roth et al., J. Pharmacol. Exp. Ther.1994, 268, pages 1403-14120, D. R. Sibley et al., Mol. Pharmacol. 1993, 43, 320-327, A. J. Sleight et al, Neurotransmission 1995, 11, 1-5, and A. J. Sleight et al. Serotonin ID Research Alert, 1997, 2 (3), 115-8.
Several arylsulfonyl compounds with 5-HT6 affinity have been disclosed in U.S. Pat. No. 5,990,105 to Bos et al., but it has been surprisingly found that the novel compounds of Formula I possess greater affinity, and therefore would be suitable and highly desirable for the treatment or prevention of central nervous disorders described herein.
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula (I):
wherein:
Ar is an optionally substituted aryl group selected from naphthyl or phenyl;
X is —CH— or —N—;
R
1
is (C
1
-C
6
)alkyl;
R
2
and R
3
are each independently in each occurrence hydrogen or (C
1
-C
6
)alkyl, or R
2
and R
3
together may form a (C
3
-C
4
)alkylene group;
R
4
is hydrogen, or R
1
and R
4
together may form a —CH═CH—, —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —O—CH
2
—, or —O—CH
2
—CH
2
— group; it is understood that R
4
and OR
1
together with the phenyl to which they are attached would form a benzofuran, a 2,3-dihydrobenzofuran, a chromane, 2,3-dihydro-benzo[1,4]dioxine, or a benzo[1,3]dioxole ring;
or pharmaceutically acceptable salts or solvates thereof.
In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I), or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier.
In another aspect, this invention relates to a method of treatment of a disease in a mammal treatable by administration of compound of Formula (I) having a selective affinity for the 5-HT6 receptor, in particular a method of treatment in a subject having a disease state comprising Alzheimer's disease, central nervous disorders, such as for example, psychoses, schizophrenia, manic depressions, neurological disorders, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. In another aspect, this invention relates to a method of treatment in a subject having a gastrointestinal disease comprising functional bowel disorder.
In a preferred embodiment, the invention further relates to processes for preparing compounds of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise.
“Alkyl” means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms inclusive, unless otherwise indicated. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
“Lower alkyl” means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms inclusive, unless otherwise indicated. Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.
“Alkoxy” means the radical —O—R, wherein R is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
“Arylsulfonyl” means the radical —SO
2
R, wherein R is an aryl radical as defined herein. Examples of arylsulfonyl radicals include, but are not limited to, benzenesulfonyl, 3-chlorobenzenesulfonyl, naphthalene-2-sulfonyl, naphthalene-1-sulfonyl, and the like.
“Aryl” means the monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, aminosulfonyl, sulfonylamino, and/or trifluoromethyl, unless otherwise indicated. Examples of aryl radicals include, but are not limited to, phenyl, naphth-2-yl, naphth-1-yl, fluorophenyl, dichlorophenyl, and the like.
“Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
“Protective group” or “protecting group” means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen atoms present in the reactants.
“Amino-protecting group” means the protecting group that refers to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.
“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
“Inert organic solvent” or “inert solvent” means the solvent is inert under the conditions of the reaction being described

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