Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-06
2004-09-07
Shah, Mukund (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254090, C514S415000, C544S366000, C544S358000, C544S373000, C548S452000, C548S469000, C548S511000, C548S503000
Reexamination Certificate
active
06787535
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to new indole 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 nervous 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). Furthermore, the effect of 5-HT6 antagonist and 5-HT6 antisense aligonucleotides to reduce food intake in rats has been reported (Br J Pharmac. 1999 Suppl 126, page 66 and J Psychopharmacol Suppl A64 1997, page 255).
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula I:
wherein:
R
1
is —S(O)
0-2
—A, —C(O)—A, or —(CH
2
)
0-1
—A, wherein A is aryl or heteroaryl, and said aryl or heteroaryl are each independently in each occurrence optionally substituted with one or more groups selected from hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, amino, alkylamino, dialkylamino, alkylaminocarbonyl, alkylcarbonylamino, alkylaminosulfonyl, and alkylsulfonylamino;
R
2
is selected from hydrogen, C
1-6
-alkyl, C
1-6
-alkoxy, and C
1-6
-alkylthio;
R
3
is selected from hydrogen and C
1-6
-alkyl;
R
4
is selected from hydrogen, halogen, C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkylthio, haloalkyl, cyano, and alkylcarbonyl; and
one of R
5
, R
6
or R
7
is a group of general Formula B, wherein W is a —CH— group or a nitrogen atom, and R
8
, R
9
and R
10
are each independently selected from hydrogen, C
1-10
-alkyl and benzyl, or R
8
and R
9
together may form a C
3
-C
4
alkylene;
and the others are each independently in each occurrence selected from hydrogen, halogen, C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkylthio, haloalkyl, cyano, and alkylcarbonyl;
or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, 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 a 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 irritable bowel syndrome (IBS).
In another aspect, the invention relates to a process which comprises:
i) reacting a compound having a general Formula 4
wherein P is a protecting group and R
2
, R
4
, R
9
, and R
10
are as defined herein, with a compound of general formula (A—S)
2
, wherein A is aryl or heteroaryl, to provide an adduct 4a
ii) oxidation of the sulfur atom of 4a;
iii) optional alkylation of the nitrogen of the indole group of oxidized 4a; and
iv) removal of the protecting group P;, to provide a compound of the general Formula I,
wherein R
8
is hydrogen, and A, R
2
, R
3
, R
4
, R
9
, and R
10
are as defined in the summary of the invention, and
v) optional alkylation of the nitrogen of the piperazine or piperidine group; to provide a compound of the general Formula I, wherein R
8
is C
1-10
-alkyl, and A, R
2
, R
3
, R
4
, R
9
, and R
10
are as defined in the Summary of the Invention.
In another embodiment, the invention further relates to a process which comprises:
i) reacting a compound having a general Formula 4
wherein P is a protecting group and R
2
, R
4
, R
9
and R
10
are as defined herein, with a compound of general formula (A—S)
2
, wherein A is aryl or heteroaryl,
ii) optional alkylation of the nitrogen of the indole group,
iii) removing the protecting group P;
to provide a compound of the general Formula I,
wherein R
8
is hydrogen, and A, R
2
, R
3
, R
4
, R
9
, and R
10
are as defined in the summary of the invention, and
iv) optional alkylation of the nitrogen of the piperazine or piperidine group to provide a compound of the general Formula I, wherein R
8
is C
1-10
-alkyl, and A, R
2
, R
3
, R
4
, R
9
, and R
10
are as defined in the Summary of the Invention.
In another embodiment, the invention further relates to a process which comprises:
i) reacting a 1-halo-2-nitrobenzene with a halomethanesulfonyl benzene to provide a 1-benzenesulfonylmethyl-2-nitrobenzene;
ii) amination of the 1-benzenesulfonylmethyl-2-nitrobenzene with a 1-alkylpiperazine to provide a piperazinylated nitrobenzene;
iii) reduction of the nitro group of the piperazinylated nitrobenzene, and
iv) addition of an orthoformate, followed by cyclization to yield a compound of Formula 18a,
wherein R
8
is C
1-10
-alkyl and A, R
9
, and R
10
are as defined in the summary of the invention.
REFERENCES:
patent: 6187805 (2001-02-01), Pineiro et al.
patent: 0941994 (1999-09-01), None
patent: WO 96/03400 (1996-02-01), None
patent: WO 98/27081 (1998-06-01), None
patent: 9850358 (1998-11-01), None
patent: WO 01/32660 (2001-05-01), None
Kelley et al, PubMed Abstract 12117573, also cited as Physiol. Behav.,76/3,365-77(2002).*
Chabrier et al, PubMed Abstract 10442086, also cited as Cell.Mol.Life SDci.,55/8-9, 1029-35(1999).*
Meltzer HV, PubMed Abstract 7583621, also cited as Clin. Neurosci.,3/2,64-75(1995).*
Monsma, Jr., Frederick J., et al., “Cloning and Expression of a Novel Serotonin Receptor with High Affinity for Tricyclic Psychotropic Drugs,”Molecular Pharmacology, 1993, 43:320-327, The American Society for Pharmacology and Experimental Therapeutics.
Isaac, Methvin et al., “6-Bicyclopiperazinyl-1-arylsulfonylindoles and 6-Bicyclopiperidinyl-1-arylsulfonylindoles Derivatives as Novel, Potent, andSelective 5-HT6Receptor Antagonists,”Bioorganic&Medicinal Chemistry Letters, (2000), pp. 1719-1721, vol. 10, Pergamon.
Beard Colin Charles
Clark Robin Douglas
Fisher Lawrence Emerson
Harris, III Ralph New
Putman David George
Hall Robert C.
Patel Sudhaker B.
Shah Mukund
Syntex (U.S.A.) LLC
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