Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-10
2004-02-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S113000
Reexamination Certificate
active
06686374
ABSTRACT:
This invention relates to azaindole compounds having affinity for serotonin receptors, to pharmaceutical and diagnostic compositions containing them and to their medical use, particularly in the diagnosis and treatment of CNS conditions.
According to one aspect of the invention, there are provided compounds of Formula I and a salt, solvate of hydrate thereof:
wherein:
R represents a group of Formula II or Formula III;
one of A, B D or E is a N atom, the remainder being CH groups;
R
1
is selected from the group consisting of SO
2
Ar, C(O)Ar, CH
2
Ar and Ar;
R
2
, R
3
and R
4
are independently selected from the group consisting of H and alkyl;
represents a single or double bond, with the proviso that there is only one double bond in the ring at a time;
n is an integer of from 1-3;
Z is selected from the group consisting of C, CH and N, provided that when
is a double bond, Z is C and when
is a single bond, Z is selected from CH and N;
Ar is an optionally substituted aryl group;
with the proviso that when R is a group of Formula II, R
1
is SO
2
Ar.
It is an aspect of the invention to provide compounds which bind to the 5-HT
6
receptor.
Certain compounds of the invention also bind to the 5-HT
7
receptor, and a further object of the invention provides such compounds having mixed 5-HT
6
and 5-HT
7
activity.
According to another aspect of the invention, there are provided pharmaceutical compositions comprising a compound of Formula I, in an amount effective to antagonize the 5-HT
6
receptor, and a pharmaceutically acceptable carrier.
In another aspect of the invention there are provided compositions containing a compound of Formula I, in amounts for pharmaceutical use, to treat CNS conditions where a 5-HT
6
antagonist is indicated, for example, for the treatment or prevention of central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances, Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease.
In another aspect of the invention, there are provided compounds useful as intermediates in the preparation of a compound of Formula I, and having a general structure according to Formula IV:
wherein
R represents a group of Formula II or Formula III;
one of A, B D or E is a N atom, the remainder being CH groups;
R
2
, R
3
and R
4
are independently selected from the group consisting of H and alkyl;
represents a single or double bond, with the proviso that there is only one double bond in the ring at a time;
n is an integer of from 1-3;
Z is selected from the group consisting of C, CH and N, provided that when
is a double bond, Z is C and when
is a single bond, Z is selected from CH and N.
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 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 “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 “aryl” as used herein means an optionally substituted 5-10 membered mono- or bi-cyclic aromatic group which can contain up to 2 heteroatoms, wherein the optional substituents are independently selected from 1-4 members of the group consisting of halo, hydroxy, alkyl, alkoxy, thioalkyl, trifluoromethyl and trifluoromethoxy, and includes phenyl, naphthyl, indanyl, indolyl, quinolyl, furyl, thienyl and the like.
The term halo as used herein means halogen and includes fluoro, chloro, bromo, iodo and the like, in both radioactive and non radioactive forms.
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. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of a compound 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. It should be noted that compounds of Formula I wherein Z is N are not stable in the presence of strong acid (for example 1N HCl), therefore when preparing acid addition salts of such compounds, care must be taken to select an appropriately mild acid, for example citric acid.
“Solvate” means a compound of Formula I, or the pharmaceutically acceptable salt of a compound of Formula I, wherein molecules of a suitable solvent are incorporated in a crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
The term “stereoisomers” is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
The term “treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
The term “therapeutically effective amount” means an amount of the compound which is effective in treating the named disorder or condition.
The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.
The term “schizophrenia” means schizophrenia, schizophreniform disorder, schizoaffective disorder and psychotic disorder wherein the term “psychotic” refers to delusions, prominent hallucinations, disorganized speech or disorganized or catatonic behavior. See Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington, D.C.
The present invention includes within its scope prodrugs of the compounds of Formula I. In general, such prodrugs will be functional derivatives of the compounds of Formula I which are readily convertible in vivo into the required compound of Formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
Compounds
Edwards Louise
Slassi Abdelmalik
Tehim Ashok
Xin Tao
McKenzie Thomas
NPS Allelix Corp.
Rothwell Figg Ernst & Manbeck
LandOfFree
Azaindoles having serotonin receptor affinity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Azaindoles having serotonin receptor affinity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Azaindoles having serotonin receptor affinity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3345080