Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-13
2001-06-05
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S369000, C544S392000
Reexamination Certificate
active
06242448
ABSTRACT:
BACKGROUND OF THE INVENTION
WO 9109857 (Sanofi SA) describes aminosubstituted heterocycles that are antagonists of platelet activating factor. WO 9407489 (Salt Inst.) describes the (heteroaryl-alkyl)piperazine compounds to inhibit neuronal nicotinic acetyl choline receptors e.g. to treat hypertension of nicotine addiction. DE 4425146 (BASF) describes heteroaryl and aryl substituted (heteroaryl-alkyl)-piperazine compounds as selective dopamine D3 receptor ligands.
DESCRIPTION OF THE INVENTION
This invention relates to novel 4-(arylpiperazin-1-yl) oxazole derivatives which are agonists and antagonists of the 5HT1A receptor subtype. By virtue of their high binding affinity to the 5HT1A receptor, compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic, OCD, sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer's disease, Parkinson's disease, obesity and migraine.
Compounds of the present invention are represented by the general formula (
1
),
in which:
R
1
is aryl or heteroaryl;
R
2
is alkyl, alkylcycloalkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycloalkyl, or alkylheterocycloalkyl; provided that the point of attachment is a carbon atom;
R
3
is alkyl, alkylcycloalkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycloalkyl or alkylheterocycloalkyl; n is 0 or 1 and m is an integer from 1 to 3; or a pharmaceutical salt thereof.
“Alkyl”, whether used alone or as part of a group such as “alkoxy”, means a branched or straight chain having from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. Lower alkyl refers to alkyl having from 1 to 6 carbon atoms. The alkyl may be substituted with one or more substituents.
“Aryl” whether used alone or as part of a group such as “aralkyl”, means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Preferred aryl groups are phenyl, 1-naphthyl and 2-naphthyl. The aryl may be substituted with one to three substituents. “Heteroaryl” whether used alone or as part of a group such as “heteroaralkyl”, means 5 to 10 membered mono or bicyclic aromatic ring having from 1 to 3 heteroatoms selected from N, O and S. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, benzopyranyl and benzodioxanyl. Preferred heteroaryl groups include pyridyl, furyl, thienyl, quinolyl, isoquinolyl, indolyl, benzodioxanyl and benzopyranyl. Still more preferred heteroaryls include 1,4-benzodioxan-5-yl and benzopyranyl The heteroaryl may also be substituted with one to 3 substituents.
“Cycloalkyl” means a cyclic alkyl of 3 to 8 carbon atoms. Exemplary cycloalkyl groups include cyclopentyl and cyclohexyl. The cycloalkyl group may be substituted with 1 to 3 substituents.
“Heterocycloalkyl” means a cyclic alkyl of 3 to 8 member having 1 to 3 heteroatoms selected from N, O and S. The heterocycloalkyl group may be substituted with 1 to 3 substituents.
“Alkoxy” means an alkyl-O group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy. The cycloalkyl may bs substituted with 1 to 3 substituents.
“Halogen” includes fluorine, chlorine, iodine and bromine.
Suitable substituents include, unless otherwise noted, halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino and aryl.
Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
It is understood that the definition of compounds of Formula (
1
) include racemates, racemic mixtures, and individual enantiomers and diasteromers. All asymmetric forms, individual isomers and combinations thereof are within the scope of the present invention.
Optically active isomers may be prepared, for example, by resolving the racemic mixtures. The resolution can be carried out by methods known to those skilled in the art such as in the presence of resolving agent, by chromatography, or combinations thereof.
Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
Compounds of the present invention may be prepared using conventional methods, utilizing for example the disconnections A and B shown in Scheme 1 below.
Aryl piperazines (2) are either commercially available or readily prepared by those skilled in the art of organic synthesis, for example by the reaction of an aniline (R
1
NH
2
,) with bis(2-chloroethyl)amine.
In path A, the amidoalkyl chloride of formula (3) (X=Cl, n=0) may be prepared from the corresponding amine (5) using standard acylating conditions known to those skilled in the art of organic synthesis.
The alkyl chloride (5) is readily available, and may be prepared from the corresponding protected amino acid (6) using, for example, the Arndt-Eistert reaction. For example, reaction of the acid chloride of (6) with diazomethane and treatment of the resulting &agr;-diazoketone (7) with HCl affords the required product
Reaction of (2) with an alkyl chloride (3) affords the ketoamide (8). This product can be cyclized to the desired oxazole (1) by the action of a dehydrating agent such as the chlorinating agent POCl3.
In path B, the chloroalkyloxazole (4) (X═Cl, n=0 or 1) may be prepared from the ketoamide (3) by the action of a dehydrating agent such as POCl3. The subsequent alkylation of an arylpiperazine (2) with the chloroalkyloxazole (4) may be conducted in a suitable solvent (e.g. acetone), optionally utilizing a base (e.g. potassium carbonate or triethylamine) as an acid scavenger.
Alternatively, the chloroalkyloxazole (4) (X═Cl, n=0) can be homologated to the nitrile (11) by the action of sodium cyanide, which can provide the carboxylic acid (9) upon acid or base mediated hydrolysis.
Derivatives of the 2,4-disubstituted oxazole-5-acetic acid (9) can also be prepared by alternative routes. Such methods are known, and have been described, for example by Dow R. L.,
J. Org. Chem.,
(1990), 55(1), 386-8. Condensation of the acid (a) with the piperazine (
2
) affords the amide (
10
) which can be reduced to the required product using a hydride reducing agent such as lithium aluminium hydride or borane.
The following non-limiting specific examples are included to illustrate the synthetic procedures used for preparing compounds of the formula 1. In these examples, all chemicals and intermediates are either commercially available or can be prepared by standard procedures found in the literature or are known to those skilled in the art of organic synthesis. Several preferred embodiments are described to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.
REFERENCES:
patent: 704839 (1995-07-01), None
patent: WO9109857 (1991-07-01), None
patent: WO9407489 (1994-04-01), None
patent: 9938864 (1999-08-01), None
Greenblatt Lynne Padilla
Kelly Michael Gerard
Nelson Frances Christy
American Home Products Corporation
Barrett Rebecca R.
Patel Sudhaker B.
Shah Mukund J.
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