Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-13
2001-05-29
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212010, C514S218000, C514S235500, C514S255030, C514S307000, C514S314000, C514S318000, C514S326000, C514S330000, C514S331000, C540S481000, C540S544000, C540S553000, C544S130000, C544S360000, C546S146000, C546S169000, C546S193000, C546S194000, C546S208000, C546S209000, C546S210000, C546S231000, C546S232000
Reexamination Certificate
active
06239126
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,882,432 teaches adamantyl and noradamantyl piperazine carbarnates and ureas with high 5-HT1A receptor affinities. These compounds, as well as those disclosed in U.S. Pat. No. 4,797,489 are useful for the treatment of CNS disorders.
EP 661266-A1 describes piperidino and piperazino 5-HT2 receptor antagonists and blood platelet aggregation inhibitors.
WO 9504042 describes 4-phenyl-4-phenylpropyl(enyl) piperidine tachykinin antagonists for treating pain or inflammation or emesis.
DESCRIPTION OF THE INVENTION
This invention relates to novel arylpiperidine urea and aryl-1,2,5,6-tetrahydropyridine urea derivatives. In accordance with this invention are provided novel arylpiperidine urea and aryl-1,2,5,6 tetrahydropyridine urea derivatives which are 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, obsessive-compulsive disorder (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 (A),
in which:
R0 and R1 are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl alkylcycloalkyl, alkylheterocycloalkyl, aryl or heteroaryl, or taken together R0 and R1 form a heterocycloalkyl, provided that R0 and R1 are not both hydrogen;
R2 is hydrogen, alkyl or CH
2
(R
5
);
R3 is hydrogen or alkyl;
R4 is aryl or heteroaryl;
R5 is alkyl, alkenyl or alkynyl;
X is hydrogen, halogen, perhaloalkyl, hydroxy, alkoxy, perhaloalkoxy; n is an integer from 1 to 3; and the dotted line is an optional double bond, or a pharmaceutical salt thereof.
X is preferably halogen substituted at positions 4- or 5-, more preferably is 4-fluoro or 5-fluoro and most preferably is 5-fluoro-.
When R2 is an alkyl group, R2 is preferably a straight chain alkyl of 1 to 5 carbon atoms. R3 is preferably a straight chain alkyl of 1 to 4 carbon atoms.
In some preferred embodiments of the present invention, R0 and R1 are independently hydrogen or cycloalkyl or taken together are cycloalkyl or heterocycloalkyl. More preferably R0 and R1 are independently hydrogen or cyclohexyl or taken together are morpholino.
In still more preferred embodiments of the present invention, R0 and R1 are independently hydrogen or cyclohexyl, or taken together are morpholino, X is 5-fluoro, and R4 is phenyl.
“Alkyl” as used herein means a branched or straight chain having from 1 to 6 carbon atoms and more preferably from 1 to 5 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
“Alkenyl” as used herein means a branched or straight chain alkyl having from 2 to 6 carbon atoms. Exemplary alkenyl groups include ethylene and propylene. In some embodiments of the present invention the alkenyl group may be substituted.
“Alkynyl” as used herein means a branched or straight chain alkyl of 2 to 6 carbon atoms and at least one carbon-carbon triple bond. Exemplary alkynyl groups include ethynyl and propynyl. In some embodiments of the present invention the alkynyl group may be substituted with one or more substituents.
“Alkoxy” as used herein 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.
“Aryl” as used herein 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. Exemplary aryl groups include phenyl and naphthyl In some preferred embodiments aryl is phenyl, 1-naphthyl or 2-naphthyl. In still more preferred embodiments aryl is phenyl. The aryl group may be substituted with one or more substituents. Substituted aryl groups preferably have one to three substituents.
“Cycloalkyl” as used herein means a monocyclic alkyl group having from 3 to 8 carbon atoms. In some preferred embodiments cycloalkyl may be substituted with from 1 to 3 substituents.
“Heterocycloalkyl” as used herein means a monocyclic alkyl group having from 3 to 8 members containing one or more, and preferably one or two, heteroatoms selected from N and O. Exemplary heterocycloalkyl groups include piperidinyl, piperazinyl and morpholino. In some embodiments heterocycloalkyl groups may be substituted with from 1 to 3 substituents.
Halogen, as used herein means fluorine, chlorine, iodine and bromine.
“Heteroaryl” 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 and benzodioxanyl. Preferred heteroaryl groups include thienyl, pyridyl, and furyl. More preferred are heteroaryl groups including 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, and 3-furyl. The heteroaryl group may be substituted with one or more substituents.
Suitable substituents, unless otherwise noted, include 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.
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.
The compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing conventional methods which utilize readily available reagents and starting materials.
The compounds A and intermediate 4-(halo-2-methoxy-phenyl)-piperidines F or 4-(halo-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridines H of the present invention can be prepared by conventional methods by those skilled in the organic synthesis. For example, in Scheme I, metal-halogen exchange of an appropriately substituted aryl halide B with a base, such as butyllithium, forms a carboanion, and treatment of the resulting mixture with an N-protected-4-piperidone C affords a tertiary alcohol D. An example of the nitrogen protecting group Rx of the 4-piperidone C is benzyl, which can be removed by hydrogenation of D to afford amine G. Dehydration of G with an acid, such as sulfuric acid can provide the desired 4-(halo-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine H. Dehydration of the tertiary alcohol D, removal of the nitroen protecting group, Rx and hydrogenation of the double bond can afford 4-(halo-2-methoxy-phenyl)-piperidine F.
The des-halo intermediates 4-(2-methoxyphenyl)-piperidine F (X=H) and 1,2,3,6-tetra hydro-4-(2-methoxyphenyl)-pyridine H (X=H) are both known compounds and may be prepared by the following literature procedures: Van Wijngaarden Ineke et al
Kelly Michael G.
Zhang Gan
American Home Products Corporation
Barrett Rebecca R.
Covington Raymond
Rotman Alan L.
LandOfFree
Arylpiperidine and aryl-1,2,5,6-tetra-hydropyridine urea... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Arylpiperidine and aryl-1,2,5,6-tetra-hydropyridine urea..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Arylpiperidine and aryl-1,2,5,6-tetra-hydropyridine urea... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2479528