Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-13
2001-07-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252180, C514S253090, C514S253110, C514S254010, C514S254090, C514S295000, C540S598000, C544S295000, C544S360000, C544S364000, C544S372000
Reexamination Certificate
active
06255302
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,977,159 describes 2-[(4-piperidyl) methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-B]indole derivatives and their application in treating depressive state, anxiety state or hypertension.
DESCRIPTION OF THE INVENTION
This invention relates to novel arylpiperidine derivatives. In accordance with this invention are provided novel arylpiperadine 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
A
in which:
R1 is aryl or heteroaryl;
A is NR2 or CH2 and B is N, NR2 or CH2, provided that A is not equal to B;
R2 is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylhetero-cycloalkyl, aryl, aralkyl, heteroaryl, alkylheteroaryl or COR3;
R3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
n is an integer from 0 to 2, or a pharmaceutical salt thereof.
In some preferred embodiments of the present invention R1 is phenyl; 2-, 3- or 4-pyridyl; 2-pyrimidyl; benzodioxan-5-yl; indol-4-yl; 3-thienyl; 1-, or 2-naphthyl. In still more preferred embodiments RI is phenyl or indol-4-yl.
In some preferred embodiments of the present invention R2 is aralkyl, alkylheterocycloalkyl or COR3.
“Alkyl” as used herein means a branched or straight chain having from 1 to 6 carbon atoms and more preferably from 1 to 4 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.
“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, naphthyl, and biphenyl. 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, benzopyranyl and benzodioxanyl. Preferred heteroaryl groups include thienyl, pyridyl, furyl, indolyl and benzodioxanyl. More preferred are heteroaryl groups including 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 3-indolyl, indol-4-yl and benzodiox-5-yl. The heteroaryl group may be substituted with one or more substituents. Substituted heteroaryl groups preferably have from 1 to 3 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.
For example, condensation of an aryl substituted piperazine with a suitably protected nipecotic acid or isonipecotic acid derivative provides the amides shown in scheme A and scheme B below. The reaction may be conducted in the presence of activating reagents such as 1-(3-dimethylarninopropyl)-3-ethylcarbodiimide hydro-chloride (DAEC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM).
A tert-butyl carbamate is an example of a suitable protection group (P) which can be removed by the action of acid. Deprotection to the amine, and subsequent reduction of the amide using lithium aluminum hydride or borane-tetrahydrofuran complex can afford the required unsubstituted product A. The product may be alkylated with alkyl halides under the influence of a base such as sodium hydride or potassium carbonate to afford further derivatives, or alternatively may be acylated with carboxylic acid derivatives and the amide subsequently reduced under the above noted conditions to afford further derivatives.
The following non-limiting specific examples are included to illustrate the synthetic procedures used for preparing compounds of the formula A. 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.
Intermediate 1
N-tert-Butoxycarbonyl-(1-(2-methoxy-phenyl)-piperazine)-4-isonipecotamide
4-(2-Methoxyphenyl)piperazine hydrochloride (5.0 g, 21.8 mmol) was added to a mixture of DAEC (4.18 g, 21.8 mmol), HOBT (1.3 equivalents, 3.83 g, 28.3 mmol) and N-t-butoxycarbonyl isonipecotic acid (5 g, 21.8 mmol) in DMF (35 mL), and the resulting solution was treated with NMM (2.5 equivalents, 6.0 mL, 54.5 mmol) and stirred at 0° C. for 16 hours. Water (100 mL) was added, the product extracted into ethyl acetate (3×50 mL) and the combined organics were washed with IN-HCl (20 mL), saturated NaHCO
3
(25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum afforded the product as a white solid (8.79 g, 99% yield)
Elemental Analysis for: C
22
H
33
N
3
O
4
Calculated: C, 65.48; H. 8.24; N, 10.41 Found: C, 65.23; H, 8.15; N, 10.23
Intermediate 2
1-(2-Methoxy-phenyl)-
Kelly Michael G.
Palmer Yvette L.
American Home Products Corporation
Barrett Rebecca R.
McKenzie Thomas
Shah Mukund J.
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