AU3123100A

AU3123100A - 1,4-piperazine derivatives having 5ht1a receptor activity

Info

Publication number: AU3123100A
Application number: AU31231/00A
Authority: AU
Inventors: Michael Gerard Kelly; Yvette Latko Palmer
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1998-12-17
Filing date: 1999-12-16
Publication date: 2000-07-03
Also published as: WO2000035878A1; JP2002532473A; CA2351859A1; EP1140838A1; BR9916185A

Description

WO 00/35878 PCT/US99/29881 -1 1,4-PIPERAZINE DERIVATIVES HAVING 5HT1A RECEPTOR ACTIVITY Background of the Invention 5 US patent 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 10 This invention relates to novel arylpiperidine derivatives. In accordance with this invention are provided novel arylpiperadine derivatives which are agonists and antagonists of the 5HTIA receptor subtype. By virtue of their high binding affinity to the 5HTIA receptor, compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic, OCD, sleep 15 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), RK n 20 A in which:

R

1 is aryl or heteroaryl; A is NR 2 or CH 2 and B is NR, or CH 2 , provided that A is not equal to B;

R

2 is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylhetero 25 cycloalkyl, aryl, aralkyl, heteroaryl, alkylheteroaryl or COR 3 ;

R

3 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 R 1 is phenyl; 2-, 3 30 or 4-pyridyl; 2-pyrimidyl; benzodioxan-5-yl; indol-4-yl; 3-thienyl; I-, or 2-naphthyl.

WO 00/35878 PCT/US99/29881 -2 In still more preferred embodiments R, is phenyl or indol-4-yl. In some preferred embodiments of the present invention R 2 is aralkyl, alky1heterocycloalkyl or COR 3 . "Alkyl" as used herein means a branched or straight chain having from 1 to 6 5 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 10 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 15 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. 20 "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. 25 "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. 30 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 35 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring WO 00/35878 PCT/US99/29881 -3 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 5 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, 10 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 15 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. 20 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 25 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 30 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 35 available reagents and starting materials.

WO 00/35878 PCT/US99/29881 -4 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-dimethylaminopropyl)-3-ethylcarbodiimide hydro 5 chloride (DAEC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM). ANH ArKN Scheme A Scheme B HOOC N NP HOOC.n V NvN~ RieNIIj NNv~ ' .I p Ri "IN N.RillN,_,,J L,.NH H 7 R,,O RO/ A A tert-butyl carbamate is an example of a suitable protection group (P) which 10 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 WO 00/35878 PCT/US99/29881 -5 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. 5 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 10 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-phenvl)-piperazine) 15 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 20 stirred at 0 0 C for 16 hours. Water (100 mL) was added, the product extracted into ethyl acetate (3 x 50 mL) and the combined organics were washed with IN-HCI (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) 25 Elemental Analysis for: C, 2

H

3

N

3 04 Calculated: C, 65.48; H, 8.24; N, 10.41 Found: C, 65.23; H, 8.15; N, 10.23 Intermediate 2 30 1-(2-Methoxv-phenvl)-piperazine)-4-isonipecotamide The carbamate from intermediate 1 (8.79 g, 21.8 mmol) was dissolved in 4M-HCl dioxan (40 mL) and the solution stirred at ambient temperature for 6 hours. The mixture was concentrated in vacuum, diethyl ether (50 mL) added and the WO 00/35878 PCT/US99/29881 -6 precipitated product collected by filtration and washed with ether (50 mL) to afford a white solid (7.28 g, 98% yield) Elemental Analysis for: C,7H 26

N

3 02 Calculated: C, 60.08; H, 7.71; N, 10.43 5 Found: C, 59.99; H, 7.56; N, 10.23 Intermediate 3 N-tert-Butoxvcarbonvl-(1-(2-methoxy-phenvl)-piperazine) 4-nipecotamide 10 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 nipecotic 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 0 C for 16 hours. Water (100 mL) was added, the product extracted into 15 ethyl acetate (3 x 50 mL) and the combined organics were washed with IN-HCl (20 mL), saturated NaHCO, (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

3 3

N

30 4 20 Calculated: C, 65.48; H, 8.24; N, 10.41 Found: C, 65.45; H, 8.23; N, 10.32 Intermediate 4 (1-(2-methoxy-phenyl)-piperazine)-4-nipecotamide 25 The carbamate from intermediate 3 (8.79 g, 21.8 mmol) was dissolved in 4M-HCl dioxan (40 mL) and the solution stirred at ambient temperature for 6 hours. The mixture was concentrated in vacuum, diethyl ether (50 mL) added and the precipitated product collected by filtration and washed with ether (50 mL) to afford a white solid (7.28 g, 98% yield) 30 Elemental Analysis for: C17H,6N302 Calculated: C, 60.08; H, 7.71; N, 10.43 Found: C, 60.22; H, 7.56; N, 10.39 WO 00/35878 PCTIUS99/29881 -7 Example 1 1-( 2 -Methoxv-phenyl)-4-piperidin-4-vlmethyl-piperazine A solution of the amide from intermediate 2 (7.28 g, 21.8 mmol) and triethylamine (6 mL) in THF (100 mL) was treated with the dropwise addition of borane-THF (1.0 M, 5 76 mL) at 0 0 C under nitrogen. The mixture was refluxed for 16 hours and after cooling to 0 0 C, the reaction was terminated by the addition of 2N-HCl (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product extracted into ethyl acetate (3 x 35 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. Filtration 10 and concentration in vacuum gave the required product (4.4 g, 78% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid. M' = 289 15 Elemental Analysis for: C 17

H,

7 NO 1 .0LC 4

H

4 0 4 1.1H,O Calculated: C, 59.30; H, 7.87; N, 9.88 Found: C, 58.80; H, 7.63; N, 10.34 Example 2 20 Cyclohexyl-{4-[4-(2-methoxy-phenvl)-piperazin- 1-vlmethyll piperidin-1-vyl}-methanone Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2 methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, I mL) in CH 2 Cl 2 (30 mL) and the solution stirred 25 under N, at 0 0 C for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (0.765 g, 55% yield). An 30 ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.

WO 00/35878 PCT/US99/29881 -8

M

' = 399 Elemental Analysis for: C 24

H

37 30, 1.0C 4

H

4 0 4 Calculated: C, 65.22; H, 8.01; N, 8.15 Found: C, 65.00; H, 8.19; N, 8.18 5 Example 3 1-(1-Cyclohexvlmethyl-piperidin-3-vlmethyl)-4 (2-methoxy-phenvl)-piperazine Borane-THF (1.0M, 4 mmol) was added dropwise to a THF solution of 1-(2-methoxy 10 phenyl)- 4 -piperidin-4-ylmethyl-piperazine (0.382 g, 0.957 mmol) from example 1 at 0)C under nitrogen. The mixture was refluxed for 16 hours and after cooling to 0 0 C, the reaction was terminated by the addition of 2N-HCI (50 mL). After stirring for I hour, the solution was made basic with NaOH and the product extracted into ethyl acetate (3 x 35 mL). The combined organics were washed with water (50 mL), brine 15 (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum gave the required product (0.19 g, 51% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (2.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid. M' = 385 20 Elemental Analysis for: C,_H 3 9

N

3 0 1.(0C 4

H

4 0 4 Calculated: C, 62.22; H, 7.67; N, 6.80 Found: C, 62.25; H, 7.50; N, 6.92 Example 4 25

{

4 -[4-(2-Methoxy-phenvl)-piperazin-1-ylmethyll piperidin-1-vyl}-phenyl-methanone Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of 1-(2 methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH,C1l, (30 mL) and the solution stirred 30 under N, at 0 0 C for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate WO 00/35878 PCT/US99/29881 -9 (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (0.91 g, 66% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light 5 yellow colored solid. M = 393 Elemental Analysis for: C, 4

H

31

N

3 0, 1.0C 4

H

4 0 4 Calculated: C, 65.99; H, 6.92; N, 8.25 Found: C, 66.17; H, 6.91; N, 8.30 10 Example 5 1-(1-Benzvl-piperidin-4-vlmethyl)-4-(2-methoxy-phenvl)-piperazine 4-(2-Methoxyphenyl)piperazine hydrochloride (1.0 g, 4.35 mmol) was added to a mixture of DAEC (0.83 g, 4.35 mmol), HOBT (1.5 equivalents, 0.88 g) and N 15 benzoylisonipecotic acid (1 g, 4.35 mmol) in DMF (15 mL), and the resulting solution was treated with NMM (2.5 equivalents, 1.2 mL) and stirred at 0C for 16 hours. Water (50 mL) was added, the product extracted into ethyl acetate (3 x 50 mL) and the combined organics were washed with IN-HCI (10 mL), saturated NaHCO 3 (15 mL) and dried over anhydrous sodium sulfate. Filtration and 20 concentration in vacuum afforded the required amide product as a white solid (1.77 g, 88% yield). M' = 407 Elemental Analysis for: C , H ,

N

3 03 Calculated: C, 70.74; H, 7.10; N, 10.31 25 Found: C, 70.40; H, 7.21; N, 10.37 A THF solution (25 mL) of the bis-amide (1.56 g, 3.8 mmol) was stirred under nitrogen at 0 0 C and treated with the dropwise addition of a 1M solution of lithium aluminium hydride in THF (38 mL, 10 equivalents). Once addition was complete, the reaction mixture was refluxed for 16 hours. After cooling to 0"C, the excess 30 hydride reagent was destroyed by the addition of a saturated ammonium chloride solution, the mixture was filtered and the filtrate washed with ethyl acetate (50 mL). The organic solution was washed with water (2 x 50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave the amine which WO 00/35878 PCT/US99/29881 - 10 was treated with ethereal HBr to afford the salt of the titled compound as a yellow colored solid (0.67 g).

M

' = 379 Elemental Analysis for: C 24

H

33

N

3 0 2.0HBr 1.25HO 5 Calculated: C, 51.12; H, 6.70; N, 7.45 Found: C, 50.72; H, 6.31; N, 7.34 Example 6 1-( 2 -Methoxy-phenvl)-4-piperidin-3-vlmethvl-piperazine 10 A solution of the amide from intermediate 4 (7.4 g, 21.8 mmol) and triethylamine (6 mL) in THF (100 mL) was treated with the dropwise addition of borane-THF (1.0 M, 76 mL) at 0 0 C under nitrogen. The mixture was refluxed for 16 hours and after cooling to 0 0 C, the reaction was terminated by the addition of 2N-HCI (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product 15 extracted into ethyl acetate (3 x 35 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum gave the required product (4.6 g, 81% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of 1-(2-Methoxy-phenyl)-4 20 piperidin-3-ylmethyl-piperazine as a light yellow colored solid. M = 289 Elemental Analysis for: C17H,27N30 1.0CHO0 4 2.0HO Calculated: C, 57.13; H, 7.99; N, 9.52 Found: C, 57.09; H, 7.84; N, 9.97 25 Example 7 Cyclohexvl-{3-[4-(2-methoxv-phenvl)-piperazin-1-vimethyll piperidin-1-yl }-methanone Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2 30 methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH 2 C1, (30 mL) and the solution stirred under N, at 0 0 C for 16 hours. The mixture was concentrated under vacuum, water WO 00/35878 PCT/US99/29881 - 11 (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (1.13 g, 81% yield). An 5 ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid. M' = 399 Elemental Analysis for: C 2 4H 3 7 302 1.0C 4

H

4 0 4 10 Calculated: C, 65.22; H, 8.01; N, 8.15 Found: C, 65.35; H, 8.23; N, 8.01 Example 8 {3-[4-(2-Methoxy-phenvl)-piperazin-1-vlmethyll 15 piperidin-1-vi}-phenvl-methanone Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of 1-(2 methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH 2 C1, (30 mL) and the solution stirred under N, at 0 0 C for 16 hours. The mixture was concentrated under vacuum, water 20 (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (1.08 g, 79% yield). An ethanolic solution of the product was treated 25 with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid. M'= 393 Elemental Analysis for: C, 4

H

3 1

N

3 0, 0.75C 4

H

4 0 4 Calculated: C, 67.48; H, 7.13; N, 8.74 30 Found: C, 67.76; H, 7.11; N, 8.88 WO 00/35878 PCT/US99/29881 - 12 Example 9 1-(1-Benzvl-piperidin-3-ylmethyl)-4-(2-methoxy-phenvyl)-piperazine Borane-THF (1.0M, 5 mmol) was added dropwise to a THF solution (8 mL) of {3 [4-(2-methoxyphenyl)-piperazin- 1 -ylmethyl]-piperidin-1-yl }-phenyl-methanone 5 (0.54 g, 1.37 mmol) from example 8 at 0 0 C under nitrogen. The mixture was refluxed for 16 hours and after cooling to 0 0 C, the reaction was terminated by the addition of 2N-HCI (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product extracted into ethyl acetate (3 x 35 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried over anhydrous 10 sodium sulfate. Filtration and concentration in vacuum gave the required product (0.36 g, 69% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (2.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid. M' = 379 15 Elemental Analysis for: C 24

H

3 3

N

3 0 1.0C 4

H

4 O 4 1 H,0 Calculated: C, 64.91; H, 7.69; N, 8.11 Found: C, 64.70; H, 7.37; N, 8.06 Example 10 20 3

-(

2 -{3-[4-(2-Methoxy-phenvl)-piperazin- 1-vlmethyll piperidin- I -vyl} -ethyl)- I H-indole A mixture of 1-( 2 -methoxy-phenyl)-4-piperidin-3-ylmethyl-piperazine (0.5 g, 1.72 mmol) from example 6, 3-(2-bromoethyl)indole (0.38 g, I equivalent) and potassium carbonate (0.48 g, 2 equivalents) in acetonitrile (25 mL) were refluxed for 24 hours 25 under a nitrogen atmosphere. Water (100 mL)) was added and the product extracted into ethyl acetate (3 x 50 mL). The combined organics were washed with water (25 mL), brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum afforded the required product. Treatment with excess ethereal HCI gave the hydrochloride salt of the above titled compound as a white 30 solid. M'= 432 WO 00/35878 PCT/US99/29881 - 13 Elemental Analysis for: C 27

H

36 N40 2.0HC1 1HO Calculated: C, 61.94; H, 7.70; N, 10.70 Found: C, 61.82; H, 7.41; N, 10.36 5 Example 11 [4-(1H-Indol-4-vl)-piperazin-1-yi]-piperidin-4-yl-methanone 4-(Indol-4-yl)piperazine (1.75 g, 8.7 mmol) was added to a mixture of DAEC (1.67 g, I equivalent), HOBT (1.3 equivalents, 1.53 g,) and N-butoxycarbonylisonipecotic acid (2 g, 8.7 mmol) in DMF (15 mL), and the resulting solution was treated with 10 NMM (1.5 equivalents, 1.5 mL) and stirred at 0 0 C for 16 hours. Water (100 mL) was added, the product extracted into ethyl acetate (3 x 50 mL) and the combined organics were washed with IN-HCI (20 mL), saturated NaHCO, (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum afforded the product as a white solid (3.07 g, 85% yield). A sample of the carbamate (1.5 g, 3.63 15 mmol) was dissolved in 4M-HCI dioxan (20 mL) and the solution stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuum, diethyl ether (50 mL) added and the precipitated product collected by filtration and washed with ether (50 mL) to afford a tan colored solid (1.2 g, 98% yield) m.p. > 240 0 C 20 M' = 313 Elemental Analysis for: C,,H44 0 2HCI Calculated: C, 56.10; H, 6.80; N, 14.54 Found: C, 55.76; H, 6.65; N, 14.11 25 Example 12 4

-[

4 -(1-Methvl-piperidin-4-vlmethvl)-piperazin-1-vyl]-IH-indole Under a nitrogen atmosphere, a sample of the carbamate (1.5 g, 3.63 mmol) from example 11 in THF (20 mL) was treated with the dropwise addition of 1.0M lithium aluminium hydride in THF (35 mL, 10 equivalents) at 0C and the solution refluxed 30 for 16 hours. After cooling to ambient temperature, the excess hydride was destroyed by the addition of ammonium chloride solution and the mixture filtered. Ethyl acetate (50 mL) was added, the solution washed with water (50 mL), brine (25 mL) WO 00/35878 PCT/US99/29881 - 14 and dried over anhydrous sodium sulfate. Filtration and concentration gave the titled product, which was converted to its hydrochloride salt by the action of ethereal-HC1. M = 312 Elemental Analysis for: C 1 9

H

28 N 1HC1 0.5HO 5 Calculated: C, 63.76; H, 8.45; N, 15.65 Found: C, 63.96; H, 8.31; N, 15.43 Compounds of the present invention bind with very high affinity to the 5-HT1A receptor and consequently, they are useful for the treatment of central 10 nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems in addition to the treatment of Alzheimer's disease, Parkinson's disease, obesity and migraine. 15 5-HTIA Receptor Binding Assay High affinity for the serotonin 5-HT1A receptor was established by testing the claimed compound's ability to displace [3H] 8-OH-DPAT binding in CHO cells stably transfected with the human 5HT1A receptor. Stably transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino 20 acids. Cells are scraped off the plate, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min., 4"C) in buffer (50 mM Tris pH 7.5). The resulting pellets are aliquoted and placed at -80"C. On the day of assay, the cells are thawed on ice and resuspended in buffer. The binding assay is performed in a 96 well microtiter plate in a total volume of 250 pL. Non-specific binding is determined 25 in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in 0.5% PEI. Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0.1, and 0.01 mM, and Ki values are determined for the active 30 compounds.

WO 00/35878 PCT/US99/29881 - 15 5-HT1A Receptor Intrinsic Activity Assay The intrinsic activity of compounds of the present invention was established by testing the claimed compounds ability to reverse the stimulation of cyclic adenosinemonophosphate (cAMP) in CHO cells stably transfected with the human 5 5-HT IA receptor. Stably transfected CHO cells were grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. The cells are plated at a density of x10 () 6 cells per well in a 24 well plate and incubated for 2 days in a CO, incubator. On the second day, the media is replaced with 0.5 mL treatment buffer (DMEM + 25 10 mM HEPES, 5 mM theophylline, 10 pM pargyline) and incubated for 10 minutes at 37 0 C. Wells are treated with forskolin (1 RM final concentration) followed immediately by the test compound (0.1 and 1 pM for initial screen) and incubated for an additional 10 minutes at 370C. The reaction is terminated by removal of the media and addition of 0.5 mL ice cold assay buffer (supplied in the RIA kit). Plates are 15 stored at -20(C prior to assessment of cAMP formation by RIA. EC5 values are determined for the active test compounds. Compounds shown to have no agonist activities (Emax = 0 %) are further analyzed for their ability to reverse agonist induced activity. In separate experiments, 6 concentrations of antagonist are preincubated for 20 minutes prior to the addition of agonist and forskolin. Cells are 20 harvested as described above. The cAMP kit is supplied by Amersham and the RIA is performed as per kit instructions, and calculations of ICso) performed by GraphPad Prism. Compound 5-HTIA binding cAMP 25 Ki (nM) Emax Example 1 TBD 0% Example 3 8.4 89% Example 6 2.0 0% Example 9 14 79% 30 Hence, compounds of the present invention exhibit high affinity for the 5HTIA receptor subtype and exhibit intrinsic activity as evidenced by their ability to reverse WO 00/35878 PCT/US99/29881 - 16 stimulation of cyclic adenosinemonophosphate (cAMP). Accordingly, compounds of the present invention are useful for treatment of disorders of the central nervous system and may be administered to a patient suffering from one or more of said disorders. Treatment, as used herein, refers to the alleviation or amelioration of symptoms of a 5 particular disorder in a patient. In addition, compounds of the present invention may be administered as part of a treatment regime that includes other agents which act on the central nervous system. In some preferred embodiments, compounds of the present invention are part of a combination therapy including a serotonin reuptake inhibitor. Serotonin reuptake inhibitors useful in combination therapies of the present invention 10 fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. Said agents may be administered at the same time, where they may be combined into a single dosage form, or at a different time, as compounds of the present invention, while still being part of the regime of the combination therapy. Compounds of the invention may be administered to a patient either neat or 15 with a convention pharmaceutical carrier. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely 20 divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl 25 cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic 30 solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly 35 containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and WO 00/35878 PCT/US99/29881 - 17 polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. 5 Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form. Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets 10 or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package 15 form. The therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient. The novel method of the invention for treating 20 conditions related to or are affected by the 5-HTIA receptor comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of Formula A and its non-toxic, pharmaceutically acceptable addition salts. The compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method 25 of treatment and condition treated. The usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.

Claims

2. A compound of Claim 1 wherein R 1 is phenyl; 2-, 3- or 4-pyridyl; 2-pyrimidyl; benzodioxan-5-yl; indol-4-yl; 3-thienyl; 1-, or 2-naphthyl.
3. A compound as claimed in any one of Claims 1 through 2 wherein R 1 20 is phenyl or indol-4-yl.
4. A compound as claimed in any one of Claims 1 through 3 wherein R 2 is aralkyl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl or COR 3 . 25 5. A compound of Claim 1 wherein R 1 is phenyl or indol-4-yl, R 2 is CO R 3 and R 3 is cyclohexyl, phenyl or piperadin-4-yl.
6. A compound of Claim 1 which is 1-(2-Methoxy-phenyl)-4-piperidin 4 -ylmethyl-piperazine, or a pharmaceutical salt thereof. WO 00/35878 PCT/US99/29881 - 19
7. A compound of Claim 1 which is Cyclohexyl-{4-[4-(2-methoxy phenyl)-piperazin-1-ylmethyl]-piperidin-1-yl }-methanone, or a pharmaceutical salt thereof. 5
8. A compound of Claim 1 which is l-(1-Cyclohexylmethyl-piperidin-3 ylmethyl)-4-(2-methoxy-phenyl)-piperazine, or a pharmaceutical salt thereof.
9. A compound of Claim 1 which is {4-[4-(2-Methoxy-phenyl) 10 piperazin- 1 -ylmethyl]-piperidin- l-yl}-phenyl-methanone, or a pharmaceutical salt thereof.
10. A compound of Claim I which is 1-(1-Benzyl-piperidin-4-ylmethyl) 4 -( 2 -methoxy-phenyl)-piperazine, or a pharmaceutical salt thereof. 15
11. A compound of Claim 1 which is 1-(2-Methoxy-phenyl)-4-piperidin 3-ylmethyl-piperazine, or a pharmaceutical salt thereof.
12. A compound of Claim I which is Cyclohexyl-{3-[4-(2-methoxy 20 phenyl)-piperazin- I -ylmethyl]-piperidin- l-yl }-methanone, or a pharmaceutical salt thereof.
13. A compound of Claim 1 which is {3-[4-(2-Methoxy-phenyl) piperazin-1-ylmethyl]-piperidin-1l-yl}-phenyl-methanone, or a pharmaceutical salt 25 thereof.
14. A compound of Claim I which is 1-(1-Benzyl-piperidin-3-ylmethyl) 4 -( 2 -methoxy-phenyl)-piperazine, or a pharmaceutical salt thereof. 30 15. A compound of Claim I which is 3-(2-{3-[4-(2-Methoxy-phenyl) piperazin- I -ylmethyl]-piperidin- l-yl} -ethyl)- 1 H-indole, or a pharmaceutical salt thereof. WO 00/35878 PCT/US99/29881 - 20
16. A compound of Claim 1 which is [4-(1H-Indol-4-yl)-piperazin-1-yl] piperidin-4-yl-methanone, or a pharmaceutical salt thereof.
17. A compound of Claim 1 which is 4-[4-(1-Methyl-piperidin-4 5 ylmethyl)-piperazin-1-yl]-1H-indole, or a pharmaceutical salt thereof.
18. A method of treating a patient suffering from a disorder of the central nervous system associated with the 5-hydroxytryptamine 1IA receptor subtype comprising administering a therapeutically effective amount of a compound of 10 Formula A, RN^' )n A in which: R l is aryl or heteroaryl; 15 A is NR- or CH- and B is NR 2 or CH 2 , provided that A is not equal to B; R 2 is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylhetero cycloalkyl, aryl, aralkyl, heteroaryl, alkylheteroaryl, or COR 3 ; R 3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; n is an integer from 0 to 2, or a pharmaceutical salt thereof. 20
19. The method of Claim 18 wherein the disorder is depression, anxiety or panic.
20. The method of Claim 18 wherein the disorder is sleep disorder or 25 sexual dysfunction.
21. The method of Claim 18 wherein the disorder is drug or alcohol addiction. 30 22. The method of Claim 18 wherein the disorder is a cognitive disorder. WO 00/35878 PCT/US99/29881 -21 23. The method of Claim 18 wherein the disorder is a neurodegenerative disease. 5 24. The method of Claim 23 wherein the neurodegenerative diseases is Parkinson's disease or Alzheimer's disease.
25. The method of Claim 18 wherein the disorder is migraine. 10 26. The method of Claim 18 wherein the disorder is obesity.
27. The method of Claim 18 further comprising administration of a serotonin reuptake inhibitor. 15 28. The method of Claim 27 wherein the serotonin reuptake inhibitor is selected from the group consising of fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine.