CA2241845C

CA2241845C - 4,5-dihydronaphth[1,2-c]isoxazoles and derivatives thereof having cns activity

Info

Publication number: CA2241845C
Application number: CA002241845A
Authority: CA
Inventors: Nicholas J. Hrib
Original assignee: Aventis Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1996-01-05
Filing date: 1996-12-12
Publication date: 2002-10-01
Anticipated expiration: 2016-12-12
Also published as: CN1214046A; BR9612578A; AR005347A1; ZA9725B; NZ325587A; HUP9903706A3; WO1997025317A1; AU1412697A; IL125197A0; HUP9903706A2; KR100308748B1; KR19990077033A; CA2241845A1; NO983100D0; JP3161737B2; JPH11510816A; NO983100L; AU710059B2; EP0874833A1

Abstract

4,5-Dihydronaphth[1,2-c]isoxazole derivatives of general formula (I), where A, X and n are defined herein are disclosed. Such compounds are useful as serotonin 5-HT3 antagonists. These compounds are useful for the treatment of anxiety, psychiatric disorders, nausea, vomiting and drug dependency.

Description

WO 97!25317 PCT/LTS96/i9569 4,5-DIHYDRONAPHTH[I,2-CIISOXAZOLES AND DERIVATIVES THEREOF HAVING CNS
ACTIVITY
The present invention is directed to certain novel compounds and their use as pharmaceutical agents having unique central nervous system acti~rity.
This invention relates to 4,5-dihydronaphth(1,2-c]isoxazoles and derivatives thereof, and their use as serotonin 5-FiT~ antagonists. which may be useful for the treatment of anxiety, psychiatric disorders. schizophrenia, nausea, vomiting and the control of drug dependency, of general formula (I?:
N-~
t~) X ~ )n \ H2 wherein A is hydrogen. hydroxy, _ HIV ~(C fi2~ ~ ,O
or yR N~R
t i U
wherein Rt is hydrogen. an alkyl group o~ 1 to 6 carbons, optionally substituted with hydroxy, alkoxy or amino substitution; aryl or heteroaryl, optionally substituted with halogen, hydroxy or alkoxy; or benzyl optionally substituted with halogen, hydroxy or alkoxy;
n is an integer o~ 1 or 2;
Z is nitrogen, CH or CEOH);
m is an integer o~ I to 3; and X is hydrogen, hydroxy or alkoxy:

or a pharmaceutically acceptable additional salt thereof, or -where applicable, a geometric or optical isomer or racemic mixture thereof.
The present invention also relates to a process for preparing these compounds, pharmaceutically acceptable additzcn salts thereof, as well as the pharmaceutical acceptable compositions thereof, and a method of using the compounds as seroton 5-HT~ antagonists.

Throughout the specification and appended claims, a given chemical formula or name shall encompass all stereo and optical isomers where such isomers exist. Additionally, a given chemical formula or name shall encompass the pharmaceutically acceptable additional salts thereof.
In a preferred embodiment of the invention are compounds of formula (I) wherein A is N ~(C HZ~m y Rt ' wherein R1 is hydrogen. an alkyl group of I to 6 carbons, optionally substituted with hydroxy, alkoxy or amino substitution; aryl or heteroaryl. optionally substituted with halogen, hydroxy or alkoxy; or benzyl optionally substituted with halogen, hydroxy or alkoxy;
n is an integer of 1 or 2;
Z is nitrogen;
to m is an integer of 1 to 3; and X is hydrogen, hydroxy oz alkoxy.
More preferred, are compounds of formula (I) wherein R1 is hydrogen, or an alkyl group of 1 to 3 carbons;
2Q n is 1:
Z is nitrogen;
m is 1 or 2; and WO 97/25317 ~ PCT/US96/19569 X is hydrogen.
The novel compounds of the present inventicn and the intermediates thereto may be prepared by the reaction sequence illustrated hereinbelow. The substituents Z, m, n and X are generally as defined above unless otherwise indicated.
N~OH
N-~
I
l 1 o X ~ --~, X ~ / H PO- ~
\ CH2~ ' ~CH~n Et3N

N-O N-O
,- ~ / t H_A / ~ / A
X \ ~ CHI base \ ~ [CH~n According to the preparation scheme, hydroxyisoxazoles 3 are prepared from oximes 2 in a solvent such as tetrahydrofuran (TFiF) at a temperature of from about 25'C to about reflux temperature of the solvent for a period of from about 0.25 to .about 4 hours according to the methods of Griffiths and Olofson (Jerome S. Griffiths, et al., J. Chi. Scx. C, 974 (I971) and G.N. Barber and R.A. Olofson, J. OrQ. Chess. d3, 3015 (1978)).
The hydroxyisoxazoles 3 are converted to chloroisoxazoles 4 via WO 97!253I7 ~' PCT/US96/19569 treatment with phosphorous oxychloride in the presence of a suitable base, such as triethylamine, at a temperature of from about 100' to about 200°C for a period of from about 0.25 to about 4 hours in a manner similar to that utilized by Adembri e~ , a1. (G. Adembri and P.Tedeschi, Hull. 8ci. F'ac. Chic. Ind.
BoloQns 23, 203 (I965)). Fntermediates ~ are treated with an appropriate nucleopbl1e H-A (wherein A is defined hereinbefore) at a temperature of from about 100' to about 200° C with or without added base in an appropriate solvent, such as N-methylpyrrolidinone, to provide the novel compounds 1 of the invention.
These compounds may be prepared by the following representative examples. The examples are exemplary and should not be construed as limiting the invention disclosed herein.

3-Chloro-4,5-dihydronaphth[I,2-c]isoxazole / I
~ ( v ~ w \ \
To a stirred mixture of 4,5-dihydronaphth(I,2-c]isoxazol-3-(3aH)-one (7.258, 38.77mmol) in phosphorus oxychloride (10.84m1, 116.3mmol), triethylamine (5.40m1, 38.77mmo1) was added dropwise_ After completion of addition, the mixture was heated to reflux while stirring. After 2 hours, no starting material remained as shown by T~C [silica, ethylacetate (EtOAc)]. The mixture was cooled to room temperature, poured into 300 ml of ice water, and extracted with CHZC12_ The organic extracts were combined, dried over MgSO, and concentrated irt vacuo. The resultant solid was filtered through silica using CHZClz eluent to provide 6.2g of crude product. This crude product was recrystallized from a minimum of heptane to provide a product as needles, mp of 57-59'C, homogeneous by thin layer chromatography (TLC) [silica, CH~CiZ, Rf=0.80] . The Infrared (IR) (CHC1~) , nuclear magnetic resonance (rain) (CDC1~) , and Mass Spectrum (M'=205, EI, 70eV) were consistent with the structure. The yield was 5.4178 (26.4mmol, 68.16$).

Elemental Analysis Calculated Found C 64.25 64.02 H 3.92 3.86 Cl I7.24 N 6.8I 6.77 O 7.78 3-(4-Methyl-1-piperazinyl)-4,S-dihydronaphth[1,2-c]isoxazole WO 97/25317 8 PCT/US9b/19569 N --~ L1-O
/ / ~ 1 / j / N
~N ''C H3 A stirred mixture of 3-chloro-4,5-dihydronaphth[I,2-c]isoxazole (2.658, 12.93mmo1), N-methyl piperazine (30m1, 270.4mmo1) and KZCO~ (3.578, 25.87mmol) under NZ was lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under N2 for 2 hours. At that time, TLC [CH~C1~] showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature. IC
was then partitioned between heptane/HiO. The heptane phase was washed with water, dried over MgSO" filtered and concentrated in vacuo to yield a solid. This crude product was recrystallized from heptane/ether tEt20) to provide the product as needles, mp of 92-94~C, homogeneous by TLC [silica, I:1 CH~OH:EtOAc, .Rt=0.39] . The IR (CHC1~), rain tCDCI,) and Hass Spectrum (M'=269. EZ, 70eV) were consistent with the structure.
The yield was 1.2555g (9.67mmo1, 36.090 .

Elemental Analysis Calculated Found C 71.35 71.34 H 7.11 6.98 N 15.60 15.78 O 5.94 3-(4-(2-Hydroxyethyl)-I-piperazinyl)-4,5-dihydronaphth(1,2-c]isoxazole N ~ N --a ~ / N ~
--~ \ ~ ~ '~OH
A stirred mixture of 3-chloro-4,5-dihydronaphth[1,2-c]isoxazole (3.0g, 14.63mmo1), 1-(2-hydroxyethyl)-piperazine (17.95m1, 146.3mmo1) and K20~ (4.1g, 29.3mmo1) in 18m1 of N-methlypyrrolidinone under NZ was lowered into an oil bath 2d preheated to 150'C. The mixture was heated while stirring under Nz for Z hour. At that time, TLC (CHZClZ) showed no remaining starting mater3.al_ The mixture was removed from the heating bath, allowed to cool to room temperature, and diluted with HZO.
Upon the addition of heptane, a solid precipitated. The solid was collected, washed with heptane and HZO, and dried in vacuo WO 97/Z5317 1 ~ PCT/US96/19569 (O.lmm) at 85~C overnight to provide pure product, mp oL 137-- 138~C, homogeneous by TLC (silica, 1:1 CH~OH:EtOAc, Rt=0.67).
The IR (CHC1,) , NMR (CDCI,) and Mass Spectrum (M'=299, EI, 70eV) ' were consistent with the structure. The yield was 2.6038 (8.70mmo1, 59.470 .
Elemental Analysis Calculated Found C 68.21 68.12 H 7.07 7.01 N 14.04 14.14 O 10.69 3-(1-Homopiperazinyl)-4,5-dihydronaphth(1,2-c)isoxazole K
,. ~ / !

\ ~ -~ \
A stirred mixture of 3-chloro-4,5-dihydronaphth(1,2-c~isoxazole (3.0g, 14.63 mmol) homopiperazine (I4.668, 146.3 mmol) and FC~CO~ (4.048, 29.3mmo1) in 16m1 of N-methyl-pyrrolidinone under N~ was lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under NZ for 45 minutes. At that time, TLC (CH2C1Z) showed no remaining PCT/US96l19569 starting material. The mixture was removed from the heating bath, allowed to cool to room temperature, diluted with H,O and '" extracted with EtZO. The EtZO phase was dried over MgSO"
filtered and concentrated in vacc~o. The crude solid obtained was recrystallized from heptane/EtzO and dried in vac~o (O.Imm) at 85°C overnight to provide pure product, mp of 79-81°C, homogeneous by TLC [silica, 1:1 CH,OH:EtOAc, Rf=0.17j_ The IR
(CHC13) , NMR (CDC1~) and Mass Spectrum (M'=269, EI, 70eV) were consistent with the structure. The yield was 1.9698 (7.32nnmol, 50.03~k) .
Elemental Analysis Calculated Found C 71.35 71.45 H 7.11 7.29 N 15.60 15.56 O 5.94 2.0 3- ( 1-Piperazinyl) -4, S-dihydronaphth [ 1, 2-cJ isoxazole N -U N --~
~ / I / ~ / N
_N H
\ ~ ~/\

WO 97/25317 1 PC'T/US96/19569 A stirred mixture of 3-chloro-4,5-dihydronaphth[1,2-- c]isoxazole (5.0g, 24.9mmo1), piperazine (34.28, 397.7mmo1) and K2C03 (6.738, 48.7mmo1) in 40m1 of N-methylpyrrolidinone under N2 -was lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under NZ for 45 minutes. At that time, TLC (CHzClZ) showed no remaining starting material. The mixture was removed from the heating bath, allowed to cool to room temperature and extracted with Et20. This organic phase was washed twice with H20, dried over MqSO" filtered and concentrated in vacuo to obtain a crude solid. The solid was collected, recrystallized from heptanelEt=O and dried in vacuo (O.lmm) at 85'C to provide pure product, mp of 97-99'C, homogeneous by TLC (silica, I:1 CH~OH:CHZC12, Rf=0.35). The IR
(CHC13) , NMR (CDCl3f and Mass Spectrum (M'=255, EI, 70eVy were consistent with the structure. The yield was 3.3728 (I3.22mmo1, 54.19$) .
Elemental Analysis Calculated Found C 70.56 70.38 H 6.71 6.67 N 16.46 16.47 O 6.27 - 3-(4-Benzyl-1-piperazinyl)4,5-dihydronaphth(I,2-cjisoxazole N -O N _.p S / r ~ ) / I / N
~N
A stirred mixture of 3-chloro-4,5-dihydronaphth(1,2-. cjisoxazole (2.0g, 9.75mmol), 1-benzylpiperazine (17m1, IO 97.5mmo1) and KZCO~ !2.7g, 19.5mmo1) in 18m1 of N-methylpyrrolidinone under NZ was lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under N~ for 2 hours. At that time, TLC (CF~ZC1Z) showed no remaining starting material. The mixture was removed from the heating 15 bath, allowed to cool to room temperature and extracted with heptane. The organic phase was dried over MgSO" filtered and ccncentrated_in vacuo to obtain a crude solid. The solid was collected. titrated with Et20. recrystallized from EtZO and dried in vacuo i0.lmm) at 85'C to provide pure product. mp of 164-20 166'C, homogeneous by TLC (silica, 1:1 EtOAc, Rf=0.80J. The IR
(CFiCI~) , NMR (CDC1~) and Mass Spectrum (M'=345, EI, 70eV) were consistent with the structure. The yield was 1.219g (3.53mmol, 36.240 .

Elemental Analysis Calculated Found C 76.49 76.49 H 6.71 ' 6.85 N 12.16 12.09 O 4.63 3-Hydroxy-8-methoxy-4,5-dihydronaphth[I,2-cjisoxazole CH3 N'C~ CH; N--0 d ~ / A
l ~ ~
To a mechanically stirred mixture or 7-methoxy a-tetralone oxime (5.0g, 26.1Bmmo1) in anhydrous THF (150m1) at 0°C under Nz was slowly added n-butyl-lithium (n-HuLi) (23.0m1 of a 2.5M
solution in hexane, 57.60mmol). The mixture was stirred at 0°C
for 30 minutes, then CO~ gas was bubbled into the solution. (As this addition progressed, a solid precipitate began to form).
After 15 minutes, COi addition was stopped and NZ flow was restored. The thick mixture was stirred and warmed slowly to room temperature for I'~ hours, then 6N HMSO, (150m1) was slowly added which dissolved the solids. The TLC showed traces of starting oxime and a mixture of desired product and an intermediate which was not isolated. Stirring was continued for - 4 hours at which time the intermediate was completely converted to product. The mixture was extracted exhaustively with EtOAc.
The organic fractions were combined, washed once with HZO, once 5 with brine, dried over MgSO, and filtered. Concentration in vacuo caused the precipitation of a solid which was collected, titrated with EtOAc, and dried in vacuo to provide the product as a solid, mp of I35-138'C, homogeneous by TLC [silica, 10:90 CH~OH:EtOAc, Rf=0.46] . The ZR (KHr) , NMR (DMSO-ds) and Mass to Spectrum (M"=217, EZ, 70eV) were consistent with the structure.
The yield was 2.04968 tg.45mmo1, 36.080 .
Elemental Analysis Calculated Found 15 C 66.35 66.02 H 5.10 5.03 N 6.45 6.22 O 22.10 3-Chloro-8-methoxy-4,5-dihydronaphth(1,2-c)isoxazole CH3 N-~ CHI N-~
~ / H ~ / I / !
2 S ~ ( -a.

WO 97/25317 PCT/ITS96/t9569 To a stirred mixture of.3-hydroxy-8-methoxy-4,5-dihydronaphth[1,2-cJisoxazole (lO.Og, 46.08mmo1) in phosphorus oxychloride (I2.8m1, I37.3mmo1), triethylamine (6.42m1, ' , 46.08mmol) was added dropwise. After completion of addition, the mixture was heated to reflux while stirring. After 4 hours, no starting material remained as shown by TLC [silica, EtOAc).
The mixture was cooled to room temperature, poured into 400m1 of ice water, and extracted with heptane. The organic extracts were combined, dried over MgSO,. filtered and concentrated in vacuo. Concentration of the filtrate in vacuo caused a solid !-o precipitate. The solid was triturated with heptane and dried in vacuo to provide the product as needles, mp of 55-57'C, homogeneous by TLC [silica, CH~C12, Rf=0.45j . The IR (CHCl,) , NMR (CDC1~) and Mass Spectrum (M'=235, ET, 70eV) were consistent with the structure. The yield was 7.758 t32.98mmo1, 71.57~s).
Elemental Analysis Calculated Found C 61.16 61.29 H 4.28 4.16 C1 15.04 N 5.94 5.90 O 13.58 - 3-(tI-Methyl-4-piperidinyl)oxyj-4,5-dihydronaphth(1,2-c)isoxazole . 5 ~CH3 N
N --a N --a / ~ / ~ /

To a stirred solution mixture of 4-hydroxy-N-methyl piperidine (S.OSg, 43.89mmo1) in 100m1 of N-methyipyrrolidinoae under NZ was added NaH (1.758 of a 608 dispersion in oil, 43.89mmo1). The mixture was stirred at room temperature for 15 minutes, then a solution of 3-chloro-4,5-dihydronaphth(I,2-c)isoxazole t3-Oq. I4.63mmo1) in 15m1 N-methylpyrrolidinone was added in one portion. The stirred mixture was lowered into an oil bath preheated to 150'C. After 20 minutes TLC (CFiZCI2J
showed no starting materials remaining. The mixture was removed from the heating bath and allowed to cool to room temperature.
it was then partitioned between heptane/KzO. The heptane phase was washed with water, dried aver MgSO" filtered and concentrated in vacuo. This crude oil obtained was taken up in EtZO, filtered, and the FiCl salt precipitated by the addition of ethanoiic HC1. This salt was recrystallized from CFiiClz/EtZO to provide the product as a solid, mp of 147-150'C, homogeneous by - TLC [silica, 1:I CH,OH:EtOAc, Rfa0.02j. The IR (KBr), NHR
(CDC1~) and Mass Spectrum (M'+1=285, CI, methane) were consistent with the structure. The yield was 1.2994g (4.05mmol, 36.090 .
Elemental Analysis Calculated Found C 63.65 63.55 H 6.60 6.63 C1 11.05 N 8.73 8.78 O 9.97 3-(I-Piperazinyl)-8-methoxy-4,5-dihydronaphth[1,2-cjisoxazole CH3 N--a ~H3 ; -O
/ !
/ N
~" ~ \ _NH
\ \\
A stirred mixture of 3-chloro-8-methoxy-4,5-dihydronaphth[1,2-cjisoxazole (2.0g, B.Slmmol), piperazine (7.0g, 80.6mmo1) and KiCO, (2.4g, l7.lmmol) in 8.0m1 of N-methylpyrrolidinone under NZwas lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under NZ for 20 minutes. At that time TLC [CHZClZj showed no starting material remai:~ed. The mixture was removed from the heating - bath and allowed to cool to room temperature. Upon dilution of the reaction mixture with HzO, a solid precipitated which was collected and dried in vacuo to provide pure product, mp of 86-88°C, homogeneous by TLC (silica. 1:I CH~OH:CH~Cil, Rf=0.37], The IR (CHCl,) , NMR (CDC1,) and Mass Spectrum (M'=285, EI, 70eV~
were consistent with the structure. The yield was 1.9328 (6.78nnmol, 79.668) .
Elemental Analysis Calculated Found C 67.35 66.99 H 6.71 6.77 N 14.73 14.53 O 11.21 3-(I-Homopiperazinyl)-8-methoxy-4,5-dihydronaphth(1,2-c]isoxazole CH3 N-~ CH3 N--O
d , ~ ~ N~H
-~ W
A stirred mixture of 3-chloro-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole (2.66q, II.32mmo1), homopiperazine (11.40g, 113.2mo1) and KzCO~ (3.138, 22.68mmoi) in IO.Oml of N-- methylpyrrolidinone under NZ was lowered into an oil bath preheated to 150°C. The mixture was heated while stirring under ' Nz for 20 minutes. At that time, TLC (CHZC12) showed no starting material remained. The mixture was removed from the heating bath, allowed to cool to room temperature and diluted with H20, which caused a solid to precipitate. The crude solid was dried, recrystallized from EtZO and dried in vacvo (O,lmm) at 85°C, to provide pure product, mp of 106-109°C, homogeneous by TLC
(silica, 1 : 1 CH~OFi:CH2ClZ, Rf=0.18] . The IR (CHC1~) . NP~iR (CDC1,) and Mas3 Spectrum (M'=299, EI, 70e~) were consistent with the structure. The yield was 1.79488 (6.OOmmol, 53.03$).
Elemental Analyai3 Calculated Found C 68.21 68.24 H 7.07 7.11 N 14.04 14.00 O 10.69 ~s 2 I.

-3-(1-(4-(p-Chlarophenyl)-4-hydroxy-piperidinyl)-8-methoxy-4,5-- dihydrvnaphth(1,2-c)isoxazole ° C H3 N --~ C H3 N -<3 ~ ~ z ~ , ~ ~ N off --- \ I
A stirred mixture of 3-chloro-8-methoxy-4,5-dihydronaphth(1.2-c)isoxazole (2.0g, 8.51mmo1), 4-(p-chlorophenyl)-4-hydroxy-dipiperidine (3.6g, 17.02mo1) and KZCO, (2.358, 17.02mmo1) in 6m1 of N-methylpyrrolidinone under NZwaa lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under NZ for 1 hour. At that time, TLC
(CHZC12] showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature. Upon dilution of the reaction mixture with H2o, a solid precipitated which was recrystallized from EtOAc and dried in vacuo (O.Imm) at 85'C to provide pure product, mp of 174-177'C, homogeneous by TLC [silica, 2:1 heptane:EtOAc, Rf=0.263].
Z0 The IR (CFIC1~}, I~MR tCDCl~) and t~iass Spectrum (M'=410, E.I., 70eV) were consistent with the structure. The yield was 2.37988 (5.60mmo1, 68.20%).

Elemental Analysis Calculated Found C 67.23 67.24 ' H 5.64 5.75 C1 8.63 N 6.82 8.78 O 11 . 68 3-[(endo)-8-Methyl-8-azabicyclo(3.2.I]oct-3-yl)oxy]-8-methoxy-4,5-dihydronaphth(1,2-c]isoxazole C H3 N --0 C H3 N ---~
/. / / I
N ~C H3 To a stirred mixture of tropine (5.418, 38.31mmo1) in i0 ml of (THF) under Nz at 0'C was slo~rly added n-BuLi tl5.Om1 of a 2.5M solution in hexanes. 38.31mmo1?. The mixture was stirred for I5 minutes while allowed to warm to room temperature, then a solution of 3-chloro-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole (3.0g, 12.76mmo1) in 30m1 N-methylpyrrolidinone was added in one portion. The internal temperature increased to 99-100'C and was maintained there. After 3 hours, TLC (CHZClz] showed no starting material remaining. The mixture was removed from the heating bath and allowed to cool to room temperature. It was then partitioned between heptane/HZO. The heptane phase was washed - with HiO, dried over MgSO" filtered and concentrated in vacuo, whereupon it solidified. This crude solid was recrystallized from a minimum of heptane and dried in vacuo to provide the product as a solid, mp of 102-104'C,~homogeneous by TLC [silica, 1:1 CH~OH:CHZClz, Rf$0.20] . The IR (CHC1~) , HI~iR (CBCll) and Mass Spectrum (M'+341, CI, methane) were consistent with the structure. The yield was 1.37298 (4.038mmo1, 31.640 .
Elemental Analysis Calculated Found C 70.57 70.47 H 7.I1 7.25 ., , ca a . c .7 t3 . I 4 O 14.10 3-C(endo-8-Methyl-8-azabicyclo[3.2.1)oct-3-yl)oxy]-4,5-dihydronaphth[1,2-c]isoxazole hydrochloride hemihydrate N--~ N-0 ~ / I ~ / / , F~IC1 ~ ~N~CH3 o-s H20 To a stirred mixture of tropine (4.48, 3I.16mmo1) in IOml of THF under NZ at 0°C was slowly added n-HuLi (12.47m1 of a 2.5M
solution in hexanes, 31.16mmo1). The mixture was stirred for 15 minutes while allowed to warm to room temperature, then a solution of 3-chloro-4.5-dihydronaphth[1,2-cJisoxazole (2.138, 10.39mmo1) in 30m1 N-methylpyrrolidinone was added in one portion. The stirred mixture was lowered izito an oil bath preheated to 150'C. The internal temperature increased to 85'C
and was maintained there. After 3 hours, TLC [CHZC12J showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature. It was.
then partitioned between heptane/H~O. The heptane phase was washed with HZO, dried over MgSO" filtered and concentrated in vacuo, to provide the free base as an oil, which resisted attempts at crystallization. The oil was taken up in Et20 and the HC1 salt was precipitated by the addition of ethanolic HC1.
This crude solid was recrystallized from EtZO/CH2Clz and dried in vacuo at 85'C to provide the product as a solid, mp o8 167-170'C, (darkens at ca. 150°C) homogeneous by TLC [silica, 1:1 CH30H:CHiCIZ, R~=0.14] . The IR (CHCl~), NMR (CDC13) and Mass Spectrum (M'+1=311, CI, methane) were consistent with the structure. Analysis and NMR confirmed the hemihydrate structure. The yield was 1.2688 (3.563mmol, 34.29$).

WO 97/25317 PCTlLJS96/19569 Elemental Analysis Calculated Found C 64.12 64.25 H 6.80 6,77 N 7.87 7.70 O 9.23 3-tl-(4-(6-Fluorobenzisoxazol-3-yl)-piperidinyl)-e-methoxy-4,5-dihydronaphth[1,2-c)isoxazole CHj N -0 CH3 N -O
i ;
I - I rr-o r / \
A stirred mixture of 3-chloro-8-methoxy-4,5 dihydronaphth[1,2-c]isvxazole (2.0g, B.Slmmol), 4-(6 F
fluorobenzisoxazol-3-yl)-piperidine (2.8g, 12.76mmo1) and KZCO, (2.35g, 17.02mmo1) in IOml of N-methylpyrzolidinone under NZwas lowered into an oii bath preheated to I50'C. The mixture was heated while stirring under N2 for 90 minutes. At that time TLC
iCH2Clz) showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature. Upon dilution of the reaction mixture with H,C, a .
-solid precipitated which was collected, dried, dissolved in CHzCl2 and filtered through neutral alumina. The fractions containing desired product were combined and concentrated, and S the resultant solid obtained was triturated with EtzO to provide a solid, mp of 18I-183'C, homogeneous by TLC [silica, 2:1 Heptane:EtOAc, Rf=O.15J. The IR (CHClj), NMR (CDC1~) and Mass Spectrum (M'=419, EI, 70eV) were consistent with the structure.
The yield was 1.13188 (2.70mmol, 31.700 .
Elemental Analysis Calculated Found C 68.72 68.47 H 5.29 5.28 F 4.53 N 10.02 9.97 O 11.44 WO 97/25317 2 ~ PCT/LJS96/19569 rvwuor c l c 3-(1-(4-2-Oxo-1-benzimidazoiinyl)piperidinyl))-B-methoxy-4,5-- dihydronaphth(1,2-cjisoxazole CH3 N--~ CHI N-~

t a ~ ~ /
-" \ I N NH
A stirred mixture of 3-chloro-8-methoxy-4,5-dihydronaphth(I.2-c]isoxazole t2.57g, 10.9mmo1), 4-t2-oxo-1-benzimidazolinyl)piperidine t4.74g, 21.8mmo1) and KZCO~ (3.028, 21.8mmo1) in I2m1 of N-methylpyrrolidinone under Nz was lowered into an oil bath preheated to I50'C. The mixture was heated I5 while stirring under NZ for 4 hours. At that time, TLC tCH2C12) showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature.
Upon dilution of the reaction mixture with H20. a solid precipitated which was collected, dried, dissolved in CHZC12 and 20~ filtered through neutral alumina using CHZClz and then 1:1 CH2CIz:EtzO. The fractions containing desired product were combined and concentrated, and the resultant solid obtained was triturated with EtOAc and dried in vacuo (O.lamn Hg, 85'C) to provide a solid, mp of 211-214'C. homogeneous by TLC [silica, WO 97!25317 2$ PCT/US96l19569 EtOAc, Rf=0.38]. The IR (CHC1,), NMR iCDCl,) and Mass Spectrum .
(M'=416, EI, 70eV) were consistent with the structure. Tr.e yield was 1.6028 (3.85mmo1, 33.33$).
Elemental Analysis Calculated Found C 69.2I 68.88 H 5.8I 5.90 N 13.45 13.14 O 11.52 3-[(Quinuclidin-3-yl)oxy]-8-methoxy-4,5-dihydronaphth[1,2-c)isoxazole hydrochloride CH3 N--p CH3 N--~ L~-~l / i ~ , ~
1 --- ~ i H-m To a stirred mixture of 3-quinuclidinol (4.878, 38.28mmo1) in IOml of THF under NZ at 0'C was slowly added n-BuLi (15.328 0~
a 2.5M solution in hexanes, 38.28mmo1). The mixture was stirred for 10 minutes while allowing to warm to room temperature, then a solution of 3-chloro-e-methoxy-4,5-dihydronaphth(1,2-c]isoxazole (3.0g, i2.76mmo1) in 30m1 N-methyipyrrolidinone was added in one portion. The stirred mixture was lowered into an oil bath preheated to 150°C. The internal temperature increased to 85°C and was maintained there. After 3 hours, TLC (CHZClZ]
showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature.
It was then partitioned between heptane/HZO. The heptane phase was dried over MgSO" filtered and concentrated in vacuo to provide the free base as an oil. The oil was taken up in Et20 and the HC1 salt was precipitated by the addition of ethanolic HC1. This solid was collected and dried in vacuo (O.Imm Hg, 85°C) to provide the product as a solid, mp o~ 133-136°C, homogeneous by TLC (silica, 1:1 CH~OH:CH2C12, Rf=0.23]. The IR
(KBr), NMR (DMSO-d,) and Mass Spectrum (M'+1=326, EI, 70eV) were consistent with the structure. The yield was 0.965g (2.39mmol, 18.79$).
Elemental Analysis Calculated Found C 62.89 62.91 H 6.39 6.28 C1 9.77 N 7.72 7.51 O 13.23 r v." "., . .. . ..
_ 5,6-Dihydro-4H-benzo[6,7]cyclohept[I,2-c]isoxazol-3-01 ,OH O
N
5 ' . E ~ H
To a mechanically-stirred mixture of I-benzosuberone oxime (lO.Og, 57.1mmo1) in anhydrous THF (200m1) at 0'C under N2 was iQ slowly added n-BuLi (50.3m1 of a 2.5M solution in hexane, 125.62mmo1). The mixture was stirred at 0'C for 30 minutes, then COz gas was bubbled into the solution. After 15 minutes, COZ addition was stopped and N2 flow was restored. The thick mixture was stirred and warmed slowly to room temperature for 1'-~
15 hours, then 6N HZSO, (220m1) was slowly added, which dissolved the solids. Stirring way continued for 18 hours, at which time the TLC [EtOAc] showed a mixture of starting oxime and product (starting oxime was beat visualized using 2:1 heptane:EtOAc eluent). The mixture was poured into a separatory funnel, and 2a the organic phase drawn oft. The aqueous phase was extracted with EtQAc, and the organic phase and the EtOAc extracts were combined, washed with HZO, dried over MgSO, and filtered.
Concentration in vacuo caused the precipitation of a solid which was collected and dried in vacuo to provide the product as a solid, mp of 165-168'C, homogeneous by TLC (silica, EtzO, -Rf~0.28] . The IR (KBr) , NMR (DMSO-d6) and Mass Spectrum (M'=201, EI, 70 eV) were consistent with the structure. The yield was 3.03248 (15.09mmo1, 26.42$).
Elemental Analysis Calculated Found C 71.63 71.45 H 5.51 5.50 IO N 6.96 6.91 O 15.90 3-(1-(4-(2-Oxo-I-benzimidazolinyl)piperidinyl))-4,5-dihydronaphth(I,2-c]isoxazole hemihydrate N~ N-0 O
/ ~ / 1 / ~ / N
-'~' \ ~ N NH
o.s HZO
A stirred mixture of 3-chloro-4,5-dihydronaphth(I,2-c]isoxazole (3.18, 15.12mmo1), 4-(2-oxo-I-benzimidazolinyl)-piperidine (8.28, 37.8mmo11 and KZCO, (4.28, 30.24mmo1) in I9ml of N-methylpyrrolidinone under N=was lowered into an oil bath PCT!l1JS96/19569 preheated to 150'C. The mixtuze was heated while stirring under _N2 far 90 minutes. At that time, TLC tCHzClz) showed no remaining starting material. The mixture was removed from the -heating bath and allowed to cool to room temperature. Upon dilution of the reaction mixture with H20, a solid precipitated which was collected, dried, dissolved in CHZC12 and filtered through neutral alumina using CHZCI~ and then I:1 CHZCI~:Et20.
The fractions containing desired product were combined and concentrated, and the solid obtained was recrystallized from l0 EtOAc and dried in vacuo (O.lmm Hg, lI0'C) to provide a solid, mp of 229-233°C, homogeneous by TLC [silica, EtOAc, Rf=0.54].
The IR (KHr), NMA (CDC13) and Mass Spectrum (M'=386, EI, 70eV) were consistent with the structure. Analysis and NMR confirmed a hemihydrate structure. The yield was 1.I03g t2.79mmol, 18.45$).
Elemental Analysis Calculated Found C 69.82 70.25 H 5.86 5.64 N 14.17 14.22 O 8.28 Preferred pharmaceutically acceptable addition salts -include salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids;
as well as organic acids such as tartaric, citric, acetic, succinic. malefic, fumaric, and oxalic acids.
The active compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules ar compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs. suspensions, syrups, waters, chewing gums and the like.
These preparations should 'contain or form at least 0.5~ of ZS active compound, but may be varied depending upon the particular form and may conveniently be from about 4 to about 75~ of the weight of the unit. The amount of compound present in such composition is such that a suitable dosage of active compound will be obtained_ Preferred compositions and preparations 2o according to the present invention are prepared so that an oral dosage unit form contains from about I.0 to about 300mqs of active compound.
The tablets, pills. capsules, troches and the like may also 25 contain the following ingredients: a binder such as WO 97/25317 34 ~'CT/US96/19569 microcrystalline cellulose, gum tragacanth or gelatin; an -excipient such as starch or lactose, a disintegrating agent such as alginic acid. Primogel'°t, corn starch and the like; a ' lubricant such as magnesium stearate or Sterotex~; a glidant such as colloidal silicon dioxide: and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type. a liquid carrier such as fatty oil.
Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings an flavors.
Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1~ of the aforesaid compound, but may be varied from about 0.5 to about 30~ of the weight thereof. The amount of compound in such composition is such that a suitable dosage of ' active compound will be obtained. Preferred compositions and WO 9'7/25317 35 PCT/US96119569 preparations according to tre invention are prepared so that a -parenteral dosage unit contains from about 0.5 to about 100mgs - of active compound.
The solutions or suspensions may'also include the following components; a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens: antioxidants l0 such a3 ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple done vials made of glass or plastic.
The compounds of the invention may be useful as 5-HT, antagonists on the coronary chemoreflex for the treatment of anxiety, psychiatric disorders, nausea and vomiting by virtue of their ability to bind to rat entorhinal cortex membranes.
'H-GR 65630 Binding to Rat Entorhinal Cortex Membranes Studies have been performed to determine the affinity of the compounds of the invention for the SHT, binding site in the brain. This study or assay may be useful for predicting the potential of compounds to exhibit antiemetic, anxiolytic or _atypical antipsychotic profiles.
Originally, it was believed that SHT~ binding sites existed only in the periphery. However, with the recent introduction of potent and selective SHT, antagonist drugs such as GR65630, Zacopride, ICS 205 930 and MDL 72222 (Bemesetron, CtSHt,C12N02) , data from binding studies have indicated that SHT, binding sites are also located in selected areas of the brain. The highest levels of SHT~ binding sites have been detected in limbic and dopamine containing brain areas tentorhinal cortex, amygdala, nucleus accumbens and tubezculum olfactorium) (Kilpatrick, G.J.
et a1. Identification and distribution of SHT~ receptors in rat brain using radioliqand binding. Nstur~ 330: 746-748). Besides possessing selective binding in dopamine rich areas, SHT, antagonists have been reported to block behavioral effects associated with certain drugs of abuse tnicotine and morphine?
and to be active in behavioral tests predictive of anxiolytic activity. Based vn these selective regional binding results and behavioral studies, SHT; antagonists may have a therapeutic benefit in disease states believed to be associated with excessive dopaminergic activity, i.e., schizophrenia. anxiety and drug abuse_ In accardance with the above-discussed assay, a 0.05M of _Krebs-Hepes buffer, pH 7.4 was prepared as follows:
11.928 Hepes 10.528 NaCl 0.3738 KCl 0.2778 CaCl2~
0.2448 MgC12.6Hz0 q.s. to 1 liter with distilled HZO, bring pH up to 7.4 (at 4~C) with 5N NaOH
['H]-GR65630 (87.OCi/mmoi) was obtained from New England Nuclear. For .ICSa determinations: ['H]-GR65630 was made up to a concentration of l.OnM in Krebs-Hepes buffer such that when 1001 is added to each tube. a final concentration of 0.4nM is attained in the 250t,~1 assay.
GR38032F was obtained from Research Biochemical Inc.
GR38032F was made up to a concentration of 500E~H in Krebs-Hepes a0 buffer. SO~cl of Krebs-Hepes were added to each of 3 tubes for determination of nonspecific binding (yields a final concentration of 100E,~H in the 2501.c1 assay? .
For most assays, a 50~s1 stock solution was prepared in a suitable solvent and serially diluted with Krebs-Hepes buffer WO 97J25317 PCT/US96/i9569 such that when 501 of drug is combined with the total 2501 _ assay, a final concentration from 10's to 10'9M was attained.
Characteristically, seven concentrations may be used for each assay; however, higher or lower concentrations may be used, depending on the potency of the drug.
During tissue preparation, Male Wistar rats (I5-200g) were decapitated, the entorhinal cortex removed, weighed and homogenized in IO volumes of ice cold O.OSM Krebs-Hepes buffer, IO pH 7.4. The homogenate is centrifuged at 48,000q for 15 minutes at 4'C. The resulting pellet was rehomogenized in fresh Kreba-Hepes buffer and recentrifuged at 48,000q for I5 minutes at 4'C.
The final pellet was resuspended in the original volume of ice-cold Krebs-Hepes buffer. This yielded a final tissue concentration of I.2 tv l.6mg/ml with the addition of 100u1 to the assay. Specific binding was approximately 55 to 65$ of the total bound ligand.
In conducting the assay, the followinq volumes were utilized:
100E,c1 of Tissue suspension;
IOOul of ['HJ-GR65630; and 501 SOOM GR38032F (Vehicle for binding) or appropriate drug concentration i~I

Sample tubes were kept on ice for additions, then vortexed and -incubated with continuous shaking for 30 minutes at 37a~, At the end of the incubation period, the incubate is diluted witty S ml of ice-cold Krebs-Hepes buffer and immediately vacuum filtered through G~lhatmanTM GF/B filters, followed by two 5m1 washes with' ice-cold Krebes-Hepes buffer. The filters are dried and counted in 10 ml of liquid scintillation cocktail. Specific GR 55630 binding is defined as the difference between the total binding and that bound in the presence of 100E.c,H GR38032F. ICsa values 14 were derived from computer-derived log-prabit analysis.
Various compounds of the invention wEare subjected to the above-described assay and the results the affinity for 5 HT, receptors are reported in Table I, below.
~5 TABLE I
Affinity for 5-HT~ Receptor-Displacement of 'H-GR 65630 Compound ICS, ~.
,-Ex. 3 0.868 Ex. 4 0.083 Ex. S 0.056 Ondansetron 0.089 (standard) ICS 205 930 0.039 (standard) Measurement of 5 HT, Antagonist Effects in the Bezold-Jarisch Assay This assay evaluates the effect of these compounds as 5-HT, to antagonists. They were examined in this aissay on the coronary chemoreflex (Bezold-Jarisch) initiated by 5-HT~ in vivo and characterized by leading inhibition of sympathetic outflow and increased activity of the cardiac vagus, Leading. to profound bradycardia and hypotension. The values «btained allow for 15 continuous monitoring of arterial pressure and heart rate responses by these compounds over an extended period of time to determine their effecicy for 5 HT~ antagonism.
The catheters were prepared from TygonTM tubing (45cm length, 20 0.05mm, ID) bonded to TeflonTM tubing (0.38mm, ID). The mechanical bonding was achieved by insertion of the TeflonTM
tubing (5mm) into the dilated (ethylene dichloride, 3-4 min.) tip of the TygonTM tubing. The junction was then sealed with vinyl glue, the catheters were soaked in cold sterilization 25 solution (Amerse instrument germicide) an,d flushed thoroughly with saline prior to implantation.
Long Evans rats were anesthetized with sodium pentobarbital (50mq/kg, ip). The catheters filled with hepranized saline (100 U/ml) were inserted in the left femoral artery and vein and passed into the abdominal aorta and inferior vena cava, respectively. The catheters were then sutured to the underlying muscle and the free ends were passed subcutaneously and exteriorized through an incision on the top of the skull. The l0 catheters were then secured to the skin with sutures, nitrafurazone powder was dusted aver the area of the incision and the incision was closed using 3-O silk sutures. The catheters were flushed with saline and sealed with metal obturators. Patentcy of the two catheters was maintained by daily flushing with hepranized saline (0.2 ml of 100 U/ml). The rata were given 48 hours recovery prior to obtaining cardiovascular data.
In the anesthetized rat model the catheters were not exteriorized, data was collected acutely under the influence of general anesthesia.
The baseline data Arterial Blood Pressure(mm Hg, ' systalic/diastolic) and Heart Rate (beats/min) were recorded and the rats were injected with 5-HT (3-7.5ug/kg, iv). The WO 97/25317 PCTlUS96/19569 individual response to the 5-EiT intervention was determined and the compound was then administered singlely or in an ascending dose range. The rata were challenged with 5-HT again at ' intervals postdosing and the peak response was recorded.
Several compounds o~ the invention were tented according to the above-described assay and the results are reported in Table Ii, below.

TABLE II
-Inhibitory Potency of 5-HT~ Antagonists on Reflex Hradycardia Induced by Intravenous 5-HT3 in the Anesthetized Long-Evans Rat Compound Dose, mg/kg, ip ~S Inhibition of Bezold-Jarisch Reflex (Values are mean SEH, 2-3 rats/dose!

Ondansetron 3.0 57.3 t 9.7 Ondansetron 10.0 94.6 t 2.7 Ex. 4 0.03 58.6 t 16.4 Ex. 4 0.05 83.3 t 8.2 Ex. 4 O.IO 93.0 t 1.0 Ex. 5 1.0 55.6 t 9.7 Ex. 5 3.0 89.3 t 2.9 In accordance with Table II, maximal reductions in heart rate induced by SFiT, (e.g. Bezold-Jarisch reflex) occurred 15 to 60 minutes after administration.

Claims

I Claim:

1. A compound of the formula:
where A is hydroxy, chloro, where R1 is hydrogen, an alkyl group of 1 to 6 carbons.
optionally substituted with hydroxy,C1-C6alkoxy or amino;
phenyl, benzisoxazole or 2-oxo-1-benzimidazolinyl, optionally substituted with halogen, hydroxy or C1-C6alkoxy; or benzyl optionally substituted with halogen, hydroxy or C1-C6alkoxy; n is an integer or 1 or 2; Z is N or C(OH); m is an integer of 1 to 3; and X is hydrogen, hydroxy or C1-C6alkoxy; the pharmaceutically acceptable salts thereof, the geometric or optical isomers thereof, or the racemic mixtures thereof.

2. The compound according to Claim 1, wherein A is

3. The compound according to Claim 1, wherein A is

4. The compound according to Claim 1, wherein A is

5. The compound according to Claim 1, wherein A is

6. The compound according to Claim 1, which is 3-chloro-4,5-dihydronaphth[1,2-c] isoxazole, its salt, isomer or racemic mixture.

7. The compound according to Claim 1, which is 3-hydroxy-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

8. The compound according to Claim 1, which is 3-chloro-8-methoxy-4,5-dihydronaphth [1,2-c]isoxazole, its salt, isomer or racemic mixture.

9. The compound according to Claim 1, which is 5,6-dihydro-4H-benzo[6,7]cyclohept[1,2-c]isoxazol-3-ol, its salt, isomer or racemic mixture.

10. The compound according to Claim 2, which is 3-(4-methyl-1-piperazinyl)-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture

11. The compound according to Claim 2, which is 3-(4-(2-hydroxyethyl)-1-piperazinyl)-4,5-dihydronaphth[1, 2-c]isoxazole, its salt, isomer or racemic mixture.

12. The compound according to Claim 2, which is 3-(1-homopiperazinyl)-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

13. The compound according to Claim 2, which is 3-(1-piperazinyl)-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

14. The compound according to Claim 2, which is 3-(4-benzyl-1-piperazinyl)4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

15. The compound according to Claim 2, which is 3-(1-piperazinyl)-8-methoxy-4,5-dihydronaphth[1,2-c] isoxazole, its salt, isomer or racemic mixture.

16. The compound according to Claim 2, which is 3-(1-homopiperazinyl)-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

17. The compound according to Claim 2, which is 3-(1-(4-(p-chlorophenyl)-4-hydroxy-piperidinyl)-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

18. The compound according to Claim 2, which is 3-(1-(4-(6-fluorobenzisoxazol-3-yl)-piperidinyl)-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

19. The compound according to Claim 2, which is 3-(1-(4-2-oxo-1-benzimidazolinyl)piperidinyl))-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

20. The compound according to Claim 2, which is 3-(1-(4-(2-oxo-1-benzimidazolinyl)piperidinyl))-4,5-dihydronaphth[1,2-c]isoxazole hemihydrate, its salt, isomer or racemic mixture.

21. The compound according to Claim 3, which is 3-[(1-methyl-4-piperidinyl)oxy]-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

22. The compound according to Claim 4, which is-[(endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy]-8-methoxy-4,5-dihydronaphth[1,2-c]isoxazole, its salt, isomer or racemic mixture.

23. The compound according to Claim 4, which is 3-[(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy]-4,5-dihydronaphth[1,2-c]isoxazole hydrochloride hemihydrate, its salt, isomer or racemic mixture.

24. The compound according to Claim 5, which is 3-[(quinuclidin-3-yl) oxy]-8-methoxy-4,5-dyhydronaphth[1,2-c]isoxazole hydrochloride, its salt, isomer or racemic mixture.

25. A process for the preparation of a compound of the formula:
Where A is, a group of the formula a group of the formula a group of the formula a group of the formula wherein R1 is hydrogen, an alkyl group of 1 to 6 carbon atoms, optionally substituted with hydroxy, C1-C6 alkoxy or amino;
phenyl, benzisoxazole or 2-oxo-1-benzimidazolinyl, optionally substituted with halogen, hydroxy or C1-C6 alkoxy; or benzyl optionally substituted with halogen, hydroxy or C1-C6 alkoxy; n is an integer of 1 or 2; Z is N or C(OH); m is an integer of 1 to 3; and X is hydrogen, hydroxy or C1-C6 alkoxy, which comprises contacting a compound of the formula wherein X and n are as hereindefined with a compound of the formula a compound of the formula a compound of the formula a compound of the formula wherein R1 and m are as hereindefined.

26. The process according to Claim 25, wherein the process is performed in the absence of a solvent.

27. The process according to Claim 25, wherein the process is performed in the presence of a solvent.

28. The process according to Claim 27, wherein the solvent is N-methylpiperidine.

29. The process according to Claim 27, wherein the solvent is tetrahydrofuran.

30. The process according to Claim 27, wherein the solvent is hexanes.

31. The process according to Claim 25, wherein a base is employed.

32. The process according to Claim 31, wherein the base is potassium carbonate.

33. The process according to Claim 31, wherein the base is N-butyllithium.

34. The process according to Claim 31, wherein the base is sodium hydride.

35. The process according to Claim 25, wherein the process is performed at a temperature from about 100°C to about 200°C.

36. A use of an effective amount of a compound according to any one of Claims 1 to 24 for treating psychiatric disorders, nausea, vomiting and control of drug use in a patient in need thereof.

37. A use of an effective amount of a compound according to any one of Claims 1 to 24 for treating a condition ameliorated by the use of a 5-HT3 antagonist, in a patient in need thereof.

38. A pharmaceutical composition comprising the compound of any one of Claims 1 to 24, and a pharmaceutically acceptable carrier therefor.

39. A compound according to any one of Claims 1 to 24 for use as an active pharmaceutical substance in the treatment of anxiety, psychiatric disorders, nausea, vomiting and control of drug use.

40. The use of a compound of any one of Claims 1 to 24 for the production of a medicament for the treatment of psychiatric disorders, nausea, vomiting and control of drug use.

41. The use of a compound of any one of Claims 1 to 24 for the production of a medicament for the treatment of a condition ameliorated by the use of a 5-HT3 antagonist.