EP0874833A1

EP0874833A1 - 4,5-dihydronaphth 1,2-c]isoxazoles and derivatives thereof having cns activity

Info

Publication number: EP0874833A1
Application number: EP96944274A
Authority: EP
Inventors: Nicholas J. Hrib
Original assignee: Hoechst Marion Roussel Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1996-01-05
Filing date: 1996-12-12
Publication date: 1998-11-04
Also published as: ZA9725B; NO983100D0; JP3161737B2; BR9612578A; CA2241845A1; AU1412697A; HUP9903706A2; AU710059B2; NO983100L; NZ325587A; HUP9903706A3; IL125197A0; KR100308748B1; WO1997025317A1; CA2241845C; CN1214046A; KR19990077033A; JPH11510816A; AR005347A1

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

4 ,5-DIHYDR0NAPHTH [l ,2-C]IS0XAZ0LES AND DERIVATIVES THEREOF HAVING CNS ACTIVITY

The present invention is directed to certa in nove l compounds and thei r use as pharmaceutical agents having unique central nervous sys tem act ivity .

This invention relates to 4, 5-dιhydronaphth[1, 2- c) isoxazoles and derivatives thereof, and their use as serotonin 5-HTj 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) :

wherein A is hydrogen, hydroxy,

wherein

R, is hydrogen, an alkyl group of 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 of 1 or 2;

Z ia nitrogen, CH or C(0H); m is an integer of 1 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 addition 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 clai s, 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

wherein R_t is hydrogen, an alkyl group of 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 of 1 or 2;

Z is nitrogen;

m is an integer of 1 to 3; and

X is hydrogen, hydroxy or alkoxy.

More preferred, are compounds of formula (I) wherein

R_t is hydrogen, or an alkyl group of 1 to 3 carbons,

n is 1;

Z is nitrogen;

is 1 or 2; and X i s hydrogen .

The novel compounds of the present invention 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.

According to the preparation scheme, hydroxyisoxazoles 3 are prepared from oximes 2 in a solvent such as tetrahydrofuran (THF) 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. C m. Soc. C, 974 (1971) and G.N. Barber and R.A. Olofson, J. Org. Ch*β. 43_, 3015 (1978)) . The hydroxyisoxazoles 3 are converted to chloroisoxazoles 4 via 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 ec al . (G. Adembri and P.Tedeschi, Bull. 8ci. F»c. Ch±m. Ind.

Bologna 23_, 203 (1965)) . Intermediates 4 are treated with an appropriate nucleophile 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- met ylpyrrolidinone, 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.

EXAMPLE 1 3-Chloro-4, 5-dihydronaphth[l, 2-cJ isoxazole

To a stirred mixture of 4, 5-dihydronaphth[1, 2-c] isoxazol-3- (3aH)-one (7.25g, 38.77mmol) in phosphorus oxychloride (10.84ml, 116.3mmol), triethylamine (5.40ml, 38.77mmol) 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 TLC [silica, ethylacetate (EtOAc) ]. The mixture was cooled to room temperature, poured into 300 ml of ice water, and extracted with CH₂C1_2. The organic extracts were combined, dried over MgSO, and concentrated in vacuo . The resultant solid was filtered through silica using CH-C1, 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_:Clj, R_f-0.80). The Infrared (IR) (CHC1₅) , nuclear magnetic resonance (NMR) (CDCl,) , and Mass Spectrum (M^*«205, El, 70eV) were consistent with the structure. The yield was 5.417g (26.4mmol, 68.16%) .

Elemental Analysis

EXAMPLE 2 3-(4-Methyl-l-piperazinyl)-4, 5-dihydronaphth[l, 2-c] isoxazole A stirred mixture of 3-chloro-4, 5-dihydronaphth[ 1, 2- cjisoxazole (2.65g, 12.93mmol), N-methyl piperazine (30ml, 270.4mmol) and K₂C0₃ (3.57g, 25.87mmol) under N₂ 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 [CH₂C1₂] 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/H-O. 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 (Et₂0) to provide the product as needles, mp of 92-94^βC, homogeneous by TLC [silica, 1:1 CH_jOHtEtOAc, R_f«0.39]. The IR (CHClj) , NMR (CDC1,) and Mass Spectrum (M*-269, El, 70eV) were consistent with the structure. The yield was 1.2555g (4.67mmol, 36.09%) .

Elemental Analysis

EXAMPLE 3 3- (4- (2-Hydroxyethyl) -1-piperazinyl) -4, 5-dihydronaphth[ 1, 2 - c] isoxazole

A stirred mixture of 3-chloro-4, 5-dihydronaphth[l, 2- c] isoxazole (3.0g, 14.63mmol), 1- (2-hydroxyethyl) -piperazine (17.95ml, l'46.3mmol) and K₂0₃ (4.1g, 29.3mmol) in 18ml of N- methlypyrrolidinonβ under N_: was lowered into an oil bath preheated to 150*C. The mixture was heated while stirring under N₂ for 1 hour. At that time, TLC (CHjCl₂) showed no remaining starting material. The mixture was removed from the heating bath, allowed to cool to room temperature, and diluted with H₂0. Upon the addition of heptane, a solid precipitated. The solid was collected, washed with heptane and H₂0, and dried in vacuo (0.1mm) at 85«C overnight to provide pure product, mp of 137- 138°C, homogeneous by TLC [silica, 1:1 CH₃0H:Et0Ac, Rf»0.67| . The IR (CHCl,), NMR (CDC1₃) and Mass Spectrum (M^*=»299, El, 70eV) were consistent with the structure. The yield was 2.603g (8.70mmol, 59.47%) .

Elemental Analysis

EXAMPLE 4 3- (1-Homopiperazinyl) -4, 5-dihydronaphth(1, 2-c] isoxazole

A stirred mixture of 3-chloro-4, 5-dihydronaphth[l, 2- c] isoxazole (3.0g, 14.63 mmol) homopiperazine (14.66g, 146.3 mmol) and K,C0₃ (4.04g, 29.3mmol) in 16ml of N-methyl- pyrrolidinone under N₂ was lowered into an oil bath preheated to 150*C. The mixture was heated while stirring under N₂ for 45 minutes. At that time, TLC (CH₂C1₂) showed no remaining starting material. The mixture was removed from the heating bath, allowed to cool to room temperature, diluted with H,0 and extracted with Et₂0. The Et₂0 phase was dried over MgSO,, filtered and concentrated in vacuo . The crude solid obtained was recrystallized from heptane/Et₂0 and dried i n vacuo (0.1mm) at 85^*C overnight to provide pure product, mp of 79-81^*C, homogeneous by TLC [silica, 1:1 CH₃OH:EtOAc, Rf-0.17) . The IR (CHCl,) , NMR (CDClj) and Mass Spectrum (M^*=-269, El, 70eV) were consistent with the structure. The yield was 1.969g (7.32mmol, 50.03%) .

Elemental Analysis

EXAMPLE 5 3- (1-Piperazinyl) -4, 5-dihydronapht [1,2-c] isoxazole

A stirred mixture of 3-chloro-4, 5-dihydronaphth[1, 2- c]isoxazole (5.0g, 24.4mmol⁾, piperazine (34.2g, 397.7mmol) and K₂C0, ⁽6.73g, 48.7mmol⁾ in 40ml of N-methylpyrrolidinone under _N was lowered into an oil bath preheated to 150^*C. The mixture was heated while stirring under N₂ for 45 minutes. At that time, TLC ⁽CH₂C1₂ ⁾ 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 MgSO_«, filtered and concentrated in vacuo to obtain a crude solid. The solid was collected, recrystallized from heptane/Et₂0 and dried in vacuo

(0.1mm) at 85^*C to provide pure product, mp of 97-99*C, homogeneous by TLC (silica, 1:1 CH₃0H:CH₂C1₂, Rf-0.35]. The IR

(CHCl,), NMR (CDClj) and Mass Spectrum (M^*-255, El, 70eV) were consistent with the structure. The yield was 3.372g (13.22mmol,

54.19%) .

Elemental Analysis

EXAMPLE 6 3- (4-Benzyl-l-piperazinyl) 4, 5-dihydronaphth[l, 2-cJ isoxazole

A stirred mixture of 3-chloro-4, 5-dihydronaphth[l, 2- c] isoxazole (2.0g, 9.75mmol), 1-benzylpiperazine (17ml, 97.5mmol) and K₂C0₃ (2.7g, 19.5mmol) in 18ml of N- methylpyrrolidinone under N₂ 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 (CH₂C1₂) showed no remaining starting material. The mixture was removed from the heating bath, allowed to cool to room temperature and extracted with heptane. The organic phase was dried over MgSO,, filtered and concentrated_. in vacuo to obtain a crude solid. The solid was collected, titrated with Et₂0, recrystallized from Et₂0 and dried in vacuo (0.1mm) at 85^*C to provide pure product, mp of 164- 166^*C, homogeneous by TLC [silica, 1:1 EtOAc, Rf-0.80]. The IR (CHCl,) , NMR (CDC1₃) and Mass Spectrum (M^*-345, El, 70eV) were consistent with the structure. The yield was 1.219g (3.53mmol, 36.24%) . Elemental Analysis

3-Hydroxy-8-methoxy-4, 5-dihydronaphth[l, 2-c] isoxazole

To a mechanically stirred mixture of 7-methoxy α-tetralone oxime (5.0g, 26.18mmol) in anhydrous THF (150ml) at 0^*C under N₂ was slowly added n-butyl-lithium (n-BuLi) (23.0ml of a 2.5M solution in hexane, 57.60mmol) . The mixture was stirred at O'C for 30 minutes, then C0₂ gas was bubbled into the solution. (As this addition progressed, a solid precipitate began to form) . After 15 minutes, C0₂ addition was stopped and N₂ flow was restored. The thick mixture was stirred and warmed slowly to room temperature for 14 hours, then 6N H₂SO, (150ml) 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 H₂0, once with brine, dried over MgSO, and filtered. Concentration m vacuo caused the precipitation of a solid which was collected, titrated with EtOAc, and dried i n vacuo to provide the product as a solid, mp of 135-138^*C, homogeneous by TLC [silica, 10:90 CH,OH:EtOAc, Rf-0.46]. The IR (KBr), NMR (DMSO-d,) and Mass Spectrum (M^*-217, El, 70eV) were consistent with the structure. The yield was 2.0496g (9.45mmol, 36.08%) .

Elemental Analysis

EXAMPLE 8 3-Chloro-8-mβthoxy-4, 5-dihydronaphth(1,2-c] isoxazole

To a stirred mixture of 3-hydroxy-8-methoxy-4, 5- dihydronaphth[l,2-c] isoxazole (10. Og, 46.08mmol) in phosphorus oxychloride (12.8ml, 137.3mmol), triethylamine (6.42ml, 46.0θmmol) 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 400ml of ice water, and extracted with heptane. The organic extracts were combined, dried over MgSO,, filtered and concentrated in vacuo . Concentration of the filtrate i n vacuo caused a solid to 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, CH₂C1₂, Rf-0.45]. The IR (CHCl,), NMR (CDCl,) and Mass Spectrum (M^*-235, El, 70eV) were consistent with the structure. The yield was 7.75g (32.98mmol, 71.57%) .

Elemental Analysis

EXAMPLE 9 3-t (l-Methyl-4-ρiperidinyl)oxy] -4, 5-dihydronapht [ 1, 2- c] isoxazole

To a stirred solution mixture of 4-hydroxy-N-methyl piperidine (5.05g, 43.89mmol) in 100ml of N-methylpyrrolidinone under N₂ was added NaH (1.75g of a 60% dispersion in oil, 43.89mmol) . The mixture was stirred at room temperature for 15 minutes, then a solution of 3-chloro-4, 5-dihydronaphth[l, 2- c] isoxazole (3.0g, 14.63mmol) in 15ml N-methylpyrrolidinone was added in one portion. The stirred mixture was lowered into an oil bath preheated to 150'C. After 20 minutes TLC [CH₂C1₂] 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 heptanβ/H₂0. The heptane phase was washed with water, dried over MgSO,, filtered and concentrated in vacuo . This crude oil obtained was taken up in Et₂0, filtered, and the HCl salt precipitated by the addition of ethanolic HCl. This salt was recrystallized from CH₂C1₂/Et₂0 to provide the product as a solid, mp of 147-150'C, homogeneous by TLC (silica, 1:1 CH,0H:Et0Ac Rf-0.02] . The IR (KBr), N R (CDCl,) and Mass Spectrum (M^*+l=-285, CI, methane) were consistent with the structure. The yield was 1.2994g (4.05mmol, 36.09%) .

Elemental Analysis

EXAMPLE 10 3- ( 1-Piperazinyl) -θ-methoxy-4, 5-dihydronaphth(l, 2-c] isoxazole

A stirred mixture of 3-chloro-8-methoxy-4, 5- dihydronaphth(l,2-c) isoxazole (2.0g, 8.51mmol), piperazine (7.0g, 80.6mmol) and K₂C0₃ (2.4g, 17.1mmol) in 8.0ml of N- methylpyrrolidinone under N₂ was lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under N₂ for 20 minutes. At that time TLC [CH₂C1₂] showed no starting material remained. 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 and dried in vacuo to provide pure product, mp of 96- 88'C, homogeneous by TLC (silica, 1:1 CH,0H:CH₂C1₂, Rf-0.37] . The IR (CHCl,), NMR (CDCl,) and Mass Spectrum (M^*-285, El, 70eVl were consistent with the structure. The yield was 1.932g (6.78mmol, 79.66%) .

Elemental Analysis

EXAMPLE 11 3- ( 1-Homopiperazinyl ) -8-methoxy-4 , 5-dihydronaphth [ l , 2- c ] isoxazole

A stirred mixture of 3-chloro-θ-methoxy-4, 5- dihydronaphth[l, 2-c] isoxazole (2.66g, 11.32mmol), homopiperazine (11.40g, 113.2mol) and K₂CO, (3.13g, 22.68mmol) in 10.0ml of N- ethylpyrrolidinone under N₂ was lowered into an oil bath preheated to 150^*C. The mixture was heated while stirring under N₂ for 20 minutes. At that time, TLC (CH₂C1₂) 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 Et₂0 and dried m vacuo (0.1mm) at 85'C, to provide pure product, mp of 106-109^*C, homogeneous by TLC [silica, 1:1 CH₃0H:CH₂C1₂, Rf-0.18) . The IR (CHCl,), NMR (CDCl,) and Mass Spectrum (M^*-299, El, 70eV) were consistent with the structure. The yield was 1.7948g (^β.OOmmol, 53.03%) .

Elemental Analysis

EXAMPLE 12 3- (1- (4- (p-Chlorophenyl) -4-hydroxy-piperidinyl) -9-methoxy-4, 5- dihydronaphth [1, 2-c] isoxazole

A stirred mixture of 3-chloro-8-methoxy-4, 5- dihydronaphth (1, 2-c) isoxazole (2.0g, 8.51mmol), 4-(p- chlorophenyl) -4-hydroxy-dipiperidine (3.6g, 17.02mol) and K₂CO, (2.35g, 17.02mmol) in 6ml of N-methylpyrrolidinone under N₂ was lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under N₂ for 1 hour. At that time, TLC [CH₂C1₂] 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 recrystallized from EtOAc and dried in vacuo (0.1mm) at 85^*C to provide pure product, mp of 174- 177^*C, homogeneous by TLC [silica, 2:1 heptane:EtOAc, Rf-0.263] . The IR (CHC1₃), NMR (CDCl,) and Mass Spectrum (M^*-410, E.I., 70eV) were consistent with the structure. The yield was 2.3798g (5.60mmol, 68.20%) . Elemental Analysis

EXAMPLE 13 3- [ (endo) -θ-Methyl-8-azabicyclo[3.2.1]oct-3-yl) oxy] -8-methoxy- 4, 5-dihydronaphth[l, 2-c] isoxazole

To a stirred mixture of tropinβ (5.41g, 38.31mmol) in 10 ml of (THF) under N₂ at O'C was slowly added n-BuLi (15.0ml of a 2.5M solution in hexanes, 38.31mmol) . The mixture was stirred for 15 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, 12.76mmol) in 30ml N-methylpyrrolidinone was added in one portion. The internal temperature increased to 99-100^*C and was maintained there. After 3 hours, TLC [CH₂C1₂] 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/H₂0. The heptane phase was washed with H₂0, dried over MgSO,, filtered and concentrated m 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, rap of 102-104'C, homogeneous by TLC [silica, 1:1 CH,0H:CH₂C1₂, Rf-0.20]. The IR (CHCl,), NMR (CDCl,) and Mass Spectrum (M^*+-341, CI, methane) were consistent with the structure. The yield was 1.3729g (4.038mmol, 31.64%).

Elemental Analysis

EXAMPLE 14 3-[ (endo-8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy]-4,5- dihydronaphthd,2-c]isoxazole hydrochloride hemihydrate

To a stirred mixture of tropine (4.4g, 31.16mmol) in 10ml O f

- THF under N₂ at 0"C was slowly added n-BuLi (12.47ml of a 2.5M solution in hexanes, 31.16mmol) . 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-c] isoxazole (2.13g, 10.39mmol) in 30ml N-methylpyrrolidinone 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 [CH₂C1₂] 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/H₂0. The heptane phase was washed with H₂0, dried over MgSO,, filtered and concentrated i n vacuo, to provide the free base as an oil, which resisted attempts at crystallization. The oil was taken up in Et₂0 and the HCl salt was precipitated by the addition of ethanolic HCl. This crude solid was recrystallized from Et₂0/CH₂C1₂ and dried in vacuo at 85*C to provide the product as a solid, mp of 167- 170*C, (darkens at ca. 150^*C) homogeneous by TLC (silica, 1:1 CH,0H:CH₂C1₂, Rf-0.14]. The IR (CHCl,), NMR (CDCl,) and Mass Spectrum (M*+l»311, CI, methane) were consistent with the structure. .Analysis and NMR confirmed the hemihydratβ structure. The yield was 1.268g (3.563mmol, 34.29%) . Elemental Analysis

EXAMPLE 15

3- (1- (4- (6-Fluorobenzisoxazol-3-yl) -piperidinyl) -8-methoxy-4, 5- dihydronaphthd, 2-c] isoxazole

A stirred mixture of 3-chloro-8-methoxy-4, 5- dihydronaphthfl, 2-cJ isoxazole (2.0g, 8.51mmol), 4-(6- fluorobenzisoxazol-3-yl) -piperidine (2.8g, 12.76mmol) and K₂CO, (2.35g, 17.02mmol) in 10ml of N-methylpyrrolidinone under N, was lowered into an oil bath preheated to 150^*C. The mixture was heated while stirring under N₂ for 90 minutes. At that time TLC (CH₂C1₂) 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-0, ^"solid precipitated which was collected, dried, dissolved n CH₂C1₂ and filtered through neutral alumina. The fractions containing desired product were combined and concentrated, and trie resultant solid obtained was triturated with Et₂0 to provide a solid, mp of 181-183'C, homogeneous by TLC (silica, 2:1 Heptane:EtOAc, Rf-0.15) . The IR (CHCl,), NMR (CDCl,) and Mass Spectrum (M^*-419, El, 70eV) were consistent with the structure. The yield was 1.1318g (2.70mmol, 31.70%) .

Elemental Analysis

EXAMPLE 16 3- (1- ( -2-Oxo-1-benzimidazolinyl) piperidinyl) ) -θ-methoxy-4, 5- dihydronaphthd, 2-c] isoxazole

A stirred mixture of 3-chloro-β-methoxy-4, 5- dihydronaphthd, 2-c] isoxazole (2.57g, 10.9mmol), 4-(2-oxo-l- benzimidazolinyl)piperidine (4.74g, 21.8mmol) and K₂C0₃ (3.02g, 21.8mmol) in 12ml of N-methylpyrrolidinone under N₂ was lowered into an oil bath preheated to 150^*C. The mixture was heated while stirring under N₂ for 4 hours. At that time, TLC (CH₂C1₂) 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 CH₂C1₂ and filtered through neutral alumina using CH₂C1₂ and then 1:1 CH₂Cl₂:Et₂0. The fractions containing desired product were combined and concentrated, and the resultant solid obtained was triturated with EtOAc and dried i n vacuo (0.1mm Hg, 85^βC) to provide a solid, mp of 211-214'C homogeneous by TLC (silica, EtOAc, Rf-0.38] . The IR (CHCl,), NMR (CDCl,) and Mass Spectrum (M^*-416, El, 70eV) were consistent with the structure. The yield was 1.602g (3.85mmol, 33.33%) .

Elemental .Analysis

EXAMPLE 17 3-[ (Quinuclidin-3-yl)oxy] -8-methoxy-4, 5-dihydronaphth[1,2- c] isoxazole hydrochloride

To a stirred mixture of 3-quinuclidinol (4.87g, 38.2θmmol) in 10ml of THF under N₂ at 0^*C was slowly added n-BuLi (15.32g of a 2.5M solution in hexanes, 38.29mmol) . The mixture was stirred for 10 minutes while allowing to warm to room temperature, then a solution of 3-chloro-8-methoxy-4, 5-dihydronaphth[l, 2- c] isoxazole (3.0g, 12.⁷6mmol) in 30ml N-methylpyrrolidinone 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 [CH₂C1₂] 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/H₂0. 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 HCl salt was precipitated by the addition of ethanolic HCl. This solid was collected and dried in vacuo (0.1mm Hg, 85'C) to provide the product as a solid, mp of 133-136'C, homogeneous by TLC (silica, 1:1 CH,0H:CH₂C1₂, Rf-0.23] . The IR (KBr), NMR (DMS0-d«) and Mass Spectrum (M^*+l-326, El, 70eV) were consistent with the structure. The yield was 0.965g (2.39mmol, 18.79%) .

Elemental Analysis

EXAMPLE 18

5, 6-Dihydro-4H-benzo⁽6, 7]cyclohept[l, 2-c] isoxazol-3-ol

To a mechanically-stirred mixture of 1-benzosuberone oxime ilO.Og, 57.lmmol) in anhydrous THF (200ml) at 0*C under N₂ was slowly added n-BuLi (50.3ml of a 2.5M solution in hexane,

125.62mmσl) . The mixture was stirred at O'C for 30 minutes, then C0₂ gas was bubbled into the solution. After 15 minutes, COj addition was stopped and N₂ flow was restored. The thick mixture was stirred and warmed slowly to room temperature for 14 hours, then 6N H₂SO, (220ml) was slowly added, which dissolved the solids. Stirring was continued for 18 hours, at which time the TLC [EtOAc] showed a mixture of starting oxime and product (starting oxime was best visualized using 2:1 heptane:EtOAc eluent) . The mixture was poured into a separatory funnel, and the organic phase drawn off. The aqueous phase was extracted with EtOAc, and the organic phase and the EtOAc extracts were combined, washed with H₂0, 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, Et O Rf-0.28] . The IR (KBr⁾, NMR ⁽DMSO-d and Mass Spectrum (M*-201, El, 70 eV) were consistent with the structure. The yield was 3.0324g (15.09mmol, 26.42%) .

Elemental Analysis

EXAMPLE 19 3- (1- (4- (2-Oxo-l-benzimidazolinyl)piperidinyl) )-4, 5- dihydronaphth[1,2-c]isoxazole hemihydrate

A stirred mixture of 3-chloro-4,5-dihydronaphth[1,2- c]isoxazolβ (3.1g, l5.12mmol), 4-(2-oxo-l-benzimidazolinyl)- piperidine (8.2g, 37.8mmol) and K₂CO, (4.2g, 30.24mmol) in 19ml of N-methylpyrrolidinone under N₂ was lowered into an oil bath preheated to 150'C. The mixture was heated while stirring under -N₂ for 90 minutes. At that time, TLC (CH₂CI₂) showed no remaining starting material. The mixture was removed from the heating bath and allowed to cool to room temperature. Upon cilution of the reaction mixture w th H₂0, a solid precipitated which was collected, dried, dissolved in CH₂C1₂ and filtered through neutral alumina using CH₂C1₂ and then 1:1 CH₂Cl₂:Et₂0. The fractions containing desired product were combined and concentrated, and the solid obtained was recrystallized from EtOAc and dried m vacuo (0.1mm Hg, llO'C) to provide a solid, mp of 229-233^βC, homogeneous by TLC (silica, EtOAc, Rf-0.54] . The IR (KBr), NMR (CDCl,) and Mass Spectrum (M*-3Θ6, El, 70eV) were consistent with the structure. Analysis and NMR confirmed a hemihydrate structure. The yield was 1.103g (2.79mmol, 18.45%) .

Elemental Analysis

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, maleic, 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 or 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 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 according to the present invention are prepared so that an oral dosage unit form contains from about 1.0 to about 300mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as πucrocrystallme cellulose, gum tragacanth or gelatin; an ^"excipient such as starch or lactose, a disintegrating agent such as alginic acid, Pri ogel¹*, corn starch and the like; a lubricant such as magnesium stearate or SterotexΦ; 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 m such composition is such that a suitable dosage of active compound will be obtained. Preferred compositions and preparations according to the invention are prepared so that a -parenteral dosage unit contains from about 0.5 to about lOOmgs 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 such as 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 dose 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.

³H-GR 65630 Binding to Rat Entorhinal Cortex Membranes Studies have been performed to determine the affinity of the compounds of the invention for the 5HT, 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 5HT, binding sites existed only in the periphery. However, with the recent introduction of potent and selective 5HT, antagonist drugs such as GR65630, Zacopnde, IC3 205 930 and MDL 72222 (Bemesetron, C,_jH Cl₂N0₂) , data from binding studies have indicated that 5HT, binding sites are also located in selected areas of the brain. The highest levels of 5HT, binding sites have been detected in limbic and dopamine containing brain areas (entorhinal cortex, amygdala, nucleus accumhens and tuberculum olfactorium) (Kllpatrick, G.J. et al . Identi ication and distribution of 5HT, receptors in rat brain using radioligand binding. Nature 330: 746-748) . Besides possessing selective binding in dopamine rich areas, 5HT, antagonists have been reported to block behavioral effects associated with certain drugs of abuse (nicotine and morphine) and to be active in behavioral tests predictive of anxiolytic activity. Based on these selective regional binding results and behavioral studies, 5HT, 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 accordance with the above-discussed assay, a 0.05M of -Krebs-Hepes buffer, pH 7.4 was prepared as follows:

11.92g Hepes 10.52g NaCl

0.373g KC1

0.277g CaC

0.244g MgCl₂.6H₂0 q.s. to 1 liter with distilled H₂0, bring pH up to 7.4 (at 4»C) with 5N NaOH

(³H]-GR65630 (87.OCi/mmol) was obtained from New England Nuclear. For .IC₅₀ determinations: (⁵H]-GR65630 was made up to a concentration of l.OnM in Krebs-Hepes buffer such that when lOOμl is added to each tube, a final concentration of 0.4nM is attained in the 250μl assay.

GR38032F was obtained from Research Biochemical Inc. GR38032F was made up to a concentration of 500μM in Krebs-Hepes buffer. 50μl of Krebs-Hepes were added to each of 3 tubes for determination of nonspecific binding (yields a final concentration of lOOμM in the 250μl assay) .

For most assays, a 50μl stock solution was prepared in a suitable solvent and serially diluted with Krebs-Hepes buffer such that when 50μl of drug s combined with the total 250μl assay, a final concentration from 10^"5 to 10^"*M 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 (15-200g) were decapitated, the entorhinal cortex removed, weighed and homogenized in 10 volumes of ice cold 0.05M Krebs-Hepes buffer, pH 7.4. The homogenate is centrifuged at 48,000g for 15 minutes at 4'C. The resulting pellet was rehomogenized in fresh Krebβ- Hepes buffer and recentrifuged at 48,000g for 15 minutes at 4*C. The final pellet was resuspended m the original volume of ice- cold Krebs-Hepes buffer. This yielded a final tissue concentration of 1.2 to 1.6mg/ml with the addition of lOOμl to the assay. Specific binding was approximately 55 to 65% of the total bound ligand.

In conducting the assay, the following volumes were utilized:

lOOμl of Tissue suspension; lOOμl of [^]H]-GR65630; and 50μl 500M GR38032F (Vehicle for binding) or appropriate drug concentration Sam le tubes were kept on ice for additions, then vortexed and incubated with continuous shaking for 30 minutes at 37>c. At the end of the incubation period, the incubate is diluted with 5 ml of ice-cold Krebs-Hepes buffer and immediately vacuum filtered through Whatman GF/B filters, followed by two 5ml washes with ice-cold Krebes-Hepes buffer. The filters are dried and counted in 10 ml of liquid scintillation cocktail. Specific GR 65630 binding is defined as the difference between the total binding and that bound in the presence of lOOμM GR38032F. IC₅₀ values were derived from computer-derived log-probit analysis.

Various compounds of the invention were subjected to the above-described assay and the results the affinity for 5 HT, receptors are reported in Table I, below.

TABLE I Affinity for 5-HT, Receptor-Displacement o f ³H-GR 65630

Measurement of 5 HT, Antagonist Effects in the Bezold-Jarisch Assay

This assay evaluates the effect of these compounds as 5-HT, antagonists. They were examined in this assay on the coronary chemoreflex (Bezold-Jarisch) initiated by 5-HT, i n vivo and characterized by leading inhibition of sympathetic outflow and increased activity of the cardiac vagus, leading. to profound bradycardia and hypotension. The values obtained allow for 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 Tygon tubing (45cm length, 0.05mm, ID) bonded to Teflon tubing (0.38mm, ID) . The mechanical bonding was achieved by insertion of the Teflon tubing (5mm) into the dilated (ethylene dichloride, 3-4 min.) tip of the Tygon tubing. The junction was then sealed with vinyl glue, the catheters were soaked in cold sterilization solution (Amerse instrument germicide) and flushed thoroughly with saline prior to implantation.

Long Evans rats were anesthetized with sodium pentobarbital (50mg/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 catheters were then secured to the skin with sutures, nitrofurazone powder was dusted over the area of the incision and the incision was closed using 3-0 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 rats 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, systolic/diastolic) and Heart Rate (beats/min) were recorded and the rats were injected with 5-HT (3-7.5ug/kg, ιv) . The individual response to the 5-HT intervention was determined and the compound was then administered singleiy or in an ascending dose range. The rats were challenged with 5-HT again at intervals postdosing and the peak response was recorded.

Several compounds of the invention were tested according to the above-described assay and the results are reported in Table II, below.

TABLE I I

Inhibitory Potency of 5-HT, Antagonists on Reflex Bradycardia Induced by Intravenous 5-HT, in the Anesthetized Long-Evans Rat

In accordance with Table II, maximal reductions in heart rate induced by 5HT, (e.g. Bezold-Jarisch reflex) occurred 15 to 60 minutes after administration.

Claims

I Claim:

1. A compound of the formula:

where A is hydrogen, hydroxy,

where R_t is hydrogen, an alkyl group of 1 to 6 carbons, optionally substituted with hydroxy, alkoxy cr 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 N, CH or C(OH); m is an integer of 1 to 3; and X is hydrogen, hydroxy or alkoxy; and the pharmaceutically acceptable salts thereof, and its geometric or optical isomers, or the racemic mixtures, where applicable.

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

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

v

^

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- dihydronaphthd, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

7. The compound according to Claim 1, which is 3-hydroxy-8- methoxy-4, 5-dihydronaphth(l, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

8. The compound according to Claim 1, which is 3-chloro-8- methoxy-4, 5-dihydronaphth[1, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

9. The compound according to Claim 1, which is 5, 6-dihydro-4H- benzo(6, 7] cycloheptd, 2-c] isoxazol-3-ol, its salts, isomers and racemic mixtures, where applicable.

10. The compound according to Claim 2, which is 3- ( -methyl-l- piperazinyl) -4, 5-dihydronaphth(l, 2-cJ isoxazole, its salts, isomers and racemic mixtures, where applicable.

11. The compound according to Claim 2, which is 3- (4- (2-hydroxy ethyl) -1-piperazinyl) -4, 5-dihydronaphth[1, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

12. The compound according to Claim 2, which is 3-(l- homopiperazinyl) -4, 5-dihydronaphth[l, 2-cJ isoxazole, its salts, isomers and racemic mixtures, where applicable.

13. The compound according to Claim 2, which is 3-(l- piperazinyl) -4, 5-dihydronaphth[1, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

14. The compound according to Claim 2, which is 3- (4-benzyl-l- piperazinyl) 4,5-dihydronaphth[l,2-c]isoxazole, its salts, isomers and racemic mixtures, where applicable.

15. The compound according to Claim 2, which is 3-{l- piperazinyl) -8-methoxy-4, 5-dihydronaphth(1, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

16. The compound according to Claim 2, which is 3-(i- homopiperazinyl) -8-methoxy-4, 5-dihydronaphth[l, 2- c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

17. The compound according to Claim 2, which is 3-(l-(4-(p- chlorophenyl) -4-hydroxy-piperidinyl) -8-methoxy-4, 5- dihydronaphth(l, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

18. The compound according to Claim 2, which is 3-(l-(4-(6- fluorobenzisoxazol-3-yl) -piperidinyl) -8-methoxy-4, 5- dihydronaphthd, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

19. The compound according to Claim 2, which is 3- (1- (4-2-oxo- 1-benzimidazolinyl)piperidinyl) ) -8-methoxy-4, 5- dihydronaphth , 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

20. The compound according to Claim 2, which is 3- (1- ( - (2-oxo- 1-benzimidazolinyl) piperidinyl) ) -4, 5-dihydronaphth{ 1, 2- c] isoxazole hemihydrate, its salts, isomers and racemic mixtures, where applicable.

21. The compound according to Claim 3, which is 3- [(l-methyl-4- piperidinyl)oxy] -4, 5-dihydronaphth[l, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

22. The compound according to Claim 4, which is 3-[(endo)-8- methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy]-8-methoxy-4, 5- dihydronaphthd, 2-c] isoxazole, its salts, isomers and racemic mixtures, where applicable.

23. The compound according to Claim 4, which is 3-[(endo-8- methyl-8-azabicyclo[3.2.l]oct-3-yl)oxy]-4, 5- dihydronaphthd, 2-c] isoxazole hydrochloride hemihydrate, its salts, isomers and racemic mixtures, where applicable.

24. The compound according to Claim 5, which is 3-

( (quinuclidin-3-yl) oxy] -8-methoxy-4, 5-dihydronaphth[1, 2- c] isoxazole hydrochloride, its salts, isomers and racemic mixtures, where applicable.

25. A method of preparing a compound of the formula

comprising the sequential reaction steps of:

26. A method of treating a patient in need of relief from a psychiatric disorder, nausea, vomiting and control of drug use, comprising providing to said patient an effective amount of the compound of Claim 1.

27 A method of treating a condition ameliorated by the use of a 5-HT₃ antagonist, comprising administering to a patient an effective amount to relief said condition of the compound of claim 1 .

28. A pharmaceutical composition, comprising an effective amount of the compound of Claim 1 , and a pharmaceutically acceptable carrier therefor

29. A compound of Claim 1 for use as an active pharmaceutical substance

30 The use of a compound of Claim 1 for the production of a medicament for the treatment of psychiatric disorders, nausea, vomiting and control of drug use

31 The use of a compound of Claim 1 for the production of a medicament for the treatment of a condition ameliorated by the use of a 5-HT₃ antagonist