KR100308748B1 - 4,5-Dihydronaphth[1,2-C]Isoxazoles and Derivatives Thereof Having CNS Activity - Google Patents

Abstract

4,5-Dihydronaphth [1,2-C] isoxazole derivatives of formula (I). Such compounds are useful as serotonin 5-HT ₃ antagonists. Such compounds are useful for the treatment of anxiety, psychiatric disorders, schizophrenia, motion sickness, vomiting and drug dependence.

<Formula I>

Wherein A, X and N are described herein.

Description

4,5-Dihydronaphth [1,2-c] isoxazole and its derivatives having CNS activity {4,5-Dihydronaphth [1,2-C] Isoxazoles and Derivatives Thereof Having CNS Activity}

The present invention relates to certain novel compounds and their use as medicaments with unique central nervous system activity.

The present invention relates to 4,5-dihydronaphth [1,2-c] isoxazoles of formula (I) and derivatives thereof, pharmaceutically acceptable salts thereof, or, if present, geometric isomers or optical isomers or racemic Mixtures, and their use as serotonin 5-HT ₃ antagonists, which may be useful in the treatment of anxiety, psychiatric disorders, schizophrenia, nausea, vomiting and the regulation of drug dependence.

Wherein A is hydrogen, hydroxy, chloro

, , or

Wherein R ₁ is hydrogen; an alkyl group of 1 to 6 carbon atoms optionally substituted with hydroxy, alkoxy or amino substituents; aryl or heteroaryl optionally substituted with halogen, hydroxy or alkoxy; or halogen, hydroxy or alkoxy Benzyl optionally substituted Z is nitrogen, CH or C (OH); m is an integer from 1 to 3;

n is an integer of 1 or 2;

X is hydrogen, hydroxy or alkoxy.

The present invention also relates to such compounds, pharmaceutically acceptable addition salts thereof, as well as their pharmaceutically acceptable compositions and methods of using these compounds as serotonin 5-HT ₃ antagonists.

Throughout the specification and the appended claims, the given formula or name, if present, includes all stereo and optical isomers thereof. In addition, a given formula or name includes pharmaceutically acceptable addition salts thereof.

Preferred embodiments of the invention

A Is a compound of formula (I).

Wherein R ₁ is hydrogen; Alkyl groups of 1 to 6 carbon atoms optionally substituted with hydroxy, alkoxy or amino substituents; 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 from 1 to 3;

X is hydrogen, hydroxy or alkoxy.

R ₁ is hydrogen or alkyl of 1 to 3 carbon atoms;

n is 1;

Z is nitrogen;

m is 1 or 2;

More preferred are compounds of formula (I), wherein X is hydrogen.

The novel compounds and intermediates of the present invention can be prepared in the following reaction sequence. Substituents Z, m, n and X are generally as defined above unless otherwise stated.

According to Scheme (1), according to the method of Griffiths and Olofson, hydroxyisoxazole (3) is tetrahydrofuran for about 0.25 to about 4 hours at reflux temperature of about 25 ° C. to about solvent. It is prepared from oxime (2) in a solvent such as (THF). Generally, a solution of oxime (2) in a solvent such as tetrahydrofuran is treated with n-butyllithium and the resulting solution of dirithio salt is poured into carbon dioxide. The mixture is then acidified to give 3-hydroxyisoxazole (3). See Jerome Griffiths, et al., J. Chem. Soc. C. 974 (1971) and G.N. Barber and R.A. Olofson, J. Org. Chem. 43, 3015 (1978). Hydroxyisoxazoles (3) have been described in Adembri et al., G. Adembri and P. Tedeschi, Bull. Sci. Fac. Chim. Ind. Bologna 23, 203 (1965)] is converted to chloroisoxazole (4) via treatment with phosphorus oxychloride in the presence of a suitable base (e.g. triethylamine). Intermediate (4) is a suitable nucleophile HA with or without addition of a base in a suitable solvent (eg, N-methylpyrrolidinone) at a temperature of about 100 ° C. to about 200 ° C., where A is as described above. Treatment with provides a novel compound (1) of the present invention.

Such compounds can be prepared by the following examples. The examples are illustrative only and should not be construed as limiting the invention described herein.

Example 1

3-chloro-4,5-dihydronaphth [1,2-c] isoxazole

Triethyl in a stirred mixture of 4,5-dihydronaphth [1,2-c] isoxazol-3- (3aH) -one (7.25 g, 38.77 mmol) in phosphorus oxychloride (10.84 mL, 116.3 mmol) Amine (5.40 mL, 38.77 mmol) was added dropwise. After the addition was complete, the mixture was heated to reflux with stirring. After 2 hours, no starting material remained as confirmed by TLC [silica, ethyl acetate (EtOAc)]. The mixture was cooled to room temperature, poured into 300 mL of ice water and extracted with CH ₂ Cl ₂ . Organic extracts were combined, dried over MgSO ₄ and concentrated in vacuo. The resulting solid was filtered through silica using CH ₂ Cl ₂ eluent to afford 6.2 g of crude product. This crude product was recrystallized from a minimum of heptane to give the product as a needle, the melting point of 57-59 ℃, thin layer chromatography (TLC) [silica, CH ₂ Cl ₂ , R _f = 0.80] was the same. Infrared (IR) (CHCl ₃ ), nuclear magnetic resonance (NMR) (CDCl ₃ ), and mass spectrum (M ⁺ = 205, EI, 70 eV) matched the structure. Yield was 5.417 g (26.4 mmol, 68.16%).

Elemental analysis

Calculation Analysis C 64.25 64.02 H 3.92 3.86 Cl 17.24 N 6.81 6.77 O 7.78

Example 2

3- (4-methyl-1-piperazinyl) -4,5-dihydronaft [1,2-c] isoxazole

3-chloro-4,5-dihydronaft [1,2-c] isoxazole (2.65 g, 12.93 mmol), N-methyl piperazine (30 mL, 270.4 mmol) and K ₂ CO ₃ (3.57 g, 25.87 mmol) of the stirred mixture was placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 2 h. At this time, TLC [CH ₂ Cl ₂ ] showed no starting material remaining. The mixture was removed from the heated bath and cooled to room temperature. Then partitioned over heptane / H ₂ O. The heptane phase was washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo to give a solid. This crude product was recrystallized from heptane / ether (Et ₂ O) to give the product as a needle, with the same melting point 92-94 ° C., TLC [silica, 1: 1 CH ₃ OH: EtOAc, R _f = 0.39]. Infrared (IR) (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 269, EI, 70 eV) matched the structure. Yield was 1.2555 g (4.67 mmol, 36.09%).

Elemental analysis

Calculation Analysis C 71.35 71.34 H 7.11 6.98 N 15.60 15.78 O 5.94

Example 3

3- (4- (2-hydroxyethyl) -1-piperazinyl) -4,5-dihydronaft [1,2-c] isoxazole

3-chloro-4,5-dihydronaphth [1,2-c] isoxazole (3.0 g, 14.63 mmol), 1- (2-hydroxyethyl) -pipe in 18 ml N-methylpyrrolidinone A stirred mixture of lazine (17.95 mL, 146.3 mmol) and K ₂ CO ₃ (4.1 g, 29.3 mmol) was placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 1 h. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath, cooled to room temperature and diluted with H ₂ O. After heptane was added, the solid precipitated out. The solid was recovered, washed with heptane and H ₂ O and dried under vacuum at 85 ° C. overnight (0.1 mmHg) to afford the pure product, melting point 137-138 ° C., TLC [silica, 1: 1 CH ₃ OH: EtOAc, R _f = 0.67] was the same. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 299, EI, 70 eV) were consistent with the structure. Yield was 2.603 g (8.70 mmol, 59.47%).

Elemental analysis

Calculation Analysis C 68.21 68.12 H 7.07 7.01 N 14.04 14.14 O 10.69

Example 4

3- (1-homopiperazinyl) -4,5-dihydronaft [1,2-c] isoxazole

3-chloro-4,5-dihydronaft [1,2-c] isoxazole (3.0 g, 14.63 mmol), homopiperazine (14.66 g, 146.3 mmol) in 16 mL N-methyl-pyrrolidinone And a stirred mixture of K ₂ CO ₃ (4.04 g, 29.3 mmol) in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 45 min. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath, cooled to room temperature, diluted with H ₂ O and extracted with Et ₂ O. The Et ₂ O phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product obtained was recrystallized from heptane / Et ₂ O and dried overnight under vacuum at 85 ° C. (0.1 mmHg) to give the pure product, melting point 79-81 ° C., TLC [silica, 1: 1 CH ₃ OH: EtOAc, R _f = 0.17]. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 269, EI, 70 eV) were consistent with the structure. Yield was 1.969 g (7.32 mmol, 50.03%).

Elemental analysis

Calculation Analysis C 71.35 71.45 H 7.11 7.29 N 15.60 15.56 O 5.94

Example 5

3- (1-piperazinyl) -4,5-dihydronaft [1,2-c] isoxazole

3-chloro-4,5-dihydronaft [1,2-c] isoxazole (5.0 g, 24.4 mmol), piperazine (34.2 g, 397.7 mmol) and K in 40 mL N-methylpyrrolidinone A stirred mixture of ₂ CO ₃ (6.73 g, 48.7 mmol) was placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 45 min. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath, cooled to room temperature and extracted with Et ₂ O. The organic phase was washed twice with H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo to afford a crude solid. The recovered solid was recrystallized from heptane / Et ₂ O and dried under 85 ° C. vacuum (0.1 mmHg) to give the pure product, melting point 97-99 ° C., TLC [silica, 1: 1 CH ₃ OH: CH ₂ Cl ₂ , R _f = 0.35] is identical. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectrum (M ⁺ = 255, EI, 70 eV) were consistent with the structure. Yield was 3.372 g (13.22 mmol, 54.19%).

Elemental analysis

Calculation Analysis C 70.56 70.38 H 6.71 6.67 N 16.46 16.47 O 6.27

Example 6

3- (4-benzyl-1-piperazinyl) 4,5-dihydronaft [1,2-c] isoxazole

3-chloro-4,5-dihydronaphth [1,2-c] isoxazole (2.0 g, 9.75 mmol), 1-benzylpiperazine (17 mL, 97.5 mmol in 18 mL N-methylpyrrolidinone ) And K ₂ CO ₃ (2.7 g, 19.5 mmol) were placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 2 h. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath, cooled to room temperature and extracted with heptane. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo to afford a crude solid. To recover the solid treated with Et ₂ O, which was recrystallized from Et ₂ O and dried under vacuum to give the 85 ℃ (0.1 mmHg) of pure product, melting point 164-166 ℃, TLC [silica, 1: 1 CH ₃ OH : EtOAc, R _f = 0.80] were the same. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 345, EI, 70 eV) were consistent with the structure. Yield was 1.219 g (3.53 mmol, 36.24%).

Elemental analysis

Calculation Analysis C 76.49 76.49 H 6.71 6.85 N 12.16 12.09 O 4.63

Example 7

3-hydroxy-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole

N-butyl-lithium (n-BuLi) (2.5 in hexane) to a mechanically stirred mixture of 7-methoxy α-tetralon oxime (5.0 g, 26.18 mmol) in dry THF (150 mL) under 0 ° C. N ₂ . 23.0 mL M solution, 57.60 mmol) was added slowly. The mixture was stirred at 0 ° C. for 30 minutes, and then CO ₂ gas was bubbled into the solution. (As this addition proceeded, a solid precipitate began to form). After 15 minutes, CO ₂ addition was stopped and the N ₂ flow rate was returned. The thick mixture was stirred and slowly warmed to room temperature for 1½ hours, followed by the slow addition of 6N H ₂ SO ₄ (150 mL) to dissolve the solids. TLC showed a small amount of starting oxime and a mixture of intermediates not isolated with the desired product. Agitation was continued for 4 hours to convert the intermediate to the product completely. The mixture was extracted thoroughly with EtOAc. The organic fractions were combined, washed once with H ₂ O, washed once with brine, dried over MgSO ₄ and filtered. Concentration in vacuo to precipitate a solid and the recovered solid was treated with EtOAc and dried in vacuo to yield the product as a solid, melting point 135-138 ° C., TLC [silica, 10:90 CH ₃ OH: EtOAc, R _f = 0.46] was the same. IR (KBr), NMR (DMSO-d ₆ ), and mass spectra (M ⁺ = 217, EI, 70 eV) were consistent with the structure. Yield was 2.0496 g (9.45 mmol, 36.08%).

Elemental analysis

Calculation Analysis C 66.35 66.02 H 5.10 5.03 N 6.45 6.22 O 22.10

Example 8

3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole

To a stirred mixture of 3-hydroxy-8-methoxy-4,5-dihydronaphth [1,2-c] isoxazole (10.0 g, 46.08 mmol) in phosphorus oxychloride (12.8 mL, 137.3 mmol) Triethylamine (6.42 mL, 46.08 mmol) was added dropwise. After the addition was complete, the mixture was heated to reflux with stirring. After 4 hours, TLC [silica, EtOAc] showed no starting material left. The mixture was cooled to rt, poured into 400 ml of ice water and extracted with heptane. The organic extracts were combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The filtrate was concentrated in vacuo to precipitate a solid. The solid was treated with heptane and dried in vacuo to give the product as needles, with a melting point of 55-57 ° C., TLC [silica, CH ₂ Cl ₂ , R _f = 0.45] equal. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 235, EI, 70 eV) were consistent with the structure. Yield was 7.75 g (32.98 mmol, 71.57%).

Elemental analysis

Calculation Analysis C 61.16 61.29 H 4.28 4.16 Cl 15.04 N 5.94 5.90 O 13.58

Example 9

3-[(1-methyl-4-piperidinyl) oxy] -4,5-dihydronaft [1,2-c] isoxazole

To a stirred solution mixture of 4-hydroxy-N-methyl-piperidine (5.05 g, 43.89 mmol) in 100 ml of N-methylpyrrolidinone under N ₂ was added 1.75 g of a 60% dispersion in oil, 43.89. Mmol) was added dropwise. The mixture was stirred at room temperature for 15 minutes, and then a solution of 3-chloro-4,5-dihydronaphth [1,2-c] isoxazole (3.0 g, 14.63 mmol) in 15 mL N-methylpyrrolidinone Was added at once. The stirred mixture was placed in an oil bath preheated to 150 ° C. After 20 minutes, TLC [CH ₂ Cl ₂ ] showed no starting material left. The mixture was removed from the heated bath and cooled to room temperature. Then partitioned over heptane / H ₂ O. The heptane phase was washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude oil obtained was dissolved in Et ₂ O, filtered and the HCl salt precipitated by the addition of ethanolic HCl. This salt was recrystallized from CH ₂ Cl ₂ / Et ₂ O to give the product as a solid. Melting point 147-150 ° C., TLC [silica, 1: 1 CH ₃ OH: EtOAc, R _f = 0.02] was identical. IR (KBr), NMR (CDCl 3), and mass spectrum ^{(M + + 1 = 285,} CI, methane) were consistent with the structure. Yield was 1.2994 g (4.05 mmol, 36.09%).

Elemental analysis

Calculation Analysis C 63.65 63.55 H 6.60 6.63 Cl 11.05 N 8.73 8.78 O 9.97

Example 10

3- (1-piperazinyl) -8-methoxy-4,5-dihydronaft [1,2-c] isoxazole

3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole (2.0 g, 8.51 mmol) in 8.0 mL N-methylpyrrolidinone, piperazine (7.0 g, 80.6 mmol) and K ₂ CO ₃ (2.4 g, 17.1 mmol) were placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 20 minutes. At this time, TLC [CH ₂ Cl ₂ ] showed no starting material remaining. The mixture was removed from the heated bath and cooled to room temperature. After diluting the reaction mixture with H ₂ O, the precipitated solid was recovered and dried in vacuo to give the pure product, melting point 86-88 ° C., TLC [silica, 1: 1 CH ₃ OH: CH ₂ Cl ₂ , R _f = 0.37] was the same. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 285, EI, 70 eV) were consistent with the structure. Yield was 1.932 g (6.78 mmol, 79.66%).

Elemental analysis

Calculation Analysis C 67.35 66.99 H 6.71 6.77 N 14.73 14.53 O 11.21

Example 11

3- (1-homopiperazinyl) -8-methoxy-4,5-dihydronaphth [1,2-c] isoxazole

3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole (2.66 g, 11.32 mmol) in 10.0 mL N-methylpyrrolidinone, homopiperazine (11.40 g) , 113.2 moles) and K ₂ CO ₃ (3.13 g, 22.68 mmol) were placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 20 minutes. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath, cooled to room temperature and diluted with H ₂ O to precipitate a solid. The crude solid was dried, recrystallized from Et ₂ O and dried under vacuum at 85 ° C. (0.1 mmHg) to give the pure product, melting point 106-109 ° C., TLC [silica, 1: 1 CH ₃ OH: CH ₂ Cl ₂ , R _f = 0.18] are identical. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 299, EI, 70 eV) were consistent with the structure. Yield was 1.7948 g (6.00 mmol, 53.03%).

Elemental analysis

Calculation Analysis C 68.21 68.24 H 7.07 7.11 N 14.04 14.00 O 10.69

Example 12

3- (1- (4- (p-chlorophenyl) -4-hydroxy-piperidinyl) -8-methoxy-4,5-dihydronaphth [1,2-c] isoxazole

3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole (2.0 g, 8.51 mmol), 4- (p-chloro in 6 mL of N-methylpyrrolidinone A stirred mixture of phenyl) -4-hydroxy-dipiperidine (3.6 g, 17.02 mol) and K ₂ CO ₃ (2.35 g, 17.02 mmol) was placed in a preheated oil bath at 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 1 h. At this time, TLC [CH ₂ Cl ₂ ] showed no starting material remaining. The mixture was removed from the heated bath and cooled to room temperature. The reaction mixture was diluted with H ₂ O and the precipitated solid was recrystallized from EtOAc and dried under 85 ° C. vacuum (0.1 mmHg) to give the pure product, melting point 174-177 ° C., TLC [silica, 2: 1 heptanes: EtOAc, R _f = 0.263]. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 410, EI, 70 eV) were consistent with the structure. Yield was 2.3798 g (5.60 mmol, 68.20%).

Elemental analysis

Calculation Analysis C 67.23 67.24 H 5.64 5.75 Cl 8.63 N 6.82 8.78 O 11.68

Example 13

3-[(endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] -8-methoxy-4,5-dihydronaft [1,2-c] Sasol

N-BuLi (15.0 mL, 2.5.31 mmol) of 2.5M solution in hexane was slowly added to a stirred mixture of tropine (5.41 g, 38.31 mmol) in THF (10 mL) under 0 ° C. N ₂ . The mixture was stirred for 15 minutes while warming to room temperature, followed by 3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole (3.0 in 30 mL N-methylpyrrolidinone). g, 12.76 mmol) was added in one portion. The internal temperature was increased to and maintained at 99-100 ° C. After 3 hours, TLC [CH ₂ Cl ₂ ] showed no starting material remained. The mixture was removed from the heated bath and cooled to room temperature. Then decomposed in heptane / H ₂ O. The heptane phase was washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo to solidify. This crude solid was recrystallized from a minimum of heptane and dried under vacuum to give the product as a solid, melting point 102-104 ° C., TLC [silica, 1: 1CH ₃ OH: CH ₂ Cl ₂ , R _f = 0.20] equal It was. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 341, CI, methane) were consistent with the structure. Yield was 1.3729 g (4.038 mmol, 31.64%).

Elemental analysis

Calculation Analysis C 70.57 70.47 H 7.11 7.25 N 8.23 8.14 O 14.10

Example 14

3-[(endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] -4,5-dihydronaphth [1,2-c] isoxazole hydrochloride hemihydrate

N-BuLi (12.47 mL, 31.16 mmol) of a 2.5M solution in hexane was slowly added to a stirred mixture of tropin (4.4 g, 31.16 mmol) in THF (10 mL) under 0 ° C. N ₂ . The mixture was stirred for 15 minutes while warming to room temperature, followed by 3-chloro-4,5-dihydronaphth [1,2-c] isoxazole (2.13 g, 10.39 mmol) in 30 mL N-methylpyrrolidinone. Solution was added at once. The stirred mixture was placed in an oil bath preheated to 150 ° C. The internal temperature was increased to 85 ° C. and maintained. After 3 hours, TLC [CH ₂ Cl ₂ ] showed no starting material remained. The mixture was removed from the heated bath and cooled to room temperature. Then decomposed in heptane / H ₂ O. The heptane phase was washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo to give the free base as an oil, which did not crystallize. This oil was dissolved in Et ₂ O, and the HCl salt precipitated by the addition of ethanol HCl. This crude solid was recrystallized from Et ₂ O / CH ₂ Cl ₂ and dried under vacuum at 85 ° C. to yield the product as a solid, melting point 167-170 ° C. (darkened at about 150 ° C.) TLC [silica, 1: 1 CH ₃ OH: CH ₂ Cl ₂ , R _f = 0.14] is identical. _{IR (CHCl 3), NMR (} CDCl 3), and mass spectrum ^{(M + + 1 = 311,} CI, methane) were consistent with the structure. Analysis and NMR confirmed the hemihydrate structure. Yield was 1.268 g (3.563 mmol, 34.29%).

Elemental analysis

Calculation Analysis C 64.12 64.25 H 6.80 6.77 Cl N 7.87 7.70 O 9.23

Example 15

3- (1- (4- (6-fluorobenzisoxazol-3-yl) -piperidinyl) -8-methoxy-4,5-dihydronaphth [1,2-c] isoxazole

3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole (2.0 g, 8.51 mmol), 4- (6-fluoro in 10 mL of N-methylpyrrolidinone A stirred mixture of Robenzisoxazol-3-yl) -piperidine (2.8 g, 12.76 mmol) and K ₂ CO ₃ (2.35 g, 17.02 mmol) was placed in an oil bath preheated to 150 ° C. under N ₂ . . The mixture was heated while stirring under N ₂ for 90 minutes. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath and cooled to room temperature. A solid precipitated when the reaction mixture was diluted with H ₂ O, which was recovered, dried, dissolved in CH ₂ Cl ₂ and filtered through neutral alumina. Fractions containing the desired product were combined, concentrated and the resulting solid was treated with Et ₂ O to give a solid, melting point 181-183 ° C., TLC (silica, 2: 1 heptane: EtOAc, R _f = 0.15] IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 419, EI, 70 eV) were consistent with the structure, yield was 1.1318 g (2.70 mmol, 31.70%).

Elemental analysis

Calculation Analysis C 68.72 68.47 H 5.29 5.28 F 4.53 N 10.02 9.97 O 11.44

Example 16

3- (1- (4- (2-oxo-1-benzimidazolinyl) piperidinyl))-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole

3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole (2.57 g, 10.9 mmol), 4- (2-oxo in 12 ml of N-methylpyrrolidinone A stirred mixture of -1-benzimidazolinyl) piperidine (4.74 g, 21.8 mmol) and K ₂ CO ₃ (3.02 g, 21.8 mmol) was placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated with stirring under N ₂ for 4 h. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath and cooled to room temperature. The reaction mixture was a solid that precipitated when diluted with H ₂ O, collected it, dried, dissolved in CH ₂ Cl ₂ and, CH ₂ Cl ₂ and 1: 1 CH ₂ Cl _2: using Et ₂ O Neutral Filter through alumina. Fractions containing the desired product were combined, concentrated and the resulting solid was treated with EtOAc and dried under vacuum (0.1 mmHg, 85 ° C.) to give a solid, melting point 211-214 ° C., TLC [silica, EtOAc, R _f = 0.38] was the same. IR (CHCl ₃ ), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 416, EI, 70 eV) were consistent with the structure. Yield was 1.602 g (3.85 mmol, 33.33%).

Elemental analysis

Calculation Analysis C 69.21 68.88 H 5.81 5.90 N 13.45 13.10 O 11.52

Example 17

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

To the stirred mixture of 3-quinuclidinol (4.87 g, 38.28 mmol) in THF (10 mL) under 0 ° C. N ₂ was slowly added n-BuLi (15.32 g, 38.28 mmol) of 2.5M solution in hexanes. The mixture was stirred for 10 minutes while warming to room temperature, followed by 3-chloro-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole (3.0 in 30 mL N-methylpyrrolidinone). g, 12.76 mmol) was added in one portion. The stirred mixture was placed in an oil bath preheated to 150 ° C. The internal temperature was increased to 85 ° C. and maintained. After 3 hours, TLC [CH ₂ Cl ₂ ] showed no starting material remained. The mixture was removed from the heated bath and cooled to room temperature. Then decomposed in heptane / H ₂ O. The heptanes phase was dried over MgSO ₄ , filtered and concentrated in vacuo to give the free base as an oil. This oil was dissolved in Et ₂ O, and the HCl salt precipitated by the addition of ethanol HCl. The solid was recovered and dried in vacuo (0.1 mmHg, 85 ° C.) to give the product as a solid, melting point 133-136 ° C., TLC [silica, 1: 1 CH ₃ OH: CH ₂ Cl ₂ , R _f = 0.23 ] Was the same. IR (KBr), NMR (DMSO -d 6), and mass spectrum ^{(M + + 1 = 326,} EI, 70 eV) were consistent with the structure. Yield was 0.965 g (2.39 mmol, 18.79%).

Elemental analysis

Calculation Analysis C 62.89 62.91 H 6.39 6.28 Cl 9.77 N 7.72 7.51 O 13.23

Example 18

5,6-dihydro-4H-benzo [6,7] cyclohept [1,2-c] isoxazol-3-ol

Slowly add n-BuLi (50.3 mL 2.5M solution in hexane, 125.62 mmol) to a mechanically stirred mixture of 1-benzosuberon oxime (10.0 g, 57.1 mmol) in dry THF (200 mL) at 0 ° C. N ₂ . It was. The mixture was stirred at 0 ° C. for 30 minutes, and then CO ₂ gas was bubbled into the solution. After 15 minutes, CO ₂ addition was stopped and the N ₂ flow rate was returned. The thick mixture was stirred and slowly warmed to room temperature for 1½ hours, followed by the slow addition of 6N H ₂ SO ₄ (220 mL) to dissolve the solids. After stirring for 18 hours, TLC [EtOAc] showed the presence of a mixture of starting oxime and product (starting oxime was best seen when using a 2: 1 heptane: EtOAc eluent). The mixture was poured into a separating funnel and the organic phase was withdrawn. The aqueous phase was extracted with EtOAc, the organic phase and EtOAc extracts combined, washed with H ₂ O, dried over MgSO ₄ and filtered. Concentration in vacuo precipitated the solid, recovered and dried in vacuo to yield the product as a solid, with melting point 165-168 ° C., TLC [silica, Et ₂ O, R _f = 0.28] equal. IR (KBr), NMR (DMSO-d ₆ ), and mass spectrum (M ⁺ = 201, EI, 70 eV) were consistent with the structure. Yield was 3.0324 g (15.09 mmol, 26.42%).

Elemental analysis

Calculation Analysis C 71.63 71.45 H 5.51 5.50 N 6.96 6.91 O 15.90

Example 19

3- (1- (4- (2-oxo-1-benzimidazolinyl) piperidinyl))-4,5-dihydronaphth [1,2-c] isoxazole hemihydrate

3-chloro-4,5-dihydronaphth [1,2-c] isoxazole (3.1 g, 15.12 mmol) in 18 ml of N-methylpyrrolidinone, 4- (2-oxo-1-benzimimi A stirred mixture of dazolinyl) piperidine (8.2 g, 37.8 mmol) and K ₂ CO ₃ (4.2 g, 30.24 mmol) was placed in an oil bath preheated to 150 ° C. under N ₂ . The mixture was heated while stirring under N ₂ for 90 minutes. At this time, TLC (CH ₂ Cl ₂ ) showed no starting material remaining. The mixture was removed from the heated bath and cooled to room temperature. It was a solid that precipitated when the reaction mixture was diluted with H ₂ O, collected it, dried, dissolved in CH ₂ Cl ₂ and, CH ₂ Cl ₂ and 1: 1 CH ₂ Cl _2: using Et ₂ O Neutral Filter through alumina. Fractions containing the desired product were combined, concentrated and the resulting solid was recrystallized from EtOAc and dried under vacuum (0.1 mmHg, 110 ° C.) to give a solid, melting point 229-233 ° C., TLC [silica, EtOAc, R _f = 0.54]. IR (KBr), NMR (CDCl ₃ ), and mass spectra (M ⁺ = 386, EI, 70 eV) were consistent with the structure. Analysis and NMR confirmed the hemihydrate structure. Yield was 1.103 g (2.79 mmol, 18.45%).

Elemental analysis

Calculation Analysis 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 acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid, as well as salts of organic acids such as tartaric acid, citric acid, acetic acid, succinic acid, maleic acid, fumaric acid and oxalic acid.

The active compounds of the present invention can be administered orally, for example in combination with an inert diluent or an edible carrier. The active compound may be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compound may be mixed with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, homemade, chewing gums and the like. Such formulations should contain at least 0.5% of the active compound, but can vary depending on the particular form and typically can be from about 4 to about 75 weight percent of the unit. The amount of compound present in such a composition is the amount from which a suitable dosage of the active compound is obtained. Preferred compositions and preparations according to the invention are prepared in oral dosage units containing from about 1.0 to about 300 mg of the active compound.

Tablets, pills, capsules, troches, and the like may also contain the following ingredients: binders such as microcrystalline cellulose, tragacanth rubber or gelatin; Excipients such as starch or lactose; Disintegrants such as alginic acid, Primogel ^™ and corn starch; Lubricants such as magnesium stearate or sterotex ^R ; Lubricants such as colloidal silicon dioxide; And sweetening agents such as sucrose or saccharin or flavoring agents such as peppermint, methyl salicylate or orange flavor. When the dosage unit form is a capsule, it may contain a liquid carrier such as an aliphatic oil in addition to the substance of the above form. Other dosage unit forms may contain various materials (eg, coatings) that modify the physical form of the dosage unit. Thus, tablets or pills can be coated with sugars, shellac or other enteric coatings. Syrups may include sucrose, certain preservatives, dyes, colorants and flavoring agents as sweeteners in addition to the active compound. The materials used to prepare these various compositions must be pharmaceutically pure and nontoxic in the amounts used.

For parenteral therapeutic administration, the active compounds of the invention can be incorporated into solutions or suspensions. Such formulations should comprise at least 0.1% by weight of the aforementioned compounds, but may vary from about 0.5 to about 30% by weight of the formulation. The amount of compound in such a composition is that amount in which a suitable dosage of the active compound is obtained. Preferred compositions and formulations according to the invention are prepared such that the parenteral dosage unit contains from about 0.5 to about 100 mg of the active compound.

Solutions or suspensions may also include the following components; Sterile diluents such as water for injection, saline solution, nonvolatile oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; Antibacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid or sodium hydrogen sulfite; Chelating agents such as EDTA; Buffers such as acetates, citrates or phosphates and osmotic modulators such as sodium chloride or dextrose. Parenteral formulations may be sealed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

The compounds of the present invention are useful as 5-HT ₃ antagonists in coronary chemical reflexes for the treatment of anxiety, psychiatric disorders, nausea and vomiting due to their ability to bind to the rat inner cortex.

³ H-GR 65630 Binding to Rat Inner Cortex

A study was conducted to determine the affinity of the compounds of the invention for 5HT ₃ binding sites in the brain. This study and analysis is useful for predicting the potential of compounds with anti-atomic, antischizophrenic or abnormal antipsychotic profiles.

Originally, it was believed that the 5HT ₃ binding site was present only at the nerve endings. However, with the recent introduction of potent and selective 5HT ₃ antagonist agents such as GR65630, Zacopride, ICS 205 930 and MDL 72222 (Bemesetron, C ₁₅ H ₁₇ Cl ₂ NO ₂ ), binding study data has 5HT ₃ binding sites were also located in selective regions of the brain.The highest levels of 5HT ₃ binding sites were detected in the limbic system and dopamine containing brain regions (medial cortex, cerebellar tonsil, septal left nucleus, and nodule posterior). . Patrick (Kilpatrick, GJ) et al Identification and distribution of 5HT 3 receptors in rat brain using radioligand binding Nature 330:.. 746-748] 5HT 3 antagonist is other than having a selective binding in dopamine rich areas, the particular drug (nicotine And morphine) are reported to be active in behavioral tests that block behavioral transitions associated with abuse and predict anxiety relief activity. And, 5HT ₃ antagonists may have therapeutic benefit in activity, i.e., a disease state that is thought to be related to schizophrenia, anxiety and drug abuse due to excessive dopaminergic based on.

According to the assay discussed above, 0.05M Krebs-Hepes buffer, pH 7.4, was prepared as follows.

11.92 g Hepes

10.52 g NaCl

0.373 g KCl

0.277 g CaCl ₂

0.244 g MgCl ₂ .6H ₂ O

Sufficient to 1 liter of distilled water,

PH 7.4 (4 ° C.) with 5N NaOH.

[ ³ H] -GR65630 (87.0 Ci / mmol) was purchased from New England Nuclear. IC ₅₀ Measurement: [ ³ H] -GR65630 was prepared at 1.0 nM concentration in Krebs-Hepes buffer to a final concentration of 0.4 nM in 250 μl analyte when 100 μl was added to each tube.

GR38032F was purchased from Research Biochemical Inc. GR38032F was prepared at a concentration of 500 μM in Krebs-Hepes buffer. 50 μl of Krebs-Hepes buffer was added to each of the three tubes for measurement of nonspecific binding (final concentration of 100 μM was obtained in 250 μl analyte).

For most assays, 50 μl stocks were prepared with a suitable solvent and 50 μl of drug was serially diluted with Krebs-Hepes buffer to a final concentration of 10 ⁻⁵ to 10 ⁻⁸ M when combined with a total of 250 μl analyte. . Characteristically, seven concentrations may be used for each analyte; However, larger or smaller concentrations may be used depending on the efficacy of the medicament.

During tissue preparation, male Wistar rats (15-200 g) were guillotined, the medial cortex was cut out and weighed, and homogenized with a 10-fold volume of ice cold 0.05M Krebs-Hepes buffer, pH 7.4. Homogenates were centrifuged at 4 ° C., 48,000 g for 15 minutes. The resulting pellet was re-homogenized with just prepared Krebs-Hepes buffer and recentrifuged at 48,000 g for 15 minutes. The final pellet was resuspended in the initial volume of ice cold Krebs-Hepes buffer. 100 μl of this was added to the analyte to give a final tissue concentration of 1.2 to 1.6 mg / ml. Specific binding was about 55-65% of total binding ligand.

In performing the assay, the following volumes were used:

100 μl of tissue suspension;

100 μl of [ ³ H] -GR65630; And

50 μl 500M GR38032F (binding vehicle) or appropriate drug concentration

Sample tubes were stored on ice for addition, then vortexed and incubated with continuous shaking at 37 ° C. for 30 minutes. At the end of the incubation period, the cultures were diluted with 5 ml of ice cold Krebs-Hepes buffer, immediately vacuum filtered through Whatman GF / B filters, and washed twice with 5 ml of ice cold Krebs-Hepes buffer. The filtrate was dried and counted in 10 ml liquid scintillation cocktail. Specific GR65630 binding is defined as the difference between total binding and binding in the presence of 100 μM GR38032F. IC ₅₀ values were derived from computer-derived log-probit analysis.

The above-described assays for the various compounds of the present invention were performed and the affinity for the 5HT ₃ receptor is shown in Table I below.

Affinity to the 5HT ₃ Receptor-Substitution of ³ H-GR 65630 compound IC ₅₀ , μM Example 3 0.868 Example 4 0.083 Example 5 0.056 Ondansetron (standard) 0.089 ICS 205 930 (standard) 0.039

Measurement of the 5HT ₃ Antagonist Effect in the Bezold-Jarisch Assay

This assay evaluates the effect of the compounds of the invention as 5HT ₃ antagonists. This assay is initiated by 5HT ₃ in vivo and inhibits sympathetic nervous system stimulation and increased activity of the cardiac vagus nerve and is characterized by coronary chemical reflection (Bezold-Sri), which causes severe bradycardia and hypotension. The compounds of the invention were tested. Values obtained by continuously monitoring arterial blood pressure and heart rate response by these compounds over a long period of time determined their effect on 5HT ₃ antagonism.

Catheter was made from Tygon tubing (45 cm long, 0.05 mm, ID) connected to Teflon tubing (0.38 mm, ID). Teflon tubing (5 mm) was inserted into the expanded (ethylene dichloride, 3-4 minutes) end of the tigon tubing and mechanically bound. The connection was then sealed with a vinyl adhesive, the catheter was immersed in a cold sterilization solution (Amerse instrument sterilizer) and flushed thoroughly with saline before injection.

Long Evans rats were anesthetized with sodium pentobarbital (50 mg / kg, ip). A catheter filled with heparinized saline (100 U / ml) was inserted into the left femoral artery and vein and passed through the abdominal aorta and the lower vena cava respectively. The catheter was then sewn under the muscle and the unfixed end was subcutaneously pulled out through the incision at the top of the skull. The catheter was then sutured to the skin with sutures, nitropurazone powder was sprinkled onto the incision area, and the incision site was closed using a 3-O silk suture. The catheter was flushed with saline and sealed with a metal closure device. The opening of the two catheters was maintained by flushing with heparinized saline (0.2 ml of 100 U / ml) daily. Rats gave a 48 hour recovery period before obtaining cardiovascular data.

In the anesthetized rat model, the catheter was not pulled out and the data was accurately collected under general anesthesia.

Baseline data Arterial blood pressure (mm Hg, systolic / dilator) and heart rate (beats / minute) were recorded and rats were injected with 5-HT (3-7.5 μg / kg, intravenous). Each response to 5-HT intervention was measured and then the compound was administered at one time or with increasing dose range. Rats were then tested again with 5-HT at regular intervals after dosing and the peak response was recorded.

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

Inhibitory effect of 5-HT ₃ antagonist on intravenous 5-HT ₃ induced reflex bradycardia in anesthetized Long-Evans rats compound Dosage, mg / kg, intraperitoneal Bezold-Zarisch reflection inhibition% (mean ± SEM, 2-3 rats / dose) Ondansetron 3.0 57.3 ± 9.7 Ondansetron 10.0 94.6 ± 2.7 Example 4 0.03 58.6 ± 16.4 Example 4 0.05 83.3 ± 8.2 Example 4 0.10 93.0 ± 1.0 Example 5 1.0 55.6 ± 9.7 Example 5 3.0 89.3 ± 2.9

According to Table II, the maximum decrease in cardiac velocity induced by 5HT ₃ (eg, Bezold-Zarisch reflex) occurred 15 to 60 minutes after administration.

Claims (26)

Compounds of formula (I) or pharmaceutically acceptable salts thereof. <Formula I> Wherein A is hydroxy, chloro, , , or Wherein R ₁ is hydrogen; an alkyl group of 1 to 6 carbon atoms optionally substituted with hydroxy, C ₁ -C ₆ alkoxy or amino; phenyl, benzi optionally substituted with halogen, hydroxy or C ₁ -C ₆ alkoxy Soxazole or 2-oxo-1-benzimidazolinyl; benzyl optionally substituted with halogen, hydroxy or C ₁ -C ₆ alkoxy; Z is N or C (OH); m is an integer from 1 to 3 )ego; n is an integer of 1 or 2; X is hydrogen, hydroxy or C ₁ -C ₆ alkoxy. The compound of claim 1 wherein A is Phosphorus compounds. The compound of claim 1 wherein A is Phosphorus compounds. The compound of claim 1 wherein A is Phosphorus compounds. The compound of claim 1 wherein A is Phosphorus compounds. The compound according to claim 1, which is 3-chloro-4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 1, which is 3-hydroxy-8-methoxy-4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 1, which is 3-chloro-8-methoxy-4,5-dihydronaphth [1,2-c] isoxazole or a salt thereof. The compound according to claim 1, which is 5,6-dihydro-4H-benzo [6,7] cyclohept [1,2-c] isoxazol-3-ol or a salt thereof. The compound according to claim 2, which is 3- (4-methyl-1-piperazinyl) -4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 2, which is 3- (4- (2-hydroxyethyl) -1-piperazinyl) -4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 2, which is 3- (1-homopiperazinyl) -4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 2, which is 3- (1-piperazinyl) -4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 2, which is 3- (4-benzyl-1-piperazinyl) 4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 2, which is 3- (1-piperazinyl) -8-methoxy-4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound according to claim 2, which is 3- (1-homopiperazinyl) -8-methoxy-4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. The compound of claim 2, wherein the 3- (1- (4- (p-chlorophenyl) -4-hydroxy-piperidinyl) -8-methoxy-4,5-dihydronaft [1,2-c ] Isoxazole or a salt thereof. The compound of claim 2, wherein 3- (1- (4- (6-fluorobenzisoxazol-3-yl) -piperidinyl) -8-methoxy-4,5-dihydronaphth [1,2 -c] isoxazole or a salt thereof. 3. A compound according to claim 2, wherein 3- (1- (4- (2-oxo-1-benzimidazolinyl) piperidinyl))-8-methoxy-4,5-dihydronaphth [1,2 -c] isoxazole or a salt thereof. The compound according to claim 2, wherein 3- (1- (4- (2-oxo-1-benzimidazolinyl) piperidinyl))-4,5-dihydronaphth [1,2-c] isoxazole Hemihydrate or a salt thereof. The compound according to claim 3, which is 3-[(1-methyl-4-piperidinyl) oxy] -4,5-dihydronaft [1,2-c] isoxazole or a salt thereof. 5. The compound of claim 4, wherein 3-[(endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] -8-methoxy-4,5-dihydronaphth [1] , 2-c] isoxazole or a salt thereof. The compound of claim 4, wherein the 3-[(endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] -4,5-dihydronaphth [1,2-c] Isoxazole hydrochloride hemihydrate or a salt thereof. A compound according to claim 5, which is 3-[(quinuclidin-3-yl) oxy] -8-methoxy-4,5-dihydronaphth [1,2-c] isoxazole hydrochloride or a salt thereof. Chemical formula The compound of formula , , or A process for the preparation of a compound of formula (I) which comprises contacting a compound of formula (I). <Formula I> Where A is , , or Wherein R ₁ is hydrogen; an alkyl group of 1 to 6 carbon atoms optionally substituted with hydroxy, C ₁ -C ₆ alkoxy or amino; phenyl, benzi optionally substituted with halogen, hydroxy or C ₁ -C ₆ alkoxy Soxazole or 2-oxo-1-benzimidazolinyl; benzyl optionally substituted with halogen, hydroxy or C ₁ -C ₆ alkoxy; Z is N or C (OH); m is an integer from 1 to 3 )ego; n is an integer of 1 or 2; X is hydrogen, hydroxy or C ₁ -C ₆ alkoxy. A pharmaceutical composition for the treatment of a condition that is alleviated by the use of a 5-HT ₃ antagonist, including an psychiatric disorder, nausea, vomiting, drug abuse, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.