CZ346999A3 - 7-[(piperidin-1-yl)-propoxy]chromen-4-one derivatives - Google Patents

Abstract

7- [3- [4- (6-Fluoro-benzo [d] isoxazol-3-yl) -piperidin-1-yl] -propoxyl] -chromen-4-one Derivatives of formula (I), wherein R is hydrogen, CHO, CH 2 OR 2 or COOH; R 1 is hydrogen or CH 2OH; and R 2 is C 1 -C 4 alkyl provided that one of R a R a should be a hydrogen atom, and they are pharmaceutically acceptable salts. Also described are the methods and a pharmaceutical composition thereof. The compounds are useful in the treatment of psychosis, schizophrenia and allergy.

Description

Technical field

The present invention relates to 7- [3- [4- (6-fluoro-benzo [d] isoxazol-3-yl) -piperidin-1-yl] -propoxy] -chromen-4-one derivatives, and pharmaceutically acceptable salts thereof. The present invention also relates to a process for their preparation and a pharmaceutical composition containing them. The compounds are novel and useful in the treatment of psychosis, schizophrenia and allergy.

BACKGROUND OF THE INVENTION

Neuroleptic and anxiolytic chromene derivatives are described in Spanish patent applications no. 9500737 and 9600323.

SUMMARY OF THE INVENTION

Compounds of the present invention, 7- [3- [4- (6-Fluoro-benzo [d] isoxazol-3-yl) -piperidin-1-yl] -propoxy] -chromen-4-one derivatives of general formula (I):

(I) •

-2.

wherein R is hydrogen, CHO, CH ₂ OR ₂ or COOH; R 1 is hydrogen or CH ₂ OH; and R ₂ is C 1 -C 4 alkyl with the proviso that one of the substituents R and R 1 should be hydrogen, as well as their pharmaceutically acceptable addition salts, are new and are obtained by reaction of a 2 (or 3) -substituted 7-carbon atom; - (3-halopropoxy) -4H-1-benzopyran-4-one of the general formula (II), wherein R and R 1 are as defined for (I) and X represents a halogen selected preferably from chlorine or bromine, with 6-fluoro-3- (4-piperidinyl) -benzo [d] isoxazole (III), according to Scheme 1, in the presence of a base selected from an alkali metal or alkaline earth metal carbonate or bicarbonate and a catalytic amount of potassium iodide. The reaction suitably proceeds with heating and in a non-polar environment, for example composed of a solvent selected from Ν, Ν-dimethylformamide, acetonitrile and the like.

Scheme 1

Alternatively, compounds (I, R: CHO, Rf. H) and (I, R: CH ₂ OR ₂ , R 1: H) can also be obtained from 7- [3- [4- (6-fluorobenzo [d] isoxazole- 3yl) piperidin-1-yl] propoxy] -3 (hydroxymethyl) chromen-4-one (Spanish patent application No. 9600323) by oxidation or alkylation. The oxidation is conveniently carried out by treatment with oxalyl chloride and dimethylsulfoxide in a halogenated solvent, preferably dichloromethane. The alkylation is conveniently carried out with the corresponding alcohol R ₂ -OH (IV), wherein R ₂ is as defined for the compound of formula (I), under acidic conditions and at the boiling point of the mixture. From the novel compounds of formula (I), their salts can be obtained by addition of the appropriate acids by conventional methods known in organic chemistry.

The properties of the compounds of the present invention differ from those described in the above-mentioned Spanish patents. Applicants have found that compounds of formula (I) have an important action on histamine H-1 receptors in addition to potent action on D ₂ and 5-HT ₂ receptors, which is intrinsic to antipsychotic agents. In contrast, the H-antihistamine action has not been reported for any of the compounds of the foregoing patents.

Specific binding to D ₂ , 5-HT _2A and H- ₁ receptors was tested as follows:

Receptor P ₂ : A 2-nM solution of radioactive spiperone ([ ³ H] spiperone), which acts as a specific ligand, was incubated with a membrane corresponding to 20 mg of rat striatum for 20 min at 35 ° C in a pH 7.4 buffer buffer. HCl. Non-specific binding was then determined by adding micromolar concentration of unlabeled spiperone. The IC ₅₀ (inhibitory concentration for 50%) was calculated from the rate of specific binding inhibition obtained by adding eleven different concentrations of test compounds. After the incubation was complete, the sample was filtered through a glass fiber filter and then washed three times with tris.HCl buffer. Amount of radioactivity bound to · A · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The receptor remained on the membrane and was determined by liquid scintillation counting.

5-HT2A receptors. A 0.5 nM solution of radioactive ketanserin ([ ³ H] ketanserin), which behaves as a specific ligand, was incubated with a membrane corresponding to 1 mg rat cortex for 30 min at 35 ° C in a buffered pH of 7.4 tris.HCl. Non-specific binding was then determined by adding unlabeled mianserin at 5 µM concentration. IC ₅₀ (50% inhibitory concentration) was calculated from the degree of inhibition of specific binding obtained by the addition of eleven different concentrations of test compounds. After the incubation was complete, the sample was filtered through a glass fiber filter and then washed three times with tris.HCl buffer. The amount of receptor-bound radioactivity remaining on the membrane was determined by liquid scintillation counting.

Receptors Ηχ: Activity testing was performed by incubating guinea pig cerebella membranes in the presence or absence of test compounds in a 1 nM solution of [ ³ H] -pyrilamin as a specific marker at 25 ° C for 60 min. Bound radioactivity was separated by filtration (Whatman GF / B) in a Brael Harvester. The amount of receptor-bound radioactivity present in the filters was determined by a Packard 1800TR counter. Specific binding was detected using a 1 μ trip triprolidine concentration.

Biochemical results, expressed as IC 50 values in molar concentrations, are shown in comparison to the compound of Example 2 'in Spanish patent application no. No. 9600323 and standard haloperidol in Table 1 for the D ₂ and 5-HT _{2 a} receptors as compared to the compound of Example 2 'in Spanish patent application no. 9600323 and standard promethazine in Table 2 for H 1 receptors.

• · · · · · · · · · · · ·

Table 1

Compound d ₂ 5- _HT2A Example 1 1.31 x 10 ^-8 2.11 x 10 ⁹ Example 2 1.28 x 10 ^-8 5.94 x 10 ^-1 ° Ex. 2 '(ES 9600323) 1.72 x 10 ⁸ 3.08 x 10 ^-9 Haloperidol 1.37 x 10 ^-8 1.04 x 10 ^-7

From the data in Table 1, it can be concluded that the compounds of Examples 1 and 2 of the present invention have stronger effects as D ₂ and 5-HT _2A receptor ligands than the compound of Example 2 'of Spanish patent application no. 9600323. The D ₂ /5-HT _2A ratio shows that all compounds are superior to standard haloperidol, leading to a lower risk of extrapyramidal effects.

Table 2

Compound Hi Example 3 3.39 x 10 ¹⁰ Example 6 1.01 x 10 ' ⁹ Ex. 2 '(ES 9600323) 1.20 x 10 ' ⁹ Promethazine 8.93 x 10 ^-1 °

Similarly, it can be concluded from the data in Table 2 that the compounds of Examples 3 and 6 of the present invention are more potent H 1 receptor ligands than the compounds of Example 2 ' 9600323, the effects of which are of the order of magnitude equal to those of promethazine. In addition, the compound of Example 3 is more potent than standard promethazine.

The compounds of the present invention were compared to the compound of Example 2 'of Spanish patent application no. No. 9600323 in the Animal Pharmacological Tests section of the Apomorphine-Induced Climbing Inhibition Test (P. Protais et al., Psychopharmacology, 50, 1-6, 1976). Male Swiss mice weighing 22-24 g were used to practice this experiment. One week prior to the experiment, the animals were kept in the Applicant's facility at a temperature of 20-22 ° C and a light dark cycle for 12/12 hours, and had free access to food and water. Two hours before the experiment, the animals were housed in separate cages without access to food.

Animals were administered orally tested drug or 0.25% agar at time 0. After 60 min, apomorphine was injected subcutaneously at a dose of 1 mg / kg, and then the behavior of the animals was monitored for the next 70 min. Two additional observations were made at 10 min intervals.

For evaluation, each animal was placed on the bottom of a small upright box (11 x 7.5 x 4.5 cm). The box walls were made of transparent methacrylate except for one of the side walls (7.5 cm width), which was made of a 3 mm wire screen. The position of the animal was evaluated for 2 min according to the following criteria: 0 = four feet on the floor; 1 = three feet on the floor; 2 = two feet on the floor; 3 = one paw on the floor; and 4 - holding the wire mesh with all four paws. If the animal occupies several positions during the two-minute observation period, the time in seconds at each position shall be recorded. Finally, an average score was calculated. The cataleptic effect of the compounds administered by the oral route was simultaneously tested in rats and expressed as an effective dose to achieve a 50% effect (ED ₅₀ ). The results obtained are shown in Table 3 as the inhibitory dose for 50% inhibition (ID ₅₀ o, mg / kg) in the climbing behavior test and as a value of 7%.

ED ₅₀ o (mg / kg) in the catalepsy test. Table 3 also shows the therapeutic index (TI), which is a measure of safety for use of test compounds.

Table 3

Compound ID ₅ o, climbing ED50, catalepsy ti = ed ₅₀ / id ₅₀ Example 3 0.21 6.79 32.3 Example 6 5.87 > 100 (*) > 17 Ex. 2 'EC 9600323 0.25 3.8 15.2 Haloperidol 0.32 2.00 6.25

(*) not established

According to the data in Table 3, the compounds of Examples 3 and 6 of the present invention have a higher therapeutic index than the compound of Example 2 of Spanish patent application no. 9600323 and than haloperidol, confirming the benefit of a lower risk of extrapyramidal effects at therapeutic doses.

The compounds of the present invention may be used as antipsychotic agents for the treatment of psychosis and schizophrenia by the oral, injectable or rectal route at daily doses ranging from 1 to 500 mg, preferably between 2 and 50 mg inclusive. Typical forms for oral administration of antipsychotic compositions are solutions, tablets, film-coated tablets, capsules, granules, syrups, and the like. preferably between 2 and 150 mg inclusive. For oral administration of these compounds in the treatment of allergy, dosage forms of solutions, tablets, film-coated tablets, capsules, can be used.

granules, syrups and the like. As antiallergic agents, the compounds may also be administered in the form of topical agents such as creams, ointments, lotions, powders and the like in concentrations ranging from 0.5 to 5%, preferably 1 and 2% inclusive. .

DETAILED DESCRIPTION OF THE INVENTION

Example 1:

7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] propoxy] -3-formylchromen-4-one

To a solution of 2 mL (23 mmol) of oxalyl chloride in 35 mL of dry dichloromethane cooled to -70 ° C was added dropwise a solution of 3 mL (42 mmol) of dimethyl sulfoxide dissolved in 10 mL of dichloromethane and stirred for 5 min. Then 5 g (11 mmol) of 7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] propoxy] -3- (hydroxymethyl) -chromen-4-one (ES patent 9600323) was added. in several portions over 15 min and the mixture was stirred for an additional 30 min at -70 ° C. 15 ml (107 mol) of triethylamine was added dropwise and the mixture was stirred overnight while gradually warming to room temperature. While cooling to -20 ° C, 50 mL of water was added, the mixture was allowed to warm to room temperature and the organic phase was decanted, dried over sodium sulfate and evaporated. The solid obtained was purified by silica gel column chromatography. Elution of the column with CHCl ₃ : CH ₃ OH (98: 2, v / v) gave 2.12 g of 7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] -propoxy] - 163 DEG-165 DEG C. 3-formylchromen-4-one in 43% yield.

IR (KBr): 1691, 1652, 1619, 1441 cm &^lt; -1 & gt ^; .

NMR (CDCl 3): 2.10 (m, 6H), 2.20 (m, 2H), 2.60 (t, 2H), 3.10 (m, 3H), 4.19 (t, 2H), 6.96 (d, 1 H), 7.05 (m, 2 H), 7.24 (dd, 1 H), 7.69 (dd, 1 H), 8.19 (d, 1 H), 8.47 (s) 1 H, 10.37 (s, 1 H).

i 9 · - ¹ »

Example 2:

7- [3- [4- (6-Fluoro-benzo [d] isoxazol-3-yl) -piperidin-1-yl] -propoxy-4-oxo-chromene-3-carboxylic acid hydrochloride

A mixture of 0.87 g (3 mmol) of 7- (3-chloropropoxy) -4-oxochromene-3-carboxylic acid, 0.7 g (3 mmol) of 6-fluoro-3- (4-piperidinyl) -benzo [d] isoxazole hydrochloride, 0 85 g (6 mmol) of anhydrous potassium carbonate and a catalytic amount of potassium iodide in 25 ml of N, N-dimethylformamide were heated at 89-90 ° C for 24 hours. the precipitate was filtered, washed with water and dried in vacuo. The solid was dissolved in 60 mL 0.1 M NaOH, diluted to 300 mL with water, and the solution was washed with ethyl acetate. The aqueous solution was acidified with HCl to pH 1-2 and the resulting precipitate was filtered and dried in vacuo to give 0.62 g of 7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidine-] hydrochloride. 1-yl] propoxy] -4-oxochromene-3-carboxylic acid in 40% yield.

IR (KBr): 3100-3700, 1698, 1616, 1447, 1384, 1165, 1121 cm ^-1 .

NMR (DMSO): 2.13 (m, 6H), 2.30 (m, 2H, piperidine -2H _a and 6H _a ),

2.67 (t, J = 7.5 Hz, 2H, O-CH ₇ CH _{7 CH?} N). 3.16 (d + m, 3H, piperidine 2H _e, -6H _e and -4H), 4.10 (t, J = 6Hz, 2H, _O-CH2), 6.67 (s, 1H, 8- H), 6.79 (d, J = 8.7 Hz, 1H, 6-H), 7.10 (td, J = 8.4 and 2.1 Hz, 1H, benzisoxazole-5H),

7.27 (dd, J = 8.4 and 2.1 Hz, 1H, benzisoxazole-7H), 7.79 (dd, J = 8.4 and 5.4 Hz, 1H, benzisoxazole-4H), 7, 97 (d, J = 8.7Hz, 1H, -5H), 9.86 (s, 1H, 2H).

Example 3

- 10 - * • ·· ♦ v ··

7- [3- [4- (6-Fluoro-benzo [d] isoxazol-3-yl) -piperidin-1-yl-propoxyl] -3-methoxymethyl-chromen-4-one hydrochloride

A solution of 2 g (4.4 mmol) of 7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] propoxy] -3- (hydroxymethyl) chromen-4-one in 20 ml 2M HCl in methanol was heated at reflux for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with a saturated solution of CHCl3. The organic phase was evaporated, dissolved in acetonitrile and precipitated by addition of ethereal HCl. The obtained solid was recrystallized from methanol to give 0.75 g of 7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] propoxy] -3-methoxymethylchromen-4-one hydrochloride in 34% yield, mp 219-221 ° C.

IR (KBr): 1659, 1615, 1443, 1273, 1244 cm ^-1 .

NMR (CDCl 3 -CD 3 OD): 2.25 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H),

3.05 (m, 2H), 3.35 (m, 2H), 3.48 (s, 3H), 3.60 (m, 1H), 3.80 (d, 2H),

4.20 (m, 2H), 4.39 (s, 2H), 6.90 (d, 1H), 6.97 (d, 1H), 7.16 (td, 1H),

7.66 (dd, 1 H), 7.95 (s, 1 H), 8.10 (d, 1 H), 8.20 (dd, 1 H).

Example 4

7-Hydroxy-2- (hydroxymethyl) -chromen-4-one

To a suspension of 5 g (21 mmol) of ethyl 7-hydroxy-4-oxo-chromene-2-carboxylate and 5 g (45 mmol) of anhydrous calcium chloride in 100 ml of absolute ethanol cooled to 0 ° C were added 3 g of sodium borohydride in several 1 g of sodium borohydride was added and the mixture was stirred for an additional 2 hours. The reaction mixture was suspended in 200 ml of water and slowly acidified with HCl. The precipitate was filtered, washed with water, and dried in vacuo to give 2.7 g of 7-hydroxy-2- (hydroxymethyl) 4 4 Chromen-4-one as a solid, yield 66%, m.p. 250-252 ° C. ≪ tb > ______________________________________ < tb > ______________________________________ < tb >

IR (KBr): 2700 - 3500, 1650, 1634, 1570, 1458, 1326, 1250, 1101 cm ^-1 .

NMR (d 6 -DMSO): 3.50 (s, broad, 2H, OH), 4.40 (s, 2H, CH ₂ OH), δ 6.20 (s, 1H, 3-H), 6.82 (d, J = 2.4 Hz, 1H, 8-H), 6.92 (dd, J = 8.7 and 2.4

Hz, 1H, 6-H), 7.86 (d, J = 8.7, 1H, 5-H).

Example 5

7- (3-chloropropoxy) -2- (hydroxymethyl) -chromen-4-one

A mixture of 6 g (31 mmol) of the compound obtained in Example 4, 6 ml (61 mmol) of 1-bromo-3-chloropropane, 4.3 g (31 mmol) of anhydrous potassium carbonate in 100 ml of acetone and 25 ml of N, N-dimethylformamide was heated. The reaction mixture was poured into 100 mL of water and extracted with 100 mL of ethyl acetate. The organic extracts were washed with two 100 ml portions of water, dried over sodium sulfate and evaporated in vacuo. The obtained residue was suspended in 25 ml of ethyl ether, filtered and dried in vacuo to give 4.2 g of 7- (3-chloropropoxy) -2- (hydroxymethyl) -chromen-4-one in 50% yield, m.p. 110-112 ° C.

IR (KBr): 2600 - 3500, 1651, 1628, 1592, 1448, 1246, 1099 cm ^-1 .

NMR (CDCIs): 2.28 (m, 2H, O-CH? _-CH?), 3.76 (t, J = 6Hz, 2H, _CH2 Cl), 4.16 (t, J = 6Hz 2H, _O-CH2), 4.57 (s, 3H, _CH? OH + OH), 6.44 (s, 1H, 3H), 6.78 (d, J = 2.1 Hz, 1H, 8-H), 6.90 (dd, J = 8.7 and 2.1 Hz, 1H, 6-H), 7.99 (d, J = 8.7 Hz, 1H, 5-H) .

..12.,

Example 6

7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] propoxy] -2- (hydroxymethyl-chromen-4-one) hydrochloride

A mixture of 3 g (11 mmol) of the compound obtained in Example 5, 2.88 g (11 mmol) of 6-fluoro-3- (4-piperidinyl) benzo [d] isoxazole hydrochloride,

2.16 g (26 mmol) of sodium bicarbonate and a catalytic amount of potassium iodide in 80 ml of acetonitrile was heated under reflux for 48 hours. The mixture was then allowed to cool, poured into 100 ml of water and extracted with 100 ml of chloroform. The chloroform extract was washed with water, dried over sodium sulfate and evaporated. The obtained residue was suspended in ethyl ether, filtered and dried in vacuo to give 2 g of 7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] propoxy] -2- (hydroxymethyl) - chromen-4-one in 40% yield.

NMR (CDCl _3): 2.0-2.2 (m, 8H), 2.60 (t, J = 7.2 Hz, 2H, _{N-CH-CH2-CH2-O),} 3.10 (d + m, 3H, piperidine -2H _e , -4H and -6H _e ), 4.13 (t, J = 6.6 Hz, 2H, O-CH 2 -CH 2 -CH 2), 4.58 (s, 3H, CH 2 OH), 6.41 (s, 1H, 3-H), 6.89 (d, J = 2.1 Hz, 1H, 8-H), 6.94 (dd, J = 8.7 and 2.1 Hz, 1H, 6-H), 7.07 (td, J = 8.7 and 2.4 Hz, 1H, benzisoxazole-5H), 7.25 (dd, J = 8.7 and 2, 4 Hz, 1H, benzisoxazole-7H), 7.71 (dd, J = 8.7 and 5.1 Hz, 1H, benzisoxazole-4H), 8.04 (d, J = 8.7 Hz, 1H, 5 -H).

Hydrochloride: The obtained product was dissolved in chloroform / methanol (3: 1) and precipitated by addition of a solution of HCl in methanol to give 1.4 g of 7- [3- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1] hydrochloride. m.p. 248-251 ° C.

IR (KBr) 3300, 2500, 1648, 1603, 1439, 1329, 1122, 1094 cm ^-1 .

Example 7: 0.025% injectable formulation

Composition for 1 ampoule

the compound of Example 3 0.5 mg methyl p-hydroxybenzoate 1.0 mg propyl p-hydroxybenzoate 0.1 mg bidestilled water to 2.0 ml

Example 8: formulation of 0.1% oral solution

Composition for 100 ml

the compound of Example 3 100 mg methyl p-hydroxybenzoate 135 mg propyl p-hydroxybenzoate 15 mg sorbitol 70% 20 mg saccharin sodium 50 mg orange essence 0.25 ml distilled water to 100 ml

Example 9: 1 mg tablet formulation

Composition of t tablets

the compound of Example 3 1.0 mg cornstarch 32.4 mg talc 4.5 mg hydrogenated castor oil 1.5 mg lactose into 150,0 m

Example 10: 5 mg tablet formulation

4.14./

Composition 1 tablet

the compound of Example 3 5.0 mg cornstarch 43.2 mg talc 6.0 mg hydrogenated castor oil 2.0 mg lactose into 200.0 mg

Example 11: 10 mg tablet formulation

Composition 1 tablet

the compound of Example 3 10.0 mg cornstarch 40.0 mg sodium lauryl sulfate 0.50 mg pregelatinized maize starch 8,00 mg magnesium stearate 1,20 mg lactose into 240,00 y

Example 12: Formulation of 1% topical cream

Composition for 100 g Example 3 compound 1.00 g isopropyl myristate 9.00 g cetostearyl alcohol 6.00 g propylene glycol 3.00 g polyglycol fatty acid ester 5.00 g oleic acid decyl ester

6,00 g

perfume 0,30 g methyl p-hydroxybenzoate 0.15 g propyl p-hydroxybenzoate 0,02 g ethyl p-hydroxybenzoate 0,03 g demineralized water to 100,00 g

Represented by:

Claims (7)

PATENT CLAIMS 1. 7- [3- [4- (6-Fluoro-benzo [d] isoxazol-3-yl) -piperidin-1-yl] -propoxy] -chromen-4-one derivatives of formula (I): o (I) wherein R is hydrogen, CHO, CH 2 OR 2 or COOH; R 1 is hydrogen or CH ₂ OH; and R 2 is C 1 -C 4 alkyl with the proviso that one of R and R 1 should be hydrogen, and pharmaceutically acceptable salts thereof. Compounds according to claim 1 of formula (I), wherein R is CHO, CH 2 OR 2 or COOH and R 1 is hydrogen, or R is hydrogen and R 1 is CH 2 OH. Compounds of formula (I) and pharmaceutically acceptable addition salts thereof for use in the treatment of psychosis, schizophrenia and allergy. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound according to claims 1 or 2 for the manufacture of a pharmaceutical composition for the treatment of psychosis, schizophrenia and allergy. A method of treating psychosis, schizophrenia and allergy, comprising administering to the mammal an effective amount of a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable addition salt thereof. A process for the preparation of a compound of formula (I) according to claim 1 or 2, characterized in that it comprises the reaction of intermediates of formula (II): (II) wherein R and R 1 are as defined for compound (I) and X is a halogen atom selected preferably from a chlorine or bromine atom, with an intermediate of formula (III): NH (III) And, if desired, obtaining pharmaceutically acceptable salts by subsequent reaction with the corresponding acid.