CN114276340B - Chlorobenzoxazole derivative or pharmaceutically acceptable salt thereof and application thereof - Google Patents

Abstract

The invention belongs to the field of medicines, and relates to a chlorobenzoxazole derivative with better pharmacodynamic performance of an orexin receptor antagonist, in particular to a chlorobenzoxazole derivative or pharmaceutically acceptable salt thereof and application thereof. It has the structure as shown in formula I:

in the formula, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Each independently is hydrogen or deuterium and contains at least one deuterium; or R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Each independently hydrogen, fluorine, methyl or cyclopropyl. The invention provides the chloro-benzooxazole derivative with the structure shown in formula I, which has good orexin receptor antagonistic activity and excellent pharmacodynamic property, so thatAnd lower toxicity.

Description

Chlorobenzoxazole derivative or pharmaceutically acceptable salt thereof and application thereof

Technical Field

The invention belongs to the field of medicines, and relates to a chlorobenzoxazole derivative with better pharmacodynamic performance of an orexin receptor antagonist, in particular to a chlorobenzoxazole derivative or pharmaceutically acceptable salt thereof and application thereof.

Background

8/13/2014, suvorexant (Bellomra, [ (7) approved by the FDA in the United statesR) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Methanone, suvorexant) tablets are used to treat patients who fall asleep and have difficulty sleeping (insomnia). suvorexant is an orexin receptor antagonist and is the first approved drug in the class of drugs. Orexin is a chemical substance involved in the regulation of the wake-up cycle and plays an important role in maintaining the human arousal. suvorexant may alter the informative behavior of orexin in the brain.

Insomnia is a common condition, and people suffering from insomnia have difficulty falling asleep or sleeping. The degree of the disease can range from mild to severe, depending on the frequency and length of insomnia. Insomnia can cause daytime sleepiness, causing people to lack energy. It can also be anxiety, depression or irritability in humans. People with insomnia may have difficulties in attention, learning, and memory.

Orexin (hypocroteins) includes two neuropeptides produced in the hypothalamus: orexin A (OX-A), a 33 amino acid peptide, and orexin B (OX-B), a 28 amino acid peptide (Sakurai T. Et al, cell,1998, 92, 573-585). Orexin was found to stimulate food consumption in rats, suggesting a physiological role for these peptides as mediators in a central feedback mechanism regulating feeding behavior (Sakurai t. Et al, cell,1998, 92, 573-585). Orexin regulates sleep and wakefulness and opens a potential new treatment for narcolepsy or insomnia patients (Chemelli r.m. et al, cell, 1999, 98, 437-451). Orexin has also been shown to play a role in arousal, reward, learning and memory (Harris et al, trends neurosci, 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the superfamily of G protein-coupled receptors (Sakurai t. Et al, cell,1998, 92, 573-585): orexin-1 receptors (OX or OX 1R) are selective for OX-A, and orexin 2 receptors (OX 2 or OX 2R) are capable of binding OX-A and OX-B. It is presumed that the physiological role involved in orexin is expressed by one or both of OX1 receptor and OX2 receptor, which are two subtypes of orexin receptor.

"four different specifications of suvorexant, 5, 10, 15 and 20mg respectively, are approved by the FDA to help health care professionals and patients find the optimal dose to treat insomnia in an individual patient," drug evaluation and research center drug evaluation I office chief, medical doctor Unger. "use of the lowest effective dose reduces the risk of side effects, such as drowsiness the next day. "

In recent years, the number of patients suffering from insomnia is increasing, and there is a great demand for new drugs having better therapeutic effects and fewer side effects. The invention is provided to overcome the defects in the prior art and meet the increasing requirements of patients.

Disclosure of Invention

The invention provides a chlorobenzoxazole derivative or pharmaceutically acceptable salt thereof and application thereof, and the compound has good orexin receptor antagonistic activity, excellent pharmacodynamic performance and lower toxicity.

The technical scheme of the invention is realized as follows:

a chlorobenzoxazole derivative has a structure shown as formula I:

in the formula, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Each independently hydrogen or deuterium and containing at least one deuterium; or R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Each independently hydrogen, fluorine, methyl or cyclopropyl.

Preferably, theThe chlorobenzoxazole derivative of the formula II

Formula III

IV

A formula V

Formula VI

Formula VII

Or of the formula VIII

The structure shown in (a).

Further, the chlorobenzoxazole derivative is in a single crystal form or a polycrystalline form. Unless otherwise indicated, all pharmaceutically acceptable salts, hydrates, solvates, prodrugs, single crystals or polymorphs of the compounds of formula I provided herein are within the scope of the present invention.

The pharmaceutically acceptable salt of the chlorobenzoxazole derivative is a salt prepared from pharmaceutically acceptable non-toxic bases or acids.

Preferably, the pharmaceutically acceptable salt is a salt with: inorganic acids such as phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, and sulfuric acid, and one or more of acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and p-toluenesulfonic acid.

A pharmaceutical composition comprises one or more of the above chlorobenzoxazole derivative or the above pharmaceutically acceptable salts thereof.

The pharmaceutical composition is compounded with conventional auxiliary materials in the field to prepare a pharmaceutical preparation.

Preferably, the conventional adjuvant is one or more of excipient, diluent, thickener, adjuvant and antiseptic, and the conventional adjuvant has no obvious irritation to organism and no damage to bioactivity of the active compound.

Preferably, the pharmaceutical preparation is a tablet, a capsule, a pill, a suppository, a soft capsule, an oral liquid, a suspension or an injection, and the auxiliary materials added for preparing the pharmaceutical preparation are carriers, excipients, diluents, thickeners, auxiliary materials and preservatives which have no obvious stimulation effect on organisms and do not damage the biological activity and performance of the active compound.

The use of the above pharmaceutical formulation as orexin receptor antagonist.

The application of the pharmaceutical composition in preparing the medicines for treating and/or preventing the neurological and psychiatric disorders related to the orexin receptors.

The administration dose of the above pharmaceutical preparation varies depending on the physical conditions (e.g., body weight, age, type and severity of disease) of a patient, and may also vary depending on the administration route, and generally the content of the effective ingredient is about 0.01-30 mg/kg/day.

The above pharmaceutical preparations may optionally be administered orally, intravenously or intraarterially, intraadiposally or liposomally, by inhalation spray, parenterally or intraperitoneally, rectally, subcutaneously, intraadiposally or intraarticularly, nasally, via local delivery (e.g., catheters or stents), buccally, vaginally or via an implantable kit. Preferred modes of administration are oral, intraperitoneal or intravenous.

Preferably, the neurological and psychiatric disorders associated with orexin receptors are sleep disorders and sleep difficulties (insomnia), depression, anxiety, addiction, obsessive-compulsive disorders, affective neuropathies, depressive neuropathies, dysthymic disorders, behavioral disorders, mood disorders, sexual dysfunction, psychosexual dysfunction, sexual disorders, schizophrenia, manic depression, confusion, dementia, severe mental retardation and motor disorder symptoms such as huntington's disease and tourette's syndrome, eating disorders such as anorexia, bulimia, cachexia and obesity, addictive eating behaviors, binge eating behaviors, appetite \ gustatory disorders, parkinson's disease, cushing's syndrome, hypothalamic diseases, froehlich's syndrome, growth hormone deficient hypothalamic disorders, biological and circadian rhythm disorders, sleep disorders associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome, sleep disorders, pain, sleep disorders, narcolepsy, sleep disorders, insomnia, jet lag, or jet lag.

Scientific literature indicates that orexin receptors have a wide range of biological functions. This suggests that these receptors have potential roles in various disease processes in humans and other species. The prepared chlorobenzoxazole derivative or pharmaceutically acceptable salt thereof can be used as a suvorexant medicine for treating, preventing, improving, controlling or reducing the risk of nervous and mental disorders related to orexin receptors. Can also be used for: methods for preventing and treating sleep disorders and sleep disorders; treating insomnia; improving the sleep quality; enhancing sleep maintenance; increasing rapid eye movement sleep; increasing stage 2 sleep; reducing fragmentation of sleep patterns; treating insomnia; enhancing cognition; the memory is increased; treating or controlling obesity; treating or controlling depression. In treatment, an effective amount of a pharmaceutically acceptable salt of a compound of the present invention is administered to a mammalian patient in need thereof.

The invention has the following beneficial effects:

the chlorobenzoxazol derivative with the structure shown in formula I provided by the invention has good orexin receptor antagonistic activity, excellent pharmacodynamic performance and lower toxicity. Compared with Suvorexane, the compound prepared by the preparation method of the embodiment of the invention has the advantages thatThe following effects: the absolute bioavailability of the compound shown in the formula II is improved by 10 percent; AUC _0-t The improvement is 23%; the absolute bioavailability of the compound shown in the formula III is improved by 15 percent; AUC _0-t The improvement is 19 percent; compound formula IV AUC _0-t The improvement is 10%; AUC of Compound V _0-t Similarly. The compounds III-VIII prepared according to the preparation method of the examples of the present invention also resulted in a reduction in the waking hours, compared to Suvorexane, by 10-30%. The compounds of the examples have an improved orexin receptor inhibitory effect, reduced metabolism and increased sleep time in animals.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly described below.

FIG. 1 is a mass spectrum of the compound prepared in example 1.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.

Example 1

This example prepared [ (7) having the structure of formula II according to the procedure shown belowR) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-Trideuteromethyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Ketone:

step 1: preparation of intermediate 2- (4-Trideuteromethylphenyl) -2H-1,2, 3-triazole (Compound 2)

Under the protection of argon, 2- (4-bromophenyl) -2H-1,2, 3-triazole (10 mmol) is dissolved in tetrahydrofuran THF (100 ml), and after the reaction temperature is reduced to-78 ℃, tert-butyl lithium (11 mmol) is added; after 30 minutes of reaction, trideuteromethyl iodide (13 mmol) was added. Slowly heating to room temperature, adding water and dichloromethane for extraction, retaining organic phase, washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating with silica gel column to obtain compound 2, namely 2- (4-tridedeuterium methyl phenyl) -2H-1,2, 3-triazole, with yield of 81%.

MS(ESI)m/z 164.10([M+H] ⁺ )

Step 2: preparation of intermediate 2- (2H-1, 2, 3-Triazol-2-yl) -5- (Trideuteromethyl) benzoic acid (Compound 3)

To the intermediate 2- (4-Trideuteromethylphenyl) -2H-1,2, 3-triazole (compound 2) (2 mmol) in diethyl ether (10 mL) was added tBuLi (1.33 mL, 1.7M in pentane, 2.26 mmol) at-80 ℃. After 1 hour, CO ₂ Slowly bubble through the solution for 2 hours. The reaction mixture was warmed to-50 ℃ and quenched by the addition of water; and warmed to room temperature, the layers were separated and the aqueous layer was extracted with ethyl acetate. The aqueous layer containing the acid was lyophilized and purified by silica gel chromatography (0-10% MeOH in DCM containing 0.1% AcOH) to give compound 3, 2- (2H-1, 2, 3-Triazol-2-yl) -5- (Trideuteromethyl) benzoic acid.

1H NMR (500 MHz, d ⁶ -dmso) δ = 12.95 (bs, 1H), 8.04 (s, 2H), 7.62 - 7.50 (m，3H)

And step 3: preparation of formula II [ (7)R) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-Trideuteromethyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Synthesis of methanones

Under the protection of argon, commercial 5-chloro-2- [ (5R) -hexahydro-5-methyl-1H-1, 4-diazepin-1-yl ] benzoxazole (compound 4, 150 mmol) was dissolved in N, N-dimethylformamide (200 ml), and after the reaction temperature was lowered to 0 to 5 ℃ in an ice-water bath, 2- (2H-1, 2, 3-Triazol-2-yl) -5- (Trideuteromethyl) benzoic acid (compound 3) (160 mmol), HOAt (165 mmol), EDCI (165 mmol) and triethylamine (400 mmol) were added, followed by ice-water bath and stirring at room temperature overnight. Adding 500ml 10% citric acid solution, extracting with 500ml ethyl acetate three times, washing the organic layer with 5% sodium carbonate solution, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and drying under reduced pressure to obtain compound formula II with yield of 97% and ee value of 99.8%.

MS(ESI)m/z 454.20([M+H] ⁺ )。

Example 2

This example prepares [ (7)R) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-Trideuteromethyl-1H-1, 4-diazepan-1-yl][ 5-Trideuteromethyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Ketone (formula III)

The preparation process of example 1 was referenced, except that: compound 4 in example 1 was replaced with 5-chloro-2- [ (5R) -hexahydro-5-trideuteromethyl-1H-1, 4-diazepin-1-yl ] benzoxazole to give the desired product, formula III. The purity of the detected product is more than 97%; LC-MS:457 (M + 1).

Example 3

This example prepares [ (7)R) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-dideuteromethyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Ketone (formula IV)

The preparation process of example 1 was referred to, except that: the iodomethane in example 1 was replaced with dideuteroiodomethane to obtain the desired compound of formula IV. The purity of the detected product is more than 97%; LC-MS:453.2 (M + 1).

Example 4

This example prepares [ (7)R) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-monohydrodeuteromethyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Ketone (formula V)

The preparation process of example 1 was referenced, except that: the methyl iodide in example 1 was replaced with deuterium methyl iodide to obtain the target compound of formula V. The purity of the detected product is more than 97%; LC-MS:452.1 (M + 1).

Example 5

This example prepares [ (7)R) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-fluoromethyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl group]Ketone (formula VI)

The preparation process of example 1 was referenced, except that: the iodomethane in example 1 was replaced with fluoroiodomethane to obtain the target compound of formula IV. The purity of the detected product is more than 97%; LC-MS:469.15 (M + 1).

Example 6

This example prepares [ (7)R) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-ethyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Ketone (formula VII)

The preparation process of example 1 was referred to, except that: the methyl iodide in example 1 was replaced with ethyl iodide to obtain the objective product, a compound represented by formula VII. The purity of the detected product is more than 97%; LC-MS:465.95 (M + 1).

Example 7

This example prepares [ (7)R) -4- (5-chlorobenzoxazol-2-yl) hexahydro-7-methyl-1H-1, 4-diazepan-1-yl][ 5-cyclopropyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl]Ketone (formula VIII)

The preparation process of example 1 was referenced, except that: the iodomethane in example 1 was replaced with iodocyclopropane, thereby preparing the target compound represented by formula IV. The purity of the detected product is more than 97%; LC-MS:477.97 (M + 1).

Examples of the effects of the invention

1. Pharmacokinetic testing:

the compounds prepared in examples 1,2,3 and 4 and suvorexant were taken and subjected to pharmacokinetic experiments.

The pharmacokinetic study method comprises the following steps:

(1) Intragastric administration: 6 SD rats with half of male and female respectively are orally taken once, blood is collected in the orbit after administration, and the blood collection time points are 10 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 24 hours after administration;

(2) Intravenous injection: male SD rats were treated with intravenous injection of the drug solution, and blood was collected at the orbit after administration at 3 minutes, 8 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours, 12 hours, and 24 hours after administration.

Immediately after blood collection, the tube was gently inverted at least 5 times to ensure adequate mixing and placed on ice. Blood was anticoagulated with heparin, centrifuged at 8000rpm for 5 minutes, and serum was separated from erythrocytes. Serum was pipetted off to a 2mL polypropylene tube, indicating the name of the compound and the time point, and stored in a-40 ℃ freezer before LC-MS analysis to be tested. High concentration samples were diluted with rat blank plasma.

Adding 2.5 muL Meth-H into 50 muL plasma during measurement ₂ O, 5. Mu.L of internal standard solution (20 ng/mL IS), protein was precipitated with 150. Mu.L of methanol, and centrifuged at 13000 rpm. Times.5 min. And taking an upper organic phase, filtering by using a 0.22 mu M microporous filter membrane, and taking a 2 mu L sample for LC-MS analysis.

From the experimental data, according to the present inventionCompared with suvorexant, the compound prepared by the preparation method of the Ming example has the following effects: the absolute bioavailability of the compound shown in the formula II is improved by 10 percent; AUC _0-t The improvement is 23%; the absolute bioavailability of the compound of formula III is improved by 15%; AUC _0-t The improvement is 19 percent; compound formula IV AUC _0-t The improvement is 10%; AUC of Compound V _0-t Similarly.

TABLE 1 drug metabolism assessment

2. And (3) pharmacodynamic testing:

cell-based calcium accumulation function assays.

HEK-expressing human OX1R or OX2R 293 cells were cultured in Dulbecco's Minimal Essential Medium (DMEM)/10% bovine serum albumin and frozen until use. On the day before the experiment, cells were thawed and seeded at 16000 cells/well into poly-D-lysine coated 384-well plates, in culture medium and incubated overnight at 37 ℃. On the day of the experiment, the cell supernatants were replaced with assay buffer (115 mM NaCl, 5.4 nM KCl, 0.8 mM MgCl2, 1.8 mM CaCl2, 13.8 mM D-glucose, 20 mM HEPES, 0.1% bovine serum albumin) containing Calcium4 sensitive dye (FLIPR Calcium4 detection kit, molecular Devices; sanyvalel, calif., USA), and then the cells were incubated at 37 ℃ for 1 hour, followed by 15 minutes at room temperature. After transfer to the FDSS6000 apparatus (Hamamatsu Photonics; hamamatsu, japan), the compounds tested will be dissolved in assay buffer, added to the cells and allowed to equilibrate for 30 minutes at room temperature. Calcium accumulation is expressed as the ratio of the peak fluorescence intensity to the fluorescence intensity at baseline. In each experiment, the dose dependence of orexin-a was measured to confirm the condition of the cells and to calculate the median effect concentration (EC 50). The compounds tested were challenged with orexin-A at a concentration (L) equivalent to EC 80. The inhibitory potential of the test compound was expressed as the concentration required to reduce the 50% orexin a-evoked response (IC 50) by using the Cheng-Prusoff formula: ki = IC50/[1 + (L/EC 50) ], which is then converted to the inhibition constant Ki.

From the experimental data, it can be seen that the compound of formula II has a Ki that is reduced by 23% compared to suvorexant. The compound formula VI has a Ki reduced by 25%, the compound formula VII has no change in Ki, and the compound formula VIII has a Ki reduced by 15%.

TABLE 2 in vitro pharmacodynamic evaluation

3. Sleep test in animal body

C57BL/6NCrlCrlj mice (male) used in all animal experiments (Charles River laboratories) were kept in 12 hour light dark cycles with food and water available ad libitum.

Wake/sleep recording behavior:

for recording EEG and EMG activity in electrode implanted mice, sleep measurements were quantified using polysomnography. Test compounds were formulated in a solution of 10% Cremophor EL,5% DMSO and saline. The compound or vehicle was administered prior to ZT12:00 (zeitgeber time) light-off. The recording of EEG/EMG data ranged from ZT 12. Following compound or vehicle administration, EEG/EMG activity results were recorded by software, followed by visual confirmation by a sleep researcher who was experienced and not known to the treatment to determine wakefulness, sleep. The data represent the time of alert state every hour (for time course) or 3 hours after light-off (for cumulative analysis). Statistical analysis was performed using GraphPad Prism version 6.02 (GraphPad Software, inc.).

Mice were dosed orally and the effect on sleep was assessed. Within the first 3 hours after administration, compound formula II resulted in a significant reduction in waking time compared to suvorexant (77.3 minutes for compound formula II and 100.7 minutes for suvorexant).

TABLE 3 evaluation of sleep in animals

From the experimental data, it can be seen that the compounds III to VIII prepared according to the preparation method of the present example also resulted in a reduction in the wake time by 10 to 30% compared to suvorexant.

The compounds of the embodiments of the invention have better pharmacokinetics and pharmacodynamics in animals and thus better therapeutic efficacy compared to suvorexant.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.

Claims (11)

1. A chlorobenzoxazole derivative has the following structural formula:

formula II

Formula III

IV

Or

In the formula, R ₁ 、R ₂ 、R ₃ Each independently of the other being hydrogen, fluorine, methyl or cyclopropyl and not both, R ₄ 、R ₅ 、R ₆ Is hydrogen.

2. A chlorobenzoxazole derivative which is characterized in that the benzoxazole derivative is shown as a formula II

Formula III

IV

Formula VI

Of the formula VII

Or of the formula VIII

The structure shown in (a).

3. The chlorobenzoxazole derivative according to claim 1 or 2, characterized in that: the chlorobenzoxazole derivative is in a single crystal form or a polycrystalline form.

4. The pharmaceutically acceptable salt of a chlorobenzoxazole derivative of claim 1 or 2 wherein: the pharmaceutically acceptable salts are salts prepared from pharmaceutically acceptable non-toxic bases or acids.

5. The pharmaceutically acceptable salt according to claim 4, wherein the pharmaceutically acceptable salt is a salt with: one or more of phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, or p-toluenesulfonic acid.

6. A pharmaceutical composition characterized by: comprising one or more of the chlorobenzoxazole derivative of claim 1 or 2 or the pharmaceutically acceptable salt thereof of claim 4 or 5.

7. The pharmaceutical composition of claim 6 is compounded with conventional adjuvants in the field to prepare a pharmaceutical preparation.

8. The pharmaceutical formulation of claim 7, wherein: the pharmaceutical preparation is tablets, capsules, pills, suppositories, soft capsules, oral liquid, suspensions or injections.

9. Use of a pharmaceutical formulation according to claim 7 or 8 in the manufacture of an orexin receptor antagonist.

10. Use of a pharmaceutical composition according to claim 6 for the preparation of a medicament for the treatment and/or prevention of diseases related to orexin receptors, such as neurological and psychiatric disorders.

11. Use according to claim 10, characterized in that: the neurogenic and psychogenic disorder related to the orexin receptor is one or more of insomnia, depression, anxiety, addiction, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, dysthymic disorder, behavioral disorders, mood disorders, sexual dysfunction, psychosexual dysfunction, sexual disorder, schizophrenia, manic depression, confusion, dementia, severe mental retardation, movement disorders, eating disorders or addictive feeding behaviors.

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