WO2014091876A1

WO2014091876A1 - Fluorine-substituted piperidine compound

Info

Publication number: WO2014091876A1
Application number: PCT/JP2013/080976
Authority: WO
Inventors: 裕之太田; 正人阿部
Original assignee: 大正製薬株式会社
Priority date: 2012-12-13
Filing date: 2013-11-18
Publication date: 2014-06-19
Also published as: JP2016028017A

Abstract

The fluorine-substituted piperidine compound represented in formula (I) or a pharmaceutically acceptable salt thereof is useful in the treatment or prevention of disorders that are on the basis of orexin (OX) receptor antagonism including sleep disorders, depression, anxiety disorders, panic disorders, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headaches, migraines, pain, gastrointestinal diseases, epilepsy, inflammation, immunological disorders, endocrine disorders, and high blood pressure.

Description

Fluorine-substituted piperidine compounds

The present invention relates to a compound having an orexin (OX) receptor antagonistic action and a pharmaceutically acceptable salt thereof, and sleep disorders, depressions, anxiety disorders, panic disorders, schizophrenia, drug dependence containing them as active ingredients The present invention relates to a therapeutic or prophylactic agent for diseases such as infectious diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, and hypertension.

Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .

Both OX-A and OX-B act on the OX receptor. The OX receptor has been cloned so far in two subtypes of OX1 and OX2 receptors, both of which are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. . The OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
The tissue distribution varies depending on the subtype of the OX receptor. The OX1 receptor is dense in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor is dense in the papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin neurons project to the brain stem and the monoamine nervous system in the hypothalamus and have an excitatory effect on those nerves. Furthermore, the expression of OX2 receptors is also seen in the acetylcholine neurons of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).

In recent years, attention has been focused on the relationship between OX1 and OX2 receptors and sleep / wake regulation, and the usefulness of compounds having OX receptor antagonistic activity has been studied. When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous movement is increased (see Non-patent Documents 6 and 7), the normal behavior is enhanced (see Non-Patent Document 7), and the awakening time is extended (non-patent documents). 6). The effect of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8). Furthermore, administration of substances that antagonize OX1 and OX2 receptors to the same extent that can be administered orally has been reported to reduce exercise, shorten sleep onset latency, increase non-REM sleep and REM sleep (non-) (See Patent Document 9 and Non-Patent Document 10).
As OX receptor antagonistic compounds, Patent Documents 1 to 3 disclose substituted piperidine derivatives, but there is no disclosure of a piperidine compound substituted with fluorine at the 5-position described in the present application.

WO2008 / 147518 WO2010 / 048010 WO2010 / 048012

The object of the present invention is to find a novel compound having an OX receptor antagonistic action, sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, feeding The object is to provide a therapeutic or prophylactic agent for diseases such as disorders, headaches, migraines, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, and hypertension. More specifically, it is to provide a novel compound exhibiting excellent pharmacokinetics and safety as well as excellent OX receptor antagonism.

As a result of intensive studies on a novel skeletal compound having an antagonistic action on the orexin receptor, the present inventors have excellent OX receptor antagonistic action on certain fluorine-substituted piperidine compounds represented by the following formulas As a result, the present invention has been completed.
Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
(1)
Formula (I)

(Where
X represents the formula CH or a nitrogen atom)
Or a pharmaceutically acceptable salt thereof.
(2) In the above formula (I),
The fluorine-substituted piperidine compound according to (1), wherein X is the formula CH, or a pharmaceutically acceptable salt thereof.
(3) In the above formula (I),
The fluorine-substituted piperidine compound or a pharmaceutically acceptable salt thereof according to (1), wherein X is a nitrogen atom.
(4) A pharmaceutical composition comprising the fluorine-substituted piperidine compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.
(5) Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia containing the fluorine-substituted piperidine compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient Treatment, treatment, or disease of infectious diseases, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, or hypertension Preventive drugs.

It has been clarified that the fluorine-substituted piperidine compound of the present invention exhibits affinity for the OX receptor and antagonizes the stimulation of the receptor by a physiological ligand.

As used herein, “sleep disorder” refers to a disorder during sleep onset, the sleep sustaining phase, or awakening, and includes, for example, insomnia. Examples of insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.

As used herein, “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid. Salts with inorganic acids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycol And salts with organic acids such as acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalene-2-sulfonic acid. Conversion from the educt to the salt can be performed by conventional methods.

Preferred compounds among the compounds of the present invention are:
{(2R, 5S) -5-Fluoro-5-[(4-fluorophenoxy) methyl] -2-methylpiperidin-1-yl} [6-methyl-3- (pyrimidin-2-yl) pyridine-2- Il] methanone,
[(2R, 5S) -5-fluoro-5-{[(5-fluoropyridin-2-yl) oxy] methyl} -2-methylpiperidin-1-yl] [6-methyl-3- (pyrimidine-2 -Yl) pyridin-2-yl] methanone,
Or a pharmaceutically acceptable salt thereof.
In addition, when this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.

The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
The compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and halogen atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
The compound according to the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
The compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

A typical production method of the compound (I) of the present invention is shown in the following scheme A. The following method is an illustration of the production method of the compound of the present invention, and is not limited thereto. In the following examples of production methods, the compound may form a salt that does not hinder the reaction.
Scheme A

(In the formula, Boc represents a tert-butoxycarbonyl group, X has the same meaning as described above, and Y represents a hydrogen atom or a bromine atom.)

Step A-1: Compound (2) can be obtained by fluorination reaction of compound (1). Examples of the base used in this reaction include lithium diisopropylamide, and examples of the fluorinating agent include N-fluorobenzenesulfonimide. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran. This reaction can usually be performed at -78 ° C to room temperature, preferably -78 ° C.

Step A-2: Compound (3) can be obtained by the reduction reaction of compound (2). Examples of the reducing agent used in this reaction include diisobutylaluminum hydride. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran. This reaction can be carried out usually at −78 ° C. to 0 ° C., preferably 0 ° C.

Step A-3: When Y of compound (4) is a hydrogen atom, compound (5) can be obtained by arylation reaction of compound (3) using compound (4). Examples of the base used in this reaction include sodium hydride. Examples of the solvent used in this reaction include N, N-dimethylformamide. This reaction can be carried out usually at 0 ° C. to 80 ° C., preferably 80 ° C.
When Y of the compound (4) is a bromine atom, the intermediate arylated in the same manner as in the above step can be led to the compound (5) by a hydrogenation reaction. Examples of the solvent used in this reaction include alcohol solvents such as MeOH. This reaction can be performed at room temperature.

Step A-4: Compound (6) can be obtained by reacting compound (5) with an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. A comprehensive overview of the reaction in step A-4 can be found in F. W. By McOmie, Protective Groups in Organic Chemistry, and T.W. W. Greene and P.M. G. M.M. Can be found in Wuts, Protective Groups in Organic Synthesis.

Step A-5: The compound (I) of the present invention can be obtained by a condensation reaction of the compound (6) and the compound (7). Examples of the condensation reaction in Step A-5 include a method using a dehydrating condensing agent. Examples of the dehydrating condensing agent include propanephosphonic acid anhydride. Examples of the reaction solvent include N, N-dimethylformamide, chloroform and the like, and mixed solvents thereof. In this case, the reaction can be performed using a base. Examples of the base include organic amines such as pyridine, triethylamine, diisopropylethylamine, and the like. The reaction can be carried out at 0 ° C. to reflux temperature.

Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.
In the following Reference Examples and Examples, “HP-Sil” used in purification using column chromatography was Biotage's SNAP cartridge HP-Sil.

In the following Reference Examples and Examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson TritionLC
Column: Waters SunFire prep C18 OBD 5.0 μm 30 × 50 mm or YMC YMC-Actus Trian 5.0 μm 50 × 30 mm
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 11 minutes (A solution / B Liquid = 20/80), 12 to 13.5 minutes (liquid A / liquid B = 5/95)
Flow rate: 40 mL / min
Detection method: UV 254 nm

The NMR spectra described in the following Reference Examples and Examples were measured with the following measuring instruments.
Measuring equipment: JEOL JNM-ECA600 (600MHz)
In the following Reference Examples and Examples, high performance liquid chromatography mass spectrum (LCMS) was measured under any of the following conditions.
(conditions)
Measuring machine: Agilent Agilent 2900 and Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 80/20), 1.2 to 1.4 minutes (A solution / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: UV 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)

In the following reference examples, racemic resolution was performed under the following conditions.
(conditions)
Column: CHIRALPAK IC (Daicel Chemical Industries), 10cm x 25cm
Mobile phase: hexane / 2-propanol = 90/10 (v / v)
Flow rate: 142 mL / min.

In the following examples, the optical rotation analysis was measured under the following conditions.
Measuring machine: JASCO P-2300 JASCO

In the following Reference Examples and Examples, mass spectra (MS) were measured under the following conditions.
MS measuring instrument: SHIMADZU LCMS-IT-TOF or Agilent Agilent 2900 and Agilent 6150
In the following Reference Examples and Examples, compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).

In the Reference Examples and Examples, the following terms and reagents are expressed as follows.
MgSO ₄ (anhydrous magnesium sulfate), NaHCO ₃ (sodium bicarbonate), NaOH (sodium hydroxide), MeOH (methanol), THF (tetrahydrofuran), DMF (N, N-dimethylformamide), MeCN (acetonitrile), EtOAc ( Ethyl acetate), CHCl ₃ (chloroform), Boc (tert-butoxycarbonyl), DIPEA (N, N-diisopropylethylamine), TEA (triethylamine), NaH (sodium hydride), HCl (hydrogen chloride), nBuLi (normal butyl) Lithium), NH ₄ Cl (ammonium chloride), TFA (trifluoroacetic acid), DIBAL (diisobutylaluminum hydride).

Reference Example 1 1-tert-butyl 3-methyl (3R *, 6R *)-6-methylpiperidine-1,3-dicarboxylate

A racemic mixture of 1-tert-butyl 3-methyl (3RS, 6RS) -6-methylpiperidine-1,3-dicarboxylate (80.0 g, 329 mmol) was resolved under the racemic resolution conditions described above, and two peaks were obtained. (Retention times: 28.5 min, 35.8 min) were separated. Of these, the title compound (34.9 g) was obtained as a compound having a long relative retention time (retention time: 35.8 min) (colorless oil).
¹ H NMR (CHLOROFORM-d) δ ppm 1.13 (d, J = 6.61 Hz, 3 H) 1.32-1.39 (m, 1 H) 1.45 (s, 9 H) 1.74-1.84 (m, 1 H) 1.85-1.94 (m, 1 H) 1.98-2.06 (m, 1 H) 2.54-2.60 (m, 1 H) 3.06 (dd, J = 13.6, 4.13 Hz, 1 H) 3.69 (s, 3 H) 4.31-4.44 (m , 2 H)
MS (ESI pos.) M / z: 280 [M + Na] +

Reference Example 2 1-tert-butyl 3-methyl (3S, 6R) -3-fluoro-6-methylpiperidine-1,3-dicarboxylate

An nBuLi-hexane solution (11 mL, 30.4 mmol, 2.77 M) was added to a THF solution (40 mL) of diisopropylamine (4.62 mL, 32.8 mmol) in an ice bath and stirred for 30 minutes. THF solution (10 mL) of 1-tert-butyl 3-methyl (3R *, 6R *)-6-methylpiperidine-1,3-dicarboxylate (6.00 g, 23.4 mmol) in a dry ice-acetone bath Was added dropwise and stirred at −78 ° C. for 30 minutes. The mixture was stirred for 30 minutes in a salt-ice bath, and stirred for 30 minutes at 0 ° C. in an ice bath. A THF solution (60 mL) of N-fluorobenzenesulfonimide (10.3 g, 32.8 mmol) was added dropwise at −78 ° C. in a dry ice-acetone bath. After stirring for 60 minutes in a salt-ice bath, the mixture was stirred for 2 hours at room temperature. Saturated aqueous NH ₄ Cl was added and extracted with EtOAc. After drying the organic layer using MgSO ₄ , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil, hexane / EtOAc) to give the title compound (4.9 g) (colorless oil).
The absolute steric structure of the title compound is tert-butyl (2R, 5S) -5-[(2,5-dibromo-4-fluorophenoxy) methyl] -5-fluoro-, obtained through two steps described later. Determined by X-ray crystallographic analysis of 2-methylpiperidine-1-carboxylate.
¹ H NMR (CHLOROFORM-d) δ ppm 1.16 (d, J = 6.61 Hz, 3 H) 1.44 (s, 9 H) 1.47-1.55 (m, 1 H) 1.84-1.99 (m, 2 H) 2.10-2.24 (m, 1 H) 3.02 (dd, J = 14.0, 10.3 Hz, 1 H) 3.68 (s, 3 H) 4.24 -4.30 (m, 1 H) 4.43 (d, J = 14.0 Hz, 1 H)

Reference Example 3 tert-butyl (2R, 5S) -5-fluoro-5- (hydroxymethyl) -2-methylpiperidine-1-carboxylate

In a dry ice-acetone bath, a THF solution of 1-tert-butyl 3-methyl (3S, 6R) -3-fluoro-6-methylpiperidine-1,3-dicarboxylate (4.9 g, 17.8 mmol) ( To 300 mL), DIBAL (38 mL, 37.4 mmol, 1.0 M toluene solution) was added dropwise and stirred at −78 ° C. for 60 minutes. MeOH and 2M hydrochloric acid were added, and the mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO ₃ solution and dried over MgSO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) to give the title compound (3.93 g) (colorless oil).
¹ H NMR (CHLOROFORM-d) δ ppm 1.20 (d, J = 8.67 Hz, 3 H) 1.46 (s, 9 H) 1.47-1.59 (m, 2 H) 1.65-1.73 (m, 1 H) 1.77-1.91 (m, 1 H) 2.92 (dd, J = 14.0, 8.67 Hz, 1 H) 3.56-3.69 (m, 2 H) 4.15 (d, J = 14.0 Hz, 1 H) 4.20-4.26 (m, 1 H)

Reference Example 4 tert-butyl (2R, 5S) -5-[(2,5-dibromo-4-fluorophenoxy) methyl] -5-fluoro-2-methylpiperidine-1-carboxylate

tert-Butyl (2R, 5S) -5-fluoro-5- (hydroxymethyl) -2-methylpiperidine-1-carboxylate (100 mg, 0.40 mmol) in DMF (3 mL) was added 60% NaH (26 mg, 0 .61 mmol) was added and stirred at room temperature for 30 minutes. 1,4-Dibromo-2,5-difluorobenzene (220 mg, 0.80 mmol) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 4 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc) to obtain the title compound (160 mg) (colorless solid).
¹ H NMR (CHLOROFORM-d) δ ppm 1.21 (d, J = 7.02 Hz, 3 H) 1.43 (s, 9 H) 1.49-1.53 (m, 1 H) 1.57-1.64 (m, 1 H) 1.70-1.82 (m, 1 H) 1.90-2.03 (m, 1 H) 3.02 (dd, J = 13.6, 9.91 Hz, 1 H) 4.04-4.17 (m, 2 H) 4.20-4.33 (m, 2 H) 7.07 (d , J = 7.43 Hz, 1 H) 7.35 (d, J = 7.43 Hz, 1 H)

Reference Example 5 tert-butyl (2R, 5S) -5-fluoro-5-[(4-fluorophenoxy) methyl] -2-methylpiperidine-1-carboxylate

tert-Butyl (2R, 5S) -5-[(2,5-dibromo-4-fluorophenoxy) methyl] -5-fluoro-2-methylpiperidine-1-carboxylate (160 mg, 0.32 mmol), TEA ( 115 μl, 0.83 mmol) and 10% Pd / C (0.160 g, 0.150 mmol) in MeOH were stirred for 1 hour at room temperature under hydrogen atmosphere (1 atm). The reaction solution was filtered through Celite (registered trademark), the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc) to obtain the title compound (95 mg) (colorless) Oil).
¹ H NMR (CHLOROFORM-d) δ ppm 1.21 (d, J = 7.02 Hz, 3 H) 1.40 (s, 9 H) 1.49-1.62 (m, 2 H) 1.69-1.80 (m, 1 H) 1.89-2.00 (m, 1 H) 3.00 (dd, J = 13.4, 9.70 Hz, 1 H) 3.93-4.08 (m, 2 H) 4.10-4.14 (m, 1 H) 4.24-4.30 (m, 2 H) 6.84-6.90 (m, 2 H) 6.94-7.00 (m, 2 H)

Reference Example 6 (2R, 5S) -5-Fluoro-5-[(4-fluorophenoxy) methyl] -2-methylpiperidine

tert-Butyl (2R, 5S) -5-fluoro-5-[(4-fluorophenoxy) methyl] -2-methylpiperidine-1-carboxylate (95 mg, 10.28 mmol) in CHCl ₃ solution (1 mL) (1 mL) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (61 mg) (colorless oil).
¹ H NMR (CHLOROFORM-d) δ ppm 1.14 (d, J = 6.61 Hz, 3 H) 1.39-1.50 (m, 1 H) 1.61-1.79 (m, 3 H) 2.06-2.15 (m, 1 H) 2.06 -2.13 (m, 1 H) 2.59-2.71 (m, 1 H) 2.78-2.92 (m, 1 H) 3.23-3.34 (m, 1 H) 3.83-3.96 (m, 2 H) 6.83-6.87 (m, 2 H) 6.94-7.00 (m, 2 H)
LCMS retention time 0.292 min.
MS (ESI pos.) M / z: 242 [M + H] +

Reference Example 7 tert-butyl (2R, 5S) -5-fluoro-5-{[(5-fluoropyridin-2-yl) oxy] methyl} -2-methylpiperidine-1-carboxylate

Tert-Butyl (2R, 5S) -5-fluoro-5- (hydroxymethyl) -2-methylpiperidine-1-carboxylate (3.43 g, 13.9 mmol) obtained in Reference Example 3 and 2,5- The title compound (2.28 g) was obtained in the same manner as in Reference Example 4 using difluoropyridine (3.19 g, 27.7 mmol) as a starting material (colorless oil).
¹ H NMR (CHLOROFORM-d) δ ppm 1.19 (d, J = 7.02 Hz, 3 H) 1.36 (s, 9 H) 1.73-1.83 (m, 1 H) 1.73-1.82 (m, 1 H) 1.88-2.00 (m, 2 H) 2.98 (dd, J = 13.6, 9.50 Hz, 1 H) 4.29 (d, J = 13.6 Hz, 2 H) 4.33-4.46 (m, 2 H) 6.77 -6.81 (m, 1 H) 7.30-7.37 (m, 1 H) 7.94 (d, J = 3.30 Hz, 1 H)
LCMS retention time 1.184 min.
MS (ESI pos.) M / z: 343 [M + H] +

Reference Example 8 5-Fluoro-2-{[(3S, 6R) -3-fluoro-6-methylpiperidin-3-yl] methoxy} pyridine

Tert-Butyl (2R, 5S) -5-fluoro-5-{[(5-fluoropyridin-2-yl) oxy] methyl} -2-methylpiperidine-1-carboxylate obtained in Reference Example 7 (2 .28 g, 6.66 mmol) was used as a starting material, and the title compound (1.64 g) was obtained in the same manner as in Reference Example 6 (colorless solid).
¹ H NMR (CHLOROFORM-d) δ ppm 1.13 (d, J = 6.61 Hz, 3 H) 1.33-1.51 (m, 1 H) 1.53-1.75 (m, 2 H) 2.00-2.21 (m, 1 H) 2.54 -2.69 (m, 1 H) 2.71-2.87 (m, 1 H) 3.23-3.36 (m, 1 H) 4.19-4.35 (m, 2 H) 6.77 (dd, J = 9.08, 3.30 Hz, 1 H) 7.33 -7.36 (m, 1 H) 7.95 (d, J = 3.30 Hz, 1 H)

Example 1 {(2R, 5S) -5-Fluoro-5-[(4-fluorophenoxy) methyl] -2-methylpiperidin-1-yl} [6-methyl-3- (pyrimidin-2-yl) pyridine -2-yl] methanone

(2R, 5S) -5-fluoro-5-[(4-fluorophenoxy) methyl] -2-methylpiperidine (60 mg, 0.25 mmol) obtained in Reference Example 6 in CHCl ₃ solution (2 mL) was added to DIPEA ( 0.174 mL, 0.65 mmol), 6-methyl-3- (pyrimidin-2-yl) pyridine-2-carboxylic acid (70 mg, 0.33 mmol), propanephosphonic acid anhydride (1.7 M in EtOAc, 0 .51 mL, 0.88 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC to obtain the title compound (10 mg) (colorless amorphous).
LCMS retention time 0.970 min.
MS (ESI pos.) M / z: 439 [M + H] +
[Α] _D ¹⁵ = −27.2 (c = 0.61, CHCl ₃ )

Example 2 [(2R, 5S) -5-fluoro-5-{[(5-fluoropyridin-2-yl) oxy] methyl} -2-methylpiperidin-1-yl] [6-methyl-3- ( Pyrimidin-2-yl) pyridin-2-yl] methanone

5-fluoro-2-{[(3S, 6R) -3-fluoro-6-methylpiperidin-3-yl] methoxy} pyridine (150 mg, 0.62 mmol), 6-methyl-3 obtained in Reference Example 8 The title compound (200 mg) was obtained in the same manner as in Example 1 using-(pyrimidin-2-yl) pyridine-2-carboxylic acid (200 mg, 0.93 mmol) as a starting material (colorless solid).
LCMS retention time 1.018 min.
MS (ESI pos.) M / z: 440 [M + H] +
[Α] _D ¹⁵ = +5.42 (c = 0.61, CHCl ₃ )

Test example (measurement of orexin receptor antagonist activity)
Evaluation of antagonistic activity of test compounds against human orexin type 1 receptor (hOX1R) and orexin type 2 receptor (hOX2R) is described in the literature (Toshikata Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). This was done by modifying the described method. Chinese hamster ovary (CHO) cells stably expressing hOX1R and hOX2R were seeded at 20,000 in each well of a 96-well Black clear bottom plate (Nunc), 0.1 mM MEM non-essential amino acids, 0. The cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2. After removing the medium, assay buffer containing 0.5 μM Fluo-4AM (Invitrogen) (25 mM HEPES (Dojindo Laboratories), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM Probenecid, 200 μg / ml Amaranth (Sigma-Aldrich), pH 7.4) was added at 100 μL and incubated for 60 minutes. After removing the assay buffer containing Fluo-4AM, dissolve the test compound in dimethyl sulfoxide to a concentration of 10 mM, dilute with assay buffer to a final concentration of 0.3 nM to 30 nM, and add 150 μL. And incubated for 30 minutes.
Peptide substituted with 2 amino acids of human orexin-A which is an agonist (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is used for assay so that the final concentration is 1 pM to 1 μM The reaction was started by diluting with buffer and adding 50 μL of ligand solution. The reaction was measured using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics Co., Ltd.) to measure the fluorescence value as an index of intracellular Ca ²⁺ concentration. A concentration-response curve of agonist activity is generated from the maximum fluorescence values when various concentrations of agonists are added, and the negative logarithm of the concentration of the test compound necessary to translate this to the right double the concentration ( pA2 value) was calculated.
Table 1 shows the pA2 values of the test compounds.

The compound of the present invention was shown to have an OX receptor antagonistic action. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease modulated by OX receptor antagonism, such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease , Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. .

Claims

Formula (I)

(Where
X represents the formula CH or a nitrogen atom)
Or a pharmaceutically acceptable salt thereof.
In the above formula (I),
The fluorine-substituted piperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is formula CH.
In the above formula (I),
The fluorine-substituted piperidine compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom.
A pharmaceutical composition comprising as an active ingredient the fluorine-substituted piperidine compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence comprising the fluorine-substituted piperidine compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient , Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, or hypertension diseases.