JP2008001596A - Sodium channel inhibitor - Google Patents

Abstract

Sodium channel inhibitor having high analgesic effect against neuropathic pain and reduced side effects, novel piperidine derivative useful as sodium channel inhibitor or pharmaceutically acceptable salt thereof, and effective It aims at providing the pharmaceutical composition contained as an ingredient.
An active ingredient in a sodium channel inhibitor of the present invention, and a piperidine derivative of the present invention or a pharmaceutically acceptable salt thereof, wherein a piperidine ring is directly connected to a benzene ring or a heterocycle, It has a structure in which a ring or a hetero ring is directly connected to another benzene ring.
[Selection figure] None

Description

  The present invention relates to a sodium channel inhibitor, a novel piperidine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing it as an active ingredient. More specifically, a sodium channel inhibitor having a high analgesic effect on neuropathic pain and reduced side effects, a novel piperidine derivative useful as a sodium channel inhibitor, or a pharmaceutically acceptable salt thereof, and The present invention relates to a pharmaceutical composition containing as an active ingredient.

Voltage-gated sodium channels are proteins responsible for the generation and propagation of nerve action potentials. The voltage-gated sodium channel has a large α subunit in which four 6-transmembrane domains are repeated and two small β subunits as a common structure. The main channel function is the α subunit. To date, it is known that there are more than 10 subtypes of α subunit (Goldin AL, Annals of the New York Academy of Sciences 868: 38-50, 1999). Each voltage-gated sodium channel subtype has a different distribution in central and peripheral nervous tissue. They regulate nerve excitability and play an important role in regulating the physiological function of each tissue. It has also been suggested to be deeply involved in various pathologies (Goldin AL, Annual Review of Physiology 63: 871-894, 2001).
In recent years, it has become clear that voltage-gated sodium channels are deeply involved in the neurotransmission of pain, and sodium channel agonists are expected to be excellent pain therapeutic agents, particularly neuropathic pain therapeutic agents (Taylor CP, Current Pharmaceutical Design 2: 375-388, 1996).
Neuropathic pain means pain due to peripheral or central nervous system dysfunction, and includes pain of diabetic neuropathy, cancer pain, trigeminal neuralgia, phantom limb pain, postherpetic pain, thalamic pain, and the like. Clinical images of neuropathic pain are painful to tighten, pain to burn, hyperalgesia and allodynia (allodynia) and the like.

In the medical field, nonsteroidal anti-inflammatory drugs and narcotic analgesics such as morphine are used for pain relief, and in recent years, antiarrhythmic drugs and anticonvulsants, which are sodium channel inhibitors, are also used for pain relief. Came to be used.
Non-steroidal anti-inflammatory drugs are not completely satisfied with analgesic effects, and also have problems of side effects such as gastrointestinal disorders and kidney disorders. Narcotic analgesics such as morphine are mainly effective against nociceptive pain, but have serious side effects on the digestive system, respiratory system, and central nervous system. In general, these drugs have a weak effect on neuropathic pain.
Existing sodium channel inhibitors, antiarrhythmic drugs such as lidocaine and mexiletine, and anticonvulsant drugs such as carbamazepine have also been used for pain relief. However, these sodium channel inhibitors have central side effects such as convulsions and sleepiness, and peripheral side effects such as bradycardia, so that it is difficult to increase the dose sufficiently, and as a result, sufficient analgesic effect cannot be obtained. there were.

（上記式中Ｗは置換されていてもよいＣ_1-6アルキレン基等を、Ｚは置換されていてもよいＣ_6-14芳香族炭化水素環基等を、ｌは０〜６の整数を、Ｒ¹及びＲ²は水素原子等を示す。上記式中の記号の詳細は特許文献１参照。）
しかし、特許文献１に開示された化合物は、ピペリジン環が低級アルキレン基等（Ｗ）を介して、芳香族炭化水素環基等（Ｚ）と結合し、ピペリジン環の１位で低級アルキレンを介して、オキソジヒドロピリジン環と結合したものであり、本発明のナトリウムチャネル阻害薬における有効成分、並びに本発明のピペリジン誘導体又はその製薬学的に許容される塩とは基本構造を全く異にする。 As described above, an analgesic that has a useful effect for treating neuropathic pain and is excellent in safety has not yet been found. Therefore, a sodium channel inhibitor that has a high analgesic effect on neuropathic pain and has reduced side effects is desired.
As such a sodium channel inhibitor, a compound represented by the following general formula has been disclosed (see Patent Document 1).

(In the above formula, W represents an optionally substituted C _1-6 alkylene group, etc., Z represents an optionally substituted C _6-14 aromatic hydrocarbon ring group, etc., l represents an integer of 0-6.) , R ¹ and R ² represent a hydrogen atom, etc. For details of symbols in the above formula, refer to Patent Document 1.)
However, in the compound disclosed in Patent Document 1, the piperidine ring is bonded to the aromatic hydrocarbon ring group or the like (Z) via the lower alkylene group or the like (W), and the first position of the piperidine ring via the lower alkylene or the like. Thus, it is bonded to the oxodihydropyridine ring, and the basic structure is completely different from the active ingredient in the sodium channel inhibitor of the present invention and the piperidine derivative of the present invention or a pharmaceutically acceptable salt thereof.

しかしながら、特許文献２には、化合物（Ａ）はＰＡＲＰ阻害剤として神経細胞保護作用を有することが記載されているものの、化合物（Ａ）及びその合成中間体である化合物（Ｉ−１）が、ナトリウムチャネル阻害作用を有し、神経因性疼痛に対して鎮痛作用を示すことは、示唆も開示もされていない。 Moreover, compound (I-1) is disclosed as a synthetic intermediate of compound (A) represented by the following formula (see Reference Example 30 in Patent Document 2).

However, although Patent Document 2 describes that compound (A) has a nerve cell protective action as a PARP inhibitor, compound (A) and compound (I-1) which is a synthetic intermediate thereof are described below. It does not suggest or disclose that it has a sodium channel inhibitory action and exhibits an analgesic action against neuropathic pain.

しかしながら、化合物（Ｂ）は高血圧又は肥満等の治療に用いられることが記載されているものの、化合物（Ｂ）及びその合成中間体である化合物（Ｉ−２）が、ナトリウムチャネル阻害作用を有し、神経因性疼痛に対して鎮痛作用を示すことは、示唆も開示もされていない。
国際公開第ＷＯ０１／５３２８８号パンフレット 国際公開第ＷＯ０３／６３８７４号パンフレット 米国特許第５６６８１５１号 Furthermore, compound (I-2) is disclosed as a synthetic intermediate of compound (B) represented by the following formula (see Example 33 of Patent Document 3).

However, although it is described that compound (B) can be used for the treatment of hypertension or obesity, compound (B) and compound (I-2) which is a synthetic intermediate thereof have sodium channel inhibitory action. It does not suggest or disclose that it has an analgesic effect on neuropathic pain.
International Publication No. WO01 / 53288 Pamphlet International Publication No. WO03 / 63874 Pamphlet US Pat. No. 5,668,151

  The present invention relates to a sodium channel inhibitor having a high analgesic effect on neuropathic pain and reduced side effects, a novel piperidine derivative useful as a sodium channel inhibitor, or a pharmaceutically acceptable salt thereof, and It aims at providing the pharmaceutical composition which contains as an active ingredient.

  As a result of diligent research on the piperidine derivatives, the present inventors have found that a piperidine ring is directly connected to a benzene ring or a heterocycle (A ring), and further, the A ring is further directly connected to a benzene ring, or a pharmaceutical product thereof. It has been found that a pharmaceutically acceptable salt has a strong inhibitory action (activity) on sodium channels, and has a good analgesic action on streptozotocin-induced diabetic neuropathy mice, which are pathological animal models. A novel tricyclic piperidine derivative in which the ring and the piperidine ring are bonded at the ortho position of the benzene ring (A ring), and a novel tricyclic piperidine derivative in which the A ring is a thiophene ring have particularly strong inhibitory action on sodium channels. The present invention has been completed. That is, according to the present invention, the following sodium channel inhibitor, a novel piperidine derivative useful as a sodium channel inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient are provided. Is done.

（上記式（Ｉ）中の記号は、それぞれ以下の意味を有する。
Ａ環：ベンゼン環、又はＮ、Ｓ、Ｏから選択されるヘテロ原子を１〜３個有する５又は６員ヘテロ環、
Ｒ¹〜Ｒ⁶：同一又は異なって、水素原子、ハロゲン原子、低級アルキル、−Ｏ−低級アルキル、−Ｏ−アリール、アリール、シクロアルキル、−Ｃ（＝Ｏ）−低級アルキル、ＣＯＯＨ、−Ｃ（＝Ｏ）−Ｏ−低級アルキル、−Ｃ（＝Ｏ）−ＮＨ₂、−Ｃ（＝Ｏ）ＮＨ−低級アルキル、−Ｃ（＝Ｏ）Ｎ−（低級アルキル）₂、ＯＨ、−Ｏ−Ｃ（＝Ｏ）−低級アルキル、ＮＨ₂、−ＮＨ−低級アルキル、−Ｎ−（低級アルキル）₂、−ＮＨ−Ｃ（＝Ｏ）−低級アルキル、ＣＮ又はＮＯ₂） [1] A sodium channel inhibitor containing a piperidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient (hereinafter sometimes referred to as “first invention”).

(The symbols in the above formula (I) have the following meanings, respectively.
Ring A: a benzene ring or a 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from N, S and O,
R ^{1 to} R ⁶ : the same or different, hydrogen atom, halogen atom, lower alkyl, —O-lower alkyl, —O-aryl, aryl, cycloalkyl, —C (═O) -lower alkyl, COOH, —C (= O) -O- lower _{alkyl, -C (= O) -NH 2} , -C (= O) NH- lower alkyl, -C (= O) N- (lower alkyl) _2, OH, -O- C (= O) - lower alkyl, NH _2, -NH- lower alkyl,-N-(lower _{alkyl) 2, -NH-C (=} O) - lower alkyl, CN or NO ₂₎

（上記式（ａ）又は（ｂ）中の記号は、それぞれ以下の意味を有する。
Ｒ¹〜Ｒ⁶：同一又は異なって、水素原子、ハロゲン原子、低級アルキル、−Ｏ−低級アルキル、−Ｏ−アリール、アリール、シクロアルキル、−Ｃ（＝Ｏ）−低級アルキル、ＣＯＯＨ、−Ｃ（＝Ｏ）−Ｏ−低級アルキル、−Ｃ（＝Ｏ）−ＮＨ₂、−Ｃ（＝Ｏ）ＮＨ−低級アルキル、−Ｃ（＝Ｏ）Ｎ−（低級アルキル）₂、ＯＨ、−Ｏ−Ｃ（＝Ｏ）−低級アルキル、ＮＨ₂、−ＮＨ−低級アルキル、−Ｎ−（低級アルキル）₂、−ＮＨ−Ｃ（＝Ｏ）−低級アルキル、ＣＮ又はＮＯ₂） [2] A piperidine derivative represented by the following general formula (a) or (b) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “second invention”).

(The symbols in the above formula (a) or (b) have the following meanings, respectively.
R ^{1 to} R ⁶ : the same or different, hydrogen atom, halogen atom, lower alkyl, —O-lower alkyl, —O-aryl, aryl, cycloalkyl, —C (═O) -lower alkyl, COOH, —C (= O) -O- lower _{alkyl, -C (= O) -NH 2} , -C (= O) NH- lower alkyl, -C (= O) N- (lower alkyl) _2, OH, -O- C (= O) - lower alkyl, NH _2, -NH- lower alkyl,-N-(lower _{alkyl) 2, -NH-C (=} O) - lower alkyl, CN or NO ₂₎

[3] A pharmaceutical composition comprising the piperidine derivative or the pharmaceutically acceptable salt thereof according to [2] as an active ingredient.

[4] The pharmaceutical composition according to the above [3], which is a sodium channel inhibitor.

According to the present invention, a sodium channel inhibitor having a high analgesic effect on neuropathic pain and reduced side effects, a novel piperidine derivative useful as a sodium channel inhibitor, or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition containing the active ingredient is provided.
It should be noted that the active ingredient in the sodium channel inhibitor of the present invention (first invention) (piperidine derivative represented by the above general formula (I) (hereinafter referred to as “active ingredient (I)”) may be obtained by a pharmacological test described later. ) Or a pharmaceutically acceptable salt thereof) and a piperidine derivative represented by the above general formula (a) or (b) of the present invention (second invention) (hereinafter referred to as “the present compound (I)”) Or a pharmaceutically acceptable salt thereof was confirmed to be a compound having sodium channel inhibitory activity superior to mexiletine. In addition, it was confirmed that diabetic neuropathy mice, which are pathological animal models, show good analgesic effects by oral administration.

  Hereinafter, the active ingredient (I) in the sodium channel inhibitor of the present invention (first invention) and the present compound (I) of the present invention (second invention) will be specifically described.

The term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
Examples of the “lower alkyl” include C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and the like. Preferred are methyl, ethyl, propyl, butyl and tert-butyl.
Examples of the saturated or unsaturated 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from N, S and O include furan, thiophene, pyrrole, pyridine, oxazole, isoxazole, thiazole, isothiazole, Unsaturated rings such as furazane, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine; saturated rings such as pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine and the like, preferably furan, thiophene, pyrimidine, morpholine, Particularly preferred is thiophene.
Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine, and preferably fluorine and chlorine.
“Cycloalkyl” means a 1 to 3 ring aliphatic saturated hydrocarbon ring group having 3 to 14 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloheptyl. Bicyclooctyl, bicyclononyl, bicyclodecanyl, tricyclononyl, tricyclodecanyl, tricycloundecanyl, tricyclododecanyl and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl.
“Aryl” means a 1 to 3 ring aromatic hydrocarbon ring group having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl, anthryl, phenanthryl, and the like, preferably phenyl and naphthyl. is there.

The active ingredient (I) and the compound (I) of the present invention may have optical isomers (optically active substances, diastereomers, etc.) or geometric isomers depending on the type of substituent. Therefore, the active ingredient (I) and the compound (I) of the present invention include those optical isomers or mixtures of geometric isomers and those isolated.
In addition, the active ingredient (I) and the compound (I) of the present invention can form an acid addition salt or a salt with a base. For example, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, malein Acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, acid addition salts with organic acids such as glutamic acid; inorganic bases such as sodium, potassium, magnesium, calcium and aluminum And salts with organic bases such as methylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine and ornithine. Furthermore, the active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, may be able to form hydrates, solvates such as ethanol, and crystal polymorphs. .

Further, the active ingredient (I) and the compound (I) of the present invention are metabolized in vivo to be converted into the active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof. Also included are all compounds, so-called prodrugs. Examples of the group that forms a prodrug of the active ingredient (I) and the compound (I) of the present invention include those described in Prog. Med. 5: 2157-2161 (1985) and “Development of pharmaceuticals” published in 1990 by Hirokawa Shoten. "Groups described in Volume 7, Molecular Design 163-198. Specifically, it is a group that can be converted into primary amine or secondary amine, OH, HOC (= O)-, etc. as in the present invention by hydrolysis, solvolysis or under physiological conditions, and OH Examples of the prodrug include, for example, optionally substituted lower alkyl-C (═O) O—, optionally substituted aryl-C (═O) O—, and ROC (═O) -substituted. Lower alkylene-C (= O) O- (R represents H- or lower alkyl; the same applies hereinafter), ROC (= O) -optionally substituted lower alkenylene-C (= O) O-, ROC (= O) -lower alkylene-O-lower alkylene-C (═O) O—, ROC (═O) —C (═O) O—, ROS (═O) ₂ —optionally substituted lower alkenylene-C ( = O) O-, phthalidyl-O-, 5-methyl-1,3-dioxo Down 2-one-4-yl - methyloxy, and the like.
Hereinafter, representative production methods, raw material synthesis and formulation of the active ingredient (I) and the compound (I) of the present invention will be described.

[Production method]
The active ingredient (I) and the compound (I) of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. A typical production method will be described below.

（上記式中、Ｒ¹〜Ｒ⁶は、前述の基を示す。また、ＭはＬｉ、ＭｇＢｒ等を示す。Ｙはｔｅｒｔ−ブトキシカルボニル基、ベンジルオキシカルボニル基等のアミノ基の保護基を示す。以下同様である。）

(In the above formulas, R ^{1 to} R ⁶ represent the aforementioned groups. M represents Li, MgBr, etc. Y represents an amino-protecting group such as a tert-butoxycarbonyl group and a benzyloxycarbonyl group. The same applies hereinafter.)

  The active ingredient (I) and the compound (I) of the present invention can be produced by applying various synthetic methods utilizing the characteristics based on the basic skeleton or the type of substituents. Will be described. Reaction of aryl metals such as aryl lithium and aryl Grignard reagents with conventional oxopiperidine derivatives protected with an amino protecting group (Bioorg. Med. Chem., 10, 371-383 (2002); Tetrahedron., 21, 3331-3349 (1965)) and further dehydration of the resulting alcohol derivative (J. Org. Chem., 54, 4795-4800 (1989); J. Org. Chem., 66, 7804-7810 (2001); J. Org. Chem., 66, 3593-3596 (2001)), reduction (Bioorg. Med. Chem., 10, 371-383 (2002)), and deprotection (Protective groups in Organic Synthesis, third ed., Theodora W. Greene & Peter GM Wuts, INC.).

The active compound (I) and the starting compound of the compound (I) of the present invention are described in the aforementioned literature (Bioorg. Med. Chem., 10, 371-383 (2002); Tetrahedron., 21, 3331-3349 (1965); Org. Chem., 54, 4795-4800 (1989); J. Org. Chem., 66, 7804-7810 (2001); J. Org. Chem., 66, 3593-3596 (2001); Bioorg. Med Chem., 10, 371-383 (2002); Protective groups in Organic Synthesis, third ed., Theodora W. Greene & Peter GM Wuts, INC.) And (Synlett., 3, 207-210 (1992)). It can be easily produced according to the described synthesis method.
The active ingredient (I) thus produced and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, are isolated as they are free or as a pharmaceutically acceptable salt thereof. The salt of the active ingredient (I) and the compound (I) of the present invention can be produced by subjecting the active ingredient (I) which is a free base and the compound (I) of the present invention to a usual salt formation reaction.

Isolation and purification of the active ingredient (I) thus produced and the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be extracted, concentrated, distilled off, crystallized, filtered, recrystallized. It is carried out by applying ordinary chemical operations such as various chromatography.
Various isomers can be separated by selecting an appropriate raw material compound or by utilizing a difference in physical or chemical properties between isomers. For example, optical isomers can be stereoisomerized by selecting appropriate raw materials, or by racemic resolution of racemates (for example, by diastereomeric salts with general optically active acids and optical resolution). Can lead to chemically pure isomers.

[Prescription]
For the active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, various commonly used formulations can be applied. The typical prescription will be described below.
A pharmaceutical composition containing, as an active ingredient, active ingredient (I) and compound (I) of the present invention, or a pharmaceutically acceptable salt thereof as an active ingredient comprises a pharmaceutically acceptable carrier. It is possible to use tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments using carriers and excipients commonly used in formulation. It is prepared as a patch and administered orally (including sublingual administration) or parenterally.
The dosage of the active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof is individual in consideration of the symptoms, body weight, age, sex, route of administration, etc. of the patient to which the dosage is applied. In general, the dose is usually 1 mg to 1000 mg per adult per day, preferably 10 mg to 200 mg, orally administered once to several times a day, or per adult 1 It is administered intravenously in one to several times a day in the range of 1 mg to 500 mg per day, or continuously administered intravenously in the range of 1 hour to 24 hours per day. Of course, as described above, the dose varies depending on various conditions, and therefore, a dose smaller than the above dose may be sufficient.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, at least one active substance contains at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminate metasilicate. Mixed with magnesium. The composition is prepared according to conventional methods with additives other than inert diluents, for example lubricants such as magnesium stearate; disintegrants such as starch, calcium calcium glycolate; stabilizers such as lactose It may contain a solubilizing agent such as glutamic acid and aspartic acid. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate or the like, or a gastric or enteric film.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents such as Contains purified water, ethanol, etc. In addition to the inert diluent, the composition may contain solubilizing or solubilizing aids, wetting agents, suspending agents, and the like; sweeteners; flavoring agents; fragrances;
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil; alcohols such as ethanol; polysorbate 80 (trade name). Such compositions may further contain additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizing or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide, or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.

  Further, the active ingredient (I) and the compound (I) of the present invention, or a pharmaceutically acceptable salt thereof may be used together with other drugs effective for pain. Drugs effective for pain that can be used in combination include narcotic analgesics, antipyretic analgesics, non-steroidal anti-inflammatory drugs and the like.

EXAMPLES Next, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
Hereinafter, production examples of the active ingredient (I) and the compound (I) of the present invention will be specifically described. In addition, the manufacture example of the raw material compound used in an Example is demonstrated as Reference Examples 1-22.

(Reference Example 1)
15 ml of water, 1.06 g of 2,6-dimethylphenylboranoic acid, 2.25 g of sodium carbonate, and 408 mg of tetrakis (triphenylphosphine) palladium were added to a solution of 2.0 g of 1-bromo-2-iodobenzene in 30 ml of dimethoxyethane. Heated to reflux for a week. The reaction mixture was cooled to room temperature, extracted with diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane) to obtain 1.13 g of 2′-bromo-2,6-dimethylbiphenyl.

(Reference Example 2)
In the same manner as in Reference Example 1, the compounds shown in Table 1 were obtained.

(Reference Example 3)
To a solution of 945 mg of 2-bromo-4′-methoxybiphenyl in 25 ml of tetrahydrofuran was added 2.39 ml of an n-butyllithium hexane solution at −78 ° C. in an argon atmosphere, and the mixture was stirred for 20 minutes. To this was added a solution of 879 mg of benzyl 4-oxopiperidine-1-carboxylate in 10 ml of tetrahydrofuran, and the mixture was stirred for 1 hour and then at room temperature overnight. The reaction solution was poured into a saturated aqueous sodium chloride solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 941 mg of benzyl 4-hydroxy-4- (4′-methoxybiphenyl-2-yl) piperidine-1-carboxylate. Got.

(Reference Examples 4 to 14)
In the same manner as in Reference Example 3, the compounds shown in Tables 1 and 3 were obtained.
(Reference Example 15)
To a suspension of 871 mg of magnesium in 15 ml of diethyl ether, 1.38 ml of bromine was added dropwise under ice-cooling in an argon stream and stirred for 30 minutes under ice-cooling, followed by stirring at room temperature for about 1 hour. (Reaction liquid (1)) On the other hand, 40 ml of a diethyl ether solution of 4.28 g of 3-bromo-2-phenylthiophene at −78 ° C. was added dropwise to 12.5 ml of a butyllithium hexane solution under an argon stream, and then the reaction liquid (1 ) Was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 1 hour. The reaction suspension was concentrated under an argon atmosphere. (Reaction liquid (2)) Further, the reaction liquid (2) was added dropwise to 400 ml of a diethyl ether solution of 5.35 g of tert-butyl 4-oxopiperidine-1-carboxylate at −78 ° C. After completion of the addition, −78 ° C. The mixture was stirred for 1 hour, and further stirred at room temperature for 2 hours. After completion, a saturated aqueous sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate) to give tert-butyl 4-hydroxy-4- (2-phenyl-3-thienyl) piperidine-1-carboxylate 6 .35 g was obtained as a mixture with tert-butyl 4-oxopiperidine-1-carboxylate.

(Reference Example 16)
In the same manner as in Reference Example 15, the compounds shown in Table 2 were obtained.
(Reference Example 17)
22 mg of p-toluenesulfonic acid monohydrate was added to a solution of 250 mg of benzyl 4-hydroxy-4- (4′-methoxybiphenyl-2-yl) piperidine-1-carboxylate in 5 ml of toluene, and the mixture was heated to reflux for 1 and a half hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 230 mg of benzyl 4- (4′-methoxybiphenyl-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate.

(Reference Examples 18-22)
In the same manner as in Reference Example 17, the compounds shown in Tables 2 and 3 were obtained.

(Example 1)
After adding 50 mg of 10% palladium-activated carbon under argon atmosphere to a 3 ml methanol suspension of 220 mg of benzyl 4- (4′-methoxybiphenyl-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate The mixture was stirred overnight at room temperature under a hydrogen atmosphere. Further, 50 mg of palladium hydroxide was added under an argon atmosphere, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere of about 3.4 atm. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia). The purified product was dissolved in ethanol, 0.14 ml of 4M hydrochloric acid / ethyl acetate solution was added and concentrated to obtain crystals. The obtained crystals were recrystallized from ethanol-ethyl acetate to obtain 93 mg of 4- (4′-methoxybiphenyl-2-yl) piperidine monohydrochloride.

(Examples 2 to 8)
In the same manner as in Example 1, the compounds shown in Tables 4 and 5 were obtained.
Example 9
To 500 mg of a mixture of tert-butyl-4- (4′-fluorobiphenyl-2-yl) -4-hydroxypiperidine-1-carboxylate and tert-butyl 4-oxopiperidine-1-carboxylate, 2 ml of triethylsilane, 4 ml of fluoroacetic acid was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia) to obtain 179 mg of 4- (4′-fluorobiphenyl-2-yl) -1,2,3,6-tetrahydropyridine. To a solution of the obtained 4- (4′-fluorobiphenyl-2-yl) -1,2,3,6-tetrahydropyridine (179 mg) in ethanol (5 ml) was added 1M hydrochloric acid aqueous solution (1 ml), 10% palladium-activated carbon (20 mg), hydrogen Stir for 2 hours at room temperature under atmosphere. The reaction solution was filtered and the filtrate was concentrated. The obtained crystals were recrystallized from ethanol-ethyl acetate to obtain 92 mg of 4- (4′-fluorobiphenyl-2-yl) piperidine monohydrochloride.
(Examples 10 to 11)
In the same manner as in Example 9, the compounds shown in Table 5 were obtained.

Example 12
A mixture of tert-butyl 4-hydroxy-4- (2′-methylbiphenyl-2-yl) piperidine-1-carboxylate and tert-butyl 4-oxopiperidine-1-carboxylate 640 mg in ethanol 10 ml solution in 2 ml tetrahydrofuran, 100 mg of palladium hydroxide was added, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere of about 3.4 atm. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and 150 mg of tert-butyl 4- (2′-methylbiphenyl-2-yl) piperidine-1-carboxylate was added. Obtained. Subsequently, 5 ml of 4M hydrochloric acid / ethyl acetate solution was added to 2 ml of ethanol suspension of 203 mg of tert-butyl 4- (2′-methylbiphenyl-2-yl) piperidine-1-carboxylate and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the crystallized residue was recrystallized using ethanol-ethyl acetate to obtain 157 mg of 4- (2′-methylbiphenyl-2-yl) piperidine monohydrochloride.

(Example 13)
To 1.3 g of a mixture of tert-butyl-4-hydroxy- (5-phenyl-2-thienyl) piperidine-1-carboxylate and tert-butyl 4-oxopiperidine-1-carboxylate, 3 ml of triethylsilane, trifluoroacetic acid 6 ml was added and stirred in a water bath for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia). The purified product was dissolved in ethanol, and 2.0 ml of 4M hydrochloric acid / ethyl acetate solution was added and concentrated to obtain crystals. The obtained crystals were recrystallized from ethanol-ethyl acetate to obtain 320 mg of 4- (5-phenyl-2-thienyl) piperidine monohydrochloride.

(Examples 14 to 17)
In the same manner as in Example 13, the compounds shown in Table 6 were obtained.

Tables 1 to 6 show chemical structural formulas and physicochemical properties of the compounds obtained in Reference Examples and Examples. Further, the compounds described in Tables 7 to 9 are easily obtained by using the above-described production methods, reference examples, production methods of Examples, production methods known to those skilled in the art, and variations thereof. be able to.
The symbols in the table have the following meanings.
Rf. : Reference example number Ex. : Example number Me: Methyl group
Salt: salt MS: mass spectrum (FAB or ESI unless otherwise specified) m / z:
NMR: nuclear magnetic resonance spectrum (400 MHz ¹ H-NMR, DMSO-d ₆ , TMS internal standard unless otherwise specified) δ (ppm):

[Pharmacological test]
(Sodium channel inhibition test)
The sodium channel inhibitory action of representative compounds of the active ingredient (I) and the compound (I) of the present invention was confirmed by [ ¹⁴ C] guanidine incorporation experiments using rat brain tissue. [ ¹⁴ C] guanidine incorporation experiments were performed by modifying the method of Bonisch et al. (British Journal of Pharmacology 108, 436-442, 1993). [ ¹⁴ C] guanidine, a sodium tracer, was used to measure the inhibitory activity of [ ¹⁴ C] guanidine induced by veratridine, a sodium channel activator, on rat neuronal cortical primary neurons.

a. Preparation of rat cerebral cortex primary neuron culture system Pregnant rats (Wistar, female, 19 days of gestation) were anesthetized with ether and killed by carotid artery amputation. The fetus was extracted from the pregnant rat, disinfected with ethanol for disinfection, and then the cerebral cortex was extracted. Cerebral cortex was digested with papain, dispersed in a culture medium, and then seeded on a 96-well white plate coated with poly-L-lysine at a density of 2.5 × 10 ⁵ cells / well, and a CO ₂ incubator (37 ° C., 5% The cells were cultured for 2 days in CO ₂ ).

b. Evaluation of Test Compound Each well was washed once with assay buffer (135 mM Choline Cl, 5 mM KCl, 1 mM MgSO ₄ , 5.5 mM Glucose, 1 mg / mL BSA, 10 mM Hepes-Tris, pH 7.4), and then assay buffer was used. In addition, incubation was performed at 25 ° C. for 10 minutes. Thereafter, the reaction solution (test compound, [ ¹⁴ C] guanidine and 100 μM veratridine) was substituted and incubated at 25 ° C. for 15 minutes. The reaction was stopped by washing three times with a cold washing buffer (135 mM NaCl, 5 mM KCl, 1 mM MgSO ₄ , 10 mM Hepes-Tris, pH 7.4). After adding 17 μL of 0.1 N NaOH to each well and stirring, 100 μL of scintillator was added and further stirred, and the radioactivity was measured with a liquid scintillation counter. The amount of sodium channel-specific uptake in each experiment was the portion of total uptake that was inhibited by 1 mM mexiletine. The effect of the test compound on the sodium channel is expressed as a 50% inhibition rate (IC ₅₀ value) for specific uptake.

As shown in Table 10, the active ingredient (I) and the compound (I) of the present invention showed an IC ₅₀ value of about 3 to 30 μM and were more potent than mexiletine (about 70 μM).

(Analgesic action in a model of streptozotocin-induced diabetic neuropathy)
The inhibitory effect on neuropathic pain of representative compounds among the active ingredient (I) and the compound (I) of the present invention was confirmed by evaluation of analgesic action in streptozotocin (STZ) -induced diabetic neuropathy mice. Evaluation was performed by partially modifying the method of Kamei et al. (Pharmacology Biochemistry & Behavior 39, 541-544, 1991).

  200 mg / kg body weight of STZ was intraperitoneally administered to male 4-week-old ICR mice to prepare a diabetic neuropathy model. The tail pinch test was adopted as an evaluation method for analgesic action. That is, the analgesic action was detected as the extension width (seconds) of the latency from the time when the tail was sandwiched between the clams to the time when the animal turned around. On the 14th day after STZ administration, a test compound pre-administration test was conducted, and the response latency before test compound administration was measured. Only animals whose reaction latency before test compound administration was 3 seconds or less were subjected to the test compound evaluation test on the next day (15 days after STZ administration). In the test compound evaluation test, the reaction latency after administration of the test compound was measured. The test compound was orally administered at 30 mg / kg 45 minutes before measuring the response latency. The analgesic action of the test compound is expressed as an extension width (second) of the latency by a calculation formula of (response latency after test compound administration) − (response latency before test compound administration).

  As shown in Table 11, the active ingredient (I) and the compound of the present invention (I) exhibited an extended range (seconds) of latency of about 2 to 6 seconds, and had a good analgesic action.

Claims (4)

A sodium channel inhibitor comprising as an active ingredient a piperidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the above formula (I) have the following meanings, respectively.
Ring A: a benzene ring or a 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from N, S and O,
R ^{1 to} R ⁶ : the same or different, hydrogen atom, halogen atom, lower alkyl, —O-lower alkyl, —O-aryl, aryl, cycloalkyl, —C (═O) -lower alkyl, COOH, —C (= O) -O- lower _{alkyl, -C (= O) -NH 2} , -C (= O) NH- lower alkyl, -C (= O) N- (lower alkyl) _2, OH, -O- C (= O) - lower alkyl, NH _2, -NH- lower alkyl,-N-(lower _{alkyl) 2, -NH-C (=} O) - lower alkyl, CN or NO ₂₎ A piperidine derivative represented by the following general formula (a) or (b) or a pharmaceutically acceptable salt thereof.

(The symbols in the above formula (a) or (b) have the following meanings, respectively.
R ^{1 to} R ⁶ : the same or different, hydrogen atom, halogen atom, lower alkyl, —O-lower alkyl, —O-aryl, aryl, cycloalkyl, —C (═O) -lower alkyl, COOH, —C (= O) -O- lower _{alkyl, -C (= O) -NH 2} , -C (= O) NH- lower alkyl, -C (= O) N- (lower alkyl) _2, OH, -O- C (= O) - lower alkyl, NH _2, -NH- lower alkyl,-N-(lower _{alkyl) 2, -NH-C (=} O) - lower alkyl, CN or NO ₂₎   A pharmaceutical composition comprising the piperidine derivative according to claim 2 or a pharmaceutically acceptable salt thereof as an active ingredient.   The pharmaceutical composition according to claim 3, which is a sodium channel inhibitor.