JP2013028536A - Cyclic amine-1-carboxylic acid ester derivative and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful as a therapeutic agent for pain and inflammation caused by various diseases, such as neurogenic pain and rheumatoid arthritis.SOLUTION: Disclosed is a compound represented by formula (I) or a salt thereof (wherein Rrepresents a methyl group or H; Rrepresents H, an alkyl group, an alkyl carbonyl or aryl carbonyl group; Rrepresents a cycloalkyl group, a cycloalkenyl group, an aryl group or a heteroaryl group (with each group being optinally substituted by an alkyl group, an alkenyl group, a cycloalkyl group or a halogen atom), or represents an alkyl group or an alkenyl group; X represents -NH-C(=O)-NH-, -C(=O)-NH-, -NH-C(=S)-NH-, -C(=S)-NH-, -NH-C(=S)-, -NH-C(=O)-CH-, -NH-C(=O)-CH-CH-, -NH-C(=O)-O-, -O-C(=O)-NH-, -C(=O)-O-, -O-C(=O)- or -C(=O)-; n and m each represents a number of 1-3; and p represents a number of 0-2).

Description

  The present invention relates to a cyclic amine-1-carboxylic acid ester derivative useful as a therapeutic agent for pain and inflammation, and more specifically, a cyclic amine-1-carboxylic acid ester having a substituent having a 3,4-disubstituted benzyl group on the ring. The present invention relates to a derivative and a pharmaceutical composition containing it.

  Currently, narcotic analgesics such as morphine and non-narcotic analgesics such as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are mainly used as analgesics. However, narcotic analgesics are severely restricted in their use due to the development of tolerance, dependence or other serious side effects. In addition, NSAIDs are not effective for severe pain, and have problems such as a high rate of upper gastrointestinal tract disorders and liver disorders after long-term administration. Therefore, analgesics with higher analgesic effects and fewer side effects are eagerly desired. In addition, highly satisfactory analgesics have been found for neuropathic pain (neuropathic pain) such as diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, and HIV-polyneuropathy. However, the development of therapeutic agents effective for them is also expected.

  Capsaicin; (E) -8-methyl-N-vanillyl-6-nonenamide is contained in the juice of Capsicum plants, and is not only used as a spice but also has analgesic and anti-inflammatory effects It has been known. In addition, civamide, which is a geometric isomer of capsaicin; (Z) -8-methyl-N-vanillyl-6-nonenamide is also known to have analgesic action. Capsaicin exerts analgesic and anti-inflammatory effects by acting specifically on a special receptor present in primary afferent sensory nerves (mainly C fibers: capsaicin-sensitive nerves), but it exhibits intense irritation ( It is also well known to have (pain). In recent years, this receptor has been cloned and named vanilloid receptor subtype 1 (VR1) [Non-patent Document 1]. Subsequently, this receptor is classified into TRPV (transient receptor potential) superfamily TRPV and is called TRPV1 [Non-Patent Document 2].

TRPV1 is considered to be a Ca ²⁺ highly permeable cation channel having a transmembrane region 6 times from its amino acid sequence, and is activated not only by capsaicin-like compounds but also by stimulation with heat, acid, etc. It has been suggested that it may contribute to pain in the pathology. When capsaicin acts on TRPV1 on the primary afferent sensory nerve, its cation channel is opened, the membrane is depolarized, neuropeptides such as substance P are released, etc., and pain is induced. Capsaicin, which is such a pain stimulating substance, is actually used in the treatment of pain such as diabetic neuropathy and rheumatoid arthritis, as a result of persistent TRPV1 cation channel opening by capsaicin. It is understood that it becomes unresponsive (desensitization) to painful stimulation [Non-Patent Document 3].

  Therefore, it is considered that capsaicin-like compounds (TRPV1 agonists) can exert analgesic effects based on a completely different medicinal mechanism (capsaicin-sensitive sensory nerve desensitization) from existing analgesics. It is highly expected to be effective as a therapeutic drug for pain caused by various pathological conditions such as neuropathic pain not responding to rheumatoid arthritis and osteoarthritis.

  In the US, capsaicin is sold as an analgesic in the form of a cream. However, this cream has a problem that initial irritation pain is strong. Therefore, it has a capsaicin-like medicinal mechanism as a therapeutic agent for pain caused by various pathological conditions such as neuropathic pain, rheumatoid arthritis, osteoarthritis, etc. Development is desired.

  In addition, compounds with capsaicin-like medicinal mechanisms are pruritic diseases, allergic and non-allergic rhinitis, overactive bladder, stroke, irritable bowel, which is a pathological condition involving primary afferent sensory nerves (C fibers). It is also considered useful as a therapeutic agent for syndromes, respiratory diseases such as asthma / chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome.

  Furthermore, since it has been reported that capsaicin promotes the secretion of adrenaline and exhibits an anti-obesity effect [Non-patent Document 4], a compound having a medicinal mechanism of capsaicin is useful as a therapeutic agent for obesity. It is believed that. Further, since it has been reported that insulin resistance is improved by treating diabetic rats with capsaicin [Non-Patent Document 5], it is considered useful as a therapeutic agent for diabetes.

Nature, 389, 816 (1997) Annu. Rev. Neurosci., 24, 487 (2001) Pharmacol. Rev., 51, 159 (1999) Pharmacol. Rev., 38, 179 (1986) Eur .J .Endocrinol., 153, 963, (2005)

  It is an object of the present invention to have sufficient analgesic action and low irritation useful as a therapeutic or preventive agent for pain and inflammation caused by various pathological conditions such as neuropathic pain, rheumatoid arthritis and osteoarthritis. It is to provide a compound.

As a result of continual research, the present inventors have obtained a cyclic amine-1-carboxylate derivative having a substituent having a 3,4-disubstituted benzyl group on the ring, that is, represented by the following formula (I). Has been found to have a strong analgesic action but is less irritating, thus completing the present invention. That is, the present invention provides the following inventions.
Item 1: The following formula (I):

[Where
R ¹ represents a methyl group or a hydrogen atom,
R ² represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkylcarbonyl group or an arylcarbonyl group,
R ³ is a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl). Or a C _6-12 alkyl group or a C _6-12 alkenyl group;
X represents —NH—C (═O) —NH—, —C (═O) —NH—, —NH—C (═S) —NH—, —C (═S) —NH—, —NH—. C (= S) -, - NH-C (= O) -CH 2 -, - NH-C (= O) -CH 2 -CH 2 -, - NH-C (= O) -O -, - O -C (= O) -NH-, -C (= O) -O-, -O-C (= O)-or -C (= O)-
n and m are the same or different and each represents an integer of 1, 2 or 3,
p represents an integer of 0, 1 or 2. ]
Or a physiologically acceptable salt thereof.

Item 2: In the formula (I), R ³ is a C _3-8 cycloalkyl group or an aryl group (each group is a group consisting of C _1-6 alkyl, C _2-6 alkenyl and C _3-8 cycloalkyl) Or a physiologically acceptable salt thereof, wherein the compound is optionally substituted with 1 to 5 substituents which are the same or different from each other.
Item 3: In the formula (I), X represents —NH—C (═O) —NH—, —C (═O) —NH—, —NH—C (═S) —NH—, —C (= Item 3. The compound according to Item 1 or 2, or a physiologically acceptable salt thereof, which represents S) —NH— or —NH—C (═S) —.
Item 4: Item 3 in which X in the formula (I) represents —NH—C (═O) —NH—, —NH—C (═S) —NH— or —NH—C (═S) —. Or a physiologically acceptable salt thereof.
Item 5: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 4, wherein in formula (I), n and m are the same or different and each represents an integer of 1 or 2.
Item 6: The compound according to Item 5 or a physiologically acceptable salt thereof, wherein in formula (I), n and m are both 2.
Item 7: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 6, wherein p represents an integer of 1 in Formula (I).

Item 8: The compound according to any one of Items 1 to 7, or a physiologically acceptable salt thereof, wherein in Formula (I), R ¹ represents a methyl group.
Item 9: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 8, wherein R ² in formula (I) represents a hydrogen atom.
Item 10: A pharmaceutical composition comprising the compound according to any one of Items 1 to 9 or a physiologically acceptable salt thereof as an active ingredient.
Item 11: A therapeutic or prophylactic agent for pain and / or inflammation comprising the compound according to any one of Items 1 to 9 or a physiologically acceptable salt thereof as an active ingredient.
Item 12: An analgesic or anti-inflammatory agent comprising the compound according to any one of Items 1 to 9 or a physiologically acceptable salt thereof as an active ingredient.
Item 13: The compound according to any one of Items 1 to 9, or a physiologically acceptable salt thereof, a narcotic analgesic, a neuropathic pain therapeutic agent, a nonsteroidal anti-inflammatory drug, a steroidal anti-inflammatory drug, A medicament comprising at least one other drug selected from the group consisting of an antidepressant, an antiepileptic drug, an anticonvulsant, an anesthetic, an antiarrhythmic drug, a local anesthetic and an anxiolytic drug.

  Item 14: A pharmaceutical composition comprising the pharmaceutical according to Item 13 as an active ingredient.

  Item 15: A therapeutic or prophylactic agent for pain and / or inflammation, comprising the pharmaceutical according to Item 13 as an active ingredient.

According to the present invention, it is possible to provide a compound having a strong analgesic action and a weak irritation, so that analgesics and anti-inflammatory drugs, for example, neuropathic pain, inflammatory properties in which existing analgesics are not sufficiently effective A therapeutic or preventive agent for pain and / or inflammation of pain, musculoskeletal pain, visceral pain, skeletal pain, cancer pain, and combinations thereof can be provided. Pain and / or inflammation pathologies include, for example, diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-polyneuropathy, postoperative pain, central and peripheral neuropathy, neuropathic lumbar back Various types of neuropathic pain including pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain, fascia Facial pain, abdominal pain, neck pain, central pain, tooth pain, opioid resistant pain, visceral pain, surgical pain, bone injury pain, angina pain, and various pains and inflammations that require treatment.
Furthermore, according to the present invention, such as migraine or cluster headache, pruritus, allergic or non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, asthma / chronic obstructive pulmonary disease A therapeutic or prophylactic agent for respiratory diseases, dermatitis, mucositis, gastric / duodenal ulcer, inflammatory bowel syndrome and diabetes, and obesity can be provided.

  Hereinafter, the compound represented by the formula (I) of the present invention will be further described.

  The physiologically acceptable salt of the compound represented by the formula (I) is a physiologically acceptable acid addition salt of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure, Or the salt with the physiologically acceptable base of the compound of the formula (I) which has a group which can form a salt with a base in a structure is meant. Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid salt, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate Organic acid salts such as, and amino acid salts such as glutamate and aspartate. Specific examples of salts with bases include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt or calcium salt, salts with organic bases such as pyridine salt and triethylamine salt, and lysine, arginine and the like. Examples include salts with amino acids.

  Since the compounds of formula (I) and their salts may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention. The That is, the “compound of the present invention” includes these hydrates and / or solvates in addition to the compound represented by the above formula (I) and physiologically acceptable salts thereof.

  In addition, the compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore may exist as several stereoisomers. . In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.

  Terms used in this specification will be described below.

“Alkyl group” means a linear or branched saturated hydrocarbon group. For example, “C _1-4 alkyl group” or “C _1-6 alkyl” means 1 to 1 carbon atoms. 4 or 1 to 6 groups are meant. Specific examples thereof include “C _1-4 alkyl group” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and “C _1-6 alkyl” In addition to pentyl, isopentyl, neopentyl, hexyl and the like. In addition, examples of the “C _6-12 alkyl group” include hexyl, isoheptyl, octyl, nonyl, decyl and the like. The alkyl group may be linear. Further, it may be branched.

The “alkenyl group” means a linear or branched unsaturated hydrocarbon group having at least one double bond. For example, “C _2-6 alkenyl” means at least one double bond. It means an unsaturated hydrocarbon group having 2 to 6 carbon atoms. Specific examples thereof include, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 1,3-butadienyl, 2-, 3- or 4-pentenyl, and 2-methyl-2. -Butenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 4-methyl-1-pentenyl, 3,3-dimethyl-1-butenyl, 5-hexenyl and the like can be mentioned. In addition, examples of the “C _6-12 alkenyl group” include 4-methyl-3-pentenyl, 3,3-dimethyl-1-butenyl, 5-hexenyl, 3-ethyl-pentenyl, 3-octenyl and the like. . The alkenyl group may be linear. Further, it may be branched. The number of double bonds contained in the alkenyl group may be one. Two may be sufficient.

The “C _3-8 cycloalkyl group” means a monocyclic saturated hydrocarbon group having 3 to 8 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The “C _3-8 cycloalkenyl group” means a monocyclic unsaturated hydrocarbon group having 1 to 2 carbon atoms and having 3 to 8 carbon atoms. Specific examples thereof include a cyclohexenyl group, a cycloheptenyl group, a cyclopentenyl group, and a 2,4-cyclohexadienyl group. The number of double bonds contained in the cycloalkenyl group is preferably one.

  “Aryl group” means phenyl or naphthyl, with phenyl being preferred. Similarly, the “arylcarbonyl group” means phenylcarbonyl or naphthylcarbonyl.

“Heteroaryl group” means 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and 1 to 3 ring unsaturated heterocycles consisting of 1 to 12 carbon atoms. Means a formula group, each ring being a 3-8 membered ring. Specific examples thereof include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, benzisoxazolyl, benzoxiadiazolyl, benzothiadiazolyl, pyridazinyl, Examples include pyrazolopyridinyl, cinnolinyl, triazolyl, quinolyl, isoquinolyl, naphthyridinyl and the like. Examples of “halogen” include fluorine, chlorine, bromine and iodine.
Further, the number of carbon atoms in “C _1-4 alkylcarbonyl” modifies only the group or moiety that immediately follows. Therefore, the above case, since the C _{1 to 4} is modified only alkyl, corresponds to acetyl The "C ₁ alkylcarbonyl". Thus, specific examples of the “C _1-4 alkylcarbonyl group” include acetyl, propionyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl and the like.

  As the “cycloalkyl-substituted cycloalkyl group”, one or more (for example, 1 to 5, preferably 1 to 4) hydrogen atoms of the above cycloalkyl group are substituted with the above-described alkyl. Say things. Specifically, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl, 4,4-dimethylcyclohexyl, 3,5-dimethylcyclohexyl, 3 , 3,5,5-tetramethylcyclohexyl, 4,4-diethylcyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-butylcyclohexyl, 4-propylcyclohexyl, 4-isopropylcyclohexyl, 4-t-butylcyclohexyl, etc. Can be mentioned. The same applies to each of the following substituents substituted with alkyl: cycloalkenyl group, aryl group, and heteroaryl group.

  Further, the “cycloalkyl group substituted with alkenyl” is a group in which one or more (for example, 1 to 2, preferably 1) hydrogen atoms of the cycloalkyl group are substituted with the alkenyl. Say. Specifically, 2-ethenylcyclohexyl, 3-ethenylcyclohexyl, 4-ethenylcyclohexyl, 2- (1-propenyl) cyclohexyl, 3- (1-propenyl) cyclohexyl, 4- (1-propenyl) cyclohexyl, Examples include 2-isopropenylcyclohexyl, 3-isopropenylcyclohexyl, 4-isopropenylcyclohexyl, 4- (1-butenyl) cyclohexyl, 4- (2-butenyl) cyclohexyl, 4- (1-isobutenyl) cyclohexyl, and the like. The same applies to each of the following substituents substituted with alkenyl: cycloalkenyl group, aryl group, heteroaryl group.

  Further, the “aryl group substituted with cycloalkyl” refers to a group in which one or more (for example, 1 to 3, preferably 1) hydrogen atoms of the above aryl group are substituted with cycloalkyl. Say. Specifically, 2-cyclopropylphenyl, 4-cyclopropylphenyl, 2-cyclobutylphenyl, 4-cyclobutylphenyl, 2-cyclopentylphenyl, 4-cyclopentylphenyl, 2-cyclohexylphenyl, 4-cyclohexylphenyl, etc. Can be mentioned. The same applies to each of the following substituents substituted with cycloalkyl: a cycloalkyl group, a cycloalkenyl group, and a heteroaryl group.

  The “aryl group substituted with halogen” refers to a group in which one or more (for example, 1 to 5, preferably 1 to 2) hydrogen atoms of the aryl group are substituted with halogen. Specific examples include 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-iodophenyl, 4-iodophenyl, and the like. The same applies to each of the following substituents substituted with halogen: a cycloalkyl group, a cycloalkenyl group, and a heteroaryl group.

  In addition, when the hydrogen atom of a cycloalkyl group, a cycloalkenyl group, an aryl group or a heteroaryl group is substituted with a plurality of substituents, these substituents may be the same or different. As these specific examples, those obtained by appropriately combining the above examples can be exemplified.

  Examples of each group in the compound (I) of the present invention include the following.

R ¹ is a methyl group or a hydrogen atom, preferably a methyl group. R ² represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkylcarbonyl group or an arylcarbonyl group, and preferably a hydrogen atom.

R ³ represents a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl). Or may be substituted at a substitutable position with halogen, and may be substituted with, for example, the same or different 1 to 5 substituents described above, or C _{6- A 12} alkyl group or a C _6-12 alkenyl group is shown.

The cycloalkyl group is preferably a C _4-8 cycloalkyl group, more preferably a C _5-7 cycloalkyl group. The cycloalkyl group is preferably unsubstituted or substituted with 1 to 5 identical or different C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl, More preferably, it is unsubstituted or substituted with 1 to 5 identical or different C _1-4 alkyl, C _2-4 alkenyl or C _3-6 cycloalkyl groups.

The cycloalkenyl group is preferably a _C4-8 cycloalkenyl group, more preferably a _C5-8 cycloalkenyl group. The cycloalkenyl group is preferably unsubstituted or substituted with 1 to 5, preferably 1 to 2 identical or different C _1-6 alkyl, C _2-6 alkenyl or C _3-8 cycloalkyl. More preferably, it is unsubstituted or substituted with 1 to 2 identical or different C _1-4 alkyl, C _2-4 alkenyl or C _3-6 cycloalkyl groups.

The aryl group is preferably a phenyl group. The aryl group is preferably unsubstituted or substituted with 1 to 5 identical or different C _1-6 alkyl, C _2-6 alkenyl or C _3-8 cycloalkyl, more preferably May be unsubstituted or substituted with 1 to 2 identical or different C _1-5 alkyl, C _2-5 alkenyl or C _3-6 cycloalkyl.

The heteroaryl group is preferably thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, benzoisoxazolyl, benzoxiadiazolyl, benzothiadiazolyl , Pyridazinyl, pyrazolopyridinyl, cinnolinyl, triazolyl, quinolyl, isoquinolyl, naphthyridinyl and the like, more preferably thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl , Thiadiazolyl, benzisoxazolyl, benzoxiadiazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, naphthy Jiniru can be exemplified. Also, the heteroaryl group is preferably substituted with 1 to 5 identical or different C _1-6 alkyl, C _2-6 alkenyl or C _3-8 cycloalkyl at an unsubstituted or substitutable position. More preferably, it is unsubstituted or substituted with 1 to 2 identical or different C _1-5 alkyl, C _2-5 alkenyl or C _3-6 cycloalkyl.

Among these R ³ , a preferred group is a C _3-8 cycloalkyl group or an aryl group (each group is a group consisting of C _1-6 alkyl, C _2-6 alkenyl and C _3-8 cycloalkyl). And may be substituted with the same or different 1 to 5 substituents.), More preferred groups include 1 to 4 identical or different C _1-6 alkyls, C _2— C _5-7 cycloalkyl group optionally substituted with ₆ alkenyl or C _3-8 cycloalkyl group, or substituted with 1 to 2 identical or different C _1-6 alkyl or C _3-6 cycloalkyl group It may be a phenyl group.

X represents —NH—C (═O) —NH—, —C (═O) —NH—, —NH—C (═S) —NH—, —C (═S) —NH—, —NH—. C (= S) -, - NH-C (= O) -CH 2 -, - NH-C (= O) -CH 2 -CH 2 -, - NH-C (= O) -O -, - O -C (= O) -NH-, -C (= O) -O-, -O-C (= O)-or -C (= O)-, preferably -NH-C (= O ) -NH-, -C (= O) -NH-, -NH-C (= S) -NH-, -C (= S) -NH- or -NH-C (= S)-, more preferably —NH—C (═O) —NH—, —NH—C (═S) —NH— or —NH—C (═S) —.
n and m are the same or different and each represents an integer of 1, 2 or 3, preferably 1 or 2, more preferably an integer of 1 or 2, or one is 1 and the other is 2. Show. Particularly preferably, both are 2.
P represents an integer of 1, 2, or 3, preferably an integer of 1 or 2, and more preferably an integer of 1.

  Preferred compounds in the present invention are represented by the following formula (I ′)

[Where
R ³ ′ is a C _5-7 cycloalkyl group optionally substituted with 1 to 4 identical or different C _1-6 alkyl, C _2-6 alkenyl or C _3-8 cycloalkyl,
X represents —NH—C (═O) —NH—, —C (═O) —NH—, —NH—C (═S) —NH—, —C (═S) —NH— or —NH—. C (= S) −,
n and m both represent an integer of 1 or 2, or one represents 1 and the other represents 2. ]
Or a physiologically acceptable salt thereof.

  In addition, the following abbreviations may be used for simplification of description in this specification.

  Me: methyl group, t-: tert-, p-: para-, THF: tetrahydrofuran, DMF: N, N-dimethylformamide.

Process for Producing the Compound of the Present Invention The compound represented by the formula (I) or a physiologically acceptable salt thereof is a novel compound, for example, a process according to the method described below, the examples described later or known methods. Can be manufactured by.

  The compound used in the following production method may form a salt as long as the reaction is not hindered.

  In addition, in each of the following reactions, when a functional group that may participate in the reaction is included in the structure of the starting material, such as an amino group, a carboxyl group, a hydroxyl group, a carbonyl group, etc., these groups are generally It may be protected by introducing a protecting group as used, and in that case, the desired compound can be obtained by removing the protecting group as appropriate after completion of the reaction.

  Examples of the protecting group for the amino group include alkylcarbonyl such as acetyl and propionyl; formyl; phenylcarbonyl; alkyloxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; phenyloxycarbonyl; aralkyloxy such as benzyloxycarbonyl Carbonyl; trityl; phthaloyl; tosyl and the like are used.

  As the protecting group for the carboxyl group, for example, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl; phenyl; benzyl; trityl; silyl and the like are used.

  Examples of the hydroxyl-protecting group include methyl; tert-butyl; allyl; substituted methyl such as methoxymethyl and methoxyethoxymethyl; ethoxyethyl; tetrahydropyranyl; tetrahydrofuranyl; trityl; aralkyl such as benzyl; acetyl, propionyl, etc. Examples include alkylcarbonyl; formyl; benzoyl; aralkyloxycarbonyl such as benzyloxycarbonyl; silyl and the like.

The carbonyl group is protected by converting the carbonyl group into an acyclic ketal such as dimethyl ketal or diethyl ketal, or a cyclic ketal such as 1,3-dioxolane or 1,3-dioxane.
Process for the preparation of the compound of formula (I) (1)

(In the formula, R ¹ , R ² , R ³ , X, m, n and p are the same as defined in Item 1, and Y is a leaving group (for example, a halogen atom, a lower alkoxy group, a phenoxy group, Imidazolyl group, etc.)

  A compound of formula (I) is prepared by converting a compound of formula (II) into a reactive derivative represented by formula (III) and then reacting it with a compound of formula (IV) under commonly used conditions. be able to.

  The above reaction between the compound of formula (III) and the compound of formula (IV) is usually carried out in a solvent or in the absence of a solvent. The solvent to be used should be selected according to the type of raw material compound, and examples thereof include toluene, THF, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, DMF and the like. These solvents can be used alone or as a mixed solvent of two or more. Moreover, this reaction is normally performed in presence of a base. Specific examples of the base include inorganic bases such as potassium carbonate and sodium bicarbonate, or organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine. While the reaction temperature varies depending on the type of raw material compound used, it is generally about −30 ° C. to about 150 ° C., preferably about −10 ° C. to about 80 ° C. The reaction time is about 1 hour to 48 hours.

  The production of compound (III) from compound (II) is described, for example, in J. Org. Chem., 27, 961 (1962), J. Chem. Soc., Perkin Trans. 1, 1205 (1996), Tetrahedron, 61, 7153 (2005) or the like, or a method analogous thereto. In addition, the compound of formula (II) may be used in the form of an acid addition salt such as hydrochloride to generate a free base in the reaction system.

  The compound of the formula (IV) is commercially available, or can be produced by a method known per se or a method analogous thereto.

Process for the preparation of the compound of formula (I) (2)

(In the formula, R ¹ , R ² , R ³ , X, m, n and p are the same as defined in Item 1, and Y is a leaving group (for example, a halogen atom, a lower alkoxy group, a phenoxy group, Imidazolyl group, etc.)

The compound of the formula (I) can be produced by reacting the compound of the formula (II) with the compound of the formula (V) or the formula (VI) under usually used conditions.
The above reaction between the compound of formula (II) and the compound of formula (V) or formula (VI) is usually carried out in a solvent or without solvent. The solvent to be used should be selected according to the type of raw material compound, and examples thereof include toluene, THF, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, DMF and the like. These solvents can be used alone or as a mixed solvent of two or more. In addition, the compound of formula (II) may be used in the form of an acid addition salt such as hydrochloride to generate a free base in the reaction system. Moreover, this reaction is normally performed in presence of a base. Specific examples of the base include inorganic bases such as potassium carbonate and sodium bicarbonate, or organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine. While the reaction temperature varies depending on the type of raw material compound used, it is generally about −30 ° C. to about 150 ° C., preferably about −10 ° C. to about 80 ° C. The reaction time is about 1 hour to 48 hours.

  The compound of the formula (V) is commercially available, or a known method such as the method described in Synthesis, 103 (1993), J. Org. Chem., 53, 2340 (1988), or the like. Can be produced according to the methods described above. In addition, the compound of formula (VI) may be obtained by a known method such as the method described in J. Org. Chem., 27, 1901 (1962), Org. Synth., VI, 418 (1988), or the like. It can be produced according to a similar method.

Process for the preparation of the compound of formula (II ')

(Wherein R ¹ , R ² , m, n and p are the same as defined in item 1, Y represents a leaving group (for example, a halogen atom, a lower alkoxy group, a phenoxy group, an imidazolyl group, etc.)). And P ¹ represents an amino-protecting group.)

The compound of formula (II ′) can be produced by deprotecting the protecting group (P ¹ ) of formula (X). A compound of formula (X) is prepared by converting a compound of formula (VII) into a reactive derivative represented by formula (VIII) and then reacting it with a compound of formula (IX) under commonly used conditions. be able to.

  The production of compound (X) from compound (VII) can be carried out, for example, according to the method described in Tetrahedron, 61, 7153 (2005), Synthesis, 423 (1989) or the like, or a method analogous thereto. The compound of formula (VII) is commercially available or can be produced by a method known per se or a method analogous thereto, and is used in the form of an acid addition salt such as hydrochloride, The free base may be generated with

Process for the preparation of the compound of formula (II ")

(In the formula, R ¹ , R ² , m, n and p are the same as defined in item 1, and P ¹ represents an amino-protecting group.)
A compound of formula (II ″) can be prepared by deprotecting the protecting group (P ¹ ) of formula (XIII). The compound of the formula (XIII) can be produced by an amidation reaction between a compound of the formula (XI) and a compound of the formula (XII) under a commonly used reaction condition. The compound of formula (XI) may be reacted with a compound of formula (XII) after conversion to a reactive derivative at the carboxyl group.

The compound of the formula (XI) is commercially available, or can be produced by a method known per se or a method analogous thereto.
Preparation of compound of formula (I ''')

(Wherein R ¹ , R ² , R ³ , m, n and p are the same as defined in item 1).
The production of the compound of the formula (I ′ ″) from the compound of the formula (I ″) can be carried out, for example, using the Lawson reagent, as described in Tetrahedron, 41, 2567 (1985), Synthesis, 152 (1988), etc. Or it can carry out according to the method according to these.

  The compound of the formula (I ″) can be produced according to the methods described in the production methods (1) and (2) of the compound of the formula (I) described above.

  Compounds of the formula (I) such as X being —NH—C (═S) —NH—, —C (═S) —NH— and the like can also be produced according to the methods described in the above production methods and examples.

  The compound of the formula (I) obtained by the above production method can be isolated and purified according to a conventional method such as chromatography, recrystallization, reprecipitation and the like. The optical isomer can also be derived from asymmetric synthesis such as using a starting material having an asymmetric center, or by optical resolution such as using a chiral column or fractional recrystallization. Geometric isomers such as cis isomer and trans isomer can be derived synthetically and can be separated using a column. The compound of formula (I) may be obtained in the form of a salt depending on the type of functional group present in the structural formula, selection of the raw material compound, and reaction treatment conditions. Can be converted. On the other hand, for example, the compound of the formula (I) having a group capable of forming an acid addition salt in the structural formula can be converted into an acid addition salt by treating with various acids according to a conventional method.

  The compounds of the present invention and physiologically acceptable salts thereof and hydrates or solvates thereof have a strong analgesic action and are weakly irritating, so that not only oral administration but also parenteral, for example, transdermal Administration, topical administration, nasal administration and intravesical injection are also effective. Therefore, the compounds of the present invention are used as analgesics and anti-inflammatory drugs, for example, neuropathic pain, inflammatory pain, musculoskeletal pain, visceral pain, skeletal pain, cancer in which existing analgesics do not sufficiently respond It is useful as a therapeutic or prophylactic agent for sexual pain, and pain and / or inflammation of a combination thereof. Pain and / or inflammation pathologies include, for example, diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-polyneuropathy, postoperative pain, central and peripheral neuropathy, neuropathic lumbar back Various types of neuropathic pain including pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain, fascia Treatment or prevention of facial pain, abdominal pain, neck pain, central pain, toothache, opioid resistant pain, visceral pain, surgical pain, bone injury pain, angina pain, and various pains and inflammations that require treatment Useful as an agent. In addition, migraine or cluster headache, pruritus, allergic or non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, respiratory diseases such as asthma / chronic obstructive pulmonary disease, dermatitis It is also useful as a prophylactic and / or therapeutic agent for mucositis, gastric / duodenal ulcer, inflammatory bowel syndrome and diabetes, and obesity.

  “Neuropathic pain” is chronic pain caused by damage to or pathological changes in the peripheral or central nervous system and can be related to or form the basis for neuropathic pain. obtain. Examples of neuropathic pain include: diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, amputation posttraumatic pain (peripheral and / or central sensitization (eg, phantom limb pain) Cause nerve damage due to injury), neuropathic back pain, cancer, chemical injury, toxins, other major surgery, peripheral nerve damage caused by traumatic injury pressure, lumbar or cervical radiculopathy, fiber Myalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causal gear, thalamic syndrome, nerve root detachment, reflex sympathetic dystrophy or post-thoracotomy pain, malnutrition, or viral or bacterial infection (eg, herpes zoster Or human immunodeficiency virus (HIV) -multiple neuropathic pain), or combinations thereof, metastatic invasion, painful steatosis, various other Fine peripheral neuropathy or central pain conditions related to thalamic conditions, and conditions secondary to a combination thereof are also included in the definition of neuropathic pain.

  As an administration route of the compound of the present invention, oral administration or parenteral administration is possible, and transdermal administration which is one of parenteral administration is preferable. The dose of the compound of the present invention varies depending on the kind of compound, administration form, administration method, patient symptom / age, etc., but is usually 0.005 to 150 mg / kg / day, preferably 0.05 to 20 mg / kg / day. Day, which can be administered once or in several divided doses.

  The compound of this invention can also comprise a pharmaceutical in combination with another chemical | medical agent. Thereby, an additive and synergistic pharmacological effect can be obtained. For example, the compounds of the present invention include, for example, narcotic analgesics, neuropathic pain therapeutics, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, antidepressants, antiepileptic drugs, anticonvulsants, anesthetics, It can be used as a medicament in combination with at least one other drug selected from the group consisting of an antiarrhythmic drug, a local anesthetic and an anxiolytic drug. Among these, at least one other drug selected from the group consisting of narcotic analgesics, therapeutic agents for neuropathic pain, nonsteroidal anti-inflammatory drugs, antiepileptic drugs, antiarrhythmic drugs and local anesthetics is preferable. .

  Specific examples of narcotic analgesics include morphine, codeine, oxycodone, pethidine, fentanyl, pentazocine, tramadol, butorphanol and buprenorphine. Specific examples of therapeutic agents for neuropathic pain include various types, and examples include pregabalin, gabapentin, carbamazepine, lidocaine, duloxetine and mexiletine. Specific examples of non-steroidal anti-inflammatory drugs include acetylsalicylic acid, ibuprofen, loxoprofen sodium, diclofenac sodium, acetaminophen, etodolac, meloxicam, celecoxib, and rofecoxib. Specific examples of steroidal anti-inflammatory drugs include methylprezonidolone, prezonidolone and dexamethasone. Specific examples of antidepressants include amitriptyline, nortriptyline, amoxapine, paroxetine, fluvoxamine, milnacipran, and duloxetine. Specific examples of antiepileptic drugs include carbamazepine, lamotrigine, gabapentin and pregabalin. Specific examples of anticonvulsants include baclofen. Specific examples of the anesthetic include mepivacaine, bupivacaine, tetracaine, dibucaine and ketamine hydrochloride. Specific examples of antiarrhythmic drugs and local anesthetics include lidocaine, procaine, mexiletine, and flecainide. Specific examples of anxiolytic drugs include diazepam and etizolam.

  Other drugs combined with the compounds of the present invention are morphine, codeine, fentanyl, pentazocine, carbamazepine, lamotrigine, pregabalin, gabapentin, lidocaine, loxoprofen sodium, diclofenac sodium, acetaminophen, etodolac, meloxicam, celecoxib and rofecoxib At least one selected from the group consisting of

  The medicament composed of the combination of the compound of the present invention and the above-mentioned other drugs, particularly as an analgesic and an anti-inflammatory drug, for example, neuropathic pain, inflammatory pain in which existing analgesics are not sufficiently effective, It can be provided as a therapeutic or prophylactic agent for pain and / or inflammation of musculoskeletal pain, visceral pain, bone pain, cancer pain, and combinations thereof. Pain and / or inflammation pathologies include, for example, diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-polyneuropathy, postoperative pain, central and peripheral neuropathy, neuropathic lumbar back Various types of neuropathic pain including pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain, fascia Facial pain, abdominal pain, neck pain, central pain, toothache, opioid resistant pain, visceral pain, surgical pain, bone injury pain, angina pain, and various pains and inflammations that require treatment. A pharmaceutical comprising a combination of the pharmaceutical compound of the present invention and another drug can be provided as a therapeutic or prophylactic agent for pain and / or inflammation of these pathological conditions.

  A pharmaceutical comprising the compound of the present invention or a combination thereof with the above other drugs is usually administered in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier. Specific examples include tablets, capsules, granules, powders, syrups, fine granules, solutions, sublinguals, suspensions and other oral preparations, ointments, suppositories (rectal administration), intravesical External preparations such as injections, patches (tapes, transdermal patch preparations, poultices, etc.), lotions, emulsions, creams, jellies, gels, external powders, inhalants, nasal drops, etc. Examples include intradermal injections, subcutaneous injections, injections such as intraperitoneal injections, intrabody injections such as joint cavities, and the like, and drops. These pharmaceutical compositions are prepared according to conventional methods. That is, the pharmaceutical composition containing the compound represented by the formula (I) or a physiologically acceptable salt thereof is an excipient, a binder, a lubricant, a stabilizer, a disintegrant, a base, and a buffer. , Solubilizer, tonicity agent, solubilizer, pH adjuster, surfactant, emulsifier, suspending agent, dispersant, suspending agent, thickener, viscosity modifier, gelling agent, soothing Can contain pharmaceutical carriers such as agents, preservatives, plasticizers, absorption promoters, anti-aging agents, moisturizers, preservatives, fragrances, etc. You can also.

  As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specific examples of the pharmaceutical carrier include lactose, corn starch, sucrose, mannitol, calcium sulfate, crystalline cellulose, croscarmellose sodium, modified starch, carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, methylcellulose, gelatin, Arabic gum, ethyl cellulose, hydroxypropyl cellulose, povidone, light anhydrous silicic acid, magnesium stearate, talc, sucrose fatty acid ester, sorbitan fatty acid ester, hydrogenated oil, carnauba wax, hydroxypropyl methylcellulose, macrogol, cellulose acetate phthalate, hydroxypropyl methylcellulose Acetate phthalate, titanium oxide, calcium phosphate, olive oil, refined lanolin, squalane, silico Oil, castor oil, soybean oil, cottonseed oil, liquid paraffin, white petrolatum, yellow petrolatum, paraffin, lauric acid, myristic acid, oleic acid, stearic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, beeswax, beeswax, etc. , Cholesterol ester, ethylene glycol monoester, propylene glycol monoester, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, polyethylene glycol, glycerin, propylene glycol, ethanol, sorbitol solution, water, hydrophilic ointment, burnishing cream, water-absorbing ointment , Cold cream, carboxyvinyl polymer, polyvinylpyrrolidone, polyisobutylene, vinyl acetate copolymer, acrylic Polymer, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diethyl sebacate, dibutyl sebacate, acetylated monoglyceride, diethylene glycol, dodecyl pyrrolidone, urea, ethyl laurate, azone, kaolin, bentonite, zinc oxide, agarose, Carrageenan, alginic acid or salt thereof, tragacanth, acacia gum, carboxymethyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, xanthan gum, dextrin, polyvinyl alcohol, potassium laurate, potassium palmitate, potassium myristate, etc., sodium lauryl sulfate, sodium cetyl sulfate, Castor oil sulfate (funnel oil), Span (Sorbitan stearate, Sorbitan monooleate, Seth Sorbitan chioleate, sorbitan trioleate, etc.), Tween (polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, polyoxyethylene sorbitan fatty acid ester, etc.), polyoxyethylene hydrogenated castor oil (so-called HCO) , Polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyethylene glycol monolaurate, polyethylene glycol monostearate, poloxamer (so-called pluronic), lecithin (phosphatidylcholine, phosphatidylserine, etc.) Including phospholipids) or its hydrogenated derivatives, chlorofluorocarbons (fluorocarbons) -11, CFC-12, CFC-21, CFC-22, CFC-113, CFC-114, CFC-123, CFC-142c, CFC-134a, CFC-227, CFC-318, 1,1,1,2 -Tetrafluoroethane, etc.), alternative CFCs (HFA-227, HFA-134a, etc.), propane, isobutane, butane, diethyl ether, nitrogen gas, carbon dioxide, benzalkonium chloride, paraben, sodium phosphate, sodium acetate, chloride Examples thereof include sodium, concentrated glycerin, benzalkonium chloride, paraben, stearic acid salt, starch, and cellulose.

  The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, but is usually 0.0025 to 20% by weight in the total composition. These pharmaceutical compositions may also contain other therapeutically effective substances.

  A medicine that employs a combination of the compound of the present invention and the above-mentioned other drug can constitute a single pharmaceutical composition containing the above-mentioned other drug together with the compound of the present invention. Alternatively, a first pharmaceutical composition containing the compound of the present invention and a second pharmaceutical composition containing the other drug are provided separately and administered separately or simultaneously over a period of time. May be. More specifically, it may be a single preparation (compound) containing these active ingredients together, or may be a plurality of preparations in which each of these active ingredients is separately formulated. . When formulated separately, the formulations can be administered separately or simultaneously. Moreover, when it formulates separately, those formulations can be mixed using a diluent etc. at the time of use, and can be administered simultaneously.

  In these medicaments, the compounding ratio of the drugs can be appropriately selected depending on the age, sex and weight of the patient, symptoms, administration time, dosage form, administration method, combination of drugs, and the like. As a pharmaceutical administration route, oral administration and parenteral administration are possible.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples. The compound was identified by NMR spectrum (300 MHz or 400 MHz) or the like. In the structural formula, R and S both represent the absolute configuration of the stereo on the asymmetric carbon atom, and R ^* and S ^* both represent the relative configuration of the stereo on the asymmetric carbon atom.

Example 1
Preparation of cis-4-ethylcyclohexyl 4- [3- (4-hydroxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate:

(1) 4-Amino-1-t-butoxycarbonylpiperidine (331 mg) and triethylamine (182 mg) were dissolved in tetrahydrofuran (8 ml), and p-nitrophenyl chloroformate (347 mg) was added under ice-cooling. For 1 hour. To this reaction liquid, 4-benzyloxy-3-methoxybenzylamine hydrochloride (504 mg), triethylamine (415 mg) and dimethyl sulfoxide (8 ml) were added, and the mixture was warmed to room temperature and stirred for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate solution (4 times), saturated aqueous ammonium chloride solution and saturated brine in this order. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. did. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100), and t-butyl 4- [3- (4-benzyloxy-3-methoxybenzyl) ureido] 656 mg of piperidine-1-carboxylate was obtained.
(2) The product of (1) (633 mg) was dissolved in chloroform (12 ml), and 4 mol / l hydrogen chloride / ethyl acetate (4 ml) was added. After stirring at room temperature for 18 hours, hexane (30 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration to give 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea. 506 mg of hydrochloride was obtained.
(3) N, N′-carbonyldiimidazole (1.67 g) was added to a mixture of cis-4-ethylcyclohexanol (1.02 g) and dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 14 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.71 g of cis-4-ethylcyclohexyl 1H-imidazole-1-carboxylate.
(4) To the mixture of the product of (1) (136 mg) and dimethyl sulfoxide (3 ml), the product of (2) (206 mg), triethylamine (153 mg) and 4-pyrrolidinopyridine (13 mg) were added. The mixture was stirred at 13 ° C. for 13 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution, water (twice) and saturated brine in this order. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) to give cis-4-ethylcyclohexyl 4- [3- (4-benzyloxy-3-methoxybenzyl). ) Ureido] 207 mg of piperidine-1-carboxylate was obtained.

(5) The product of (4) (199 mg) is dissolved in a mixed solvent (8 ml) of ethanol / tetrahydrofuran (1/1), 10% palladium on carbon (104 mg) is added, and catalytic hydrogen is added at room temperature in a hydrogen atmosphere. The addition was made. After 3 hours, the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = gradient from 100/0 to 0/100) for the purpose. 87 mg of product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, t), 1.21-1.28 (7H, m), 1.46-1.57 (4H, m), 1.60-1.94 (4H, m), 2.89 (2H, t ), 3.73-3.80 (1H, m), 3.87 (3H, s), 4.04 (2H, t), 4.25-4.27 (3H, m), 4.60 (1H, t), 4.88 (1H, brs), 5.63 ( 1H, s), 6.77 (1H, dd), 6.82 (1H, d), 6.86 (1H, d).

Example 2
Preparation of 2,6-dimethyl-4-heptyl 4- [3- (4-hydroxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate:

Using 2,6-dimethyl-4-heptanol instead of cis-4-ethylcyclohexanol in Example 1, reaction and treatment were conducted in the same manner as in Example 1 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.91 (12H, d), 1.12-1.35 (4H, m), 1.41-1.70 (4H, m), 1.89-2.00 (2H, m), 2.81-2.97 (2H , m), 3.70-3.82 (1H, m), 3.88 (3H, s), 3.98-4.14 (3H, m), 4.27 (2H, d), 4.42-4.50 (1H, m), 4.87-5.97 (1H m), 5.58 (1H, brs), 6.76 (1H, dd), 6.83 (1H, d), 6.86 (1H, d).

Example 3
Preparation of 4,4-dimethylcyclohexyl 4- [3- (4-hydroxy-3-methoxyphenyl) ureido) piperidine-1-carboxylate:

Instead of 4-benzyloxy-3-methoxybenzylamine in Example 1, 4-benzyloxy-3-methoxyaniline which can be synthesized by the method described in J. Chem. Soc., 1863 (1961) was converted to cis-4-ethyl. Using 4,4-dimethylcyclohexanol instead of cyclohexanol, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.91 (6H, d), 1.19-1.28 (4H, m), 1.36-1.44 (2H, m), 1.49-1.60 (2H, m), 1.70-1.78 (2H , m), 1.92-1.96 (2H, m), 2.89 (2H, t), 3.79-3.87 (4H, m), 4.05 (2H, d), 4.58-4.64 (2H, m), 5.57 (1H, s ), 6.26 (1H, s), 6.59 (1H, dd), 6.85 (1H, d), 7.01 (1H, d).

Example 4
Preparation of cyclohexyl 4- [3- (4-hydroxy-3-methoxybenzyl) thioureido] piperidine-1-carboxylate:

(1) Instead of cis-4-ethylcyclohexanol in Example 1, cyclohexanol was used instead of 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea hydrochloride 4- (t-Butoxycarbonylamino) piperidine was used in the same manner as in Example 1 (3) and (4) for the reaction and treatment to give cyclohexyl 4- (t-butoxycarbonylamino) piperidine-1-carboxylate. .
(2) In place of t-butyl 4- [3- (4-benzyloxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate in Example 1, the product of (1) above was used. The reaction and treatment were carried out in the same manner as (2) to obtain cyclohexyl 4-aminopiperidine-1-carboxylate hydrochloride.

(3) A mixture of 4-isothiocyanatomethyl-2-methoxy-1- (methoxymethoxy) benzene (195 mg) and tetrahydrofuran (4 ml), which can be synthesized by the method described in US Pat. No. 6,984,647, was added to the above (2 ) Product (235 mg) and triethylamine (0.09 ml) were added and stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed successively with saturated aqueous ammonium chloride solution and saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) and purified from cyclohexyl 4- {3- [3-methoxy-4- (methoxymethoxy) benzyl] thioureido} 363 mg of piperidine-1-carboxylate was obtained.
(4) The product of (3) above was dissolved in tetrahydrofuran (4 ml), 2 mol / l hydrochloric acid (4 ml) was added, and the mixture was heated at 50 ° C. for 2 hours. 2-Propanol (2 ml) was added to the reaction solution, and the mixture was heated and stirred at 50 ° C. for 5 hours. 35% Hydrochloric acid (1 ml) was added to the reaction mixture, and the mixture was heated with stirring at 80 ° C. for 1 hr. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with water and saturated brine in that order. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (3 times purification, elution solvent: hexane / ethyl acetate = 1/2 and twice with chloroform / methanol = 100/0 to 100/2 gradient) to obtain the desired product. 53 mg was obtained.
1 ¹ H-NMR (CDCl ₃ , δ): 1.26-1.59 (8H, m), 1.65-1.69 (2H, m), 1.75-1.83 (2H, m), 1.99-2.04 (2H, m), 2.90 ( 2H, t), 3.88 (3H, s), 4.02 (2H, d), 4.27 (1H, brs), 4.46 (2H, brs), 4.62 (1H, brs), 5.59 (1H, brs), 5.67 (1H , s), 6.12 (1H, brs), 6.79 (1H, dd), 6.84 (1H, d), 6.88 (1H, d).

Example 5
Preparation of cyclohexyl 4- (4-hydroxy-3-methoxybenzylthiocarbamoyl) piperidine-1-carboxylate:

(1) 1- (t-Butoxycarbonyl) -piperidine-4-carboxylic acid (11.5 g), 4-benzyloxy-3-methoxybenzylamine hydrochloride (11.5 g), triethylamine (14.0 ml) and chloride To a mixture of methylene (300 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (12.5 g). The reaction solution was stirred at room temperature for 20 hours, washed with a saturated aqueous ammonium chloride solution and saturated brine in that order, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) to give t-butyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) -piperidine-1. -16.3 g of carboxylate was obtained.
(2) The product of (1) (16.3 g) was dissolved in ethyl acetate (270 ml), and 4 mol / l hydrogen chloride / ethyl acetate (90 ml) was added. After the mixture was stirred for 6 hours, hexane (200 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 11.4 g of N- (4-benzyloxy-3-methoxybenzyl) -4-piperidinecarboxamide hydrochloride. It was.
(3) Instead of cis-4-ethylcyclohexanol in Example 1, cyclohexanol was used instead of 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea hydrochloride The product of (2) above was used for the reaction and treatment in the same manner as in Example 1 (3) and (4) to give cyclohexyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate. Obtained.

  (4) In place of cis-4-ethylcyclohexyl 4- [3- (4-benzyloxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate in Example 1, the product of (3) above was used. The reaction and treatment were conducted in the same manner as in Example 1 (5) to obtain cyclohexyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate.

(5) The product of the above (4) (325 mg), 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson reagent) ( 185 mg) and toluene (8 ml) were heated at 80 ° C. for 2 hours. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (purified twice, elution solvent: hexane / ethyl acetate = 100/0 to 0/100 gradient and chloroform / methanol = 100/0 to 100/2. To obtain 84 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.26-1.50 (6H, m), 1.65-1.72 (2H, m), 1.79-1.87 (6H, m), 2.59-2.74 (3H, m), 3.89 (3H , s), 4.27 (2H, brd), 4.63-4.69 (1H, m), 4.73 (2H, d), 5.63 (1H, s), 6.81 (1H, dd), 6.84 (1H, d), 6.90 ( 1H, d), 7.21 (1H, brs).

Example 6
Preparation of (1R ^* , 2S ^* )-2-methylcyclohexyl 4- (4-hydroxy-3-methoxybenzylthiocarbamoyl) piperidine-1-carboxylate:

Using (1R ^* , 2S ^* )-2-methylcyclohexanol instead of cyclohexanol in Example 5, the reaction and treatment were conducted in the same manner as in Example 5 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, d), 1.26-1.36 (2H, m), 1.45-1.50 (4H, m), 1.62-1.70 (2H, m), 1.80-1.89 (5H , m), 2.59-2.69 (1H, m), 2.77 (2H, brs), 3.89 (3H, s), 4.29 (2H, d), 4.74 (2H, d), 4.82 (1H, brs), 5.64 ( 1H, s), 6.81 (1H, dd), 6.85 (1H, d), 6.90 (1H, d), 7.23 (1H, brs).

Example 7
Preparation of 2,6-dimethyl-4-heptyl 4- (4-hydroxy-3-methoxybenzylthiocarbamoyl) piperidine-1-carboxylate:

Using 2,6-dimethyl-4-heptanol instead of cyclohexanol in Example 5, the reaction and treatment were conducted in the same manner as in Example 5 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.90 (12H, dd), 1.24-1.33 (2H, m), 1.45-1.54 (2H, m), 1.60-1.67 (2H, m), 1.74-1.88 (4H , m), 2.57-2.67 (1H, m), 2.71-2.78 (2H, m), 3.89 (3H, s), 4.26 (2H, d), 4.73 (2H, d), 4.87-4.96 (1H, m ), 5.65 (1H, s), 6.81 (1H, dd), 6.84 (1H, d), 6.90 (1H, d), 7.24 (1H, brs).

Example 8
Preparation of cyclohexyl 4- (4-hydroxy-3-methoxybenzylcarbamoyloxy) piperidine-1-carboxylate:

(1) Instead of cis-4-ethylcyclohexanol in Example 1, cyclohexanol was used instead of 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea hydrochloride 4-Hydroxypiperidine-1-carboxylate was obtained by reacting and treating in the same manner as in Examples 1 (3) and (4) using 4-hydroxypiperidine.

  (2) The product of (1) above was used in place of cis-4-ethylcyclohexanol in Example 1, and the reaction and treatment were conducted in the same manner as in Example 1 (3) to prepare cyclohexyl 4- (1H-imidazole-1 -Carbonyloxy) piperidine-1-carboxylate was obtained.

  (3) Instead of 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea hydrochloride in Example 1, 4-benzyloxy-3-methoxybenzylamine hydrochloride was used. Using the product of (2) above in place of cis-4-ethylcyclohexyl 1H-imidazole-1-carboxylate, the reaction and treatment were carried out in the same manner as in Example 1 (4) to prepare cyclohexyl 4- (4-benzyloxy- 3-Methoxybenzylcarbamoyloxy) piperidine-1-carboxylate was obtained.

(4) In place of cis-4-ethylcyclohexyl 4- [3- (4-benzyloxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate in Example 1, the product of (3) above was used. The target product was obtained by reacting and treating in the same manner as in Example 1 (5).
¹ H-NMR (CDCl ₃ , δ): 1.27-1.49 (8H, m), 1.65-1.70 (2H, m), 1.82-1.91 (4H, m), 3.25 (2H, brt), 3.73-3.77 (2H , m), 3.88 (3H, s), 4.27 (2H, d), 4.63-4.70 (1H, m), 4.86-4.94 (2H, m), 5.61 (1H, s), 6.76-6.80 (2H, m ), 6.87 (1H, d).

Example 9
Preparation of cyclohexyl 4- [2- (4-hydroxy-3-methoxyphenyl) acetoxy] piperidine-1-carboxylate:

  (1) Mixture of 4-benzyloxy-3-methoxyphenylacetic acid (1.04 g), 1- (t-butoxycarbonyl) -4-hydroxypiperidine (0.698 g) and N, N-dimethylformamide solution (10 ml) To was added triethylamine (0.445 g), 1-hydroxybenzotriazole (0.047 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.861 g). The reaction mixture was stirred at room temperature for 21 hours, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water (twice), saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to give t-butyl 4- [2- (4-benzyloxy-3-methoxyphenyl) acetoxy]. 0.827 g of piperidine-1-carboxylate was obtained.

  (2) Example 1 except that the product of (1) above was used instead of t-butyl 4- [3- (4-benzyloxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate in Example 1. Reaction and treatment in the same manner as in (2) gave 4-piperidinyl 2- (4-benzyloxy-3-methoxyphenyl) acetate hydrochloride.

(3) Cyclohexanol was replaced with 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea hydrochloride in place of cis-4-ethylcyclohexanol in Example 1 ( The product of 2) was used in the same reaction and treatment as in Example 1 (3) and (4) to give cyclohexyl 4- [2- (4-benzyloxy-3-methoxyphenyl) acetoxy] piperidine-1-carboxylate. Got.
(4) In place of cis-4-ethylcyclohexyl 4- [3- (4-benzyloxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate in Example 1, the product of (3) above was used. Reaction and treatment with Example 1 (5) gave the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.24-1.70 (10H, m), 1.80-1.86 (4H, m), 3.24-3.32 (2H, m), 3.53 (2H, s), 3.64-3.68 (2H , m), 3.88 (3H, s), 4.63-4.69 (1H, m), 4.91-4.98 (1H, m), 5.55 (1H, s), 6.76 (1H, dd), 6.80 (1H, d), 6.86 (1H, d).

Example 10
Preparation of cis-4-methylcyclohexyl 4- [2- (4-hydroxy-3-methoxyphenyl) acetoxy] piperidine-1-carboxylate:

Using cis-4-methylcyclohexanol instead of cyclohexanol in Example 9, reaction and treatment were carried out in the same manner as in Example 9 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.91 (3H, d), 1.14-1.27 (2H, m), 1.39-1.66 (6H, m), 1.81-1.87 (4H, m), 3.25-3.34 (2H , m), 3.54 (3H, s), 3.64-3.72 (2H, m), 3.88 (3H, s), 4.90-4.99 (2H, m), 5.56 (1H, s), 6.76 (1H, dd), 6.80 (1H, d), 6.86 (1H, d).

Example 11
Preparation of 1-cyclohexyl 4- (4-hydroxy-3-methoxybenzyl) piperidine-1,4-dicarboxylate:

  (1) Instead of cis-4-ethylcyclohexanol in Example 1, cyclohexanol was used instead of 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea hydrochloride The reaction and treatment were carried out in the same manner as in Examples 1 (3) and (4) using ethyl isonipecotate to obtain 1-cyclohexyl 4-ethylpiperidine-1,4-dicarboxylate.

  (2) The product of (1) (484 mg) was dissolved in methanol (3 ml), and 2 mol / l sodium hydroxide aqueous solution (3 ml) was added. The mixture was stirred at room temperature for 3 hours, adjusted to pH 1 by adding 2 mol / l hydrochloric acid to the reaction solution, and the resulting crystals were collected by filtration to obtain 406 mg of 1- (cyclohexyloxycarbonyl) piperidine-4-carboxylic acid. .

(3) Diisopropyl azodicarboxylate (158 mg) was added to a mixture of the product of (2) (200 mg), vanillyl alcohol (120 mg), triphenylphosphine (205 mg) and tetrahydrofuran (4 ml) under ice cooling. The reaction mixture was stirred at room temperature for 4 days, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = gradient from 100/0 to 100/1) to obtain 28 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.25-1.54 (6H, m), 1.61-1.77 (4H, m), 1.81-1.91 (4H, m), 2.49 (1H, tt), 2.86 (2H, t ), 3.09 (3H, s), 4.06 (2H, brd), 4.62-4.69 (1H, m), 5.04 (2H, s), 5.65 (1H, s), 6.84-6.91 (3H, m).

Example 12
Preparation of cis-4-methylcyclohexyl 4- [3- (4-hydroxy-3-methoxyphenyl) propanoyl] piperidine-1-carboxylate:

(1) Instead of cis-4-ethylcyclohexanol in Example 1, cis-4-methylcyclohexanol was replaced with 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea. 1-[(cis-4-methylcyclohexyloxy) carbonyl] piperidine-4-carboxylic acid is obtained by reacting and treating in the same manner as in Example 1 (3) and (4) using isonipecotic acid instead of hydrochloride. It was.
(2) A mixture of the product of (1) (408 mg), thionyl chloride (0.5 ml) and toluene (4 ml) was heated and stirred at 80 ° C. for 3 hours, and then the reaction solution was concentrated under reduced pressure to give cis-4- 423 mg of methylcyclohexyl 4- (chlorocarbonyl) piperidine-1-carboxylate was obtained.

(3) A mixture of 1-benzyloxy-4- (2-iodoethyl) -2-methoxybenzene (736 mg), zinc (784 mg) and tetrahydrofuran (4 ml) which can be synthesized by the method described in Tetrahedron, 14, 46 (1961) Was heated to reflux for 1.5 hours. The supernatant of the reaction solution (1.8 ml) was added dropwise at 45 ° C. to a mixture of bis (triphenylphosphine) palladium (II) dichloride (56 mg), the product of (2) above (423 mg) and toluene (4 ml). The mixture was heated and stirred for 3 hours under the same conditions. The reaction mixture was diluted with ethyl acetate, filtered through celite, and washed with 1 mol / l hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine in this order. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) to give cis-4-methylcyclohexyl 4- [3- (4-benzyloxy-3-methoxyphenyl). ) Propanoyl] 263 mg of piperidine-1-carbamate was obtained.
(4) In place of cis-4-ethylcyclohexyl 4- [3- (4-benzyloxy-3-methoxybenzyl) ureido] piperidine-1-carboxylate in Example 1, the product of (3) above was used. Reaction and treatment with Example 1 (5) gave the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.91 (3H, d), 1.14-1.28 (3H, m), 1.39-1.58 (6H, m), 1.81 (4H, t), 2.44 (1H, tt), 2.72-2.86 (6H, m), 3.87 (3H, s), 4.11-4.16 (2H, m), 4.89 (1H, brs), 5.48 (1H, s), 6.64-6.68 (2H, m), 6.82 ( 1H, d).

Example 13
Preparation of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 4- [2- (4-hydroxy-3-methoxyphenyl) acetamido] -piperidine-1-carboxylate:

(1) 1-ethyl to a mixture of 4-hydroxy-3-methoxyphenylacetic acid (4.56 g), N-benzyl-4-aminopiperidine (4.76 g), triethylamine (3.52 ml) and methylene chloride (100 ml) -3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (6.23 g) and N-hydroxybenzotriazole (4.21 g) were added. The reaction solution was stirred at room temperature for 2 days, then washed in order with an aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized with a mixture of ethanol and chloroform to give 6.93 g.
(2) The product (6.93 g) of (2) above was dissolved in ethanol (150 ml), 10% palladium on carbon (500 mg) was added, and catalytic hydrogenation was performed at 40 ° C. After 24 hours, the catalyst was removed by filtration and the solvent was distilled off. The residue was crystallized with ethyl acetate to obtain 5.08 g.
(3) The product of the above (2) (200 mg) was dissolved in N, N-dimethylformamide (3 ml) and pyridine (1 ml), and (1R, 2S, 5R) -2-isopropyl-5-methyl under ice cooling Cyclohexyl chloroformate (171 mg) was added. After stirring the reaction solution for 2 hours, the solvent was distilled off under reduced pressure, and ethyl acetate was added. , Washed with an aqueous citric acid solution, water, an aqueous potassium carbonate solution, and a saturated saline solution in this order. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to obtain 170 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.76 (3H, d), 0.88 (4H, d), 0.89-1.39 (6H, m), 1.41-1.74 (4H, m), 1.77-1.92 (2H, m ), 2.76-2.98 (2H, m), 3.48 (2H, s), 3.86-4.10 (3H, m), 3.88 (3H, s), 4.46-4.58 (1H, m), 5.30 (1H, d), 5.69 (1H, s), 6.71 (1H, dd), 6.75 (1H, d), 6.88 (1H, d).

Examples 14-22
Table 1 and Table 2 were prepared by reacting and treating in the same manner as in Example 13 using various chloroformates in place of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl chloroformate in Example 13. The compound shown was obtained.

Example 23
(1R ^* , 2S ^* )-2-Methylcyclohexyl 4- [2- (4-hydroxy-3-methoxyphenyl) ethanethioamide] Preparation of piperidine-1-carbamate:

The product of Example 19 was used in place of cyclohexyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate in Example 5, and the reaction and treatment were carried out in the same manner as in Example 5 (5). The desired product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.86 (3H, d), 1.23-1.32 (4H, m), 1.42-1.49 (4H, m), 1.64-1.68 (2H, m), 1.83-1.86 (1H , m), 2.00-2.04 (2H, m), 2.94 (2H, t), 3.88 (3H, s), 4.02-4.06 (4H, m), 4.54-4.59 (1H, m), 4.79-4.81 (1H , m), 5.65 (1H, s), 6.68-6.73 (2H, m), 6.85-6.92 (2H, m).

Example 24
Preparation of cyclohexyl 4- [2- (4-hydroxy-3-methoxybenzylamino) -2-oxoethyl] piperidine-1-carboxylate:

From Example 5 (1) using 2- [1- (t-butoxycarbonyl) piperidin-4-yl] acetic acid instead of 1- (t-butoxycarbonyl) -piperidine-4-carboxylic acid in Example 5 The target product was obtained by reacting and treating in the same manner as in (4).
¹ H-NMR (CDCl ₃ , δ): 1.08-1.19 (2H, m), 1.27-1.57 (6H, m), 1.60-1.81 (6H, m), 2.04-2.11 (3H, m), 2.75 (2H , t), 3.87 (3H, s), 4.13 (2H, d), 4.35 (2H, d), 4.64-4.67 (1H, m), 5.62 (1H, s), 5.67 (1H, brs), 6.75 ( 1H, dd), 6.79 (1H, d), 6.87 (1H, d).

Example 25
Preparation of cyclohexyl 4- [3- (4-hydroxy-3-methoxybenzylamino) -3-oxopropyl] piperidine-1-carboxylate:

From Example 5 (1) using 3- [1- (t-butoxycarbonyl) piperidin-4-yl] propion instead of 1- (t-butoxycarbonyl) -piperidine-4-carboxylic acid in Example 5 The target product was obtained by reacting and treating in the same manner as in (4).
¹ H-NMR (CDCl ₃ , δ): 1.03-1.17 (2H, m), 1.23-1.54 (8H, m), 1.57-1.70 (5H, m), 1.81-1.86 (2H, m), 2.22 (2H , t), 2.69 (2H, t), 3.88 (3H, s), 4.08-4.15 (2H, m), 4.35 (2H, d), 4.62-4.68 (1H, m), 5.63 (1H, s), 5.66 (1H, brs), 6.76 (1H, dd), 6.80 (1H, d), 6.86 (1H, d).

  Below, the pharmacological test result of the typical compound of this invention is shown, and the pharmacological action about the compound of this invention is demonstrated. However, the present invention is not limited to these test examples.

Test Example 1: TRPV1 agonist activity measurement using intracellular calcium concentration as a biological activity index: fluorescence image plate reader (FLIPR) method This test was performed using rat dorsal root ganglion cultured cells rich in TRPV1 expression. BrJ Anaesth measures the agonist activity of TRPV1 of the test compound using the increase in calcium concentration as an indicator. The method of Jerman et al. (Jerman, JC, et al., Comparison of effects of anandamide at recombinant and endogenous rat vanilloid receptors. , 2002. 89 (6): p.882-7). That is, dorsal root ganglia were excised from 7 days old Wistar rats, and cells were isolated by collagenase-trypsin treatment. Thereafter, primary culture was performed for 2 days in a CO ₂ incubator set to 5% CO ₂ and 37 ° C. The culture solution used was Neurobasal ^™ medium supplemented with L-glutamine, nerve growth factor, N-2 Supplement, Penicillin-Streptomycin, 5-Fluoro-2′-deoxyuridine (only on the first day of culture).

The FLIPR ^TETRA system (Molecular Device) was used for intracellular calcium concentration measurement. By measuring the fluorescence intensity rising when the test compound was applied to the rat dorsal root ganglion primary cells into which the calcium fluorescent reagent was incorporated, it was used as an index of TRPV1 agonist activity. The results are shown in Table 3 below.

  As shown in Table 3, the compounds of the present invention caused an increase in intracellular calcium concentration similar to that of capsaicin, a TRPV1 agonist.

Test Example 2: Examination of irritation (eye-wiping test)
This test examines the degree of irritation of the compounds of the present invention. The method of Jancso et al. [Acta. Physiol. Acad. Sci. Hung., 19, 113-131 (1961)] and This was carried out according to the method of Szallasi et al. [Brit. J. Pharmacol., 119, 283-290 (1996)]. Specifically, a test compound is dissolved in physiological saline containing 5% Tween 80 and 5% ethanol so as to have each concentration (10 or 30 μg / ml), and the resulting solution is Std: ddy male male. One drop was dropped on the eyes of mice (5 mice per group, body weight 20-30 g), and the number of protective wiping behaviors in the forelimbs was counted every minute up to 5 minutes after administration. After the test, the average value of the number of times per minute was obtained, and the maximum number of times was used as a representative value. Moreover, the same test was done using physiological saline containing 5% Tween 80 and 5% ethanol as a solvent control. The results are shown in Table 4.

  As shown in Table 4, when a capsaicin with a concentration of 10 μg / ml was dropped, a violent wiping operation was observed. On the other hand, it was found that all of the Example compounds listed in Table 3 had a small number of wiping operations and weak irritation even at a concentration of 30 μg / ml.

  The compound of the present invention and physiologically acceptable salts thereof have a strong analgesic action, and are less irritating than capsaicin, and the existing analgesics are sufficiently effective as analgesics and anti-inflammatory drugs. Remedy for various types of neuropathic pain, including rheumatoid arthritis and osteoarthritis, including diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-polyneuropathy Useful as. In addition, these include migraine and cluster headache, pruritus, allergic and non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, respiratory diseases such as asthma / chronic obstructive pulmonary disease, skin It is also useful as a preventive and / or therapeutic agent for inflammation, mucositis, gastric / duodenal ulcer, inflammatory bowel syndrome and diabetes, and obesity.

Claims (11)

The following formula (I):

[Where
R ¹ represents a methyl group or a hydrogen atom,
R ² represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkylcarbonyl group or an arylcarbonyl group,
R ³ is a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl). Or a C _6-12 alkyl group or a C _6-12 alkenyl group;
X represents —NH—C (═O) —NH—, —C (═O) —NH—, —NH—C (═S) —NH—, —C (═S) —NH—, —NH—. C (= S) -, - NH-C (= O) -CH 2 -, - NH-C (= O) -CH 2 -CH 2 -, - NH-C (= O) -O -, - O -C (= O) -NH-, -C (= O) -O-, -O-C (= O)-or -C (= O)-
n and m are the same or different and each represents an integer of 1, 2 or 3,
p represents an integer of 0, 1 or 2. ]
Or a physiologically acceptable salt thereof. In the formula (I), R ³ is a C _3-8 cycloalkyl group or an aryl group (each group is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl and C _3-8 cycloalkyl) Or a physiologically acceptable salt thereof. 2. The compound according to claim 1, which may be substituted with 1 to 5 substituents which are the same or different.   In the formula (I), X represents —NH—C (═O) —NH—, —C (═O) —NH—, —NH—C (═S) —NH—, —C (═S) — The compound according to claim 1 or 2, or a physiologically acceptable salt thereof, which represents NH- or -NH-C (= S)-.   The compound according to claim 3, wherein in formula (I), X represents -NH-C (= O) -NH-, -NH-C (= S) -NH- or -NH-C (= S)-. Or a physiologically acceptable salt thereof.   The compound or physiologically acceptable salt thereof according to any one of claims 1 to 4, wherein in formula (I), n and m are the same or different and each represents an integer of 1 or 2.   6. The compound according to claim 5 or a physiologically acceptable salt thereof, wherein in formula (I), n and m are both 2.   The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 6, wherein p represents an integer of 1 in formula (I). The compound according to any one of claims 1 to 7, or a physiologically acceptable salt thereof, wherein in formula (I), R ¹ represents a methyl group. The compound according to any one of claims 1 to 8, or a physiologically acceptable salt thereof, wherein in formula (I), R ² represents a hydrogen atom.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a physiologically acceptable salt thereof as an active ingredient. A therapeutic or prophylactic agent for pain and / or inflammation comprising the compound according to any one of claims 1 to 9 or a physiologically acceptable salt thereof as an active ingredient.