JP2011102266A - N-benzyl amide derivative and pharmaceutical composition containing the same - Google Patents

Abstract

<P>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. <P>SOLUTION: The compound is an N-benzyl amide derivative represented by formula (I) [wherein R<SP>1</SP>is methoxy, OH or H; R<SP>2</SP>is H, alkyl, alkylcarbonyl or arylcarbonyl; and D is represented by formula (A)-(C) äwherein R<SP>3</SP>is a hydrocarbon group chosen from the group consisting of alkyl, alkenyl, alkynyl and alkenylalkynyl, provided that the group is optionally substituted 3-8C cycloalkyl or optionally substituted aryl}] or a physiologically acceptable salt thereof. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an N-benzylamide derivative useful as a therapeutic agent for pain and inflammation and a pharmaceutical composition containing the same.

  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.

  Non-Patent Document 6 includes the following compound:

Is disclosed. However, the compound of the present invention represented by the following formula (I) means that the compound of the present invention must have a cyclohexyl or 3-cyclohexenyl group bonded to the carbon atom of the amide, The chemical structure is different in that a 1-cyclohexenyl group is bonded to the position as an essential structure.

  Non-Patent Document 7 includes

The compound represented by these is described. However, both the compound and the compound of the present invention represented by the following formula (I) are indispensable for the compound of the present invention to bond a cyclohexyl or 3-cyclohexenyl group to the carbon atom of the amide. On the other hand, the compound differs in chemical structure in that a phenyl group or a cyclooctyl group is bonded to the position as an essential structure.

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) J. Med. Chem., 45, 3739 (2002) J. Med. Chem., 36, 2595 (1993)

  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 intensive studies, the present inventors have found that a cyclohexyl group or a 3-cyclohexenyl group having a specific substituent is bonded to the carbon atom of the amide of the N-benzylamide compound, that is, the following formula ( The compound represented by I) was found to have a strong analgesic action but low irritation, and thus completed the present invention. That is, the present invention provides the following inventions.

  [1] The following formula (I):

[Where
R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched carbon selected from the group consisting of a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, and a C _4-10 alkenyl alkynyl group. Represents a hydrogen group, the hydrocarbon group,
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group;
(2) Fluorine atom, hydroxyl group, C _1-6 alkyl group that can be substituted with 1 to 5 fluorine atoms, C _1-6 alkoxy group that can be substituted with 1 to 5 fluorine atoms, nitro group, amino group, a cyano group, C _{1 to 4} alkyloxycarbonyl group, C _{1 to 4} alkyl carbonyl group, the same or different 1 to 5 substituents selected from the group consisting of carboxyl group and methylenedioxy group An aryl group that may be present;
(3) may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom and (4) hydroxyl group,
R ³ in formula (A) and formula (B) contains at least 4 carbon atoms, and R ³ in formula (C) shows at least 3 carbon atoms}
Or a physiologically acceptable salt thereof.

[2] In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched hydrocarbon group selected from the group consisting of a C _1-10 alkyl group and a C _2-10 alkenyl group, and the hydrocarbon group is
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group;
(2) Fluorine atom, hydroxyl group, C _1-6 alkyl group that can be substituted with 1 to 5 fluorine atoms, C _1-6 alkoxy group that can be substituted with 1 to 5 fluorine atoms, nitro group, amino group, a cyano group, C _{1 to 4} alkyloxycarbonyl group, C _{1 to 4} alkyl carbonyl group, the same or different 1 to 5 substituents selected from the group consisting of carboxyl group and methylenedioxy group An aryl group that may be present;
(3) may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom and (4) hydroxyl group,
R ³ in formula (A) and formula (B) contains at least 4 carbon atoms, and R ³ in formula (C) contains at least 3 carbon atoms}. A benzylamide derivative or a physiologically acceptable salt thereof.

[3] In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched hydrocarbon group selected from the group consisting of a C _1-10 alkyl group and a C _2-10 alkenyl group, and the hydrocarbon group is
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group;
(3) may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom and (4) hydroxyl group,
R ³ in formula (A) and formula (B) contains at least 4 carbon atoms, and R ³ in formula (C) contains at least 3 carbon atoms}. A benzylamide derivative or a physiologically acceptable salt thereof.

[4] In formula (I), R ³ in formula (A) and formula (B) contains 4 to 10 carbon atoms, and R ³ in formula (C) contains 3 to 9 carbon atoms. The N-benzylamide derivative according to the above [1] or a physiologically acceptable salt thereof.

[5] In Formula (I), R ³ in Formula (A) and Formula (B) contains 4 to 8 carbon atoms, and R ³ in Formula (C) contains 3 to 7 carbon atoms. An N-benzylamide derivative or a physiologically acceptable salt thereof according to the above [1].

[6] In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched C _1-10 alkyl group,
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group; and (3 ) May be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atoms,
R ³ in formula (A) and formula (B) contains at least 4 carbon atoms, and R ³ in formula (C) contains at least 3 carbon atoms}. A benzylamide derivative or a physiologically acceptable salt thereof.

[7] In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched C _1-10 alkyl group,
(1) substituted with a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of fluorine atom, hydroxyl group and C _1-6 alkyl group You can,
R ³ in formula (A) and formula (B) contains at least 4 carbon atoms, and R ³ in formula (C) contains at least 3 carbon atoms}. A benzylamide derivative or a physiologically acceptable salt thereof.

[8] The N-benzylamide derivative or the physiologically acceptable salt thereof according to the above [1], wherein in the formula (I), R ¹ represents a methoxy group or a hydroxyl group.

[9] The N-benzylamide derivative or the physiologically acceptable salt thereof according to the above [1], wherein in formula (I), R ² represents a hydrogen atom.

[10] The N-benzylamide derivative or the physiologically acceptable salt thereof according to the above [1], wherein in formula (I), R ¹ represents a methoxy group and R ² represents a hydrogen atom.

  [11] The N-benzylamide derivative or the physiologically acceptable salt thereof according to any one of [1] to [10], wherein D is represented by the formula (A).

  [12] The N-benzylamide derivative or a physiologically acceptable salt thereof according to any one of the above [1] to [10], wherein D is represented by the formula (B).

  [13] The N-benzylamide derivative or a physiologically acceptable salt thereof according to any one of the above [1] to [10], wherein D is represented by the formula (C).

[14] The compound represented by formula (I) is:
Trans-N- (4-Hydroxy-3-methoxybenzyl) -4-pentylcyclohexanecarboxamide trans-N- (4-hydroxy-3-methoxybenzyl) -4- (4-methylpentyl) cyclohexanecarboxamide cis-4-hexyl -N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide trans-4- (2-cyclopropylethyl) -N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide trans-N- (4-hydroxy- [1], which is a compound selected from the group consisting of 3-methoxybenzyl) -4- (3-methylbutyl) cyclohexanecarboxamide and N- (4-hydroxy-3-methoxybenzyl) -4-pentylidenecyclohexanecarboxamide Record Of N- benzylamide derivative or a physiologically acceptable salt thereof.

  [15] A pharmaceutical composition comprising the N-benzylamide derivative or the physiologically acceptable salt thereof according to any one of [1] to [14] as an active ingredient.

[16]: A therapeutic or prophylactic agent for pain and / or inflammation comprising the compound according to any one of [1] to [14] above or a physiologically acceptable salt thereof as an active ingredient.
[17] An analgesic or anti-inflammatory drug comprising as an active ingredient the compound according to any one of [1] to [14] above or a physiologically acceptable salt thereof.
[18]: The compound according to any one of [1] to [14] above or a physiologically acceptable salt thereof, a narcotic analgesic, a neuropathic pain therapeutic agent, a nonsteroidal anti-inflammatory drug, a steroid A medicament comprising at least one other drug selected from the group consisting of sex anti-inflammatory drugs, antidepressants, antiepileptic drugs, anticonvulsants, anesthetics, antiarrhythmic drugs, local anesthetics and anxiolytic drugs.
[19] A pharmaceutical composition containing the medicine according to the above [18] as an active ingredient.
[20]: A therapeutic or prophylactic agent for pain and / or inflammation comprising the pharmaceutical agent according to [18] 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 compound of the general formula (I) is characterized by having an excellent analgesic action. Furthermore, it has the characteristic that irritation is weak. For the expression of the excellent properties of the compound represented by the formula (I) of the present invention,

In represented by partial structure, i.e., a specific group at the 4-position ( "R ^3" in (A), "= CH-R ^3" in "R ^3" or (C) in (B)) is coupled The partial structure consisting of a cyclohexane ring or a 3-cyclohexene ring is greatly contributing. In other words, the chemical structure of the compound represented by the formula (I) of the present invention is characterized by having the specific partial structure and the bond between the specific partial structure and the remaining structure.

  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 N-benzylamide derivatives represented by the above formula (I) and physiologically acceptable salts thereof, as well as hydrates and / or solvates thereof. Is included.

  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 exists as several stereoisomers. There are things that can be done. 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”, “C _1-6 alkyl group” or “C _1-10 alkyl”. “Group” means a group having 1 to 4, 1 to 6 or 1 to 10 carbon atoms. Specific examples thereof include “C _1-4 alkyl group” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc., and “C _1-6 alkyl group” In addition to the above, pentyl, isopentyl, neopentyl, hexyl and the like include “octyl, nonyl, decyl” and the like as the “C _1-10 alkyl group”. The alkyl group may be linear. Further, it may be branched.

“Alkenyl group” means a linear or branched unsaturated hydrocarbon group having at least one double bond. For example, “C _2-10 alkenyl group” means at least a double bond. It means one unsaturated hydrocarbon group having 2 to 10 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, 3-octenyl and the like can be mentioned. The alkenyl group may be linear. Further, it may be branched. The number of double bonds contained in the alkenyl group may be one. Moreover, two may be sufficient.

The “C _2-10 alkynyl group” means an unsaturated hydrocarbon group having 2 to 10 carbon atoms and having at least one triple bond, which is a linear or branched group. . Specific examples thereof include ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl, 1-methyl-2-propynyl, 3-hexynyl and the like.

The “C _4-10 alkenyl alkynyl group” is an unsaturated hydrocarbon group having 4 to 10 carbon atoms and having at least one double bond and triple bond regardless of position and order. A chain or branched group is meant. Specific examples thereof include 2-pentene-4-ynyl, 3-penten-1-ynyl, 3,6,8-decatrien-1-ynyl and the like.

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, cyclooctyl and the like.

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

The “C _1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy groups and the like.

  The “alkyl group substituted with a fluorine atom” is one in which one or more (for example, 1 to 5, preferably 1 to 3) hydrogen atoms of the above alkyl group are substituted with fluorine atoms. Say. Specifically, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4,4-trifluorobutyl 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl and the like. The same applies to each of the following substituents substituted with a fluorine atom: an alkenyl group, an alkynyl group, an alkenylalkynyl group, a cycloalkyl group, and an aryl group.

Furthermore, "the C _{1 to 6} alkoxy groups are substituted with a fluorine atom", one or more of the above C _{1 to 6} alkoxy group (e.g., 1-5, preferably 1-3) hydrogen An atom substituted with a fluorine atom. Specific examples include difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy and the like.

  The same applies to an alkyl group, an alkenyl group, an alkynyl group, an alkenylalkynyl group, a cycloalkyl group, and an aryl group substituted with a hydroxyl group, and one or two or more (for example, 1 to 5, preferably 1 to each group) Represents one to three hydrogen atoms substituted with hydroxyl groups. Specific examples of other substituents to be substituted can be similarly exemplified. In addition, when the hydrogen atom of an alkyl group, alkenyl group, alkynyl group, alkenyl alkynyl group, cycloalkyl group, or aryl group is substituted with a plurality of substituents, these substituents may be the same or different. Also good. Examples of these specific examples include those obtained by appropriately combining various substituents including those exemplified above.

Specific examples of the composite group containing an alkyl having a prescribed number of carbon atoms include those in which the above-described specific examples for each group are applied to the corresponding part. In addition, the number of carbon atoms in “C _1-4 alkylcarbonyl” modifies only the group or part that immediately follows. Therefore, the above case, since the C _{1 to 4} is modified only alkyl, corresponds to acetyl The "C ₁ alkylcarbonyl". For example, specific examples of “C _1-4 alkyloxycarbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like. Specific examples of “C _1-4 alkylcarbonyl group” include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl and the like. Specific examples of the “C _1-4 alkylcarbonyloxy group” include acetyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy and the like. .

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

R ¹ represents a methoxy group, a hydroxyl group or a hydrogen atom, preferably a methoxy group or a hydroxyl 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.

  D represents the following formula (A), (B) or (C):

Each R ³ in the formula (A) and the formula (B) includes at least 4 carbon atoms in total including a substituent. Specifically, 4 to 10 are included, preferably 4 to 8 (more preferably 4 to 7, more preferably 5 to 7). R ³ in the formula (C) includes at least 3 carbon atoms in total including the substituent. Specifically, 3 to 9 are included, preferably 3 to 7 are included.

R ³ is a linear or branched chain selected from the group consisting of optionally substituted C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group and C _4-10 alkenyl alkynyl group. Represents a hydrocarbon group. Preferably, a group consisting of an _optionally substituted C _1-10 alkyl group (more preferably a C _1-7 alkyl group) and a C _2-10 alkenyl group (more preferably a C _2-7 alkenyl group). A linear or branched hydrocarbon group selected from: more preferably an optionally substituted linear or branched C _1-10 alkyl group, still more preferably an optionally substituted linear or branched chain The _C1-7 alkyl group of these is shown.

Examples of the substituent of the hydrocarbon group include an optionally substituted C _3-8 cycloalkyl group, an optionally substituted aryl group, a fluorine atom, or a hydroxyl group, and preferably an optionally substituted group. C _3-8 cycloalkyl group, fluorine atom or hydroxyl group, more preferably an optionally substituted C _3-8 cycloalkyl group or fluorine atom, more preferably an optionally substituted C _3-8 cycloalkyl group It is. The hydrocarbon group may be substituted with 1 to 5 of the same or different substituents.

The substituent of the cycloalkyl group is selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group, and the cycloalkyl group is substituted with 1 to 5 identical or different substituents. Also good.

Examples of the substituent of the aryl group include a fluorine atom, a hydroxyl group, a C _1-6 alkyl group that may be substituted with 1 to 5 fluorine atoms, and a substituent with 1 to 5 fluorine atoms. Selected from the group consisting of a certain C _1-6 alkoxy group, nitro group, amino group, cyano group, C _1-4 alkyloxycarbonyl group, C _1-4 alkylcarbonyloxy group, carboxyl group and methylenedioxy group, The aryl group may be substituted with 1 to 5 identical or different substituents.

  Specific examples of the compound contained in the compound of formula (I) include physiologically acceptable salts or hydrates or solvates thereof in addition to the compounds of Examples described later.

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

  Me: methyl group, Et: ethyl group, t-: tert-, n-: normal, Ms: methanesulfonyl group, Boc: tert-butoxycarbonyl group, Ph: phenyl group, Tr: triphenylmethyl group, THF: tetrahydrofuran , DMF: N, N-dimethylformamide, DME: dimethoxyethane, TFA: trifluoroacetic acid, P-: protecting group

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 similar to the compound represented by formula (I) 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 You may protect by introduce | transducing the protecting group which is used, and the target compound can be obtained by removing a protecting group suitably in that case. The functional group in the definition of each group in each of the following production methods is not particularly defined, but shall be protected as necessary.

  Examples of amino-protecting groups include alkylcarbonyl (eg, acetyl, propionyl, etc.), formyl, phenylcarbonyl, alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), phenyloxycarbonyl, aralkyloxy Carbonyl (for example, benzyloxycarbonyl etc.), triphenylmethyl, phthaloyl, toluenesulfonyl, benzyl and the like are used.

  Examples of the protecting group for the carboxyl group include alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), substituted methyl (for example, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, benzyl, diphenylmethyl, p-methoxybenzyl, triphenylmethyl, etc.), allyl, methylthioethyl, tetrahydropyranyl, phenyl, silyl (for example, trimethylsilyl, tert-butyldimethylsilyl, etc.) and the like are used.

  Examples of the hydroxyl-protecting group include methyl, tert-butyl, allyl, substituted methyl (methoxymethyl, methoxyethoxymethyl, etc.), ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, triphenylmethyl, aralkyl (eg, benzyl, etc.) Alkylcarbonyl (eg, acetyl, propionyl, etc.), formyl, benzoyl, aralkyloxycarbonyl (eg, benzyloxycarbonyl, etc.), 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).

Manufacturing method A
The compound of the present invention can be produced by a condensation reaction between a compound of the following formula (II) and a compound of the following formula (III).

(Wherein R ¹ , R ² and D are the same as defined in [1] above)
The reaction of the compound of formula (II) and the compound of formula (III) can be carried out under the reaction conditions usually used for amide formation reactions. The compound of formula (III) may be converted to a reactive derivative at the carboxyl group and then reacted with the compound of formula (II).

  Examples of the reactive derivative at the carboxyl group of formula (III) include lower alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (particularly acid chlorides). Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, and pentafluorophenyl ester. Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, and pivalic acid.

When the compound of formula (III) itself is used, this reaction is usually carried out in the presence of a condensing agent. Specific examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole, benzotriazol-1-yl-oxytris. (Pyrrolidino) phosphonium hexafluorophosphate etc. are mentioned. These condensing agents can be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole.

  The reaction of the compound of formula (III) or a reactive derivative thereof and the compound of formula (II) is 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, tetrahydrofuran, dioxane, DME, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, dimethylformamide and the like. These solvents are used alone or as a mixed solvent of two or more. The compound of formula (II) may be used in the form of an acid addition salt such as hydrochloride and the free base may be generated in the reaction system.

  This reaction is usually performed in the 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, ethyldiisopropylamine, 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 70 ° C.

  The compound of the said formula (II) is a well-known compound, or can be manufactured according to the manufacturing method of a well-known compound. For example, methods described in Monatsh. Chem., 77, 54 (1947), Tetrahedron Lett., 43, 4281 (2002), J. Org. Chem., 54, 3477 (1989), etc., or methods based thereon Can be manufactured according to.

  Moreover, the compound of the said formula (III) is also a well-known compound, or can be manufactured according to the manufacturing method of a well-known compound. The typical manufacturing method is illustrated below.

Process for the preparation of the compound of formula (III) (1)

(In the formula, n means an integer of 0 to 3, R ³¹ has the same definition as R ³ described in [1] above, and — (CH ₂ ) _n —CH═CH—R ³¹ Contains at least 4 carbon atoms, R ^31-1 represents an ^optionally substituted alkyl group, and — (CH ₂ ) _n —CH ₂ —CH ₂ —R ^31-1 represents at least a carbon atom. 4 included.)
The compound of the above formula (III-1-1) includes, for example, the compound of formula (IV) and the corresponding triphenylphosphonium halide compound (Org. React., 14 , 270 (1965)) or phosphonic acid diester compound (Chem Rev., 74 , 87 (1974)) in the presence of a base (such as butyl lithium or potassium-t-butoxide) in a solvent such as THF or DMF at -80 ° C to 50 ° C (Wittig reaction or Horner-Emmons reaction) followed by removal of the protecting group (P). In the Wittig reaction, exclusively Z form is obtained, and in the Horner-Emmons reaction, exclusively E form is obtained, but it is not particularly limited thereto.

Moreover, the compound of the said formula (III-1-2) which is E body can be manufactured according to the method as described in Synlett, 26 (1998); Tetrahedron, 58 , 4425 (2002) etc. Specifically, first, a compound of formula (IV) and a corresponding 1-phenyl-1H-tetrazole compound having a sulfonyl group at the 5-position in the presence of a base (such as hexamethyldisilazane potassium) are added to DME or THF. It can manufacture by making it react at -70 to 50 degreeC in solvent, etc., and remove | eliminating a protecting group (P) next.

Further, the compound of the formula (III-1-3) is produced by reducing the compound of the formula (III-1-2) in which R ³¹ is an alkenyl group or an alkyl group which may be substituted by catalytic reduction or the like. can do.

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

Process for preparing compound of formula (III) (2)
When R ³ is an optionally substituted alkyl group, it can be produced by the following method.

(In the formula, R ³² represents a cycloalkyl group optionally substituted with a fluorine atom, a hydroxyl group, or an alkyl group; a fluorine atom; or an alkyl group optionally substituted with a hydroxyl group, and has at least two carbon atoms. Including)
The method for producing the compound of the above formula (VI) from the compound of the above formula (V) can be carried out, for example, in the same manner as in the method (1) for producing the compound of the above formula (III) . Thereafter, the compound of formula (III-2) can be obtained by catalytic reduction of formula (VI), for example, under pressure or in the presence of an acid.

  The compound of the above formula (V) 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 (III) (3)

(In the formula, R ³³ has the same definition as R ³ described in [1] above.)
Production of compound (VII) to compound (III-3) can be performed by, for example, J. Org. Chem., 49 ,
After the addition reaction according to the method described in 3904 (1984), it can be carried out by dehydration and deprotection. Specifically, after protecting a functional group (for example, a hydroxyl group) involved in the reaction, an R ³³ group is added to the compound (VII) using a corresponding organic cerium compound (R ³³ -CeCl ₂ or the like). Can be carried out by dehydration and deprotection.

  The compound of the formula (VII) which is a starting material can be produced by a known method.

Process for preparing compound of formula (III) (4)

(In the formula, R ³⁴ is the same as the definition of R ³ described in [1] above.)
The method for producing the compound of the above formula (III-4) from the compound of the above formula (VII) can be carried out, for example, in the same manner as in the method (1) for producing the compound of the above formula (III) . Manufacturing method B
The compound (I ′) of the present invention can also be produced by using the compound of the formula (VIII) obtained by the production method (3) of the compound of the above formula (III) .

(Wherein, R ¹ and R ² are the same as defined in [1] above, and R ³³ is the same as the definition of R ³ described in [1] above.)
Specifically, the protecting group of the compound of formula (VIII) is deprotected, and the compound of formula (X) is produced in the same manner as in Production Method A. Thereafter, the compound (I ′) can be obtained by dehydration.

Manufacturing method C
When the D group of the compound of the general formula (I) has an unsaturated bond such as an alkenyl group, a formula in which the D group is a group having no unsaturated bond such as an alkyl group by performing a reduction treatment The compound (I) can be produced.

Manufacturing method D
When R ² of the compound of the general formula (I) is a hydrogen atom, the compound of the formula (I) wherein R ² is a C _1-4 alkylcarbonyl group or an arylcarbonyl group by performing an acylation treatment Can be manufactured.

  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., and two or more kinds of pharmaceutical carrier additives can be appropriately selected and used 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, a salt of stearic acid, 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. The ratio of isomers and the ratio of cis- and trans-isomers were calculated by the area ratio of HPLC.

Example 1
Preparation of trans-4-butyl-N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide:

4-hydroxy-3-methoxybenzylamine hydrochloride (520 mg), trans-4-butylcyclohexanecarboxylic acid (500 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (550 mg) at room temperature and Triethylamine (290 mg) was mixed in ethyl acetate (10 ml) and stirred. After 12 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 (elution solvent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to obtain 240 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.80-1.00 (5H, m), 1.10-1.33 (7H, m), 1.38-1.55 (2H, m), 1.77-1.96 (4H, m), 1.98-2.10 (1H, m), 3.87 (3H, s), 4.34 (2H, d), 5.63 (1H, s), 5.67 (1H, brs), 6.75 (1H, dd), 6.79 (1H, d), 6.86 ( 1H, d).

Example 2
Preparation of trans-N- (4-hydroxy-3-methoxybenzyl) -4-pentylcyclohexanecarboxamide:

4-Hydroxy-3-methoxybenzylamine hydrochloride (1.00 g), trans-4-pentylcyclohexanecarboxylic acid (1.05 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at room temperature (1.10 g) was mixed in ethyl acetate (20 ml) and stirred. After 12 hours, water (10 ml) was added to the reaction solution for liquid separation, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a solution of hexane / ethyl acetate = 2/1 (10 ml) to obtain 570 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.84-0.95 (5H, m), 1.12-1.33 (9H, m), 1.40-1.53 (2H, m), 1.78-1.95 (4H, m), 1.98-2.08 (1H, m), 3.88 (3H, s), 4.35 (2H, d), 5.55-5.70 (2H, m), 6.75 (1H, dd), 6.79 (1H, d), 6.86 (1H, d).

Example 3
Preparation of cis-N- (4-hydroxy-3-methoxybenzyl) -4-pentylcyclohexanecarboxamide:

(1) To a solution of butyltriphenylphosphonium bromide (7.00 g) in tetrahydrofuran (50 ml) under an argon atmosphere, potassium t-butoxide (1.95 g) was added and stirred at room temperature. After 30 minutes, a tetrahydrofuran solution (20 ml) of methyl 4-formylbenzoate (2.00 g) was added dropwise and further stirred. After 10 hours, water (30 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 ml). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) to give methyl 4- (1-pentenyl) benzoate as 2 .40 g was obtained.
(2) The product of the above (1) (2.40 g) was dissolved in ethanol (20 ml), 2 mol / l aqueous sodium hydroxide solution (10 ml) was added at room temperature, and the mixture was stirred at 40 ° C. After 30 minutes, ethanol was distilled off under reduced pressure, and 2 mol / l hydrochloric acid (10.5 ml) was added to the residue to make it acidic. The precipitated crystals were collected by filtration, washed with water, and 4- (1-pentenyl) benzoic acid was removed. 2.20 g was obtained.
(3) The product (2.20 g) of (2) above was dissolved in acetic acid (20 ml), platinum oxide (200 mg) was added, and catalytic hydrogenation was performed at room temperature and 3 atm. After 2 hours, the catalyst was removed by filtration, water (50 ml) was added to the mother liquor, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed twice with water (50 ml), and the solvent was distilled off under reduced pressure to obtain 2.10 g of 4- (1-pentyl) cyclohexanecarboxylic acid. (Cis / trans mixture)
(4) The product of the above (3) (1.00 g), 4-hydroxy-3-methoxybenzylamine hydrochloride (960 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at room temperature Salt (1.05 g) and triethylamine (581 mg) were mixed in ethyl acetate (20 ml) and stirred. After 10 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 = 100/0 to 0/100 gradient). The obtained crude crystals were recrystallized from a solution of hexane / ethyl acetate = 2/1 (10 ml) to obtain 315 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, t), 1.20-1.35 (9H, m), 1.40-1.65 (6H, m), 1.75-1.90 (2H, m), 2.20-2.32 (1H , m), 3.88 (3H, s), 4.36 (2H, d), 5.62 (1H, d), 5.73 (1H, brs), 6.76 (1H, dd), 6.80 (1H, d), 6.86 (1H, d).

Example 4
Preparation of cis-N- (4-hydroxy-3-methoxybenzyl) -4- (4-methylpentyl) cyclohexanecarboxamide:

(1) Under an argon atmosphere, methyl 4-formylbenzoate (2.00 g), (3-methylbutyl) triphenylphosphonium bromide (5.10 g) and 1,5,7-triazabicyclo [4.4.0] Decan-5-ene (1.70 g) was mixed in tetrahydrofuran (50 ml) and heated to reflux. After 15 hours, the reaction solution was returned to room temperature, water (30 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to give 4- (4-methyl-1-pentenyl) benzoic acid. 1.65 g of methyl acid was obtained.
(2) The product of above (1) (1.65 g) was dissolved in methanol (20 ml), and 2 mol / l aqueous sodium hydroxide solution (10 ml) was added and stirred at room temperature. After 10 hours, methanol was distilled off under reduced pressure. The residue was acidified with 2 mol / l hydrochloric acid (10.5 ml) and extracted with ethyl acetate (50 ml), 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 obtain 1.50 g of 4- (4-methyl-1-pentenyl) benzoic acid.
(3) The product (1.50 g) of (2) above was dissolved in acetic acid (20 ml), platinum oxide (200 mg) was added, and catalytic hydrogenation was performed at room temperature and 4 atm. After 10 hours, the catalyst was removed by filtration, water (100 ml) was added to the mother liquor, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml) in this order, and the solvent was distilled off under reduced pressure to obtain 1.20 g of 4- (4-methylpentyl) cyclohexanecarboxylic acid. (Cis / trans mixture)
(4) At room temperature, the product of (3) above (500 mg), 4-benzyloxy-3-methoxybenzylamine hydrochloride (660 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (500 mg) and triethylamine (290 mg) were mixed and stirred in ethyl acetate (10 ml). After 10 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 = 100/0 to 0/100 gradient) to give N- (4-benzyloxy-3-methoxybenzyl) -4- (4-methylpentyl). ) 740 mg of cyclohexanecarboxamide was obtained. (Cis / trans mixture)
(5) The product of (4) (740 mg) was dissolved in ethanol (10 ml), 10% palladium on carbon (100 mg) was added, and catalytic hydrogenation was performed at room temperature. After 1 hour, the catalyst was filtered off 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 140 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.86 (6H, d), 1.10-1.33 (6H, m), 1.38-1.70 (8H, m), 1.75-1.92 (2H, m), 2.22-2.32 (1H , m), 3.87 (3H, s), 4.36 (2H, d), 5.61 (1H, brs), 5.73 (1H, brs), 6.75 (1H, dd), 6.80 (1H, d), 6.86 (1H, d).

Example 5
Preparation of trans-N- (4-hydroxy-3-methoxybenzyl) -4- (4-methylpentyl) cyclohexanecarboxamide:

In the same manner as in Example 4 (5), the above-mentioned target product was separated and purified to obtain 40 mg.
¹ H-NMR (CDCl ₃ , δ): 0.86 (6H, d), 0.82-0.98 (2H, m), 1.08-1.35 (7H, m), 1.40-1.57 (3H, m), 1.78-1.96 (4H , m), 1.98-2.10 (1H, m), 3.88 (3H, s), 4.35 (2H, d), 5.57 (1H, s), 5.63 (1H, brs), 6.75 (1H, dd), 6.79 ( 1H, d), 6.86 (1H, d).

Example 6
Preparation of cis-4-hexyl-N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide:

(1) Methyl 4-formylbenzoate (1.00 g), pentyltriphenylphosphonium bromide (2.50 g) and 1,5,7-triazabicyclo [4.4.0] decane-5 under argon atmosphere En (850 mg) was mixed in tetrahydrofuran (50 ml) and heated to reflux. After 15 hours, the reaction solution was returned to room temperature, water (30 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). 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) to obtain methyl 4- (1-hexenyl) benzoate as 1. .20 g was obtained.
(2) The product of (1) (1.20 g) was dissolved in methanol (20 ml), and 2 mol / l aqueous sodium hydroxide solution (10 ml) was added at room temperature and stirred. After 10 hours, methanol was distilled off under reduced pressure. The residue was acidified with 2 mol / l hydrochloric acid (10.5 ml) and extracted with ethyl acetate (50 ml), 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 obtain 900 mg of 4- (1-hexenyl) benzoic acid.
(3) The product (900 mg) of the above (2) was dissolved in acetic acid (10 ml), platinum oxide (100 mg) was added, and catalytic hydrogenation was performed at room temperature at 4 atm. After 10 hours, the catalyst was removed by filtration, water (50 ml) was added to the mother liquor, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml) in this order, and the solvent was distilled off under reduced pressure to obtain 740 mg of 4-hexylcyclohexanecarboxylic acid. (Cis / trans mixture)
(4) At room temperature, the product of (3) above (500 mg), 4-benzyloxy-3-methoxybenzylamine hydrochloride (660 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (500 mg) and triethylamine (472 mg) were mixed and stirred in ethyl acetate (10 ml). After 10 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 obtain 165 mg of N- (4-benzyloxy-3-methoxybenzyl) -4-hexylcyclohexanecarboxamide. Obtained. (Cis / trans mixture)
(5) The product of (4) (165 mg) was dissolved in ethanol (5 ml), 10% palladium on carbon (20 mg) was added, and catalytic hydrogenation was performed at room temperature. After 1 hour, the catalyst was filtered off 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 45 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, t), 1.15-1.70 (17H, m), 1.75-1.90 (2H, m), 2.20-2.32 (1H, m), 3.88 (3H, s ), 4.37 (2H, d), 5.57 (1H, s), 5.70 (1H, brs), 6.73-6.83
(2H, m), 6.86 (1H, d).

Example 7
Preparation of trans-4-hexyl-N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide:

In the same manner as in Example 5 (5), the above-mentioned target product was separated and purified to obtain 9 mg.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, t), 0.80-1.00 (2H, m), 1.10-1.70 (15H, m), 1.75-2.20 (5H, m), 3.88 (3H, s ), 4.35 (2H, d), 5.58 (1H, s), 5.64 (1H, brs), 6.72-6.82
(2H, m), 6.86 (1H, d).

Example 8
Preparation of cis-4- (2-cyclopropylethyl) -N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide:

(1) Methyl 4-formylbenzoate (1.00 g), cyclopropylmethyltriphenylphosphonium bromide (2.40 g) and 1,5,7-triazabicyclo [4.4.0] decane- under argon atmosphere 5-ene (850 mg) was mixed in tetrahydrofuran (50 ml) and heated to reflux. After 15 hours, the reaction solution was returned to room temperature, water (30 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) and methyl 4- (2-cyclopropylvinyl) benzoate. 750 mg of was obtained.
(2) The product of the above (1) (750 mg) was dissolved in methanol (10 ml), 2 mol / l aqueous sodium hydroxide solution (10 ml) was added and stirred at room temperature. After 10 hours, methanol was distilled off under reduced pressure. The residue was acidified with 2 mol / l hydrochloric acid (10.5 ml) and extracted with ethyl acetate (50 ml), 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 obtain 420 mg of 4- (2-cyclopropylvinyl) benzoic acid. (3) The product of the above (2) (420 mg) was dissolved in acetic acid (10 ml), platinum oxide (100 mg) was added, and catalytic hydrogenation was performed at room temperature at 4 atm. After 10 hours, the catalyst was removed by filtration, water (50 ml) was added to the mother liquor, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water (50 ml), and the solvent was distilled off under reduced pressure to obtain 420 mg of 4- (2-cyclopropylethyl) cyclohexanecarboxylic acid. (Cis / trans mixture)
(4) The product of the above (3) (1.30 g), 4-hydroxy-3-methoxybenzylamine hydrochloride (1.25 g), 1-ethyl-3- (3-dimethylaminopropyl) at room temperature Carbodiimide hydrochloride (1.30 g) and triethylamine (726 mg) were mixed in chloroform (20 ml) and stirred. After 10 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 = 100/0 to 0/100 gradient) to obtain 425 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.86 (4H, d), 1.08-1.70 (12H, m), 1.75-1.90 (2H, m), 2.20-2.32 (1H, m), 3.87 (3H, s ), 4.36 (2H, d), 5.61 (1H, s), 5.73 (1H, brs), 6.73-6.82
(2H, m), 6.86 (1H, d).

Example 9
Preparation of trans-4- (2-cyclopropylethyl) -N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide:

In the same manner as in Example 8 (4), the above target product was separated and purified to obtain 160 mg.
¹ H-NMR (CDCl ₃ , δ): 0.86 (3H, t), 0.84-0.94 (2H, m), 1.10-1.65 (8H, m), 1.75-1.95 (4H, m), 1.97-2.10 (1H , m), 3.87 (3H, s), 4.35 (2H, d), 5.58 (1H, s), 5.64 (1H, brs), 6.75 (1H, dd), 6.79 (1H, d), 6.86 (1H, d).

Example 10
Preparation of cis-N- (4-hydroxy-3-methoxybenzyl) -4- (3-methylbutyl) cyclohexanecarboxamide:

(1) Methyl 4-formylbenzoate (1.00 g), (2-methylpropyl) triphenylphosphonium bromide (2.40 g) and 1,5,7-triazabicyclo [4.4.0 under an argon atmosphere. Decan-5-ene (850 mg) was mixed in tetrahydrofuran (50 ml) and heated to reflux. After 15 hours, the reaction solution was returned to room temperature, water (30 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to give 4- (3-methyl-1-butenyl) benzoic acid. 510 mg of methyl acid was obtained.
(2) The product of the above (1) (510 mg) was dissolved in methanol (10 ml), 2 mol / l aqueous sodium hydroxide solution (5 ml) was added and stirred at room temperature. After 10 hours, methanol was distilled off under reduced pressure. The residue was acidified with 2 mol / l hydrochloric acid (5.5 ml), extracted with ethyl acetate (25 ml), 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 obtain 325 mg of 4- (3-methyl-1-butenyl) benzoic acid.
(3) The product of the above (2) (325 mg) was dissolved in acetic acid (10 ml), platinum oxide (50 mg) was added, and catalytic hydrogenation was performed at room temperature and 4 atm. After 10 hours, the catalyst was removed by filtration, water (50 ml) was added to the mother liquor, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml) in this order, and the solvent was distilled off under reduced pressure to obtain 335 mg of 4- (3-methylbutyl) cyclohexanecarboxylic acid. (Mixed cis / trans) (4) The product of the above (3) (335 mg), 4-benzyloxy-3-methoxybenzylamine hydrochloride (470 mg), 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide hydrochloride (350 mg) and triethylamine (363 mg) were mixed in ethyl acetate (10 ml) and stirred. After 10 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 N- (4-benzyloxy-3-methoxybenzyl) -4- (3-methylbutyl) 210 mg of cyclohexanecarboxamide was obtained. (Cis / trans mixture)
(5) The product of (4) (210 mg) was dissolved in ethanol (10 ml), 10% palladium on carbon (20 mg) was added, and catalytic hydrogenation was performed at room temperature. After 1 hour, the catalyst was filtered off 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 35 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.87 (6H, d), 1.10-1.18 (2H, m), 1.25-1.33 (2H, m), 1.40-1.65 (8H, m), 1.75-1.90 (2H , m), 2.22-2.32 (1H, m), 3.88 (3H, s), 4.37 (2H, d), 5.61 (1H, s), 5.73 (1H, brs), 6.73-6.85 (2H, m), 6.86 (1H, d).

Example 11
Preparation of trans-N- (4-hydroxy-3-methoxybenzyl) -4- (3-methylbutyl) cyclohexanecarboxamide:

The target product was separated and purified in Example 10 (5) to obtain 20 mg.
¹ H-NMR (CDCl ₃ , δ): 0.85 (6H, d), 0.83-0.98 (2H, m), 1.10-1.35 (5H, m), 1.40-1.65 (3H, m), 1.78-1.96 (4H , m), 1.98-2.10 (1H, m), 3.88 (3H, s), 4.35 (2H, d), 5.57 (1H, s), 5.64 (1H, brs), 6.76 (1H, dd), 6.79 ( 1H, d), 6.86 (1H, d).

Example 12
Preparation of 4-butyl-N- (4-hydroxy-3-methoxybenzyl) cyclohex-3-ene-1-carboxamide:

(1) Under an argon atmosphere, anhydrous cerium chloride (2.70 g) was suspended in anhydrous tetrahydrofuran (20 ml) and stirred at room temperature. After 1 hour, the suspension was cooled to −78 ° C., and a 2.6 mol / l n-butyllithium hexane solution (2.80 ml) was slowly added dropwise and stirred. After further 1 hour, an anhydrous tetrahydrofuran solution (10 ml) of ethyl 4-oxo-cyclohexanecarboxylate (1.00 g) was added and stirred. After further 3 hours, a saturated aqueous solution of ammonium chloride (5 ml) was added to the reaction solution, and the insoluble material was removed by filtration and washed with chloroform. Water (50 ml) was added to the mother liquor, followed by extraction with chloroform (100 ml), and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (10 ml), 2 mol / l aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred. After 10 hours, methanol was distilled off under reduced pressure. The residue was neutralized with 2 mol / l hydrochloric acid (5.0 ml) and extracted with chloroform (25 ml), and the solvent was distilled off under reduced pressure. -4-Hydroxycyclohexanecarboxylic acid (500 mg) was obtained.
(2) The product of the above (1) (500 mg), 4-benzyloxy-3-methoxybenzylamine hydrochloride (500 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at room temperature (500 mg) and triethylamine (269 mg) were mixed and stirred in ethyl acetate (10 ml). After 10 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 (elution solvent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to give 4-butyl-4-hydroxy-N- (4-benzyloxy-3-methoxybenzyl). 100 mg of cyclohexanecarboxamide was obtained.
(3) The above compound (2) (100 mg) and p-toluenesulfonic acid monohydrate (60 mg) were mixed in toluene (10 ml) and heated to reflux. After 1 hour, the reaction solution was returned to room temperature, and water (10 ml) was added for liquid separation, 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 20 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, t), 1.20-1.40 (4H, m), 1.68-1.85 (1H, m), 1.88-2.10 (5H, m), 2.20-2.40 (3H , m), 3.88 (3H, s), 4.37 (2H, d), 5.39 (1H, s), 5.59 (1H, s), 5.75 (1H, brs), 6.75 (1H, dd), 6.80 (1H, d), 6.86 (1H, d).

Example 13
Preparation of N- (4-hydroxy-3-methoxybenzyl) -4-pentylidenecyclohexanecarboxamide:

(1) Potassium t-butoxide (2.10 g) was added to a tetrahydrofuran (50 ml) solution of pentyltriphenylphosphonium bromide (7.50 g) in a nitrogen atmosphere at 0 ° C. and stirred. After 1 hour, a tetrahydrofuran solution (20 ml) of 4-oxocyclohexanecarboxylic acid (2.00 g) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred. After 3 hours, water (30 ml) was added to the reaction solution, followed by extraction with ethyl acetate (100 ml), and the solvent was distilled off under reduced pressure. The residue was suspended in hexane and stirred at 40 ° C. After 20 minutes, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (20 ml), 2 mol / l aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at 40 ° C. After 20 minutes, methanol was distilled off under reduced pressure. The residue was acidified with 2 mol / l hydrochloric acid (10.5 ml) and extracted twice with chloroform (50 ml). The solvent was distilled off under reduced pressure. -400 mg of pentylidenecyclohexanecarboxylic acid was obtained.
(2) The product of the above (1) (400 mg), 4-benzyloxy-3-methoxybenzylamine hydrochloride (400 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at room temperature (425 mg) and triethylamine (436 mg) were mixed in ethyl acetate (10 ml) and stirred. After 10 hours, water (10 ml) was added to the reaction solution for liquid separation, 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 = 100/0 to 0/100 gradient) to obtain 200 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, t), 1.23-1.37 (4H, m), 1.40-1.60 (1H, m), 1.65-1.83 (1H, m), 1.90-2.11 (5H , m), 2.20-2.33 (2H, m), 2.60-2.70 (1H, m), 3.87 (3H, s), 4.35 (2H, d), 5.13 (1H, t), 5.62 (1H, d), 5.69 (1H, brs), 6.75 (1H, dd), 6.79 (1H, d), 6.86 (1H, d).

Test Examples The pharmacological test results of the representative compounds of the present invention are shown below, and the pharmacological actions of the compounds of the present invention are described. However, the present invention is not limited to these test examples.

Test Example 1: Plantar heat stimulation pain test (Plantar test)
This test measures the analgesic effect using the compound of the present invention as an index to determine how much the escape latency to nociceptive heat stimulation is prolonged. The method of Hargreaves et al. [Pain, 32 , 77 -88 (1988)] and Field [J. Pharmacol. Exp. Ther., 282 , 1242-1246 (1997)].

  Specifically, Std: Wistar male rats (4 rats per group, body weight 170 to 220 g) were used, and a plant test equipment (Model 7370, Ugo Basile) was used, and an infrared beam was used as a heat source. After placing the rat in a measurement cage (an acrylic box with a glass floor) and acclimatizing it, an infrared beam is irradiated from below onto the bottom of the right hind limb through the glass floor, and the latency until the escape behavior occurs. Time was measured three times at approximately 5 minute intervals. The intensity of the infrared beam was set so that the value before administration of the test compound was about 10 seconds. The cut-off time was set to 25 seconds in order to avoid burns on the feet. The average value was obtained from these measured values and used as the pre-test compound administration value.

On the next day, 50 μl of a solution containing the test compound (the compound of the present invention and capsaicin (Sigma, USA)) or a solvent control was injected subcutaneously into the right sole using a microsyringe (intraplantar injection: i .pl. The test compound was dissolved in physiological saline containing 10% Tween 80 (Sigma, USA) and 10% ethanol to a concentration of 0.03% (W / V). As a solvent control, only physiological saline containing 10% Tween 80 and 10% ethanol was used. Four hours after administration of the test compound or the solvent control, the same test as described above was performed to determine the post-administration value. The analgesic effect was determined using the relative maximum possible effect (% MPE) calculated by the following formula as an index.
% MPE = [(value after administration of test compound−value before administration of test compound) / (25 ^* −value before administration of test compound)] × 100
*: Cut-off time The results are shown in Table 1 below.

  As shown in Table 1, many of the compounds of the present invention exhibited a strong analgesic effect equivalent to or better than capsaicin when administered i.pl.

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, the compound of the present invention 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. One drop was dropped on the eyes of male male 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 2.

  As shown in Table 2, a vigorous wiping action was observed by dropping capsaicin at a concentration of 10 μg / ml. On the other hand, it was found that the compounds listed in Table 2 had a small number of wiping operations and were less irritating even at a concentration of 30 μg / ml.

Test Example 3 Skin sensitization test (local lymph node proliferation test)
This test is to test whether administration of the compound of the present invention may cause allergic contact dermatitis. That is, the skin sensitization property of the compound of the present invention was examined by LLNA (Local Lymph Node Assay) using BrdU (bromodeoxyuridine).

  Specifically, according to the method of Suda et al. (Suda, A. et al .: Local lymph node assay with non-radioisotope alternative endpoints. J. Toxicol. Sci., 27 (3): 205-218, 2002) Tested. That is, the compounds of the present invention are dissolved in DMF (N, N-dimethylformamide) to give 1 and 3% solutions, which are continuously applied to both auricles of 9-week-old CBA / JN female mice for 3 days (from the first day to (Day 3) (25 μl / one ear, applied once a day). DNCB (dinitrochlorobenzene, strongly sensitizing substance) and HCA (α-hexyl-cinnamaldehyde, weakly sensitizing substance) were used as positive control substances. After the final application (Day 3), ALZET Osmotic Pump (release rate 0.5 μl / hour) containing 100 μl of 200 mg / mL BrdU under pentobarbital anesthesia was implanted subcutaneously in the ventral side to continuously expose BrdU. . The animal was euthanized by cervical dislocation on the 9th day from the start of application of the compound of the present invention, the lymph nodes of both ears were collected and weighed, and the lymph nodes were disrupted in PBS to float single cells. A liquid was prepared, and the number of cells was measured with a blood test apparatus ADVIA (Bayer). Next, the cells were immunofluorescently stained with a FITC-labeled anti-BrdU antibody using a BrdU Flow Kit (BD Biosciences), and the BrdU positive cell rate was measured and analyzed using a flow cytometer FACS Calibur (Becton Dickinson). The number of BrdU positive cells was calculated by multiplying the positive cell rate by the number of lymph node cells. In addition, for each parameter, the average value of the test substance group was divided by the average value of the vehicle control group to obtain a stimulation index (SI). As for the presence or absence of skin sensitization, in principle, when the BrdU positive cell count SI was 2 or more, it was determined that there was sensitization.

  As a result, among the compounds of the present invention, the compound of Example 2 was found to have low skin sensitization.

  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 (16)

The following formula (I):

[Where
R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched carbon selected from the group consisting of a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, and a C _4-10 alkenyl alkynyl group. Represents a hydrogen group, the hydrocarbon group,
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group;
(2) Fluorine atom, hydroxyl group, C _1-6 alkyl group that can be substituted with 1 to 5 fluorine atoms, C _1-6 alkoxy group that can be substituted with 1 to 5 fluorine atoms, nitro group, amino group, a cyano group, C _{1 to 4} alkyloxycarbonyl group, C _{1 to 4} alkyl carbonyl group, the same or different 1 to 5 substituents selected from the group consisting of carboxyl group and methylenedioxy group An aryl group that may be present;
(3) may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom and (4) hydroxyl group,
R ³ in formula (A) and formula (B) contains at least 4 carbon atoms, and R ³ in formula (C) shows at least 3 carbon atoms}
Or a physiologically acceptable salt thereof. In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched hydrocarbon group selected from the group consisting of a C _1-10 alkyl group and a C _2-10 alkenyl group, and the hydrocarbon group is
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group;
(2) Fluorine atom, hydroxyl group, C _1-6 alkyl group that can be substituted with 1 to 5 fluorine atoms, C _1-6 alkoxy group that can be substituted with 1 to 5 fluorine atoms, nitro group, amino group, a cyano group, C _{1 to 4} alkyloxycarbonyl group, C _{1 to 4} alkyl carbonyl group, the same or different 1 to 5 substituents selected from the group consisting of carboxyl group and methylenedioxy group An aryl group that may be present;
(3) may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom and (4) hydroxyl group,
2. The N-benzyl according to claim 1, wherein R ³ in formula (A) and formula (B) represents at least 4 carbon atoms, and R ³ in formula (C) represents at least 3 carbon atoms. Amide derivatives or physiologically acceptable salts thereof. In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched hydrocarbon group selected from the group consisting of a C _1-10 alkyl group and a C _2-10 alkenyl group, and the hydrocarbon group is
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group;
(3) may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atom and (4) hydroxyl group,
2. The N-benzyl according to claim 1, wherein R ³ in formula (A) and formula (B) represents at least 4 carbon atoms, and R ³ in formula (C) represents at least 3 carbon atoms. Amide derivatives or physiologically acceptable salts thereof. In formula (I), R ³ in formula (A) and formula (B) contains 4 to 10 carbon atoms, and R ³ in formula (C) contains 3 to 9 carbon atoms. The N-benzylamide derivative according to 1, or a physiologically acceptable salt thereof. In formula (I), R ³ in formula (A) and formula (B) contains 4 to 8 carbon atoms, and R ³ in formula (C) contains 3 to 7 carbon atoms. Item 12. The N-benzylamide derivative according to Item 1 or a physiologically acceptable salt thereof. In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched C _1-10 alkyl group,
(1) a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkyl group; and (3 ) May be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine atoms,
2. The N-benzyl according to claim 1, wherein R ³ in formula (A) and formula (B) represents at least 4 carbon atoms, and R ³ in formula (C) represents at least 3 carbon atoms. Amide derivatives or physiologically acceptable salts thereof. In the formula (I), R ¹ represents a methoxy group, a hydroxyl 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, and D represents a group represented by the following formula (A), (B) or (C) :

{In each formula, R ³ represents a linear or branched C _1-10 alkyl group,
(1) substituted with a C _3-8 cycloalkyl group which may be substituted with the same or different 1-5 substituents selected from the group consisting of fluorine atom, hydroxyl group and C _1-6 alkyl group You can,
2. The N-benzyl according to claim 1, wherein R ³ in formula (A) and formula (B) represents at least 4 carbon atoms, and R ³ in formula (C) represents at least 3 carbon atoms. Amide derivatives or physiologically acceptable salts thereof. The N-benzylamide derivative or physiologically acceptable salt thereof according to claim ¹ , wherein R ¹ in formula (I) represents a methoxy group or a hydroxyl group. The N-benzylamide derivative or physiologically acceptable salt thereof according to claim 1, wherein R ² in formula (I) represents a hydrogen atom. The N-benzylamide derivative or physiologically acceptable salt thereof according to claim 1, wherein in formula (I), R ¹ represents a methoxy group and R ² represents a hydrogen atom.   The N-benzylamide derivative or physiologically acceptable salt thereof according to any one of claims 1 to 10, wherein D is represented by the formula (A).   The N-benzylamide derivative or physiologically acceptable salt thereof according to any one of claims 1 to 10, wherein D is represented by the formula (B).   The N-benzylamide derivative or physiologically acceptable salt thereof according to any one of claims 1 to 10, wherein D is represented by the formula (C). The compound represented by formula (I) is:
Trans-N- (4-Hydroxy-3-methoxybenzyl) -4-pentylcyclohexanecarboxamide trans-N- (4-hydroxy-3-methoxybenzyl) -4- (4-methylpentyl) cyclohexanecarboxamide cis-4-hexyl -N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide trans-4- (2-cyclopropylethyl) -N- (4-hydroxy-3-methoxybenzyl) cyclohexanecarboxamide trans-N- (4-hydroxy- The compound according to claim 1, which is a compound selected from the group consisting of 3-methoxybenzyl) -4- (3-methylbutyl) cyclohexanecarboxamide and N- (4-hydroxy-3-methoxybenzyl) -4-pentylidenecyclohexanecarboxamide. Of N- benzylamide derivative or a physiologically acceptable salt thereof.   A pharmaceutical composition comprising the N-benzylamide derivative according to any one of claims 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.   A therapeutic or prophylactic agent for pain and / or inflammation comprising the N-benzylamide derivative or physiologically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient.