JP2013028537A - N-benzyl amide derivative and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful as a therapeutic agent to pains or inflammation resulting from various pathologic conditions such as neurogenic pains or rheumatoid arthritis.SOLUTION: This invention relates to a compound represented by formula (I) or a salt thereof. [In the formula, Rrepresents methyl or the like, Rrepresents H, and Z represents formulas (A) to (D)].

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.

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

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

As a result of continual research, the present inventors have found that an N-benzylamide derivative, that is, a compound represented by the following formula (I) has a strong analgesic action, but has low irritation, and the present invention. Was completed. That is, the present invention provides the following inventions.
Item 1: The following formula (I):

[Where
R ¹ represents a methyl group or a hydrogen atom,
R ² represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkylcarbonyl group or an arylcarbonyl group,
Z is a group represented by the following formula (A), (B), (C) or (D):

{In each formula, n and m are the same or different and each represents an integer of 1, 2 or 3;
R ³ is an aryl group or a heteroaryl group (each group may be substituted at a substitutable position with C _1-6 alkyl, C _2-6 alkenyl, or C _3-6 cycloalkyl). or shown, _{or, -S (= O) 2 -R} 7, -C (= O) -R 7, -C (= O) -S-R 7, -C (= O) -NR 8 R 88, ^{_{-S (= O) 2 -NR 8}} R 88, -C (= O) indicates ^{-O-R 9} or ^{-C (= S) -NR 8 R} 88,
R ⁴ is —C (═O) —O—R ⁷ , —S (═O) ₂ —R ⁷ , —C (═O) —R ⁷ , —C (═O) —S—R ⁷ , — C (═O) —NR ⁸ R ⁸⁸ or —S (═O) ₂ —NR ⁸ R ⁸⁸ ,
R ⁵ represents —C (═O) —O—R ⁷ or —O—C (═O) —NR ⁸ R ⁸⁸ ;
R ⁶ is a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl). Or a C _3-10 alkyl group, a C _3-10 alkenyl group, a C _3-8 cycloalkyl C _1-6 alkyl group, ^{-C (= O) -O-R} 7 or -O-C (= O) shows the ^-NR 8 ^{R 88,}
R ⁷ represents a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl). Or a C _6-12 alkyl group, a C _6-12 alkenyl group, or a C _3-8 cycloalkyl C _1-6 alkyl group. Show
R ⁸ and R ⁸⁸ are the same or different and are a hydrogen atom, a C _1-8 alkyl group, a C _2-8 alkenyl group, or a C _3-6 cycloalkyl group optionally substituted with a C _1-6 alkyl. Or R ⁸ and R ⁸⁸ are taken together to form a C _3-7 azacycloalkyl group (the group may be substituted with 1 to 5 C _1-6 alkyl groups). Show
R ⁹ represents a C _6-12 alkyl group or a C _6-12 alkenyl group. }. ]
Or a physiologically acceptable salt thereof.

Item 2: The compound according to any one of Items 1 or a physiologically acceptable salt thereof, wherein in formula (I), n and m are the same or different and each represents an integer of 1 or 2.
Item 3: The compound according to Item 2 or a physiologically acceptable salt thereof, wherein in formula (I), n and m are both 2.
Item 4: In the formula (I), R ³ is an aryl group (the group is the same or different and selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl and C _3-6 cycloalkyl) one to 5 substituents may be substituted.) or show, or -C (= O) shows the ^{-S-R 7} or ^{_{-S (= O) 2 -NR 8}} R 88,
R ⁴ represents —C (═O) —O—R ⁷ ,
R ⁵ represents —C (═O) —O—R ⁷ ,
R ⁶ represents a C _3-10 alkyl group or a C _3-10 alkenyl group, and R ⁷ , R ⁸ and R ⁸⁸ are the same as defined in Item 1, or a physiologically physiological compound thereof Acceptable salt.

Item 5: In the formula (I), R ⁷ is a C _3-8 cycloalkyl group (the group is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl and halogen) Which may be substituted with the same or different 1 to 5 substituents).
R ⁸ and R ⁸⁸ are the same or different and each represents a C _1-6 alkyl group or a C _2-6 alkenyl group, or R ⁸ and R ⁸⁸ together represent C _3-5 azacycloalkyl. A group wherein the group may be substituted with 1 to 5 C _1-6 alkyl groups;
Item R ⁹ is the compound according to any one of Items 1 to 4 or a physiologically acceptable salt thereof, wherein R ⁹ represents a C _7-9 alkyl group or a C _7-9 alkenyl group.
Item 6: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 5, wherein Z is represented by the formula (A).
Item 7: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 5, wherein Z is represented by the formula (B).
Item 8: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 5, wherein Z is represented by the formula (C).
Item 9: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 5, wherein Z is represented by the formula (D).
Item 10: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 9, wherein R ¹ in formula (I) represents a methyl group.

Item 11: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 10, wherein R ² in formula (I) represents a hydrogen atom.
Item 12: A pharmaceutical composition comprising the compound according to any one of Items 1 to 11 or a physiologically acceptable salt thereof as an active ingredient.
Item 13: A therapeutic or preventive agent for pain and / or inflammation comprising the compound according to any one of Items 1 to 11 or a physiologically acceptable salt thereof as an active ingredient.
Item 14: An analgesic or anti-inflammatory drug comprising the compound according to any one of Items 1 to 11 or a physiologically acceptable salt thereof as an active ingredient.
Item 15: The compound according to any one of Items 1 to 11, or a physiologically acceptable salt thereof, a narcotic analgesic, a neuropathic pain therapeutic agent, a non-steroidal anti-inflammatory drug, a steroidal anti-inflammatory drug, A medicament comprising at least one other drug selected from the group consisting of an antidepressant, an antiepileptic drug, an anticonvulsant, an anesthetic, an antiarrhythmic drug, a local anesthetic and an anxiolytic drug.

  Item 16: A pharmaceutical composition comprising the pharmaceutical according to Item 15 as an active ingredient.

  Item 17: A therapeutic or prophylactic agent for pain and / or inflammation, comprising the medicament according to Item 15 as an active ingredient.

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

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

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

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

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

  Terms used in this specification will be described below.

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

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

“Cycloalkyl group” means a monocyclic saturated hydrocarbon group. For example, “C _3-8 cycloalkyl group” means a monocyclic saturated hydrocarbon group having 3 to 8 carbon atoms. . Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The same applies to the “C _3-6 cycloalkyl group”.

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

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

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

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

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

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

The “aryl group substituted with halogen” refers to a group in which one or more (for example, 1 to 5, preferably 1 to 2) hydrogen atoms of the aryl group are substituted with halogen. Specific examples include 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-iodophenyl, 4-iodophenyl, and the like. The same applies to each of the following substituents substituted with halogen: a cycloalkyl group, a cycloalkenyl group, and a heteroaryl group.
In addition, when the hydrogen atom of a cycloalkyl group, a cycloalkenyl group, an aryl group or a heteroaryl group is substituted with a plurality of substituents, these substituents may be the same or different. As these specific examples, those obtained by appropriately combining the above examples can be exemplified.

Specific examples of “C _3-8 cycloalkyl C _1-6 alkyl group” include 4-cyclopropylbutyl, 3-cyclobutylpropyl, cyclopentylmethyl, cyclohexylmethyl and the like.

The “C _3-7 azacycloalkyl group” is a group represented by a monocyclic saturated hydrocarbon group containing one nitrogen atom and 3 to 7 carbon atoms, specifically, , Azetidinyl, pyrrolidinyl, and piperidinyl. Examples of the C _3-7 azacycloalkyl group substituted with 1 to 5 C _1-6 alkyl groups include 3-butylazetidinyl, 4-propylpiperidinyl, 4-t-butylpiperidinyl. Nil etc. can be illustrated.

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

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

  n and m are the same or different and each represents an integer of 1, 2 or 3, preferably 1 or 2, more preferably an integer of 1 or 2, or one is 1 and the other is 2. Show. Particularly preferably, both are 2.

R ³ in the formula (A) is an aryl group or a heteroaryl group (each group is substituted with C _1-6 alkyl, C _2-6 alkenyl or C _3-6 cycloalkyl at substitutable positions). Or may be substituted with the same or different 1 to 5 substituents described above, or —S (═O) ₂ —R ⁷ , —C (= O) —R ⁷ , —C (═O) —S—R ⁷ , —C (═O) —NR ⁸ R ⁸⁸ , —S (═O) ₂ —NR ⁸ R ⁸⁸ , —C (═O) — O—R ⁹ or —C (═S) —NR ⁸ R ⁸⁸ is shown. Among these R ³ , more preferably, an aryl group (the same or different one selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl and C _3-6 cycloalkyl) to five substituents may be substituted.) or show, or a ^{-C (= O) -S-R} 7 or ^{_{-S (= O) 2 -NR 8}} R 88.

R ⁴ in formula (B) is —C (═O) —O—R ⁷ , —S (═O) ₂ —R ⁷ , —C (═O) —R ⁷ , —C (═O) —S. -R ^7, showing a ^{-C (= O) -NR 8 R} 88 , or ^{_{-S (= O) 2 -NR 8}} R 88. Of these R ⁴ , —C (═O) —O—R ⁷ is more preferable.

R ⁵ in the formula (C) represents —C (═O) —O—R ⁷ or —O—C (═O) —NR ⁸ R ⁸⁸ . Among these R ⁵ , —C (═O) —O—R ⁷ is more preferable.
R ⁶ in the formula (D) is a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the respective groups are C _1-6 alkyl, C _2-6 alkenyl, C _{3 to 6} cycloalkyl or halogen, which may be substituted at substitutable positions, for example, may be substituted with 1 to 5 substituents which are the same or different, or Or C _3-10 alkyl group, C _3-10 alkenyl group, C _3-8 cycloalkyl C _1-6 alkyl group, —C (═O) —O—R ⁷ or —O—C (═O) —NR ⁸ R ⁸⁸ is shown. Among these R ⁶ , a C _3-10 alkyl group or a C _3-10 alkenyl group is more preferable.

R ⁷ in each of R ^{3 to} R ⁶ is a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _{2-6 Optionally} substituted with alkenyl, C _3-8 cycloalkyl or halogen at substitutable positions, for example with 1 to 5 substituents which may be the same or different. Or a C _6-12 alkyl group, a C _6-12 alkenyl group, or a C _3-8 cycloalkyl C _1-6 alkyl group. Among these R ⁷ , more preferably, a C _3-8 cycloalkyl group (the group is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl and halogen, It may be substituted with 1 to 5 substituents which may be the same or different.

R ⁸ and R ⁸⁸ in each of R ^{3 to} R ⁶ are the same or different and may be substituted with a hydrogen atom, a C _1-8 alkyl group, a C _2-8 alkenyl group, or a C _1-6 alkyl. _{Represents a} C _3-6 cycloalkyl group, or R ⁸ and R ⁸⁸ together represent a C _3-7 azacycloalkyl group (the group is substituted with 1 to 5 C _1-6 alkyl groups) May be). Among these R ⁸ and R ⁸⁸ , more preferably, they are the same or different and each represents a C _1-6 alkyl group or a C _2-6 alkenyl group, or R ⁸ and R ⁸⁸ are combined to form C _{A 3 to 5} azacycloalkyl group, which group may be substituted with 1 to 5 C _1-6 alkyl groups.
R ⁹ represents a C _6-12 alkyl group or a C _6-12 alkenyl group. Among these R ⁹ , a C _7-9 alkyl group or a C _7-9 alkenyl group is more preferable.

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

[Where
Z ′ is a group represented by the following formula (A), (B) or (C):

{In each formula, n and m both represent an integer of 1 or 2, or one represents 1 and the other represents 2.
R ³ represents an aryl group (the group is the same or different 1 to 5 substituents selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl and C _3-6 cycloalkyl). Optionally substituted), or —C (═O) —S—R ⁷ or —S (═O) ₂ —NR ⁸ R ⁸⁸ ,
R ⁴ is —C (═O) —O—R ⁷ ,
R ⁵ is —C (═O) —O—R ⁷ ,
R ⁷ represents C _3-8 cycloalkyl (the group is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl, and halogen; May be substituted with 5 substituents),
R ⁸ and R ⁸⁸ are the same or different and each represents a C _1-6 alkyl group or a C _2-6 alkenyl group, or R ⁸ and R ⁸⁸ are combined to form a C _3-5 azacycloalkyl group. (The group may be substituted with 1 to 5 C _1-6 alkyl groups). }. ]
Or a physiologically acceptable salt thereof.
In addition, the following abbreviations may be used for simplification of description in this specification.

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

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

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

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

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

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

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

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

(Wherein R ¹ , R ² and Z are the same as defined in item 1).
The compound of the formula (I) can be produced by an amidation reaction between a compound of the formula (II) and a compound of the formula (III) under a commonly used reaction condition. The compound of formula (III) may be reacted with a compound of formula (II) after conversion to a reactive derivative at the carboxyl group.

  Examples of the reactive derivative 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.

  In this reaction, the compound of formula (III) may be reacted with the compound of formula (II) 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 and the like. 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 above-described reaction between the compound of formula (III) or a reactive derivative thereof and the compound of formula (II) is usually carried out in a solvent or without solvent. The solvent to be used should be selected according to the type of raw material compound, and examples thereof include toluene, THF, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, DMF and the like. These solvents are used alone or as a mixed solvent of two or more. In addition, the compound of formula (II) may be used in the form of an acid addition salt such as hydrochloride to generate a free base in the reaction system.

  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 reaction time is about 1 hour to 48 hours.

  Moreover, the compound of Formula (II) is a well-known compound, or can be manufactured according to the manufacturing method of a well-known compound. For example, Monatsh. Chem., 77, 54 (1947), Tetrahedron Lett., 43, 4281 (2002), J. Org. Chem., 53, 1064 (1988), J. Org. Chem., 54, 3477 ( 1989) and the like, or a method analogous thereto.

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

Process for the preparation of compounds of formula (IA)

(Wherein R ¹ , R ² , R ³ , m and n are the same as defined in item 1, P represents an amino-protecting group, X represents a leaving group (for example, a halogen atom, lower Alkoxy group, phenoxy group, imidazolyl group, etc.)

  Compounds of formula (IA) can be prepared under the commonly used reaction conditions of compounds of formula (VI) and compounds of formula (VII).

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

  The compound of the formula (VI) is produced by using the compound of the formula (II) and the compound of the formula (IV) in the same manner as in the amidation reaction in the above-mentioned production method, It can be produced by deprotecting P). The compound of the formula (IV) may be reacted with the compound of the formula (II) after being converted into a reactive derivative at the carboxyl group, as described above.

  The compound of the said formula (IV) is a well-known compound, or can be manufactured according to the manufacturing method of a well-known compound. For example, it can be produced according to the method described in J. Pharm. Sci., 71, 1214 (1982), J. Med. Chem., 31, 613 (1988) or the like, or a method analogous thereto.

Method for producing compound of formula (IB)

(Wherein R ¹ , R ² , R ⁴ , m and n are the same as defined in item 1, P represents an amino-protecting group, and X and Y represent a leaving group (for example, a halogen atom) , A lower alkoxy group, a phenoxy group, an imidazolyl group, etc.)
The compound of the formula (IB) can be prepared under the conditions described in the process for producing the compound of the formula (IA) as described above under the reaction conditions usually used for the compound of the formula (X) and the compound of the formula (XI). Can be manufactured according to.

A compound of formula (X) can be prepared by deprotecting the protecting group (P) of formula (IV).
The compound of formula (IV) is prepared by converting the compound of formula (II) into a reactive derivative represented by formula (II ′) and then reacting with the compound of formula (VIII) under the conditions usually used. can do.

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

  The compound of the above formula (VIII) is a known compound, or can be produced according to a known compound production method. For example, it can be produced according to the method described in J. Heterocyclic Chem., 27, 1559 (1990), J. Chem. Soc., 3634 (1959) or the like, or a method analogous thereto.

  The production of the compound of the group in which Z is represented by the formula (C) or the formula (D) can be carried out by the method described in the following Examples, It can be synthesized in the same manner as described.

  The compound of the present invention includes a compound represented by the following formula (XII) or a physiologically acceptable salt thereof, and has the same utility as that of the formula (I).

{Wherein R ¹ represents a methyl group or a hydrogen atom,
R ² represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkylcarbonyl group or an arylcarbonyl group,
R ¹⁰ represents an aryl group (the group is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl and halogen, the same or different 1 to 5 substituents; Which may be substituted with a group)
n and m are the same or different and each represents an integer of 1, 2 or 3,
p represents an integer of 0, 1, 2 or 3. }

  The compound of the present invention obtained by the above production method can be isolated and purified according to conventional methods such as chromatography, recrystallization and reprecipitation. 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 the present invention may be obtained in the form of a salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions, but may be converted to the compound of the present invention according to a conventional method. it can. On the other hand, for example, the compound of the present invention having a group capable of forming an acid addition salt in the structural formula can be converted into an acid addition salt by treating with various acids according to a conventional method.

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

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

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

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

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

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

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

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

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

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

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

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

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

Example 1
Preparation of 1- (N, N-dibutylsulfamoyl) -N- (4-hydroxy-3-methoxybenzyl) piperidine-4-carboxamide:

(1) 1- (t-Butoxycarbonyl) -piperidine-4-carboxylic acid (11.5 g), 4-benzyloxy-3-methoxybenzylamine hydrochloride (11.5 g), triethylamine (14.0 ml) and chloride To a mixture of methylene (300 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (12.5 g). The reaction solution was stirred at room temperature for 20 hours, washed with a saturated aqueous ammonium chloride solution and saturated brine in that order, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) to give t-butyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) -piperidine-1. -16.3 g of carboxylate was obtained.
(2) The product of (1) (16.3 g) was dissolved in ethyl acetate (270 ml), and 4 mol / l hydrogen chloride / ethyl acetate (90 ml) was added. After the mixture was stirred for 6 hours, hexane (200 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 11.4 g of N- (4-benzyloxy-3-methoxybenzyl) -4-piperidinecarboxamide hydrochloride. It was.
(3) To the mixture of dibutylsulfamoyl chloride (239 mg) and N, N-dimethylformamide (5 ml), the product (273), triethylamine (211 mg) and 4-dimethylaminopyridine (12 mg) were added. And stirred at room temperature for 3 days. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) and purified by N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N- 301 mg of dibutylsulfamoyl) piperidine-4-carboxamide were obtained.
(4) The product (301 mg) of (3) above is dissolved in a mixed solvent (6 ml) of ethanol / tetrahydrofuran (1/2), 10% palladium carbon (102 mg) is added, and catalytic hydrogen is added at room temperature under a hydrogen atmosphere. The addition was made. After 7 hours, the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = gradient from 100/0 to 0/100) for the purpose. 248 mg of product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.93 (6H, t), 1.23-1.37 (4H, m), 1.50-1.60 (4H, m), 1.71-1.93 (4H, m), 2.17 (1H, tt ), 2.73 (2H, dt), 3.15 (4H, t), 3.64 (2H, dt), 3.88 (3H, s), 4.35 (2H, d), 5.60 (1H, s), 5.71 (1H, t) , 6.75 (1H, dd), 6.78 (1H, d), 6.86 (1H, d).

Example 2
Preparation of 1- (N, N-diisopentylsulfamoyl) -N- (4-hydroxy-3-methoxybenzyl) piperidine-4-carboxamide:

Using diisopentylsulfamoyl chloride instead of dibutylsulfamoyl chloride in Example 1, reaction and treatment were conducted in the same manner as in Example 1 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.92 (12H, d), 1.41-1.61 (6H, m), 1.70-1.95 (4H, m), 2.10-2.24 (1H, m), 2.74 (2H, dt ), 3.11-3.21 (4H, m), 3.60-3.71 (2H, m), 3.88 (3H, s), 4.35 (2H, d), 5.58 (1H, s), 5.67 (1H, brs), 6.75 ( 1H, dd), 6.78 (1H, d), 6.86 (1H, d).

Example 3
Preparation of N- (4-hydroxy-3-methoxybenzyl) -1- (octylsulfonyl) piperidine-4-carboxamide:

Using octane-1-sulfonyl chloride instead of dibutylsulfamoyl chloride in Example 1, reaction and treatment were conducted in the same manner as in Example 1 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.86 (3H, t), 1.25-1.37 (10H, m), 1.72-1.85 (4H, m), 1.90-1.95 (2H, m), 2.17-2.25 (1H , m), 2.80-2.89 (4H, m), 3.76-3.81 (2H, m), 3.86 (3H, s), 4.33 (2H, d), 5.57 (1H, s), 5.66 (1H, brs), 6.73 (1H, dd), 6.76 (1H, d), 6.85 (1H, d).

Example 4
Production of N- (4-hydroxy-3-methoxybenzyl) -1-tosylpiperidine-4-carboxamide:

Using p-toluenesulfonyl chloride instead of dibutylsulfamoyl chloride in Example 1, reaction and treatment were conducted in the same manner as in Example 1 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.80-1.90 (4H, m), 2.01-2.05 (1H, m), 2.37 (2H, dt), 2.43 (3H, s), 3.77 (2H, dt), 3.86 (3H, s), 4.32 (2H, d), 5.57-5.60 (2H, m), 6.71-6.75 (2H, m), 6.85 (1H, d), 7.32 (2H, d), 7.64 (2H, d).

Example 5
Preparation of 1- (2-ethylphenyl) -N- (4-hydroxy-3-methoxybenzyl) piperidine-4-carboxamide:

(1) A mixture of N- (4-benzyloxy-3-methoxybenzyl) -4-piperidinecarboxamide (400 mg), 1-bromo-2-ethylbenzene (287 mg), sodium t-butoxy (325 mg) and toluene (10 ml) Was added bis (tri-t-butylphosphine) palladium (52 mg) and the reaction was heated at 80 ° C. for 15 hours. The catalyst was filtered off, ethyl acetate was added, and the mixture was washed with water and saturated brine in this order. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to give 1- (2-ethylphenyl) -N- (4-benzyloxy-3-methoxybenzyl). ) 151 mg of piperidine-4-carboxamide was obtained.
(2) The product of (1) (151 mg) was dissolved in ethanol (10 ml), 10% palladium on carbon (100 mg) was added, and catalytic hydrogenation was performed. After 5 hours, the catalyst was removed by filtration and the solvent was distilled off. The residue was crystallized from ethyl acetate to obtain 46 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.23 (3H, t), 1.90-2.00 (4H, m), 2.21-2.33 (1H, m), 2.62-2.73 (2H, m), 2.69 (2H, q ), 3.08-3.17 (2H, m), 3.89 (3H, s), 4.39 (2H, d), 5.59 (1H, s), 5.73 (1H, brs), 6.76 (1H, dd), 6.82 (1H, d), 6.88 (1H, d), 7.01-7.10 (2H, m), 7.11-7.25 (2H, m).

Example 6
Production of N- (4-hydroxy-3-methoxybenzyl) -1- (2-methylphenyl) piperidine-4-carboxamide:

Using 1-bromo-2-methylbenzene instead of 1-bromo-2-ethylbenzene in Example 5, the reaction and treatment were conducted in the same manner as in Example 5 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.90-2.00 (4H, m), 2.21-2.33 (1H, m), 2.29 (3H, s), 2.60-2.73 (2H, m), 3.14-3.22 (2H , m), 3.89 (3H, s), 4.39 (2H, d), 5.58 (1H, s), 5.72 (1H, brs), 6.75 (1H, dd), 6.82 (1H, d), 6.88 (1H, d), 6.95-7.01 (2H, m), 7.14-7.19 (2H, m).

Example 7
Preparation of 1- (4-t-butylpiperidine-1-carbonyl) -N- (4-hydroxy-3-methoxybenzyl) piperidine-4-carboxamide:

  (1) To a mixture of 4-t-butylpiperidine (119 mg), triethylamine (140 mg) and tetrahydrofuran (3 ml) was added p-nitrophenyl chloroformate (135 mg) under ice cooling, and the mixture was stirred at room temperature for 4 hours. To this mixture, the product of Example 1 (2) (218 mg), triethylamine (169 mg) and dimethyl sulfoxide (3 ml) were added, and the mixture was stirred at room temperature for 14 hours and at 80 ° C. for 19 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate solution (4 times), saturated aqueous ammonium chloride solution and saturated brine in this order. The organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. did. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = gradient from 100/0 to 100/1) and purified by N- (4-benzyloxy-3-methoxybenzyl) -1- (4-t-butyl 40 mg of piperidine-1-carbonyl) piperidine-4-carboxamide were obtained.

(2) In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (1) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.85 (9H, s), 1.14-1.26 (4H, m), 1.64-1.86 (5H, m), 2.25 (1H, brt), 2.63-2.78 (4H, m ), 3.71 (4H, t), 3.87 (3H, s), 4.35 (2H, d), 5.71 (1H, s), 5.76 (1H, brs), 6.73-6.78 (2H, m), 6.86 (1H, d).

Example 8
N ¹ - (cis-4-ethyl-cyclohexyl) ^-N 4 - (4-hydroxy-3-methoxybenzyl) piperidine-1,4-dicarboxamide: Prepared

Using cis-4-ethylcyclohexaneamine p-toluenesulfonate in place of 4-t-butylpiperidine in Example 7, the reaction and treatment were conducted in the same manner as in Example 7 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.88 (2H, t), 1.09-1.18 (2H, m), 1.23-1.30 (4H, m), 1.60-1.76 (10H, m), 1.85-1.89 (2H , m), 2.26 (1H, tt), 2.80 (2H, dt), 3.87 (3H, s), 3.89-3.98 (2H, m), 4.35 (2H, d), 4.49 (1H, d), 5.64 ( 1H, s), 5.72 (1H, brs), 6.75 (1H, dd), 6.78 (1H, d), 6.86 (1H, d).

Example 9
Preparation of 1- [butyl (methyl) thiocarbamoyl] -N- (4-hydroxy-3-methoxybenzyl) piperidine-4-carboxamide:

  (1) N-methyl-1-butanamine (306 mg) was added to a mixture of N, N′-thiocarbonyldiimidazole (754 mg) and methylene chloride (3.5 ml), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (5 ml), and iodomethane (1.98 g) was added. The mixture was stirred at room temperature for 26 hours, further iodomethane (1.98 g) was added, and the mixture was stirred for 17 hours. After the reaction solution was concentrated under reduced pressure, 1.33 g of 1- [butyl (methyl) thiocarbamoyl] -3-methyl-1H-imidazol-3-ium iodide was obtained.

(2) The product (1.03 g) of Example 1 (1) was dissolved in ethanol (20 ml), 10% palladium carbon (198 mg) was added, and catalytic hydrogenation was performed at room temperature in a hydrogen atmosphere. After 2 hours, the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = gradient from 100/0 to 0/100). 807 mg of -butyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate was obtained.
(3) The product of (2) (807 mg) was dissolved in ethyl acetate (24 ml), and 4 mol / l hydrogen chloride / ethyl acetate (8 ml) was added. After the mixture was stirred for 17 hours, the precipitated crystals were collected by filtration to obtain 658 mg of N- (4-hydroxy-3-methoxybenzyl) -4-piperidinecarboxamide hydrochloride.

(4) To the mixture of the product of (1) (331 mg) and tetrahydrofuran (5 ml) was added the product of (3) (292 mg), triethylamine (246 mg) and N, N-dimethylformamide (5 ml) at room temperature. For 4 hours. Further, triethylamine (123 mg) was added to this mixture and stirred for 20 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous ammonium chloride solution, water (twice) and saturated brine in this order. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (purified twice, elution solvent: hexane / ethyl acetate = once with a gradient of 100/0 to 0/100 and chloroform / methanol = once with a gradient of 100/0 to 100/1). Purification gave 121 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.93 (3H, t), 1.23-1.37 (2H, m), 1.53-1.67 (2H, m), 1.77-1.93 (4H, m), 2.25-2.34 (1H , m), 2.87-2.96 (2H, m), 3.09 (3H, s), 3.62 (2H, t), 3.86-3.90 (5H, m), 4.36 (2H, d), 5.59 (1H, s), 5.72 (1H, brs), 6.76 (1H, dd), 6.79 (1H, d), 6.87 (1H, d).

Example 10
Preparation of S-cyclohexyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) -piperidine-1-thiocarbonate:

(1) N, N′-carbonyldiimidazole (689 mg) and methylene chloride (4 ml) were added to a mixture of cyclohexanethiol (380 mg) and tetrahydrofuran (4 ml), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 674 mg of S-cyclohexyl 1H-imidazole-1-thiocarboxylate.
(2) Triethylamine (188 mg) and 4-dimethylaminopyridine (14 mg) were added to a mixture of the product of (1) (157 mg), the product of Example 9 (3) (186 mg) and dimethyl sulfoxide (3 ml). The mixture was heated and stirred at 70 ° C. for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (twice) and saturated brine in that order and dried over magnesium sulfate, and then 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 154 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.42 (4H, t), 1.53-1.57 (2H, m), 1.61-1.77 (4H, m), 1.84-1.90 (2H, m), 1.95-2.01 (2H , m), 2.26-2.35 (1H, m), 2.87 (2H, brs), 3.42-3.48 (1H, m), 3.88 (3H, s), 4.23 (2H, brs), 4.35 (2H, d), 5.59 (1H, s), 5.65 (1H, brs), 6.74 (1H, dd), 6.78 (1H, d), 6.86 (1H, d).

Example 11
Preparation of 5-methylhexyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate:

(1) N, N′-carbonyldiimidazole (111 mg) was added to a mixture of 5-methylhexanol (69 mg) and methylene chloride (3 ml), and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water (twice) and saturated brine, and then the organic layer was dried over magnesium sulfate, and the solvent was distilled off. The product of Example 1 (2) (200 mg), triethylamine (164 mg) and 4-dimethylaminopyridine (10 mg) were added to a mixture of the obtained residue and dimethyl sulfoxide (3 ml), and the mixture was heated at 70 ° C. for 7 hours. The reaction solution was diluted with ethyl acetate, and washed with water, a saturated aqueous ammonium chloride solution, water (twice), a saturated aqueous sodium bicarbonate solution, and saturated brine in this order. The organic layer was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 0/100 gradient) to give 5-methylhexyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) -piperidine- 199 mg of 1-carboxylate was obtained.
(2) In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (1) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.87 (6H, d), 1.15-1.22 (2H, m), 1.29-1.39 (2H, m), 1.49-1.73 (5H, m), 1.84 (2H, d ), 2.26 (1H, tt), 2.79 (2H, t), 3.87 (3H, s), 4.06 (2H, t), 4.17 (2H, brs), 4.35 (2H, d), 5.60 (1H, s) , 5.66 (1H, brs), 6.75 (1H, dd), 6.78 (1H, d), 6.86 (1H, d).

Example 12
Preparation of 2,6-dimethyl-4-heptyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate:

Using 2,6-dimethyl-4-heptanol instead of 5-methyl-1-hexanol in Example 11, the reaction and treatment were conducted in the same manner as in Example 11 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ):
0.91 (12H, d), 1.19-1.32 (2H, m), 1.45-1.89 (8H, m), 2.25 (1H, tt), 2.70-2.82 (2H, m), 3.88 (3H, s), 4.11- 4.27 (2H, m), 4.35 (2H, d), 4.92 (1H, t), 5.59 (1H, s), 5.66 (1H, brs), 6.77 (1H, dd), 6.79 (1H, d), 6.87 (1H, d).

Example 13
Preparation of 1- (2-cyclohexylacetyl) -N- (4-hydroxy-3-methoxybenzyl) piperidine-4-carboxamide:

(1) N, N′-carbonyldiimidazole (100 mg) was added to a mixture of 2-cyclohexylacetic acid (87 mg) and N, N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 1 hour. To this mixture, the product of Example 1 (2) (200 mg), triethylamine (155 mg) and N, N-dimethylformamide (1 ml) were added and stirred for 5 hours. The reaction solution was diluted with ethyl acetate, and washed with water, a saturated aqueous ammonium chloride solution, water (twice), a saturated aqueous sodium bicarbonate solution, and saturated brine in this order. The organic layer was dried over magnesium sulfate and the solvent was distilled off. Hexane / ethyl acetate (4/1) was added to the residue, and the precipitated crystals were collected by filtration to give N- (4-benzyloxy-3-methoxybenzyl) -1- (2-cyclohexylacetyl) piperidine-4-carboxamide. 205 mg was obtained.
(2) In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (1) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.89-1.00 (2H, m), 1.10-1.29 (3H, m), 1.67-1.76 (8H, m), 1.84-1.92 (2H, m), 2.20 (2H , d), 2.32 (1H, tt), 2.62 (1H, t), 3.04 (1H, t), 3.88 (3H, s), 3.94 (1H, d), 4.35 (2H, d), 4.63 (1H, d), 5.61 (1H, s), 5.68 (1H, brs), 6.73-6.77 (2H, m), 6.87 (1H, d).

Example 14
Preparation of N- (4-hydroxy-3-methoxybenzyl) -1- (trans-4-methylcyclohexanecarbonyl) piperidine-4-carboxamide:

Using trans-4-methylcyclohexanecarboxylic acid instead of 2-cyclohexylacetic acid in Example 13, the reaction and treatment were conducted in the same manner as in Example 13 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, d), 0.91-0.99 (2H, m), 1.33-1.42 (1H, m), 1.58-1.78 (9H, m), 1.88 (2H, t ), 2.27-2.44 (1H, m), 2.60 (1H, t), 3.03 (1H, t), 3.87 (3H, s), 3.97 (1H, d), 4.35 (2H, d), 4.62 (1H, d), 5.64 (1H, s), 5.72 (1H, brs), 6.74 (1H, dd), 6.78 (1H, d), 6.86 (1H, d).

Example 15
Preparation of cis-4-ethylcyclohexyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperazine-1-carboxylate:

(1) To a mixture of 4-benzyloxy-3-methoxybenzylamine hydrochloride (311 mg), triethylamine (311 mg) and tetrahydrofuran (6 ml) was added p-nitrophenyl chloroformate (235 mg) under ice cooling, and at room temperature. Stir for 1 hour. To this mixture, 1- (t-butoxycarbonyl) piperazine (247 mg), triethylamine (167 mg) and dimethyl sulfoxide (6 ml) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate solution (4 times), saturated aqueous ammonium chloride solution and saturated brine in this order. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. did. The residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 100/0 to 100/2 gradient) to give t-butyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) piperazine-1-carboxyl. A rate of 429 mg was obtained.
(2) In place of t-butyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate in Example 1 (1), the product of (1) above was used. Reaction and treatment in the same manner as in (2) gave N- (4-benzyloxy-3-methoxybenzyl) piperazine-1-carboxamide hydrochloride.
(3) Instead of 5-methylhexanol in Example 11, cis-4-ethylcyclohexanol was replaced with N- (4-benzyloxy-3-methoxybenzyl) -4-piperidinecarboxamide hydrochloride above (2 ) To give cis-4-ethylcyclohexyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) piperazine-1-carboxylate in the same manner as in Example 11 (1). .
(4) In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (3) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.86 (3H, t), 1.20-1.26 (5H, m), 1.45-1.57 (4H, m), 1.82-1.86 (2H, m), 3.36 (4H, brs ), 3.46-3.50 (4H, m), 3.87 (3H, s), 4.33 (2H, d), 4.60 (1H, t), 4.91 (1H, brs), 5.56 (1H, s), 6.77 (1H, dd), 6.82 (1H, d), 6.85 (1H, d).

Example 16
Preparation of 2,6-dimethyl-4-heptyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperazine-1-carboxylate:

Using 2,6-dimethyl-4-heptanol instead of cis-4-ethylcyclohexanol in Example 15, the reaction and treatment were conducted in the same manner as in Example 15 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.91 (12H, d), 1.20-1.35 (2H, m), 1.46-1.73 (4H, m), 3.31-3.53 (8H, m), 3.89 (3H, s ), 4.34 (2H, d), 4.58-4.70 (1H, m), 4.89-5.01 (1H, m), 5.61 (1H, brs), 6.79 (1H, dd), 6.84 (1H, d), 6.87 ( 1H, d).

Example 17
Preparation of 2-isopropylphenyl trans-4- (4-hydroxy-3-methoxybenzylcarbamoyl) cyclohexanecarboxylate:

(1) Sodium hydride (651 mg) was suspended in N, N-dimethylformamide (30 ml), 2-isopropylphenol (1.11 g) was added at room temperature, and the mixture was stirred for 10 minutes. To this reaction liquid, N, N′-carbonyldiimidazole (1.32 g) was added to trans-cyclohexane-1,4-dicarboxylic acid (1.40 g) and N, N-dimethylformamide (30 ml), and the mixture was stirred for 15 minutes. The resulting mixture was added dropwise. The mixture was stirred at room temperature for 30 minutes and then stirred at 80 ° C. for 2 hours. Toluene was added to the reaction solution, followed by washing with a saturated aqueous ammonium chloride solution and saturated brine in this order. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.97 g of trans-4-[(2-isopropylphenyl) carbonyl) cyclohexanecarboxylic acid.
(2) A mixture of the product of (1) (1.96 g), 4-hydroxy-3-methoxybenzylamine (783 mg), triethylamine (2.89 ml) and methylene chloride (60 ml) was added with benzoic acid under ice-cooling. Triazol-1-yl-oxytris (pyrrolidino) phosphonium hexafluorophosphate (2.15 g) was added. The reaction solution was stirred at room temperature for 1 hour and then washed with a saturated aqueous ammonium chloride solution and saturated brine in this order. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = gradient from 100/0 to 0/100) and recrystallized from a mixed solvent of heptane and ethyl acetate to obtain 450 mg of the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.20 (6H, d), 1.60-1.71 (2H, m), 1.99-2.30 (6H, m), 2.54-2.67 (1H, m), 2.93-3.06 (1H , m), 3.89 (3H, s), 4.37 (1H, d), 5.59 (1H, s), 5.67 (1H, brs), 6.77 (1H, dd), 6.81 (1H, d), 6.88 (1H, d), 6.92-6.98 (3H, m), 7.15-7.32 (3H, m).

Example 18
Preparation of (1R ^* , 2S ^* )-2-methylcyclohexyl trans-4- (4-hydroxy-3-methoxybenzylcarbamoyl) cyclohexanecarboxylate:

Using (1R ^* , 2S ^* )-2-methylcyclohexanol instead of 2-isopropylphenol in Example 17, the reaction and treatment were conducted in the same manner as in Example 17 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.85 (6H, d), 1.21-1.60 (10H, m), 1.61-1.89 (3H, m), 1.92-2.12 (5H, m), 2.27-3.38 (1H , m), 3.88 (3H, s), 4.35 (1H, d), 4.88-4.95 (1H, m), 5.57 (1H, s), 5.64 (1H, brs), 6.76 (1H, dd), 6.80 ( 1H, d), 6.87 (1H, d).

Example 19
Preparation of cis-4- (4-hydroxy-3-methoxybenzylcarbamoyl) cyclohexyl piperidine-1-carboxylate:

  (1) A mixture of cis-4-hydroxycyclohexanecarboxylic acid (615 mg), triethylamine (431 mg) and N, N-dimethylformamide (3 ml) was cooled with ice under isobutyl chloroformate (580 mg) and N, N-dimethylformamide. (3 ml) was added and stirred at 0 ° C. for 30 minutes. 4-Benzyloxy-3-methoxybenzylamine hydrochloride (992 mg) and triethylamine (716 mg) were added to the mixture, and then the mixture was warmed to room temperature and stirred for 17 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate / chloroform / ethanol, and then washed with water (twice), a saturated aqueous sodium bicarbonate solution, and saturated brine in this order. After the organic layer was washed with magnesium sulfate, the solvent was distilled off under reduced pressure. A mixed solvent of ethyl acetate / hexane was added to the residue and the precipitated crystals were collected by filtration to obtain 928 mg of cis-N- (4-benzyloxy-3-methoxybenzyl) -4-hydroxycyclohexanecarboxamide.

(2) The product of (1) (265 mg) was dissolved in methylene chloride (5 ml), N, N′-carbonyldiimidazole (151 mg) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water (twice) and saturated brine in this order. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/0 to 100/2 gradient) to give cis-4- (4-benzyloxy-3-methoxybenzylcarbamoyl) cyclohexyl 1H-imidazole-1. -304 mg of carboxylate were obtained.
(3) Triethylamine (110 mg), piperidine (95 mg) and 4-dimethylaminopyridine (13 mg) were added to a dimethyl sulfoxide solution (3 ml) of the product (261 mg) above (2), and the mixture was stirred at 70 ° C. for 8 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution, water (twice) and saturated brine in this order. After drying the organic layer with magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 100/0 to 100/1 gradient) to give cis-4- (4-benzyloxy-3-methoxybenzylcarbamoyl) cyclohexyl piperidine-1-carboxyl. A rate of 197 mg was obtained.
(4) In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (3) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
¹ H-NMR (CDCl ₃ , δ): 1.53-1.56 (8H, m), 1.71-1.90 (4H, m), 1.95-2.04 (2H, m), 2.12-2.19 (1H, m), 3.41-3.44 (4H, m), 3.87 (3H, s), 4.36 (2H, d), 4.93 (1H, brs), 5.57 (1H, s), 5.66 (1H, brs), 6.74-6.80 (2H, m), 6.87 (1H, d).

Example 20
Preparation of cis-4- (4-hydroxy-3-methoxybenzylcarbamoyl) cyclohexyl cyclohexyl (methyl) carbamate:

Using N-methylcyclohexylamine instead of piperidine in Example 19, the reaction and treatment were conducted in the same manner as in Example 19 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.04-1.08 (1H, m), 1.28-1.41 (4H, m), 1.49-1.86 (11H, m), 1.95-2.01 (2H, m), 2.13-2.20 (1H, m), 2.79 (3H, s), 3.88 (3H, s), 3.93-4.00 (1H, m), 4.36 (2H, d), 4.94 (1H, brs), 5.58 (1H, s), 5.65 (1H, brs), 6.76 (1H, dd), 6.79 (1H, d), 6.86 (1H, d).

Example 21
Preparation of N- (4-hydroxy-3-methoxybenzyl) -4-pentylpiperidine-1-carboxamide:

(1) To a mixture of bis (trichloromethyl) carbonate (180 mg) and methylene chloride (10 ml), 4-benzyloxy-3-methoxybenzylamine hydrochloride (500 mg), N, N-diisopropylethylamine (0.63 ml) and chloride A mixture of methylene (5 ml) was added. After stirring the reaction solution for 30 minutes, a mixture of 4-pentylpiperidine (460 mg), N, N-diisopropylethylamine (0.63 ml) and methylene chloride (5 ml) was added and stirred for 1 hour. After the reaction solution was washed with water, 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-pentylpiperidine-1- 160 mg of carboxamide was obtained.
(2) In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (2) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
¹ H-NMR (CDCl ₃ , δ): 0.88 (3H, t), 1.05-1.46 (11H, m), 1.62-1.78 (3H, m), 2.75 (2H, td), 3.86-3.96 (2H, m ), 3.89 (3H, s), 4.33 (1H, d), 4.55-4.64 (1H, m), 5.57 (1H, s), 6.79 (1H, dd), 6.85 (1H, d), 6.87 (1H, d).

Example 22
Preparation of N- (4-hydroxy-3-methoxybenzyl) -4- (5-nonyl) piperidine-1-carboxamide:

Using 4- (5-nonyl) piperidine instead of 4-pentylpiperidine in Example 21, the reaction and treatment were conducted in the same manner as in Example 21 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 0.89 (6H, t), 1.08-1.60 (18H, m), 2.72 (2H, td), 3.89 (3H, s), 3.93-4.01 (2H, m), 4.34 (1H, d), 4.55-4.64 (1H, m), 5.56 (1H, s), 6.79 (1H, dd), 6.85 (1H, d), 6.87 (1H, d).

Example 23
Preparation of 2- (4-hydroxy-3-methoxyphenyl) -N- [1- (2-methylphenyl) piperidin-4-yl] acetamide:

(1) 4-hydroxy-3-methoxyphenylacetic acid (4.56 g), N- (t-butoxycarbonyl) -4-aminopiperidine (5.00 g), triethylamine (4.22 ml) and methylene chloride (80 ml) To the mixture was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.23 g) and N-hydroxybenzotriazole (4.21 g). The reaction solution was stirred at room temperature for 2 days, then washed in order with an aqueous citric acid solution, a saturated aqueous ammonium chloride solution, and saturated brine, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized with ethyl acetate to obtain 7.42 g.
(2) The product of (1) (3.64 g) was dissolved in N, N-dimethylformamide (15 ml), and benzyl bromide (2.05 g) and potassium carbonate (2.07 g) were added. The mixture was stirred at 70 ° C. for 8 hours, concentrated, chloroform was added, and the mixture was washed with an aqueous citric acid solution, water, and saturated brine in this order. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 4.00 g.
(3) The product (1.65 g) of (2) above was dissolved in methylene chloride (100 ml), and 4 mol / l hydrogen chloride / 1,4-dioxane (3 ml) was added. After the mixture was stirred for 6 hours, the solvent was distilled off under reduced pressure, and an aqueous sodium hydroxide solution and chloroform were added. The organic layer was washed with an aqueous sodium hydroxide solution and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized with ethyl acetate to obtain 0.89 g.
(4) t-Butoxy sodium in a mixture of the product of (3) (424 mg), 1-bromo-2-methylbenzene (171 mg), tris (dibenzalacetone) dipalladium (55 mg) and toluene (10 ml) (145 mg) and a toluene solution (1.5 ml) containing 40 mg / ml of tri-t-butylphosphine were added and the reaction was heated at 130 ° C. for 20 hours. Thereafter, ethyl acetate was added to the reaction solution, and then washed with an aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution in this order. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate to obtain 220 mg.
(5) The product of (4) (220 mg) was dissolved in ethanol (20 ml) and tetrahydrofuran (10 ml), 10% palladium on carbon (50 mg) was added, and catalytic hydrogenation was performed. After 24 hours, the catalyst was removed by filtration and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 100/0 to 100/2 gradient) to obtain 140 mg.
¹ H-NMR (CDCl ₃ , δ): 1.40-1.59 (2H, m), 1.91-2.03 (2H, m), 2.25 (3H, s), 2.70-2.83 (2H, m), 2.95-3.08 (2H , m), 3.51 (2H, s), 3.79-3.98 (1H, m), 3.90 (3H, s), 5.36 (1H, d), 5.66 (1H, s), 6.74 (1H, dd), 6.79 ( 1H, d), 6.90 (1H, d), 6.91-7.01 (2H, m), 7.11-7.20 (2H, m).

Example 24
Production of N- [1- (2-ethylphenyl) piperidin-4-yl] -2- (4-hydroxy-3-methoxyphenyl) acetamide:

Using 1-bromo-2-ethylbenzene instead of 1-bromo-2-methylbenzene in Example 21, the reaction and treatment were conducted in the same manner as in Example 21 to obtain the desired product.
¹ H-NMR (CDCl ₃ , δ): 1.20 (3H, t), 1.40-1.57 (2H, m), 1.90-2.02 (2H, m), 2.64 (2H, q), 2.70-2.80 (2H, m ), 2.92-3.05 (2H, m), 3.51 (2H, s), 3.82-3.97 (1H, m), 3.90 (3H, s), 5.34 (1H, d), 5.61 (1H, s), 6.75 ( 1H, dd), 6.79 (1H, d), 6.91 (1H, d), 6.921-7.06 (2H, m), 7.12-7.20 (2H, m).

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

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

The FLIPR ^TETRA system (Molecular Device) was used for intracellular calcium concentration measurement. By measuring the fluorescence intensity rising when the test compound was applied to the rat dorsal root ganglion primary cells into which the calcium fluorescent reagent was incorporated, it was used as an index of TRPV1 agonist activity.
The results are shown in Table 1 below.

  As shown in Table 1, the compounds of the present invention caused an increase in intracellular calcium concentration similar to that of capsaicin, a TRPV1 agonist.

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

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

Claims (13)

The following formula (I):


[Where
R ¹ represents a methyl group or a hydrogen atom,
R ² represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkylcarbonyl group or an arylcarbonyl group,
Z is a group represented by the following formula (A), (B), (C) or (D):

{In each formula, n and m are the same or different and each represents an integer of 1, 2 or 3;
R ³ is an aryl group or a heteroaryl group (each group may be substituted at a substitutable position with C _1-6 alkyl, C _2-6 alkenyl, or C _3-6 cycloalkyl). or shown, _{or, -S (= O) 2 -R} 7, -C (= O) -R 7, -C (= O) -S-R 7, -C (= O) -NR 8 R 88, ^{_{-S (= O) 2 -NR 8}} R 88, -C (= O) indicates ^{-O-R 9} or ^{-C (= S) -NR 8 R} 88,
R ⁴ is —C (═O) —O—R ⁷ , —S (═O) ₂ —R ⁷ , —C (═O) —R ⁷ , —C (═O) —S—R ⁷ , — C (═O) —NR ⁸ R ⁸⁸ or —S (═O) ₂ —NR ⁸ R ⁸⁸ ,
R ⁵ represents —C (═O) —O—R ⁷ or —O—C (═O) —NR ⁸ R ⁸⁸ ;
R ⁶ is a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl). Or a C _3-10 alkyl group, a C _3-10 alkenyl group, a C _3-8 cycloalkyl C _1-6 alkyl group, ^{-C (= O) -O-R} 7 or -O-C (= O) shows the ^-NR 8 ^{R 88,}
R ⁷ represents a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, an aryl group or a heteroaryl group (the groups are C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl). Or a C _6-12 alkyl group, a C _6-12 alkenyl group, or a C _3-8 cycloalkyl C _1-6 alkyl group. Show
R ⁸ and R ⁸⁸ are the same or different and are a hydrogen atom, a C _1-8 alkyl group, a C _2-8 alkenyl group, or a C _3-6 cycloalkyl group optionally substituted with a C _1-6 alkyl. Or R ⁸ and R ⁸⁸ are taken together to form a C _3-7 azacycloalkyl group (the group may be substituted with 1 to 5 C _1-6 alkyl groups). Show
R ⁹ represents a C _6-12 alkyl group or a C _6-12 alkenyl group. }. ]
Or a physiologically acceptable salt thereof.   In the formula (I), n and m are the same or different and each represents an integer of 1 or 2, or a physiologically acceptable salt thereof.   The compound or a physiologically acceptable salt thereof according to claim 2, wherein in formula (I), n and m are both 2. In formula (I), R ³ is an aryl group (the group is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl and C _3-6 cycloalkyl, the same or different in 5 substituents may be substituted.) or show, or -C (= O) shows the ^{-S-R 7} or ^{_{-S (= O) 2 -NR 8}} R 88,
R ⁴ represents —C (═O) —O—R ⁷ ,
R ⁵ represents —C (═O) —O—R ⁷ ,
The compound or a physiologically acceptable salt thereof according to claim 1, wherein R ⁶ represents a C _3-10 alkyl group or a C _3-10 alkenyl group. In the formula (I), R ⁷ is a C _3-8 cycloalkyl group (this group is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl and halogen). Or may be substituted with 1 to 5 different substituents).
R ⁸ and R ⁸⁸ are the same or different and each represents a C _1-6 alkyl group or a C _2-6 alkenyl group, or R ⁸ and R ⁸⁸ together represent C _3-5 azacycloalkyl. A group wherein the group may be substituted with 1 to 5 C _1-6 alkyl groups;
R ⁹ is a compound or a physiologically acceptable salt thereof according to any one of claims 1 to 4 showing a C _{7 to 9} alkyl group or a C _{7 to 9} alkenyl group.   The compound or physiologically acceptable salt thereof according to any one of claims 1 to 5, wherein Z is represented by the formula (A).   The compound or physiologically acceptable salt thereof according to any one of claims 1 to 5, wherein Z is represented by the formula (B).   The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 5, wherein Z is represented by the formula (C).   The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 5, wherein Z is represented by the formula (D). The compound according to any one of claims 1 to 9, or a physiologically acceptable salt thereof, wherein in formula (I), R ¹ represents a methyl group. The compound according to any one of claims 1 to 10, or a physiologically acceptable salt thereof, wherein in formula (I), R ² represents a hydrogen atom.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a physiologically acceptable salt thereof as an active ingredient. A therapeutic or prophylactic agent for pain and / or inflammation comprising the compound according to any one of claims 1 to 11 or a physiologically acceptable salt thereof as an active ingredient.