WO2011058932A1 - N-benzyl amide derivative and pharmaceutical composition containing same - Google Patents

Abstract

Disclosed is a compound represented by formula (I⁰) or a salt thereof. In the formula, R¹ represents a methyl group or the like; R² represents H or the like; L represents -NH-(C=O)- or the like; and Z represents a group that is represented by formula (A), (B), (C) or (D).

Description

N-benzylamide derivative and pharmaceutical composition containing the same

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, 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]. Thereafter, 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 for the treatment of pain such as diabetic neuropathy and rheumatoid arthritis. As a result of continuous TRPV1 cation channel opening by capsaicin, sensory nerves are used. 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 cream. However, this cream has a problem that initial irritation 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.

Compounds with capsaicin-like medicinal mechanisms include pruritus, allergic and non-allergic rhinitis, pathologies involving primary afferent sensory nerves (C fibers), overactive bladder, stroke, irritable bowel syndrome, It is also considered useful as a therapeutic agent for 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. Since it has been reported that insulin resistance is improved by treating diabetic rats with capsaicin [Non-patent document 5], it is also considered useful as a therapeutic agent for diabetes.

An object of the present invention is to have sufficient analgesic action and low irritation useful as a therapeutic or preventive agent for pain and inflammation caused by various pathologies 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 N-benzylamide derivatives, that is, compounds represented by the following formula (I ⁰ ) or (I) have a strong analgesic action but have low irritation. And the present invention was completed. That is, the present invention provides the following inventions.

Item 1: The following formula (I ⁰ ):

[Where:
R ¹ represents a methyl or hydrogen atom,
R ² represents a hydrogen _{atom, C 1 ~ 4 alkyl, C 1 ~ 4} alkyl or arylcarbonyl,
L represents —NH— (C═O) — or — (C═O) —NH—,
Z is a group represented by the following formula (A), (B), (C) or (D) (wherein azacycloalkyl in (A) is 1 to 5 identical or different C _{1 to} Optionally substituted with ₄ alkyls):

{In each formula, n and m are the same or different and each represents an integer of 1, 2 or 3;
R ³ is aryl or heteroaryl (respective group, C 1 _{~ 6} alkyl, C 2 _{~ 6} alkenyl or C _{3 ~ 6} by cycloalkyl may be substituted at substitutable position) or indicate, Alternatively, -S (= O) ₂ -R ⁷ , -C (= O) -R ⁷ , -C (= O) -SR 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 (provided that when R ² is ethyl, R ³ is —S (Not O = ₂ -NR ⁸ R ⁸⁸ ),
R ⁴ represents —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 _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 6} cycloalkyl or halogen or indicating the or) substituted at possible positions (provided that when ^{R 2} is methyl, ^{R 6} is not aryl), _{or, C 3 ~ 10 alkyl, C 3 ~ 10 alkenyl, C 3 ~ 8} cycloalkyl _{C 1 ~ 6} alkyl, indicates ^{-C (= O) -O-R} 7 or ^{-O-C (= O) -NR} 8 R 88,
R ⁷ is _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl or halogen or indicating the or) substituted at possible positions, _{or, C 6 ~ 12 alkyl, C 6 ~ 12} alkenyl or _{C 3 ~ 8} cycloalkyl _{C 1 ~ 6} represents an alkyl,
R ⁸ and ^{R 88} are the same or different, a hydrogen _{atom, C 1 ~ 8 alkyl, C 2 ~ 8} alkenyl or _{C 1 ~ 6} alkyl or represents an _{C 3 ~ 6} cycloalkyl which may be substituted, Alternatively, ^{R 8} and ^{R 88} are taken _together, show a _{C 3 - 7} azacycloalkyl (said group may be substituted with one to five _{C 1 ~ 6} alkyl),
R ⁹ is _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl, heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl or halogen may be substituted at possible _positions), shows a _{C 6 ~ 12} alkyl or _{C 6 ~ 12} alkenyl, shows a},
R ^10a and R ^10b are the same or different and each represents a hydrogen atom or C _1-4 alkyl;
Z is a group represented by the formula (A), ^{R 3} is -C (= O) a ^{-O-R 9, R 9} is _{C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or When heteroaryl, azacycloalkyl in formula (A) is substituted with _{1 to} 5 identical or different C _1-4 alkyl and / or at least one of R ^10a and R ^10b is C _1-4 alkyl. ]
Or a physiologically acceptable salt thereof.

Item 2: The following formula (I):

[Where:
R ¹ represents a methyl or hydrogen atom,
R ² represents a hydrogen _{atom, C 1 ~ 4 alkyl, C 1 ~ 4} alkyl or arylcarbonyl,
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 aryl or heteroaryl (respective group, C 1 _{~ 6} alkyl, C 2 _{~ 6} alkenyl or C _{3 ~ 6} by cycloalkyl may be substituted at substitutable position) or indicate, Alternatively, -S (= O) ₂ -R ⁷ , -C (= O) -R ⁷ , -C (= O) -SR 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 (provided that when R ² is ethyl, R ³ is — S (= O) ₂ —not NR ⁸ R ⁸⁸ ),
R ⁴ represents —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 _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 6} cycloalkyl or halogen or indicating the or) substituted at possible positions (provided that when ^{R 2} is methyl, ^{R 6} is not aryl), _{or, C 3 ~ 10 alkyl, C 3 ~ 10} alkenyl, _{C 3 ~ 8} cycloalkyl _{C 1 ~ 6} alkyl, indicates ^{-C (= O) -O-R} 7 or ^{-O-C (= O) -NR} 8 R 88,
R ⁷ is _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl or halogen or indicating the or) substituted at possible positions, _{or, C 6 ~ 12 alkyl, C 6 ~ 12} alkenyl or _{C 3 ~ 8} cycloalkyl _{C 1 ~ 6} represents an alkyl,
R ⁸ and ^{R 88} are the same or different, a hydrogen _{atom, C 1 ~ 8 alkyl, C 2 ~ 8} alkenyl or _{C 1 ~ 6} alkyl or represents an _{C 3 ~ 6} cycloalkyl which may be substituted, Alternatively, ^{R 8} and ^{R 88} are taken _together, show a _{C 3 - 7} azacycloalkyl (said group may be substituted with one to five _{C 1 ~ 6} alkyl),
R ⁹ _represents a _{C 6 ~ 12} alkyl or _{C 6 ~ 12} alkenyl. }. ]
Or a physiologically acceptable salt thereof.

Item 3: The compound or a physiologically acceptable salt thereof according to Item 1 or 2, wherein in formula (I ⁰ ) or (I), n and m are the same or different and each is an integer of 1 or 2.
Item 4: The compound or a physiologically acceptable salt thereof according to Item 1 or 2, wherein in formula (I ⁰ ) or (I), n and m are both 2.
Section 5: In the formula ^{(I 0)} or (I), ^{R 3} is aryl (said _{group, C 1 ~ 6 alkyl,} selected from _{C 2 ~ 6} alkenyl and _{C 3 ~ 6} group consisting of cycloalkyl, the same Or optionally substituted with 1 to 5 different substituents), or —C (═O) —S—R ⁷ or —S (═O) ₂ —NR ⁸ R ⁸⁸ Yes,
R ⁴ is —C (═O) —O—R ⁷ ,
R ⁵ is —C (═O) —O—R ⁷ ,
R ⁶ is The compound or a physiologically acceptable salt thereof according to claim 1 or 2 is a C 3 _{~ 10} alkyl or C _{3 ~ 10} alkenyl.

6.: In Formula ^{(I 0)} or (I), ^{R 7} _{is, C 3 ~ 8} cycloalkyl (said _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl and halogen Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of:
R ⁸ and ^{R 88} are the same or _different, or a _{C 1 ~ 6} alkyl or _{C 2 ~ 6} alkenyl, or, ^{R 8} and ^{R 88} _{together, C 3 ~ 5} azacycloalkyl (the The group may be substituted with ₁ to 5 C _1-6 alkyl),
R ⁹ is a compound or a physiologically acceptable salt thereof according to any one of claims 1 to 5, a C 7 _{~ 9} alkyl or C _{7 ~ 9} alkenyl.
Item 7: The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I ⁰ ) or (I), Z is a group represented by the formula (A).
Item 8: The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I ⁰ ) or (I), Z is a group represented by the formula (B).
Item 9: The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I ⁰ ) or (I), Z is a group represented by the formula (C).
Item 10: The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I ⁰ ) or (I), Z is a group represented by the formula (D).
Item 11: The compound according to any one of Items 1 to 10 or a physiologically acceptable salt thereof, wherein, in the formula (I ⁰ ) or (I), R ¹ is methyl.

Item 12: The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 11, wherein in the formula (I ⁰ ) or (I), R ² is a hydrogen atom.
Item 13: In the formula (I ⁰ ) or (I),
R ¹ is methyl;
R ² is a hydrogen atom,
Z is a group represented by the formula (B),
n and m are both 2;
Item 3. The compound according to Item 1 or 2, or a physiologically acceptable salt thereof, wherein R ⁴ is —C (═O) —O—R ⁷ .
Item 14: In the formula (I ⁰ ) or (I),
R ¹ is methyl;
R ² is a hydrogen atom,
Z is a group represented by the formula (A),
n and m are the same or different and an integer of 1 or 2,
Item 3. The compound according to Item 1 or 2, or a physiologically acceptable salt thereof, wherein R ³ is —S (═O) ₂ —NR ⁸ R ⁸⁸ or —C (═O) —S—R ⁷ .

Item 15: A pharmaceutical composition comprising the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.
Item 16: A therapeutic or prophylactic agent for pain and / or inflammation comprising the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.
Item 17: An analgesic or anti-inflammatory drug comprising the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.

Item 18: A method for treating or preventing pain and / or inflammation, comprising administering an effective amount of the compound or the physiologically acceptable salt thereof according to any one of Items 1 to 14 to a patient. .
Item 19: Use of the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof for producing a therapeutic or preventive agent for pain and / or inflammation.
Item 20: The compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof,
Narcotic analgesics, neuropathic pain treatments, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, antidepressants, antiepileptic drugs, anticonvulsants, anesthetics, antiarrhythmic drugs, local anesthetics and anxiolytics And at least one other drug selected from the group consisting of drugs.
Item 21: A pharmaceutical composition comprising the medicine according to Item 20 as an active ingredient.
Item 22: A therapeutic or prophylactic agent for pain and / or inflammation, comprising the medicament according to Item 20 as an active ingredient.
Item 23: A method for treating or preventing pain and / or inflammation, comprising administering an effective amount of the medicament according to Item 20 to a patient.
Item 24: Use of the medicament according to Item 20, for producing a therapeutic or preventive agent for pain and / or inflammation.

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 or peripheral neuropathy, and neuropathic Various types of neuropathic pain including low back 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 or inflammations that require treatment . Furthermore, according to the invention, such as migraine or cluster headache, pruritus, allergic or non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, asthma and chronic obstructive pulmonary disease A therapeutic or preventive agent for respiratory diseases, dermatitis, mucositis, gastric / duodenal ulcer, inflammatory bowel syndrome, diabetes, and obesity can be provided.

Hereinafter, the compound represented by the formula (I ⁰ ) or the formula (I) of the present invention will be further described.

The physiologically acceptable salt of the compound represented by the formula (I ⁰ ) or the formula (I) is a compound of the formula (I ⁰ ) or the formula (I) having a group capable of forming an acid addition salt in the structure. Physiologically acceptable acid addition salts of the compounds, or salts with physiologically acceptable bases of the compounds of the formula (I ⁰ ) or of the formula (I) having a group capable of forming a salt with a base in the structure Means. Specific examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, and other inorganic acid salts, oxalate, malonate, Maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfone Examples include organic acid salts such as acid salts, 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 and calcium salt, salts with organic bases such as pyridine salt and triethylamine salt, and lysine and arginine. And salts with amino acids.

Since the compounds of formula (I ⁰ ) or formula (I) and their salts may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also present. Included in the compounds of the invention. That is, the “compound of the present invention” includes, in addition to the compound represented by the above formula (I ⁰ ) or formula (I) and physiologically acceptable salts thereof, hydrates and / or solvents thereof. Japanese products are included.

The compounds of formula (I ⁰ ) or formula (I) may have one or more asymmetric carbon atoms and may give rise to geometric isomerism and axial chirality, so that some stereoisomers Can exist as In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compounds represented by formula (I ⁰ ) or formula (I) of the present invention.

The terms used in this specification are explained below.

“Alkyl” means a linear or branched saturated hydrocarbon group. For example, “C _1-4 alkyl” or “C _1-6 alkyl” means 1 to 4 carbon atoms or 1 to 6 groups are meant. “C _1-4 alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Examples of “C _1-6 alkyl” include pentyl, isopentyl, neopentyl, hexyl and the like in addition to the above alkyl. In addition, for example, the "C _{6 ~ 12} alkyl", hexyl, isoheptyl, octyl, nonyl, and decyl, and the like. The alkyl may be linear or branched.

“Alkenyl” means a straight or branched unsaturated hydrocarbon group having at least one double bond. For example, "C _2-6 alkenyl", at least one have a double bond, means a unsaturated hydrocarbon group having a carbon number of 2-6. Specific examples of the _{"C 2 ~ 6} alkenyl" include vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 1,3-butadienyl, 2-, 3- or 4- Pentenyl, 2-methyl-2-butenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 4-methyl-1-pentenyl, 3,3-dimethyl-1-butenyl, and 5-hexenyl It is done. The _{"C 6 ~ 12} alkenyl", 4-methyl-3-pentenyl, 3,3-dimethyl-1-butenyl, 5-hexenyl, 3-ethyl - include pentenyl, and 3-octenyl and the like. The alkenyl may be linear or branched. The number of double bonds contained in the alkenyl may be one or two.

“Cycloalkyl” means a monocyclic saturated hydrocarbon group. For example, "C _3-8 cycloalkyl", carbon atoms means a monocyclic saturated hydrocarbon group of 3 to 8. Specific examples of the "C _{3 ~ 8} cycloalkyl", cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The same applies _to “C 3-6 cycloalkyl”.

The "C _3-8 cycloalkenyl", number of carbon atoms having one or two double bonds means a monocyclic unsaturated hydrocarbon group having 3 to 8. Specific examples of the "C _{3 ~ 8} cycloalkenyl" cyclohexenyl, cycloheptenyl, cyclopentenyl, and 2,4-cyclohexadienyl and the like. The number of double bonds contained in the cycloalkenyl is preferably one.

“Aryl” means phenyl or naphthyl. Phenyl is preferred. Similarly, “arylcarbonyl” means phenylcarbonyl or naphthylcarbonyl.

“Heteroaryl” means 1 to 3 heteroatoms of 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and 1 to 12 carbon atoms. Meaning a 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, And pyrazolopyridinyl, cinnolinyl, triazolyl, quinolyl, isoquinolyl, and naphthyridinyl. Examples of “halogen” include fluorine, chlorine, bromine and iodine. Number of carbon atoms in the "C _{1 ~ 4} alkyl carbonyl" modifying only group or moiety immediately following. Therefore, in the above case, since C _1-4 modifies only alkyl, “C ₁ alkylcarbonyl” corresponds to acetyl. Therefore, specific examples of the "C _{1 ~ 4} alkyl-carbonyl" include acetyl, propionyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, iso-butylcarbonyl, and tert- butylcarbonyl and the like.

“Alkyl-substituted cycloalkyl” refers to a group in which one or more (for example, 1 to 5, preferably 1 to 4) hydrogen atoms of the above cycloalkyl are substituted with the above-described alkyl. means. Specific examples of “cycloalkyl substituted with alkyl” include 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl, 4,4-dimethyl. Cyclohexyl, 3,5-dimethylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl, 4,4-diethylcyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-butylcyclohexyl, 4-propylcyclohexyl, 4-isopropyl Examples include cyclohexyl, and 4-t-butylcyclohexyl. The same applies to each of the following substituents substituted with alkyl: cycloalkenyl, aryl, heteroaryl.

“Cycloalkyl substituted with alkenyl” refers to one in which one or more (eg, 1 to 2, preferably 1) hydrogen atoms of the cycloalkyl are substituted with the alkenyl. Specific examples of “alkenyl-substituted cycloalkyl” include 2-ethenylcyclohexyl, 3-ethenylcyclohexyl, 4-ethenylcyclohexyl, 2- (1-propenyl) cyclohexyl, and 3- (1-propenyl) cyclohexyl. , 4- (1-propenyl) cyclohexyl, 2-isopropenylcyclohexyl, 3-isopropenylcyclohexyl, 4-isopropenylcyclohexyl, 4- (1-butenyl) cyclohexyl, 4- (2-butenyl) cyclohexyl, and 4- ( 1-isobutenyl) cyclohexyl. The same applies to each of the following substituents substituted with alkenyl: cycloalkenyl, aryl, and heteroaryl.

“Aryl substituted with cycloalkyl” means a group in which one or more (eg, 1 to 3, preferably 1) hydrogen atoms of the above aryl are substituted with cycloalkyl. Specific examples of “aryl substituted with cycloalkyl” include 2-cyclopropylphenyl, 4-cyclopropylphenyl, 2-cyclobutylphenyl, 4-cyclobutylphenyl, 2-cyclopentylphenyl, 4-cyclopentylphenyl, 2 -Cyclohexylphenyl, and 4-cyclohexylphenyl. The same applies to each of the following substituents substituted with cycloalkyl: cycloalkyl, cycloalkenyl, and heteroaryl.

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

When the hydrogen atom of cycloalkyl, cycloalkenyl, aryl or heteroaryl is substituted with a plurality of substituents, the plurality of substituents may be the same or different. Specific examples of the plurality of substituents may be any combination of the substituents exemplified above.

Specific examples of the "C _{3 ~ 8} cycloalkyl C _{1 ~ 6} alkyl", 4-cyclopropyl butyl, 3-cyclobutyl-propyl, cyclopentylmethyl, and cyclohexylmethyl and the like.

The "C _{3 - 7} azacycloalkyl" includes one nitrogen atom, a group represented by the monocyclic saturated hydrocarbon group containing 3 to 7 carbon atoms, specifically, Examples thereof include azetidinyl, pyrrolidinyl and piperidinyl. As the one to five _{C 1 - C 3} substituted by _alkyl of _1-7 azacycloalkyl, 3-butyl azetidinyloxyimino, 4-propyl-piperidinylmethyl, 4-t-butyl-piperidinylmethyl and the like Can be illustrated.

Examples of the groups in the compound (I) and the formula (I ⁰ ) of the present invention include the following.

R ¹ represents a methyl or hydrogen atom, preferably methyl. R ² is a hydrogen _{atom, C 1 ~ 4 alkyl,} shows a _{C 1 ~ 4} alkyl or arylcarbonyl, preferably a hydrogen atom.

L represents —NH— (C═O) — or — (C═O) —NH—, and preferably —NH— (C═O) —.

N and m are the same or different and represent an integer of 1, 2 or 3, preferably 1 or 2. n and m are more preferably both 1 or 2, or one is 1 and the other is 2, and particularly preferably both are 2.

R ³ in formula (A) represents aryl or heteroaryl, 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 Indicates. Aryl and heteroaryl as R ³ is, C 1 _{~ 6} alkyl, by C 2 _{~ 6} alkenyl or C _{3 ~ 6} cycloalkyl, it may be substituted at a substitutable position, for example, the same or different It may be substituted with 1 to 5 of the above substituents. When L is — (C═O) —NH—, R ³ is aryl or heteroaryl, or —S (═O) ₂ —R ⁷ , —C (═O) —R ⁷ , In —C (═O) —S—R ⁷ , —C (═O) —NR ⁸ R ⁸⁸ , —S (═O) ₂ —NR ⁸ R ⁸⁸ , or —C (═S) —NR ⁸ R ⁸⁸ There may be. R ³ is more preferably aryl (said _{group, C 1 - 6} alkyl _is selected from _{C 2 - 6} alkenyl and _{C 3 - 6} the group consisting of cycloalkyl, the same or different and one to five Optionally substituted with a substituent), —C (═O) —S—R ⁷ or —S (═O) ₂ —NR ⁸ R ⁸⁸ .

R ⁴ in the formula (B) 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 is shown. R ⁴ is more preferably —C (═O) —O—R ⁷ .

R ⁵ in the formula (C) represents —C (═O) —O—R ⁷ or —O—C (═O) —NR ⁸ R ⁸⁸ . R ⁵ is more preferably —C (═O) —O—R ⁷ .

^{R 6} in the formula (D) _{are, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, or an aryl or heteroaryl, or _{C 3 ~ 10 alkyl, C 3 ~ 10 alkenyl, C 3 ~ 8} cycloalkyl C _{1 ~ 6} alkyl, indicating the ^{-C (= O) -O-R} 7 or ^{-O-C (= O) -NR} 8 R 88. _{C 3 ~ 8} cycloalkyl as R _{^6, C 3 ~ 8} cycloalkenyl, aryl and _{heteroaryl, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 6} cycloalkyl or halogen, substitutable position For example, it may be substituted with 1 to 5 substituents which are the same or different. R ⁶ _is more preferably _{C 3 ~ 10} alkyl or _{C 3 ~ 10} alkenyl.

^{R 7} in each of ^R 3 ~ ^{R 6} _{is, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, or an aryl or heteroaryl, or _{C 6 ~ 12 alkyl, C 6 ~ 12} alkenyl or, _{C 3 ~} shows the ₈ cycloalkyl _{C 1 - 6} alkyl. _{C 3 ~ 8} cycloalkyl as R _{^7, C 3 ~ 8} cycloalkenyl, aryl and _{heteroaryl, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl or halogen, substitutable position For example, it may be substituted with 1 to 5 substituents which are the same or different. R ⁷ is more _{preferably, C 3 ~ 8} cycloalkyl (said _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} selected from the group consisting of _{C 3 ~ 8} cycloalkyl and halogen, the same or different Optionally substituted with 1 to 5 substituents).

^{R 8} and ^{R 88} in each of ^R 3 ~ ^{R 6} are the same or different, a hydrogen _{atom, C 1 ~ 8 alkyl, C 2 ~ 8} alkenyl, or _may be substituted by _{C 1 ~ 6} alkyl C _{3 ~ 6} cycloalkyl shows. Alternatively, ^{R 8} and ^{R 88} _together, show a _{C 3 - 7} azacycloalkyl (which may be substituted with one to five _{C 1 - 6} alkyl). R ⁸ and ^{R 88} are more preferably either identical or different _{C 1 to 6} alkyl or _{C 2 - 6} alkenyl, or, _{C 3 ~ 5} ^{to R 8} and ^{R 88} are formed together Azacycloalkyl (the group may be substituted with _{1 to} 5 C _1-6 alkyl).

R ⁹ _{is, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, or an aryl or heteroaryl, or _shows a _{C 6 ~ 12} alkyl or _{C 6 ~ 12} alkenyl. _{C 3 ~ 8} cycloalkyl as R _{^9, C 3 ~ 8} cycloalkenyl, aryl and _{heteroaryl, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 3 ~ 8} cycloalkyl, a halogen, a substitutable position May be substituted. R ⁹ _is more preferably _{C 7 ~ 9} alkyl or _{C 7 ~ 9} alkenyl.

R ^10a and R ^10b are the same or different and each represents a hydrogen atom or C _1-4 alkyl. R ^10a and R ^10b are more preferably a hydrogen atom.

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

Or a physiologically acceptable salt thereof.

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

Indicates.

In the formulas (A), (B) and (C), n and m both represent an integer of 1 or 2, or one represents 1 and the other represents 2.
R ³ is aryl (said _groups, substituted by _{C 1 - 6} alkyl _is selected from _{C 2 - 6} alkenyl and _{C 3 - 6} the group consisting of cycloalkyl, the same or different and 1 to 5 substituents Or —C (═O) —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 ⁷ _{is, C 3 - 8} cycloalkyl (said _{groups, C 1 - 6 alkyl, C 2 - 6 alkenyl,} selected from the group consisting of _{C 3 - 8} cycloalkyl and halogen, the same or different 1 was ~ Optionally substituted with 5 substituents),
R ⁸ and ^{R 88} are the same or different and either indicate a _{C 1 ~ 6} alkyl or _{C 2 ~ 6} alkenyl, or is ^{R 8} and ^{R 88} together _{form, C 3 ~ 5} azacycloalkyl (base May be substituted with ₁ to 5 C _1-6 alkyl).

In order to simplify the description in this specification, the following abbreviations may be used.
Me: methyl, t-: tert-, p-: para-, THF: tetrahydrofuran, DMF: N, N-dimethylformamide.

Method for Producing the Compound of the Present Invention The compound represented by the formula (I ⁰ ) or the formula (I) or a physiologically acceptable salt thereof is a novel compound, and includes, for example, the methods described below, examples described later or publicly known It can manufacture by the method according to this method.

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

In each of the following reactions, if the structure of the starting material contains functional groups that may participate in the reaction, such as amino, carboxyl, hydroxyl group, and carbonyl, protection as commonly used for these groups It may be protected by introducing a group, and in that case, the desired compound can be obtained by removing the protecting group as appropriate after completion of the reaction.

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

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

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 and the like. Aralkyloxycarbonyl such as alkylcarbonyl; formyl; benzoyl; benzyloxycarbonyl; silyl is used.

The carbonyl can be protected by converting the carbonyl to a cyclic ketal such as dimethyl ketal and diethyl ketal, or a cyclic ketal such as 1,3-dioxolane and 1,3-dioxane.

Process for the preparation of compounds of formula (I)

In formulas (II) and (III), R ¹ , R ² and Z are defined similarly to R ¹ , R ² and Z in formula (I), including preferred embodiments thereof.

The compound of the formula (I) can be produced by an amidation reaction of a compound of the formula (II) and a compound of the formula (III) under usually used reaction conditions. 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 the 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, and hexafluorophosphate. 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 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 the like, and examples thereof include toluene, THF, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, and DMF. These solvents are used alone or as a mixed solvent of two or more. The compound of the 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 kind of starting compound used, etc., it is generally about −30 ° C. to about 150 ° C., preferably about −10 ° C. to about 70 ° C. The reaction time is about 1 to 48 hours.

The compound of the formula (II) is a known compound, or can be produced according to a known compound production method. For example, Monatsh. Chem., 77, 54 (1947), Tetrahedron Lett., 43, 4281 (2002), J. Org. Chem., 53, 1064 (1988), J. Org. Chem., 54, 3477 ( 1989) or the like, or a method analogous thereto, can be used to produce the compound of formula (II).

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

Method for producing compound of formula (IA) (compound in which Z is a group represented by formula (A) in formula (I))

In formulas (II), (IV), (V), (VI), (VII) and (IA), R ¹ , R ² and R ³ , including preferred embodiments thereof, include formula (I) and Defined similarly to R ¹ , R ² and R ³ in formula (A). P represents an amino protecting group, and X represents a leaving group (for example, a halogen atom, lower alkoxy, phenoxy, or imidazolyl).

The compound of the formula (IA) can be produced under the reaction conditions usually used for the compound of the formula (VI) and the compound of the 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 type of raw material compound, and examples thereof include toluene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, and DMF. 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 kind 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 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 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 carboxyl as described above.

The compound of the above formula (IV) is a known compound, or can be produced according to a known compound production method. For example, the compound of formula (IV) is 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. can do.

Method for producing compound of formula (IB) (compound of formula (I) wherein Z is a group represented by formula (B))

In formulas (II), (II ′), (IV), (X), (XI) and (IB), R ¹ , R ² and R ⁴ , including preferred embodiments thereof, are represented by formula (I) And R ¹ , R ² and R ⁴ in the formula (B). P represents an amino protecting group, and X and Y represent a leaving group (for example, a halogen atom, lower alkoxy, phenoxy, or imidazolyl). The compound of formula (IB) can be prepared under the conditions described in the process for preparing the compound of formula (IA) described above under the reaction conditions usually used for the compound of formula (X) and the compound of formula (XI). Can be manufactured according to.

The compound of the formula (X) can be produced by deprotecting the protecting group (P) of the formula (IV). The compound of the formula (IV) is prepared by converting the compound of the formula (II) into a reactive derivative represented by the formula (II ′) and then reacting with the compound of the formula (VIII) under usual conditions. 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 the like, and examples thereof include toluene, THF, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, and DMF. 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 kind 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 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, the compound of formula (VIII) can be produced according to the method described in J. Heterocyclic Chem., 27, 1559 (1990), J. Chem. Soc., 3634 (1959), or a method analogous thereto. it can.

The production of the compound in which Z is a group represented by the formula (C) or the formula (D) is carried out by the method described in the following examples, or the group in which Z is represented by the formula (A) or the formula (B). The compound can be synthesized by the same method as described above for a certain compound. The compound represented by the formula (I ⁰ ) can also be synthesized by the method described in the following Examples or the same method as described above with respect to the compound of the formula (I).

The compounds of the present invention include compounds represented by the following formula (XII), that is, compounds represented by the formula (I ⁰ ) and L is — (C═O) —NH—, or physiologically acceptable compounds thereof. Salt is also included. This compound has similar utility as the compound of formula (I).

In the formula, R ¹ represents a methyl or hydrogen atom,
R ² represents a hydrogen _{atom, C 1 ~ 4 alkyl, C 1 ~ 4} alkyl or arylcarbonyl,
R ¹⁰ is aryl (said _{group, C 1 - 6 alkyl, C 2 - 6 alkenyl, C 3 - 8} cycloalkyl and a halogen selected from the group, the same or different and 1 to 5 substituents And may be substituted with
n and m are the same or different and represent an integer of 1, 2 or 3.

The compound of the present invention obtained by the above production method can be isolated and purified according to a conventional method such as chromatography, recrystallization, reprecipitation and the like. Optical isomers can be derived from asymmetric synthesis such as using a starting material having an asymmetric center, or can be derived by optical resolution such as use of 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. 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 Facial pain, abdominal pain, neck pain, central pain, toothache, opioid resistance pain, visceral pain, surgical pain, bone injury pain, angina pain, and various pain and / or inflammation treatments that require treatment Or it is useful as a preventive agent. Furthermore, migraine or cluster headache, pruritus, allergic or non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, respiratory diseases such as asthma and 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 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 infiltration, painful steatosis, various other central and peripheral neuropathies other than those listed above, or Central pain conditions related to bottom state, and the state secondary to a combination thereof are also included in the definition of neuropathic pain.

As the 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 type of compound, administration form, administration method, patient symptom, age, etc., but is usually 0.005 mg / kg / day to 150 mg / kg / day, preferably 0.05 mg / day. kg / day to 20 mg / kg / day, which can be administered once or in several divided doses.

The compound of the present invention can be combined with other drugs to form a medicine. Thereby, additive and synergistic pharmacological effects can be obtained. 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, antiarrhythmic drugs It can be used as a medicament in combination with at least one other drug selected from the group consisting of drugs, local anesthetics and anxiolytics. 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 such as 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 are carbamazepine, lamotrigine, gabapentin and pregabalin. A specific example of an anticonvulsant is baclofen. Specific examples of anesthetics include mepivacaine, bupivacaine, tetracaine, dibucaine and ketamine hydrochloride. Specific examples of antiarrhythmic and local anesthetics include lidocaine, procaine, mexiletine and flecainide. Specific examples of anxiolytic drugs are diazepam and etizolam.

Other agents 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 medicament 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 Injections, patches (tapes, transdermal patch preparations, poultices, etc.), lotions, emulsions, creams, jellies, gels, external powders, inhalants, and nasal preparations, skin Examples thereof include injections such as internal injections, subcutaneous injections, intraperitoneal injections, intrabody injections such as joint cavities, and infusions. These pharmaceutical compositions are prepared according to conventional methods. That is, a pharmaceutical composition containing a compound represented by formula (I ⁰ ) or formula (I) or a physiologically acceptable salt thereof is an excipient, a binder, a lubricant, a stabilizer, a disintegrant. , Base, buffer, solubilizer, tonicity agent, solubilizer, pH adjuster, surfactant, emulsifier, suspending agent, dispersant, suspending agent, thickener, viscosity modifier, Can contain pharmaceutical carriers such as gelling agents, soothing agents, preservatives, plasticizers, absorption enhancers, anti-aging agents, moisturizers, preservatives, and fragrances. Addition of two or more kinds of pharmaceutical carriers A thing can also be selected and used suitably.

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 a salt thereof, tragacanth, acacia gum, carboxymethylcellulose, hydroxyethylcellulose, 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 and sorbitan trioleate), Tween (polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, and 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, and phosphatidylserine). Including isolated purified phospholipids) or its hydrogenated derivatives, CFCs, CFC-12, CFC-12, CFC-22, CFC-22, CFC-113, CFC-114, CFC-123, CFC-142c, CFC-134a, CFC-227, CFC-318 , 1,1,2-tetrafluoroethane, etc.), alternative CFCs (HFA-227, HFA-134a, etc.), propane, isobutane, butane, diethyl ether, nitrogen gas, carbon dioxide, benzalkonium chloride, paraben, phosphorus Examples thereof include sodium acid, sodium acetate, sodium chloride, concentrated glycerin, benzalkonium chloride, paraben, a salt of stearic acid, starch, and cellulose.

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

A pharmaceutical 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 medicines, the compounding ratio of the drugs can be appropriately selected depending on the age, sex, weight, symptoms, administration time, dosage form, administration method, combination of drugs and the like of the patient. As the administration route of the medicine, 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 = 100/0 to 0/100 gradient) and purified by t-butyl 4- (4-benzyloxy-3-methoxybenzylcarbamoyl) -piperidine-1. 16.3 g of carboxylate were obtained.

(2) The product of the above (1) (16.3 g) was dissolved in ethyl acetate (270 ml), and an ethyl acetate solution of hydrogen chloride (4 mol / l, 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 = 100/0 to 0/100 gradient) to give N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N- 301 mg of dibutylsulfamoyl) piperidine-4-carboxamide were obtained.

(4) The product of (3) (301 mg) is dissolved in a mixed solvent (6 ml) of ethanol / tetrahydrofuran (1/2), 10% palladium on carbon (102 mg) is added, and contact hydrogen at room temperature in 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, the 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) Bis (tri-t-butylphosphine) palladium (52 mg) was added to the reaction solution, and the reaction solution 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 (eluent: 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 were 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 in place of 1-bromo-2-ethylbenzene in Example 5, 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) p-Nitrophenyl chloroformate (135 mg) was added to a mixture of 4-t-butylpiperidine (119 mg), triethylamine (140 mg) and tetrahydrofuran (3 ml) 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. After the mixture was stirred at room temperature for 26 hours, iodomethane (1.98 g) was further added and 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 of Example 1 (1) (1.03 g) 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 (807 mg) of (2) above was dissolved in ethyl acetate (24 ml), and an ethyl acetate solution of hydrogen chloride (4 mol / l, 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), the product of (3) (292 mg), triethylamine (246 mg) and N, N-dimethylformamide (5 ml) were added. 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-thiocarboxylate:

(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 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 above product (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 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, 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 (eluent: chloroform / methanol = gradient from 100/0 to 100/2) to give t-butyl-4- (4-benzyloxy-3-methoxybenzylcarbamoyl) piperazine-1- 429 mg of carboxylate 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 (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 in place 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 mixture, 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. The organic layer was dried over sodium sulfate, and then 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 the above (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 (elution solvent: 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) in the above (2) and 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
Production 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 (elution solvent: 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 of product.

(2) The product of above (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 the solvent was distilled off under reduced pressure to obtain 4.00 g of product.

(3) The product (1.65 g) of (2) above was dissolved in methylene chloride (100 ml), and a 1,4-dioxane solution (4 mol / l, 3 ml) of hydrogen chloride 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 of product.

(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 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 of product.

(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 (eluent: chloroform / methanol = gradient from 100/0 to 100/2) to give 2- (4-hydroxy-3-methoxyphenyl) -N- [1- (2-methyl 140 mg of (phenyl) piperidin-4-yl] acetamide were obtained.
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 23, reaction and treatment were conducted in the same manner as in Example 23 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).

Hereinafter, the pharmacological test results of the representative compounds of the present invention will be shown, and the pharmacological action of the compounds of the present invention will be described. 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 culture 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 at 37 ° C. with 5% CO ₂ . 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 compound 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 μg / ml or 30 μg / ml), and the resulting solution is Std: ddy. One drop was dropped on the eyes of male male mice (5 mice per group, body weight 20 g to 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 operation 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 compounds of the present invention and physiologically acceptable salts thereof have a strong analgesic action and are less irritating than capsaicin, and as an analgesic and anti-inflammatory drug, existing analgesics are sufficiently effective. Remedy for various types of neuropathic pain such as diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-multiple neuropathic pain, and pain caused by rheumatoid arthritis and osteoarthritis Useful as. In addition, these include migraine and cluster headaches, pruritus, allergic and non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, respiratory diseases such as asthma and 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 (23)

1. The following formula (I ⁰ ):
   

   

   [Where:
   R ¹ represents a methyl or hydrogen atom,
   R ² represents a hydrogen _{atom, C 1 ~ 4 alkyl, C 1 ~ 4} alkyl or arylcarbonyl,
   L represents —NH— (C═O) — or — (C═O) —NH—,
   Z is a group represented by the following formula (A), (B), (C) or (D) (wherein azacycloalkyl in formula (A) is 1 to 5 identical or different C ₁ Optionally substituted with up _{to 4} alkyls):
   

   

   {In each formula, n and m are the same or different and each represents an integer of 1, 2 or 3;
   R ³ is aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6} alkenyl or _{C 3 ~ 6} may be substituted by cycloalkyl) or show, or, -S (= O) ₂ —R ⁷ , —C (═O) —R ⁷ , —C (═O) —SR 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 (provided that when R ² is ethyl, R ³ is —S (═O) ₂ — Not NR ⁸ R ⁸⁸ ),
   R ⁴ represents —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 _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 6} cycloalkyl or halogen it is either showing also may) have (provided that when ^{R 2} is methyl, ^{R 6} is not aryl), _{or, C 3 ~ 10 alkyl, C 3 ~ 10 alkenyl, C 3 ~ 8} cycloalkyl _{C 1 ~ 6} Alkyl, —C (═O) —O—R ⁷ or —O—C (═O) —NR ⁸ R ⁸⁸ ,
   R ⁷ is _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl or halogen or showing also may) have been, _{or, C 6 ~ 12 alkyl, C 6 ~ 12} alkenyl or _{C 3 ~ 8} cycloalkyl _{C 1 ~ 6} represents an alkyl,
   R ⁸ and ^{R 88} show the same or different and each represents a hydrogen _{atom, C 1 ~ 8 alkyl, C 2 ~ 8} alkenyl, _or an optionally _{C 3 ~ 6} cycloalkyl optionally substituted with _{C 1 ~ 6} alkyl or, alternatively, ^{R 8} and ^{R 88} are taken _together, show a _{C 3 - 7} azacycloalkyl (said group may be substituted with one to five _{C 1 ~ 6} alkyl),
   R ⁹ is _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl or halogen or showing also may) have been, or _shows a _{C 6 ~ 12} alkyl or _{C 6 ~ 12} alkenyl. },
   R ^10a and R ^10b are the same or different and each represents a hydrogen atom or C _1-4 alkyl;
   A group Z is represented by the formula (A), with ^{R 3} is ^{-C (= O) -O-R} 9, R 9 is _{C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl The azacycloalkyl in formula (A) is substituted with _{1 to} 5 identical or different C _1-4 alkyl and / or at least one of R ^10a and R ^10b is C _{1 ~ 4} alkyl. ]
   Or a physiologically acceptable salt thereof.
2. The following formula (I):
   

   

   [Where:
   R ¹ represents a methyl or hydrogen atom,
   R ² represents a hydrogen _{atom, C 1 ~ 4 alkyl, C 1 ~ 4} alkyl or arylcarbonyl,
   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 aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6} alkenyl or _{C 3 ~ 6} may be substituted by cycloalkyl) or show, or, -S (= O) ₂ —R ⁷ , —C (═O) —R ⁷ , —C (═O) —SR 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 (provided that when R ² is ethyl, R ³ is —S (═O) ₂ -Not NR ⁸ R ⁸⁸ ),
   R ⁴ represents —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 _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 6} cycloalkyl or halogen it is either showing also may) have (provided that when ^{R 2} is methyl, ^{R 6} is not aryl), _{or, C 3 ~ 10 alkyl, C 3 ~ 10 alkenyl, C 3 ~ 8} cycloalkyl _{C 1 ~ 6} alkyl, —C (═O) —O—R ⁷ or —O—C (═O) —NR ⁸ R ⁸⁸ ,
   R ⁷ is _{substituted, C 3 ~ 8 cycloalkyl, C 3 ~ 8} cycloalkenyl, aryl or heteroaryl (respective _{group, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl,} a _{C 3 ~ 8} cycloalkyl or halogen or showing also may) have been, _{or, C 6 ~ 12 alkyl, C 6 ~ 12} alkenyl or _{C 3 ~ 8} cycloalkyl _{C 1 ~ 6} represents an alkyl,
   R ⁸ and ^{R 88} are the same or different, a hydrogen _{atom, C 1 ~ 8 alkyl, C 2 ~ 8} alkenyl or _{C 1 ~ 6} alkyl or represents an _{C 3 ~ 6} cycloalkyl which may be substituted, Alternatively, ^{R 8} and ^{R 88} are taken _together, show a _{C 3 - 7} azacycloalkyl (said group may be substituted with one to five _{C 1 ~ 6} alkyl),
   R ⁹ _represents a _{C 6 ~ 12} alkyl or _{C 6 ~ 12} alkenyl. }. ]
   Or a physiologically acceptable salt thereof.
3. The compound or a physiologically acceptable salt thereof according to claim 1 or 2, wherein n and m are the same or different and are an integer of 1 or 2.
4. 3. The compound according to claim 1 or 2, wherein n and m are both 2, or a physiologically acceptable salt thereof.
5. R ³ is aryl (said _groups, substituted by _{C 1 - 6} alkyl _is selected from _{C 2 - 6} alkenyl and _{C 3 - 6} the group consisting of cycloalkyl, the same or different and 1 to 5 substituents 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 ⁶ _is a _{C 3 ~ 10} alkyl or _{C 3 ~ 10} alkenyl, a compound or a physiologically acceptable salt thereof according to any one of claims 1-4.
6. R ⁷ _{is, C 3 - 8} cycloalkyl (said _{groups, C 1 - 6 alkyl, C 2 - 6 alkenyl,} selected from the group consisting of _{C 3 - 8} cycloalkyl and halogen, the same or different 1 was ~ May be substituted with 5 substituents),
   R ⁸ and ^{R 88} are the same or _different, and represent a _{C 1 ~ 6} alkyl or _{C 2 ~ 6} alkenyl, or, ^{R 8} and ^{R 88} _{together, C 3 ~ 5} azacycloalkyl (the Group may be substituted with ₁ to 5 C _1-6 alkyl),
   R ⁹ is a C 7 _{~ 9} alkyl or C _{7 ~ 9} alkenyl, compound, or a physiologically acceptable salt thereof according to any one of claims 1-5.
7. The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 6, wherein Z is a group represented by the formula (A).
8. The compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, wherein Z is a group represented by the formula (B).
9. The compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, wherein Z is a group represented by the formula (C).
10. The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 6, wherein Z is a group represented by the formula (D).
11. The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 10, wherein R ¹ is methyl.
12. The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 11, wherein R ² is a hydrogen atom.
13. R ¹ is methyl;
    R ² is a hydrogen atom,
    Z is a group represented by the formula (B),
    n and m are both 2;
    The compound according to claim 1 or 2, or a physiologically acceptable salt thereof, wherein R ⁴ is -C (= O) -O-R ⁷ .
14. R ¹ is methyl;
    R ² is a hydrogen atom,
    Z is a group represented by the formula (A),
    n and m are the same or different and an integer of 1 or 2,
    The compound according to claim 1 or 2, or a physiologically acceptable salt thereof, wherein R ³ is -S (= O) ₂ -NR ⁸ R ⁸⁸ or -C (= O) -SR ⁷ .
15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.
16. A therapeutic or prophylactic agent for pain and / or inflammation comprising the compound according to any one of claims 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.
17. A method for treating or preventing pain and / or inflammation, comprising administering an effective amount of the compound according to any one of claims 1 to 14 or a physiologically acceptable salt thereof to a patient.
18. Use of the compound according to any one of claims 1 to 14 or a physiologically acceptable salt thereof for the manufacture of a therapeutic or preventive agent for pain and / or inflammation.
19. A compound according to any one of claims 1 to 14 or a physiologically acceptable salt thereof,
    Narcotic analgesics, neuropathic pain treatments, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, antidepressants, antiepileptic drugs, anticonvulsants, anesthetics, antiarrhythmic drugs, local anesthetics and anxiolytics And at least one other drug selected from the group consisting of drugs.
20. A pharmaceutical composition comprising the medicine according to claim 19 as an active ingredient.
21. A therapeutic or prophylactic agent for pain and / or inflammation, comprising the medicament according to claim 19 as an active ingredient.
22. A method for treating or preventing pain and / or inflammation, comprising administering an effective amount of the pharmaceutical agent according to claim 19 to a patient.
23. Use of the medicament according to claim 19 for producing a therapeutic or preventive agent for pain and / or inflammation.