WO2006118307A1

WO2006118307A1 - Therapeutic agent for pain

Info

Publication number: WO2006118307A1
Application number: PCT/JP2006/309173
Authority: WO
Inventors: Yasushi Taguchi
Original assignee: Mochida Pharmaceutical Co., Ltd.
Priority date: 2005-05-02
Filing date: 2006-05-02
Publication date: 2006-11-09
Also published as: JP2008179541A

Abstract

A therapeutic agent for pains characterized by containing as an active ingredient at least one of a compound represented by the following formula (I): [Chemical formula 1] (I) [wherein A is L-W (L is a bond or methylene and W is -NR7- (R7 is H or lower alkyl); G is (CH2)m (m is 0 or 1); Y is lower alkylene or (R4-substituted) benzylidene; Z is a bond or O, provided that when Z is a bond, then Y may form a 5- or 6-membered ring in cooperation with carbon atoms on the benzene ring; R1 is NO2, lower alkoxycarbonyl, (substituted) carbamoyl, OH, etc.; R2 and R3 each is H, halogeno, lower (halo)alkyl, lower (halo)alkoxy, or NO2; R4 and R5 each is H, halogeno, lower (halo)alkyl, lower (halo)alkoxy, CN, lower alkylthio, lower alkylsulfinyl, etc.; and R6 is H or lower alkyl), a pharmaceutically acceptable salt of the compound, and solvates of these. The therapeutic agent for pains can be orally administered. It is safer and is reduced in side effects such as central action. It has excellent effectiveness.

Description

Specification

Pain medicine

Technical field

[0001] The present invention contains, as an active ingredient, a ligand of sigma 1 receptor having a low ability to enter the brain and acting specifically on peripheral tissues, more specifically, a specific derivative having a pyrrolidine ring or a azetidine ring. The present invention relates to a preventive and Z or therapeutic agent for pain characterized by. Background art

[0002] Research on sigma receptor-binding ligands began in the 1970s, and the compounds found in the development process of force opioid receptor agonists were known before the receptor itself was identified (The Journal of Pnarmacology ana Experimental Therapeutics, (USA), 1976, 197, p. 517-532). At that time, the sigma receptor was recognized as one of the opioid receptors.Since subsequent studies showed that naloxone that competitively inhibits all opioid receptors does not inhibit binding, it may not be an opioid receptor. (Proceedings of the National Academy of Sciences, (USA), 1984, 81st pp. 5618-5621). Many sigma receptor ligands, for example, benzomorphans and (+) pentazocine, are then synthesized to produce analgesic, neuroprotective, antidepressant, anxiolytic, and antitussive effects. However, development as a pharmaceutical has been promoted in expectation of various actions. However, a compound whose main action is still binding to the sigma receptor while being strong has not been promoted.

[0003] The sigma receptor is thought to have two ligands: the sigma 1 receptor and the sigma 2 receptor, of which the sigma 1 receptor was identified in 1996 ( Proceedings of the National Academy of Sciences ”, (USA), 1996, 93, p. 8072-8077). The reported sigma 1 receptor is composed of 223 amino acids. A force that was a membrane protein with a molecular weight of about 25 KDa. The structure was completely different from other known proteins, and showed only a slight homology to yeast sterol isomerase. In addition, the power that many studies have continued energetically, the intracellular signal transduction pathways such as GPCR, where information is still lacking, has not yet been clarified, and the effect of sigma 1 receptor ligands on pain responses It is not clearly proven.

Many sigma-1 receptor ligands have been developed with the aim of exhibiting antidepressant and neuroprotective effects by being highly lipid-soluble and moving into the brain, and inevitably have an effect on central tissues. As a reminder, it was difficult to develop a safe analgesic aimed solely at suppressing the pain response elicited in peripheral tissues.

“Pain is substantial in the organization! /, Including unpleasant sensory and emotional experiences that occur based on potential injuries, as well as sensory emotional experiences described using such expressions. "Is defined. Pain is broadly classified into three categories: 1. nociceptive pain, 2. neuropathic pain, 3. psychogenic pain.

Nociceptive pain is physical pain caused by mechanical stimulation, temperature stimulation, and chemical stimulation, and is generally called acute pain. These pains act as biosensors based on an unpleasant sensory experience to protect the danger and danger. However, pain such as rheumatism is certainly chronic pain due to the prolonged period from the onset of force, which was thought to be acute pain, and chronic inflammation.

Hyperalgesia to thermal and mechanical stimuli occurs after tissue damage and during inflammation. Sensitization of pain-inducing substances and receptors to pain-inducing stimuli has been reported as an explanation of hyperalgesia to thermal and mechanical stimuli. Inflammatory mediators appearing in inflamed areas and sensitization of pain receptors by lowering pH and inflammation Examples include increased responsiveness to bradykinin and histamine due to local temperature rise, and further sensitization with nerve growth factor (NGF). (Reference: Pain-Basics, Diagnosis, Treatment-Kazuo Hanaoka [edit] Asakura Shoten 2004 ). Specific examples of diseases include rheumatoid arthritis and knee osteoarthritis. Non-steroidal anti-inflammatory drugs (NS AIDs) have long been used for inflammatory pain, including pain caused by chronic rheumatoid arthritis and knee osteoarthritis. Due to side effects, the use was limited. In recent years The cycloxygenase 2-selective inhibitor (COX2 inhibitor) developed to reduce the side effects of NSAIDs has developed into a social problem due to concerns about the side effects that cause heart failure. Accordingly, there is a need for a therapeutic agent for inflammatory pain that exhibits higher efficacy by oral administration and has fewer side effects.

[0005] Post-operative pain is basically inflammatory pain associated with tissue damage, and also includes elements of neurogenic pain resulting from nerve damage. Postoperative pain is broadly divided into somatic pain and visceral pain. Somatic pain is further divided into shallow pain and deep pain. Of these, if strong postoperative pain is left untouched, nerve sensitization occurs and you feel pain against non-noxious stimuli such as touching and pressing (Alodia). When such pain occurs, there are many intractable cases that cannot be controlled by drug administration such as nerve block therapy or NSAIDs, antiepileptic drugs, opioid agonists, etc.In addition, each drug used is, for example, NSAIDs If it is gammapentin, if it is gabapentin Side effects such as dizziness; opioid agonists have their side effects such as constipation, and therefore there is a need for postoperative pain treatment agents that exhibit higher efficacy and fewer side effects.

Neuropathic pain is chronic pain that is caused by primary damage anywhere in the nerve transmission system from the periphery to the center or caused by dysfunction (illustration latest latest intoxication science series 4, pain (Clinical Chapter 1, Kenjiro Dan, 1998, Medical View). The nerve injury that causes neuropathic pain is typically trauma or injury to the peripheral nerves, the nerve plexus or the perineural soft tissue, but the central somatosensory pathway (the spinal cord, It can also be caused by injury to the brain stem, thalamus, or ascending somatosensory pathways at the cortical level. For example, it can be caused by any of neurodegenerative diseases, bone degenerative diseases, metabolic disorders, cancer, infection, inflammation, surgical operation, trauma, radiation therapy, treatment with anticancer agents, and the like. However, its pathophysiology, or in particular the molecular mechanism of the onset, has been fully elucidated! /.

[0006] Diabetic pain is largely divided into acute pain that develops when hyperglycemia is rapidly corrected, and chronic pain that develops due to factors such as demyelination and nerve regeneration. Among these diabetic pains, chronic pain is caused by inflammation of the dorsal root ganglion due to a decrease in blood flow due to diabetes and continues to occur. This is neuropathic pain that causes spontaneous nerve firing and excitability due to regeneration of nerve fibers. Non-steroidal anti-inflammatory drugs, antidepressants, kabusaicin cream, etc. are used as treatment methods, but there is no satisfactory treatment for diabetic pain that can cure various types of diabetic pain with a single drug ( Reference: History of Medicine No. 211 卷 No. 5, 2004, Special Issue “Pain Signal Control Mechanisms and Latest Treatment Evidence”).

[0007] As an abnormal skin reaction that characterizes neuropathic pain, for example, Alodinia is known. Alodiure is a state in which normal humans do not feel pain, but feel pain when stimulated. In Alodya, pain is caused by tactile stimulation, that is, there is a qualitative change in sensory response, and the threshold itself is considered to be a basic characteristic of Alodiure. In postherpetic neuralgia, which is representative of neuropathic pain, 87% of patients have alodia. And the intensity of postherpetic neuralgia is said to be proportional to the degree of alodyya. Alodia is attracting attention as a treatment target for postherpetic neuralgia as a symptom that significantly restricts patient freedom.

Herpes is a disease that develops when a herpesvirus once infected is reactivated in the nerve, and 70% of herpes patients are strongly painful. This pain disappears with healing of the disease About 10% of patients suffer from so-called postherpetic neuralgia, with pain remaining for many years after healing. The onset mechanism is that herpes reproliferation occurs from the ganglia, and the nerve injury that occurs at this time promotes synapse reorganization and causes neuropathic pain. I'm told. In clinical practice, older adults develop postherpetic neuralgia and more than 70% are 60 years or older. Anticonvulsants, non-steroidal anti-inflammatory drugs, steroids, etc. are used as therapeutic agents, but there is no complete treatment (Reference: Pain-Basic · Diagnosis' Treatment-Kazuo Hanaoka [edit] Asakura Shoten 2004) .

[0008] Analgesic therapy for a patient who complains of neuropathic pain and who has chronic pain symptoms and that pain itself interferes with daily life is directly related to life (life ) Quality of life. However, for neuropathic pain, central analgesics such as morphine, nonsteroidal anti-inflammatory analgesics and steroids are said to be ineffective. In actual drug therapy, antidepressants such as amitriptyline Prescriptions, anti-epileptic drugs such as gabapentin, pregaparin, carbamazepine, and feutoin, mexiletine, etc. Antiarrhythmic drugs are diverted and prescribed. However, these drugs have side effects such as lox, drowsiness, sedation, constipation, difficulty in urinating, etc. for amitriptyline, and carbamazepine, phenytoin, light rash, rash, digestive symptoms, cardiotoxicity, etc. Somnolence and dizziness are known, and mexiletine is known to have dizziness and nausea symptoms. These drugs, which are not specific neuropathic pain treatments, have low levels of satisfaction with treatments due to poor discrepancies between drug efficacy and side effects. Accordingly, there is a need for a neuropathic pain treating agent that exhibits higher efficacy by oral administration and has fewer side effects.

[0009] Further, among chronic pain, cancer pain and the like are mentioned as those having a chronic pain.

Cancer pain can be broadly divided into three types: those directly related to tumors, those related to treatment, and those unrelated to tumors and treatments. The neurological classification important for differentiation of physical pain in cancer is divided into somatic pain, visceral pain, and neuropathic pain, but often cannot be clearly classified. Opioid agonists such as morphine are often used to treat these pains, but their effectiveness is limited to 50-60% and patient satisfaction is not necessarily high. In addition, side effects such as constipation have become a problem as a side effect of opioid agonists, and analgesics to improve patients' quality of life are often a factor that reduces them. Accordingly, there is a need for a therapeutic agent for vaginal cancer pain that exhibits higher efficacy by oral administration and has fewer side effects.

[0010] As a compound having a structure in which an alkylene chain having a hetero atom (particularly a nitrogen atom) is bonded to the 3-position of the pyrrolidine ring or azetidine ring, Patent Document 1 discloses a novel pyridone which is extremely excellent as an antibacterial agent. An intermediate of carboxylic acid, or is disclosed as a 5HTllike receptor ligand in Patent Document 2 as a compound used for the treatment of migraine and the like. However, there is no disclosure of compounds having an aryl group directly bonded to the heteroatom. Patent Document 3 discloses a 3-hydroxy-pyrrolidine derivative or a 3-hydroxy-azetidine derivative and describes that it is used as an antitussive. However, in any of these patent documents, there is also a disclosure of pain suppression effects such as sigma receptor effects and chronic pain such as inflammatory pain, postoperative pain, neuropathic pain, and cancer pain. Nor. In drug development, it is required to meet strict criteria in various aspects such as absorption, distribution, metabolism and excretion as well as the intended pharmacological activity. For example, drug interaction, desensitization or tolerance, gastrointestinal absorption after oral administration, transfer rate into the small intestine, absorption rate and first-pass effect, organ barrier, protein binding, induction of drug metabolizing enzymes, excretion route and body Various considerations are required for clearance, application methods (application site, method, purpose), etc., and it is difficult to find one that meets these requirements.

In recent years, the proarrhythmic effect of pharmaceuticals, especially the QT interval prolonging effect in electrocardiograms, has attracted attention.

Since QT prolongation by drugs can induce subsequent fatal side effects (such as ventricular tachycardia or sudden death), detecting the presence or absence of such effects is very important for the development of highly safe drugs. The necessity is also taken up by ICH (International Conference on Harmonization of EU-Japan Pharmaceutical Regulations). In addition to the measurement of electrocardiograms in animal hearts and action potentials of cardiomyocytes, hERG (human ether-a-) is used as an evaluation method for evaluating drugs that are safe for humans, that is, for predicting the QT interval prolongation effect in humans. Go-go related gene) A method for examining the effect on channels is known. Recognizing the importance of side effects on the heart Finding drugs that have no effect on hERG channels is one of the important issues in developing safer drugs for humans.

There is always a comprehensive problem in the development of these drugs for pain treatments. In addition, for inflammatory pain and postoperative pain treatments, in addition to the conventional drugs currently used for treating inflammatory pain, such as gastrointestinal disorders, kidney disorders, and heart attacks, There is a need for a therapeutic agent for inflammatory pain that has few side effects and is highly useful. In addition, neuropathic pain treatment agents and cancer pain treatment agents have fewer side effects such as central effects and are more useful than conventional drugs that have been diverted to the treatment of pain described above. There is a need for a high-level pain treatment.

Patent Document 1: International Publication No. 93Z13101 Pamphlet

Patent Document 2: Pamphlet of International Publication No. 97Z42189

Patent Document 3: International Publication No. 2004Z048326 Pamphlet

Disclosure of the invention Problems to be solved by the invention

[0012] Under such circumstances, oral administration is possible, and there are few central side effects (for example, depressive action, abnormal behavior, excessive exercise, etc.) and cardiotoxicity. Prophylactic and Z or therapeutic agents, in particular, prophylactic and Z or therapeutic agents for chronic pain, more specifically, prophylactic and Z or therapeutic agents for inflammatory pain, including pain caused by rheumatoid arthritis and osteoarthritis, surgery Post-pain prevention and Z or treatment, diabetic pain · Prevention and Z or treatment of neuropathic pain, including postherpetic neuralgia, prevention and Z or treatment of cancer pain, or anti-allody Etc. are required.

In particular, the problems in the prior art as described above, more specifically, アミ, sleepiness, sedation, constipation, difficulty in urination, etc., which are side effects of amitriptyline, rash, digestion, which are side effects of carbamazepine, At least one or more of the symptoms such as dizziness and dizziness, which are side effects of gabapentin, such as genital symptoms, cardiotoxicity, etc. Drugs that can be administered orally to mammals, including overcoming humans, are particularly urgently needed for clinical use, self-help, prevention and Z or treatment of neuropathic pain.

In addition, there is a need for a prophylactic and effective Z- or therapeutic agent for inflammatory pain that can be administered orally and has fewer side effects such as gastrointestinal disorders, kidney disorders, and heart attacks, and is safer and more effective. . In particular, the problems in the prior art as described above, more specifically,

Drugs that can be administered orally to mammals, including humans, who have overcome at least one of the side effects of COX2 inhibitors, such as gastrointestinal disorders and kidney disorders, which are side effects of NSAIDs, such as heart attacks. There is an urgent need for the prevention and / or treatment of inflammatory pain.

Furthermore, there is a need for pain prevention and Z or therapeutic agents that overcome at least one of the side effects of opioid agonists that exhibit analgesic effects in general pain, that is, constipation, tolerance, dependence, etc. Speak.

Means for solving the problem

[0013] sigma 1 receptor ligand with low brain penetration and specific action in peripheral tissues, especially A prophylactic and Z or therapeutic agent for pain, comprising at least one of the compounds represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, , Prevention and Z or treatment of chronic pain, more specifically, prevention and Z or treatment of inflammatory pain, including pain caused by rheumatoid arthritis and osteoarthritis, prevention and Z or treatment of postoperative pain Drugs, diabetic pain, prevention and Z or treatment of neuropathic pain including post-herpetic neuralgia, prevention and Z or treatment of cancer pain, or an anti-allodynic agent.

The invention's effect

[0014] The inventors of the present invention should be surprised as a result of intensive research to obtain a compound having an analgesic action with excellent efficacy and less side effects that solves the above problems. In particular, a specific derivative having a pyrrolidine ring or a azetidine ring represented by formula (I) or a pharmaceutically acceptable salt thereof has (1) excellent pain suppression via the sigma 1 receptor. (2) It does not show a central action with little brain transportability, and (3) It is highly unsafe such as hERG channel inhibitory action. It was found to have characteristics. The compound represented by the formula (I) is an orally administrable pain prevention and Z or treatment agent, particularly chronic pain prevention and Z or treatment agent, more specifically, rheumatoid arthritis and osteoarthritis. Prevention and Z or treatment of inflammatory pain, including pain caused, prevention and Z or treatment of postoperative pain, prevention and Z or treatment of neuropathic pain including diabetic pain and postherpetic neuralgia, It is expected to be used as a preventive and Z or therapeutic agent for cancer pain, or as an anti-allody agent.

Brief Description of Drawings

FIG. 1 is a graph showing analgesic activity in a rat spinal nerve ligation model.

FIG. 2 is a graph showing analgesic activity in a rat acetate rising model.

FIG. 3 is a graph showing analgesic activity in a rat carrageenin-induced pain model.

BEST MODE FOR CARRYING OUT THE INVENTION

[0016] The present invention contains, as an active ingredient, at least one of the compound represented by the formula (I) shown in the following embodiment, a pharmaceutically acceptable salt thereof, or a solvate thereof. Inflammation, including pain caused by rheumatoid arthritis and osteoarthritis, more particularly, prevention and z or treatment of pain Prophylaxis and Z or treatment of sexual pain, prevention and treatment of postoperative pain, Z or treatment, diabetic pain and prevention of neuropathic pain including postherpetic neuralgia and Z or treatment, cancer pain Prophylactic and Z or therapeutic agents, or anti-alloy agents.

Hereinafter, each aspect of the present invention will be described.

[Aspect of the Invention]

[1]

A first aspect of the present invention is the following formula (I)

[Chemical 1]

In the formula, A represents a group: L—W (L represents a bond or methylene, W represents a group: —NR′— (R ⁷ represents a hydrogen atom or a lower alkyl group), and G represents ( CH) m (m is 0 or 1)

2

Y represents lower alkylene or a benzylidene group which may be substituted with R ⁴ , Z represents a bond or an oxygen atom, and when Z represents a bond, Y represents 5 to 5 carbon atoms on the benzene ring. R ¹ which may form a 6-membered ring is mono- or di-substituted with a -tro group, a lower alkoxycarbonyl group, or a lower alkyl group !, may! /, Force rumomoyl group, protected Hydroxyl groups that may be protected, carboxyl groups that may be protected, protected! N-hydroxycarbamoyl group, protected !, may! /, A lower alkyl group substituted with a hydroxyl group, a protected lower alkyl group substituted with a carboxyl group, or Represents a tetrazolyl group, and R ² and R ³ each independently represents a hydrogen atom, a halogen atom, It may be substituted with a rogen, or it may be substituted with a lower alkyl group or a halogen! /, Represents a lower alkoxy group or -tro group, and R ⁴ and R ⁵ each independently represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a halogen, or a halogen substituted. Preferred lower alkoxy group, cyano group, lower alkylthio group, lower alkylsulfuryl group or lower alkylsulfol group, and R ⁶ represents a hydrogen atom or a lower alkyl group. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, and a preventive and Z or therapeutic agent for pain, preferably chronic Prevention and Z or treatment of pain, more preferably prevention and Z or treatment of inflammatory pain including pain caused by rheumatoid arthritis and osteoarthritis, prevention and Z or treatment of postoperative pain, diabetic Pain · Prevention and Z or treatment of neuropathic pain including postherpetic neuralgia, prevention and Z or treatment of cancer pain, or anti-alodysia.

[0018] Each group in the above formula (I) will be specifically described below.

In the definition of the group in each formula of the present invention,

“Lower” means a straight, branched, or cyclic carbon chain having 1 to 4 carbon atoms, unless otherwise specified, and is also expressed as “C1-4”. Accordingly, examples of the “lower alkyl group” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a sec butyl group, a tert butyl group, and a cyclobutyl group.

The term “lower alkoxycarbo group” means a C1 4 alkoxycarbol group having 1 or 4 carbon atoms in the alkoxy group, and is either a methoxycarboxyl group or an ethoxycarbonyl bonoleol. Group, propoxy carbonyl group, isopropoxy carbonyl group, cyclopropyl carboxylic group, butoxy carbo yl group, iso but oxy carboxy group, sec-butoxy carbo ol group, tert but oxy carboxy group, And cyclobutyloxy carbo yl group.

[0019] The "force rubamoyl group optionally mono- or di-substituted with a lower alkyl group" means that one or two hydrogen atoms on the nitrogen atom of the force rubamoyl group are substituted with the "lower alkyl group". It may be a power ruberamoyl group. Specifically, the power ruberamoyl group , Methyl carbamoyl group, ethyl carbamoyl group, propyl strength rubamoyl group, isopropyl strength rubamoyl group, cyclopropyl strength rubamoyl group, butyl carbamoyl group, isobutyl carbamoyl group, sec butyl carbamoyl group, tert butyl carbamoyl group, cycloptyl carbamoyl group , Dimethylcarbamoyl group, jetylcarbamoyl group, dipropyl-powered rubermoyl group, diisopropyl-powered rubamoyl group, dicyclopropyl-powered rubamoyl group, dibutylcarbamoyl group, diisoptylcarbamoyl group, disec-butyl-powered rubermoyl group, di-tert-butylcarbamoyl group , Dicyclobutylcarbamoyl group, ethylmethylcarbamoyl group, methylpropyl strength rubamoyl group, ethylpropylcarbamoyl group, butylmethylcarbamoyl group, butylethylcarbyl Moil groups include Buchirupu port pill force Rubamoiru group.

“Lower alkylene group” means an alkylene group having 1 to 4 carbon atoms, and examples thereof include a methylene group, an ethylene group, and a propylene group.

The “oxoalkylene group” means a group in which one methylene of the above-described alkylene group is converted to a carbo group.

Examples of the protecting group for the “optionally protected hydroxyl group” in the present specification include an alkyl-based protecting group such as methyl group “tert-butyl group” benzyl group ”trityl group“ methoxymethyl group ”, trimethylsilyl group · tert-butyl Examples include silyl protecting groups such as dimethylsilyl group, acyl protecting groups such as formyl group, acetyl group and benzoyl group, and carbonate protecting groups such as methoxycarbon group and benzyloxycarbonyl group.

In this specification, “protected, but carboxyl group” is a protective group such as methyl ester, ethyl group, tert-butyl group, benzyl group, diphenylmethyl group, trityl group, etc. And silyl ester protecting groups such as trimethylsilyl group and butyldimethylsilyl group.

Examples of the protective group for “protected or N-hydroxycarbamoyl group” include a tetrahydrobiranyl group.

The “lower alkyl group substituted with a hydroxyl group, which may be protected” includes a case where a hydroxyl group is substituted on the lower alkyl group. Specifically, as the “optionally protected C 1-4 alkyl group substituted with a hydroxyl group”, for example, a hydroxymethyl group, 1-hydro Chichetyl group, 2-hydroxyethyl group, 1-hydroxy 1 methylethyl group, 1-hydroxypropyl group, 2 hydroxypropyl group, 3 hydroxypropyl group, 1-hydroxy 1 methylpropyl group, 1-hydroxybutyl group, 2 hydroxybutyl group, Examples include 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxycyclopropyl group, 1-hydroxycyclopropylmethyl group, and those in which the hydroxyl group of these groups is protected with the above-mentioned corresponding protecting group.

“When Z represents a bond, Y may form a 5- or 6-membered ring with a carbon atom on the benzene ring” means that when Z is a bond and Y is a lower alkylene group, Means that two carbon atoms and a carbon atom on the benzene ring are bonded by a lower alkylene group, for example, Y is an ethylene group, a carbon atom adjacent to the nitrogen atom of the ethylene group and a carbon atom on the benzene ring. Are connected via a methylene group or an ethylene group. Specific examples include a 2-indanyl group and a 1,2,3,4-tetrahydro-2-naphthyl group.

The “lower alkyl group which may be protected or substituted with a carboxyl group” includes the case where a carboxyl group is substituted on the lower alkyl group. Specifically, as “protected !, may! /, C1 4 alkyl group substituted by carboxyl group”, for example, carboxymethyl group, 1 carboxyethyl group, 2-carboxyethyl group, 1 Carboxy 1 Methylethyl group, 1 Carboxypropyl group, 2 Carboxypropyl group, 3 Carboxypropyl group, 1 Carboxy 1 methylpropyl group, 1 Carboxybutyl group, 2 Carboxybutyl group, 3 Carboxybutyl group, 4 Carboxybutyl group, 1 Examples thereof include carboxycyclopropyl group, 1 carboxycyclopropylmethyl group, and those in which the carboxyl group of these groups is protected with the above-mentioned corresponding protecting group.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The “lower alkyl group that may be substituted with a halogen atom” includes a case where a halogen atom is substituted on the lower alkyl group and the alkyl group. Specifically, as the “C 1-4 alkyl group substituted with a halogen atom”, for example, a fluoromethyl group, a 1 fluoroethyl group, a 2-fluoroethyl group, a 1 fluoro-1 methylethyl group, 1 Fluoropropyl group, 2 Fluoropropyl group, 3 Fluoropropyl group, 1 Fluoro 1 Methylpropyl group, 1 Fluorobutyl group, 2 Fluorobutyl group, 3 Fluorobutyl group, 4 Fluorobutyl group, 1 Fluorocyclopropyl group, 1 Fluorocyclopropylmethyl group Chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-methylethyl, 1-methylethyl, 1-chloropropyl, 2-chloropropyl, 3-chloromethyl, etc. 1-methylpropyl group, 1-chlorobutyl group, 2 chlorobutinole group, 3 chlorobutinole group, 4 chlorobutynole group, 1 chlorocyclopropyl group, 1 chlorocyclopropylmethyl group, trichloromethyl group, etc. Bromomethyl group, 1 bromoethyl group, 2-bromoethyl group, 1 Bromo 1 methylethyl group, 1 bromopropyl group, 2 bromopropyl group, 3 bromopropyl group, 1-bromo-1 methinorepropinole group, 1-bromobutinole group, 2 bromobutinole group, 3 bromobutinole group, 4 bromobutyl group, 1-bromocyclopropyl Group, 1-bromocyclopropylmethyl group, tribromomethyl group and the like. Preferably, a trifluoromethyl group is used. Examples of the “lower alkoxy group” include methoxy group, ethoxy group, propoxy group, isopoxy group, butoxy group, isobutoxy group, sec butoxy group, tert butoxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopropylmethyl An oxy group, and the like.

The “lower alkoxy group that may be substituted with a halogen atom” includes the case where the lower alkoxy group and the alkoxy group thereof are substituted with a halogen atom. Specifically, as the “C 1-4 alkoxy group substituted with a halogen atom”, for example, a fluoromethoxy group, a 1 fluoroethoxy group, a 2-fluoroethoxy group, a 1 fluoro-1 methyl ethoxy group, a 1 fluoropropoxy group, 2 Fluoropropoxy group, 3 Fluoropropoxy group, 1 Fluoro 1 Methylpropoxy group, 1 Fluorobutoxy group, 2-Fluorobutoxy group, 3 Fluorobutoxy group, 4 Fluorobutoxy group, 1 Fluorocyclopropyloxy group, 1-Fluorocyclopropylmethyl Oxymethoxy group, trifluoromethoxy group, etc .; chloromethoxy group, 1-capped ethoxy group, 2-capped ethoxy group, 1-chloro-1-methyloxy group, 1-capped propoxy group, 2-capped-propoxy group, 3-capped port Propoxy group, 1—Black mouth 1-Methylpropoxy group, 1— Rorobutokishi group, a 2-chlorobutoxy group, 3 chlorobutoxy group, 4 chlorobutoxy group, 1 chloro-cyclopropoxy group, 1 chloro-cyclopropylmethoxy group, trichloromethoxy group, etc .; bromomethoxy group, 1-bromoethoxy group, 2-bromoethoxy group, 1 -Bromo-1 methylethoxy group, 1 bromopropoxy group, 2 bromopropoxy group, 3 bromopropoxy group, 1-bromo-1-methyl propoxy group, 1 bromobutoxy group, 2 bromobutoxy group, 3 bromobutoxy group, 4 bromobutoxy group, 1 -Bromocyclopropoxy group, 1-bromocyclopropylmethoxy group, tripromomethoxy group and the like. Preferably, a trifluoromethoxy group is used.

[0024] Examples of the "lower alkylthio group" include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a sec butylthio group, a tert-butylthio group, a cyclopropylthio group, and a cyclobutylthio group. Group, cyclopropylmethylthio group, and the like.

Examples of the “lower alkyl sulfiel group” include a methyl sulfiel group, an ethyl sulfiel group, a propyl sulfiel group, an isopropyl sulfiel group, a butyl sulfyl group, an isobutyl sulfiel group, a sec butyl sulfiel group, and a tert butyl sulfyl group. Group, cyclopropylsulfuryl group, cycloptylsulfyl group, cyclopropylmethylsulfiel group and the like.

The “lower alkylsulfol group” is a group: —SO— (C 1-4 alkyl group), and “C1

2

Also referred to as “4 alkylsulfol group”. Examples include methylsulfol group, ethylsulfol group, propylsulfol group, isopropylsulfol group, butylsulfol group, isobutylsulfol group, sec butylsulfol group, tert butylsulfol group, etc. .

Examples of the “lower alkanol group” include formyl group, acetyl group, propionyl group and the like.

[0025] Preferred aspects of the definition of the substituent in the compound represented by the formula (I) used in the present invention are as follows.

[1-1]

In the compound represented by the formula (I), R ¹ represents a nitro group, a lower alkoxycarbo group, A rubamoyl group which may be mono- or di-substituted with a lower alkyl group, protected, a carboxyl group, or a tetrazolyl group.

[1-1 -a]

Preferably, R ¹ is a nitro group, a methoxycarbol group, an ethoxycarb group, a carbamoyl group, a dimethylcarbamoyl group, a jetylcarbamoyl group, a carboxyl group, or a tetrazolyl group, more preferably It is a carboxyl group.

[1 1 b]

Examples of the substitution position of R ¹ include an ortho position, a meta position, and a para position with respect to the carbon atom to which A is bonded, and the para position (the 4th position) is preferred.

[1 1 c]

R ¹ is more preferably a carboxyl group bonded to the para position of A.

[1-2]

In the compound represented by the formula (I), R ⁴ is a halogen atom, a lower alkoxy group, a cyano group, a lower alkylthio group or a lower alkylsulfol group.

[l-2-a]

Preferably, R ⁴ is a fluorine atom, a chlorine atom, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a cyano group, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a methylsulfol group, or an ethylsulfol. Group, propylsulfol group or isopropylsulfol group, more preferably a cyan group.

[l-2-b]

Examples of the substitution position of R ⁴ include an ortho position, a meta position, and a no position with respect to the carbon atom to which Z is bonded, and a para position is preferable.

[l-2-c]

R ⁴ is more preferably a cyano group bonded to the para position! /.

[13]

In the compound represented by the formula (I), R ⁵ is a hydrogen atom or a lower alkoxy group. R ⁵ is preferably a hydrogen atom, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, more preferably a hydrogen atom.

[l-3-b]

When R ⁴ is a lower alkoxy group, R ⁵ is a lower alkoxy group.

[14]

In the compounds of the formula (I), W is a group: NR ⁷

[1-5]

In the compound represented by the formula (I), R ⁷ is a lower alkyl group.

[1 5— a]

Preferably, R ⁷ is a methyl group or an ethyl group.

[1 6] Formula (Ila)

[Chemical 2]

(Wherein R ⁷ represents a hydrogen atom or a lower alkyl group, and R ¹ ′ may be mono- or di-substituted with a lower alkoxy carbo group or a lower alkyl group, but may be a protected rubermoyl group, A hydroxyl group which may be protected, a carboxyl group which may be protected, V which is protected, a lower alkyl group which is substituted with a hydroxyl group, a protected lower alkyl group which is substituted with a carboxyl group Or a tetrazolyl group, wherein R ⁴ ′ is a halogen atom, a lower alkyl group optionally substituted with halogen, a lower alkoxy group optionally substituted with halogen, a cyano group, a lower alkylthio group, or a lower alkylsulfinyl group. Or a lower alkylsulfol group, and R ⁵ ′ represents a hydrogen atom or a lower alkoxy group.), A pharmaceutically acceptable compound thereof Comprising at least one of a salt or a solvate thereof as an active ingredient, and Z or therapeutic agent, preferably prevention and treatment of chronic pain, Z or therapeutic agent, more preferably prevention of inflammatory pain including pain caused by rheumatoid arthritis / osteoarthritis and Z or therapeutic agent, postoperative pain Prophylactic and Z or therapeutic agent, diabetic pain · Preventive and z or therapeutic agent for neuropathic pain including postherpetic neuralgia, preventive and Z or therapeutic agent for cancer pain, or anti-allodynic agent.

[0028] According to the definition of the substituent in the compound of the formula (Ila) of formula 16, preferred U, the embodiment of the substituent is as follows.

[1 6— a]

In the compound represented by the formula (Ila), R ¹ ′ is a lower ruber alkoxyl group, a rubamoyl group optionally substituted mono- or di-substituted with a lower alkyl group, a hydroxyl group or a carboxyl group.

[1 6— a— 1]

Preferably, R ¹ ′ is a methoxycarbol group, an ethoxycarbol group, a strong rubamoyl group, a dimethylcarbamoyl group, a jetylcarbamoyl group or a carboxyl group, and more preferably a carboxyl group.

[1 6— a— 2]

Examples of the substitution position of R ¹ ′ include ortho, meta, and para positions with respect to the carbon atom to which —NR ⁷ is bonded, and the para position (the 4th position) is preferred.

[1 6— a— 3]

R ¹ 'is more preferably a carboxyl group bonded in the para position to the carbon atom to which —NR ⁷ is bonded! /.

[0029] [1 6— b]

In the compound represented by the formula (Ila), R ⁴ ′ is a halogen atom, a lower alkoxy group, a cyan group, a lower alkylthio group or a lower alkylsulfol group.

[1 6— b— 1]

Preferably, R ⁴ ′ is a fluorine atom, chlorine atom, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyano group, methylthio group, ethylthio group, propylthio group, isopropylthio group, methylsulfol group, ethylsulfo- Group, propylsulfol group, iso A propylsulfol group or a butylsulfol group is preferred, and a cyano group is more preferred.

[1 6— b— 2]

The substitution position of R ⁴ ′ is ortho, meta, or bonded to the carbon atom to which CH 2 CH— is bonded.

twenty two

La position is mentioned, and it is preferable that it is para position.

[1 6— b— 3]

R ⁴ ′ is more preferably a cyano group bonded to the para position.

[l -6-c]

In the compound represented by the formula (Ila), R ⁵ ′ is preferably a hydrogen atom, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, more preferably a hydrogen atom.

[l -6-c- l]

When R ⁴ ′ is a lower alkoxy group, R ⁵ ′ is a lower alkoxy group.

[l -6-d]

In the compound represented by the formula (Ila), R ⁷ is a lower alkyl group.

[l-6-d-l]

Preferably, R ⁷ is a methyl group or an ethyl group.

[1 7] Formula (lib)

[Chemical 3]

(Wherein R ⁷ represents a hydrogen atom or a lower alkyl group, and R ¹ ′ may be mono- or di-substituted with a lower alkoxy carbo group or a lower alkyl group, but may be a protected rubermoyl group, A hydroxyl group which may be protected, a carboxyl group which may be protected, V which is protected, or a lower alkyl group which is substituted with a hydroxyl group, which may be protected, R ⁴ ′ represents a halogen atom, a lower alkyl group optionally substituted with a halogen, a lower alkoxy group optionally substituted with a halogen, or a cyano group. Represents a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and R ⁵ ′ represents a hydrogen atom or a lower alkoxy group. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, and a preventive and Z or therapeutic agent for pain, preferably chronic Prevention and Z or treatment of pain, more preferably prevention and Z or treatment of inflammatory pain including pain caused by rheumatoid arthritis and osteoarthritis, prevention and Z or treatment of postoperative pain, diabetic Pain · Prevention and z or treatment of neuropathic pain, including postherpetic neuralgia, prevention and Z or treatment of cancer pain, or anti-allodynic agent.

[0031] According to the definition of the substituent in the compound of the formula (lib) of 7 is preferable! /, The embodiment of the compound is as follows.

[1 7-a]

In the compound represented by the formula (lib), R ¹ ′ is a lower alkoxycarbonyl group, a strong rubermoyl group which may be mono- or disubstituted with a lower alkyl group, a hydroxyl group or a carboxyl group.

[1 7-a-1]

[1 7— a— 2]

[1 7— a— 3]

[0032] [1 7— b] In the compound represented by the formula (lib), R ⁴ ′ is a halogen atom, a lower alkoxy group, a cyan group, a lower alkylthio group or a lower alkylsulfol group.

[l-7-b- l]

Preferably, R ⁴ ′ is a fluorine atom, chlorine atom, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyano group, methylthio group, ethylthio group, propylthio group, isopropylthio group, methylsulfol group, ethylsulfo- Group, propylsulfol group, isopropylsulfol group or butylsulfol group, more preferably a cyan group.

[1 7— b— 2]

twenty two

La position is mentioned, and it is preferable that it is para position.

[1 7— b— 3]

R ⁴ ′ is more preferably a cyano group bonded to the para position.

[l-7-c]

In the compound represented by the formula (lib), R ⁵ ′ is preferably a hydrogen atom, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, more preferably a hydrogen atom.

[l-7-c- l]

When R ⁴ ′ is a lower alkoxy group, R ⁵ ′ is a lower alkoxy group.

[l-7-d]

In the compound represented by the formula (lib), R ⁷ is a lower alkyl group.

[l-7-d- l]

Preferably, R ⁷ is a methyl group or an ethyl group.

[18] Examples of preferred compounds include

4— ({1— [2— (4 cyanophyl) ethyl) 3 hydroxypyrrolidine-3-ylmethyl} methylamino) benzoic acid;

4— ({1— [2— (4 fluorophenyl) ethyl] 3 hydroxyazetidine 3 ylmethyl} methylamino) methyl benzoate;

4— ({1— [2— (4 Fluorophenyl) ethyl] 3 Hydroxyzetidine 3 Rumethyl} methylamino) benzoic acid;

4- ({1- [2- (4-methylthiophenyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) methyl benzoate;

4 ({1 [2- (4-Methylthiopheyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid;

4— ({1— [2— (4 Methylsulfurylphenyl) ethyl] 3 hydroxyazetidine-3-ylmethyl} methylamino) methyl benzoate;

4— ({1— [2— (4 Methylsulfuolphenyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid;

4— ({1— [2— (3, 4 dimethoxyphenyl) ethyl)] -3 hydroxyazetidine-3-ylmethyl} methylamino) methyl benzoate;

4— ({1— [2— (3, 4 dimethoxyphenyl) ethyl)] -3 hydroxyazetidine-3-ylmethyl} methylamino) benzoic acid;

4— ({1— [2— (4 cyanophyl) ethyl) 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid;

4— ({1— [2— (4 cyanophyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} amino) benzoic acid tert-butyl;

4— ({1— [2— (4 Cyanophyl) ethyl) 3 hydroxyazetidine 3-ylmethyl} amino) benzoic acid

Alternatively, a prophylactic and Z or therapeutic agent for pain, preferably chronic pain, comprising at least one of a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. Prophylactic and Z or therapeutic agents, more preferably rheumatoid arthritisPreventive and Z or therapeutic agents for inflammatory pain, including pain caused by osteoarthritis, preventive and Z or therapeutic agents for postoperative pain, diabetic pain 'Preventive and Z or therapeutic agents for neuropathic pain, including postherpetic neuralgia, preventive and Z or therapeutic agents for cancer pain, or anti-allodynic agents.

More preferred is a compound having a azetidine ring, wherein R ^{1 in the} formula (I) is a carboxyl group bonded to the para position of A. For example, 4— ({1— [2— (4 fluorophenyl) ethyl] 3 hydroxyazetidine 3 ylmethyl} methylamino) benzoic acid;

4- ({1-[2- (4-Methylthiopheyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid;

4— ({1— [2— (4 Methylsulfurylphenyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid;

4— ({1— [2— (3,4 Dimethoxyphenyl) ethyl] -3 hydroxyazetidine-3-ylmethyl} methylamino) benzoic acid;

4 — ({1— [2— (4 cyanophyl) ethyl) 3 hydroxyazetidine 3-ylmethyl} amino) benzoic acid and the like.

[2]

A second aspect of the present invention is characterized in that it contains at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for pain caused by rheumatoid arthritis or osteoarthritis.

[3]

A third aspect of the present invention is characterized by containing as an active ingredient at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a preventive and Z or therapeutic agent for postoperative pain.

[Four]

A fourth aspect of the present invention is characterized by containing as an active ingredient at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof. , Prevention and Z or treatment of diabetic pain.

[Five]

The fifth aspect of the present invention contains at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and / or therapeutic agent for postherpetic neuralgia characterized by

[6]

A sixth aspect of the present invention is characterized by containing as an active ingredient at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof. , Prevention and Z or treatment of cancer pain.

[7]

A seventh aspect of the present invention is characterized by containing as an active ingredient at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof. It is an anti-allody agent.

[8]

An eighth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (Ila) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for pain caused by rheumatoid arthritis or osteoarthritis.

[9]

A ninth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (Ila) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for postoperative pain.

[Ten]

A tenth aspect of the present invention comprises at least one of the compound represented by the formula (Ila) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. , Prevention and Z or treatment of diabetic pain.

[11]

An eleventh aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (Ila) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for postherpetic neuralgia.

[12]

A twelfth aspect of the present invention is a compound represented by the formula (Ila), or a pharmaceutically acceptable A preventive and Z or therapeutic agent for cancer pain, comprising at least one of a salt thereof or a solvate thereof as an active ingredient.

[13]

A thirteenth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (Ila) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is an anti-allody agent.

[14]

A fourteenth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (lib) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for pain caused by rheumatoid arthritis or osteoarthritis.

[15]

A fifteenth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (lib) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for postoperative pain.

[16]

A sixteenth aspect of the present invention is characterized by containing as an active ingredient at least one of the compound represented by the formula (lib) or a pharmaceutically acceptable salt or solvate thereof. , Prevention and Z or treatment of diabetic pain.

[17]

A seventeenth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (lib) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for postherpetic neuralgia.

[18]

An eighteenth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (lib), or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. , Prevention and Z or treatment of cancer pain.

[19] A nineteenth aspect of the present invention is characterized in that it contains at least one of the compound represented by the formula (lib) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is an anti-allody agent.

In the second to nineteenth embodiments, in the compound represented by the formula (1), (Ila) or (lib), preferable substituents or combinations thereof are described in the first embodiment. .

[20]

In a twentieth aspect of the present invention, the compound according to the above aspect [1-8], or a pharmaceutically acceptable salt thereof, or a solvate thereof is contained as an active ingredient. It is characterized by the prevention and Z or treatment of pain caused by rheumatoid arthritis or osteoarthritis.

[twenty one]

A twenty-first aspect of the present invention contains at least one of the compound according to the above-mentioned aspect [1-8], or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. It is characterized by the prevention and Z or treatment of postoperative pain.

[twenty two]

A twenty-second aspect of the present invention contains at least one of the compound according to the above-mentioned aspect [1-8], or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is characterized by the prevention and Z or treatment of diabetic pain.

[twenty three]

A twenty-third aspect of the present invention contains at least one of the compound according to the above-mentioned aspect [1-8], or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. It is characterized by the prevention and Z or treatment of postherpetic neuralgia.

[twenty four]

A twenty-fourth aspect of the present invention is characterized in that it contains at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and Z or therapeutic agent for cancer pain.

[twenty five] A twenty-fifth aspect of the present invention contains at least one of the compound described in the above-mentioned aspect [1-8], or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a characteristic anti-allody agent.

The compound of the formula (I), the formula (Ila) or the formula (lib) (ligand of the sigma 1 receptor) used in each of the embodiments described in the above [1] to [25] of the present invention is:

(1) Sigma 1 receptor binding activity (for example, Experimental Example 1 described below)

Ki value ΙΟηΜ ~: LO μΜ, preferably 10ηΜ ~ 1 μΜ,

(2) Transferability to the brain (for example, Experimental Example 6 described later)

The ratio of brain concentration is 5% or less, preferably 3% or less,

(3) hERG channel inhibitory activity (for example, Experimental Example 8 described later), 10 / z M

50% or less inhibitory activity, preferably 50 μm or less at 30 μΜ, more preferably 50 μm or less at 100 μΜ,

It is preferable to use a compound that satisfies at least one of the following.

[26]

In a twenty-sixth aspect of the present invention, there is provided at least one of the compound (sigma 1 receptor ligand) used in the above-mentioned aspect [1-8], or a pharmaceutically acceptable salt thereof or a solvate thereof. Central side effects (eg, depressive action / abnormal behavior / hyperactivity etc.) are reduced (preferably substantially unaccompanied! / ヽ) for treating pain A pharmaceutical composition for the treatment of chronic pain, more preferably a pharmaceutical composition for the treatment of inflammatory pain including pain caused by rheumatoid arthritis and osteoarthritis, A pharmaceutical composition for the treatment of postoperative pain, a pharmaceutical composition for the treatment of neuropathic pain including post-herpetic neuralgia, a pharmaceutical composition for the treatment of cancer pain, or Physician for treatment of Alodiyu's symptoms An invention of the composition.

In the above-mentioned twenty-sixth aspect of the present invention, more preferably, each of the aspects described above is characterized in that the ligand or agonist is substantially free of hERG channel inhibition at a therapeutic dose for pain. It is. According to a twenty-seventh aspect of the present invention, there is provided a compound (sigma 1 receptor ligand) or a pharmaceutically acceptable salt thereof used in each of the aspects described in the above [1] to [25]. A method for the prevention and / or treatment of pain, characterized in that at least one effective dose of is administered to a patient.

Rheumatoid arthritis that is preferably chronic pain · Inflammatory pain including pain caused by osteoarthritis, postoperative pain, diabetic pain, postherpetic neuralgia More preferably, it is neuropathic pain, cancer pain, or alodia.

[28]

According to a twenty-eighth aspect of the present invention, there is provided a compound (sigma) used in each of the aspects described in the above [1] to [25] for producing a medicament for the prevention and Z or treatment of pain. 1 receptor ligand). Rheumatoid arthritis, which is preferably chronic pain, inflammatory pain including pain caused by osteoarthritis, postoperative pain, diabetic pain, neuropathic pain including postherpetic neuralgia, More preferably cancer pain, or alodynia!

[29]

A thirty-ninth aspect of the present invention is characterized in that (1) the ability to enter the brain is extremely low (2) a strong ligand of sigma 1 receptor (preferably a strong agonist of sigma 1 receptor) is used as an active ingredient Centralized side effects (such as depressive action, abnormal behavior, hyperactivity, etc.) with reduced (preferably substantially unrelated wrinkles) pain prevention and Z or therapeutic agents, preferably chronic pain prevention and Z or therapeutic agent, more preferably, rheumatoid arthritis · prevention of inflammatory pain including pain caused by osteoarthritis and Z or therapeutic agent, postoperative pain prevention and Z or therapeutic agent, diabetic pain · herpes It is an invention of a preventive and Z or therapeutic agent for neuropathic pain including post-neural neuralgia, a preventive and Z or therapeutic agent for cancer pain, or an anti-alodia agent.

In other words, the twenty-ninth aspect of the present invention uses (1) a remarkably low ability to enter the brain (2) a strong ligand of sigma 1 receptor (preferably a strong ligand of sigma 1 receptor). Thus, a method for preventing and / or treating pain in mammals, particularly patients, with reduced (preferably substantially no) central side effects. Alternatively, in the twenty-ninth aspect of the present invention, the centrality of (1) a remarkably low ability to enter the brain (2) a strong ligand of sigma 1 receptor (preferably a strong sigma 1 receptor ligand) Use in the manufacture of a medicament for the treatment of pain with reduced (preferably substantially unaccompanied! /,) Side effects.

In the above-mentioned twenty-ninth aspect of the present invention, more preferably, each of the above-described aspects is characterized in that the ligand or agonist is substantially free of hERG channel inhibition at a therapeutic dose for pain. It is.

Here, (1) “remarkably low ability to enter the brain” is defined as satisfying one or more properties, more preferably two or more properties, of the following parameters 1) to 4).

1)

In vitro blood-brain barrier (BBB) permeability (a) is remarkably low. Specifically, the method is based on the method of Wang et al. (Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier: International Journal of Pharmaceutics 288 (2005) 349-359). , MDR in drug permeability test for CNS migration evaluation using MDCK model of a drug Papp (A- B) value of less than 5 X 10- ⁶ cmZs, more preferably 3 X 10 ^"6 cmZs less, more preferably, to exhibit a value of less than 1 X 10- ⁶ cm / s.

2)

In vitro blood-brain barrier (BBB) permeability (b) is extremely low. Specifically, Stefan et al. (Prediction of Drug Transport tnrough the Blood-Brain Barrier in ivo: A Com parison between Two in Vitro Cell Models: Pharmaceutical Research, Vol. 19, No. 7, July (2002) 976- 981), the ln [Pe X MW] value is — 7.5 cmZs in the pseudo BBB model system based on the coculture of brain capillary end othelial cells and astrocytes. Below, more preferably -8 or less. Alternatively, less than Pe value 2 X 10- ³ cm / min, more preferably it takes a value less than 1 X 10- ³ cm / min.

3)

In vivo blood-brain barrier (BBB) permeability (c) is extremely low. Specifically, it must be less than the value of ln [BUI X MW] calculated according to the report by Stefan et al. Four)

In vivo blood-brain barrier (BBB) permeability (d) is extremely low. Specifically, the ratio of the brain concentration to the plasma concentration of the drug in the test animal or human is 5% or less, preferably 3% or less. The concentration ratio can be calculated using, for example, the technique shown in Experimental Example 6 described later.

In addition, (2) “a strong ligand of sigma 1 receptor (preferably a strong ligand of sigma 1 receptor)” is defined as satisfying the properties of the following parameters. That is, in the case of sigma 1 receptor binding activity (for example, Experimental Example 1 described later), the Ki value is M or less, preferably 1 μΜ or less, 1 μΜ to 10ηΜ, or ΙΟηΜ or less. Also good.

Furthermore, in the twenty-ninth aspect of the present invention, as a more preferred aspect, “the ligand or agonist is used at a therapeutic dose for pain which is substantially free of hERG channel inhibition” is used. A certain force This is hERG channel inhibitory activity (for example, Experimental Example 8 to be described later), 10 μΜ less than 50% inhibitory activity (ie, IC ≥1 μΜ),

50

Preferably 30 μΜ with 50% or less inhibitory activity (IC ≥30 ^ M), more preferably

50

Defined as a compound that exhibits 50% or less inhibitory activity (IC ≥ 100 M) at 100 M

50

It is.

In addition, the Magnus test using the guinea-pig vas deferens, for example, the method of Vaupel et al. (“Eurbian 'Journal' of 'Falma Collodi", 1987, 289, p251-260) It is possible to determine whether the ligand is an antagonist by checking the function of the body ligand.

In all of the above embodiments, when the term “a compound” is used, “the pharmaceutically acceptable salt” is also referred to. In addition, the compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers, optical isomers, and isolated compounds. It is. Powerful stereoisomers can be isolated and purified by those skilled in the art using conventional techniques through optical resolution or asymmetric synthesis using column chromatography once the preferential crystals are obtained.

The compounds of formula (1), formula (Ila) and formula (lib) of the present invention may form acid addition salts. Depending on the type of substituent, a salt with a base may be formed. As a powerful salt, Although it is not particularly limited as long as it is a pharmaceutically acceptable salt, specifically, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, propion Acids, butyric acid, valeric acid, enanthic acid, strong puric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, mandelic acid and other aliphatic monocarboxylic acids, benzoic acid, salicylic acid and other aromatic monocarboxylic acids Organic powers such as aliphatic dicarboxylic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acid such as citric acid; methanesulfonic acid, ethanesulfonic acid , Aliphatic sulfonic acids such as 2-hydroxyethanesulfonic acid, organic sulfonic acids such as benzenesulfonic acid, aromatic sulfonic acids such as p-toluenesulfonic acid; asparagine Acid addition salts with acidic amino acids such as acid and glutamic acid, and salts with alkali metals or alkaline earth metals such as sodium, potassium, magnesium, calcium and aluminum, methylamine, ethylamine, ethanolamine, pyridine , Salts with organic bases such as lysine, arginine and ortin, and ammonium salts.

These salts can be obtained by a conventional method, for example, by mixing an equivalent amount of the compound of the present invention with a solution containing the desired acid or base, and collecting the desired salt by filtration or distilling off the solvent. wear. In addition, the compounds of formula (1), formula (IIa) and (lib) of the present invention or salts thereof can form solvates with solvents such as water, ethanol and glycerol.

Further, the salt of the formula (1), the formula (Ila) and the formula (lib) of the compound of the present invention includes a mono salt and a di salt. Alternatively, the compounds of the formulas (1), (Ila) and (lib) of the present invention can form both an acid addition salt and a base salt at the same time depending on the side chain substituent.

Furthermore, the present invention includes hydrates of compounds represented by formula (1), formula (Ila), and formula (lib), various pharmaceutically acceptable solvates, and polymorphs. . Of course, the present invention is not limited to the compounds described in the examples below, but the compounds represented by formula (1), formula (IIa), (lib) or pharmaceutically acceptable All salts are included.

[Method for producing compound of the present invention]

Hereinafter, a method for producing the compounds of formula (1), formula (Ila) and formula (lib) used in the present invention will be described.

The compounds of formula (1), formula (Ila), formula (lib) of the present invention, pharmaceutically acceptable salts thereof and These solvates can be produced by a production method described in International Publication No. 2004Z048326 pamphlet, pages 29-43, or a method analogous thereto. Compounds represented by Formula (VII) of Reaction Scheme 1 on page 30 of the publication, for example, tert-butyl 4 [(3 hydroxypyrrolidine 3-ylmethyl) methylamino] benzoate (Step 4 of Example 8 of the publication), Or 4-[(3-hydroxyazetidine-3-ylmethyl) methylamino] methyl benzoate (step 5 of Example 10 of the publication) and the like as a raw material to react with the compound represented by formula (VIII) Can be manufactured.

(1) Remarkably little ability to enter the brain (2) A strong ligand of sigma 1 receptor (preferably a strong ligand of sigma 1 receptor) according to the 29th aspect of the present invention, It is possible to select by this method.

For example, (1) a ligand (preferably a compound) having “remarkably low ability to enter the brain” is used for one or more of the parameters using the test methods 1) to 4) described in the 29th aspect of the present invention. It is possible to select a target ligand by selecting one that satisfies the above properties, more preferably two or more properties.

In addition, (2) “a strong ligand of sigma 1 receptor (preferably a strong ligand of sigma 1 receptor)” is, for example, the sigma 1 receptor binding activity of Experimental Example 1 described below. The target ligand can be selected by selecting one having a Ki value of 10 / z M or less, preferably 1 / ζ Μ to 10ηΜ, or ΜηΜ or less.

Furthermore, in the twenty-ninth aspect of the present invention, as a more preferred aspect, “the ligand or agonist is used at a therapeutic dose for pain which is substantially free of hERG channel inhibition” is used. This is, for example, the hERG channel inhibitory activity of Experimental Example 8 to be described later, and the inhibitory activity of 50% or less at 10 μΜ (that is, IC ≥ 10 Μ), preferably

50

Has an inhibitory activity of 50% or less at 30 μΜ (IC ≥30 M), more preferably 100 μ

50

The purpose is to select those that exhibit 50% or less inhibitory activity (IC ≥ 100 μΜ)

50

It is possible to select one of the ligands.

In addition, the Magnus test using the guinea pig vas deferens, for example, the method of Vaupel et al. (“Eurbian 'Journal' of 'Falma Collodi", 1987, No. 289, p251-260) Confirm the function of body ligands Can be determined to be an antagonist.

[0041] [Pharmacological experiment example]

The ability to specifically explain the present invention by giving experimental examples below The present invention is not limited by these.

[Radioligand binding assay of human sigma 1 receptor using membrane fraction]

Ganapathy et al. ( "The journal O blanking Pharmacology and Ekusuperi Mentanore Sefupyu ¹ ~ ~ Aikusu,丄, he Journal of Pharmacology and Experimen tal Therapeutics) ", (the United States), 1999, 289 Certificates, p. 251- 260 ) In other words, in a 5 OmM Tris'HCl buffer solution (pH 7.5) containing the membrane fraction prepared from Jurkat cells expressing the human sigma 1 receptor, the final concentration of 6. OnM tritium labeled (+)-pent azocine and the test The buffer containing the compound was prepared and incubated at room temperature for 120 minutes. Next, it was filtered through a Multiscreen—FC plate (Millipore) pretreated with 0.5% polyethyleneimine, then washed three times with ice-cold washing solution, and the radioactivity bound to the filter with a single scintillation counter. Was measured. Nonspecific binding was calculated by adding lO ^ MOhaloperidol. Then, the inhibition rate of the test compound against the binding of the label to the sigma 1 receptor was determined. As a result, the binding activity of the compound of Example 12 to the human sigma 1 receptor was 0.7 M in Ki value.

In addition, the compound of Example 12 was prepared by the method of Vaupel et al. (“Eurbian 'Journal' of Boar McCoroji”, 1987, 289, p251-260), that is, a general sigma 1 receptor ligand. A Magnus test using the guinea pig vas deferens, a method for confirming the function, confirmed that it was an agonist. This agonist activity was inhibited by Sigma 1 Antagonist.

When the compound of formula (I) of the present invention is measured for the sigma 1 receptor binding activity by the above method, the Ki value shows an intensity of ΙΟηΜ˜: L0 μΜ, preferably 10ηΜ˜1 μΜ.

[0042] <Experimental example 2>

[Efficacy in rat spinal nerve ligation model (Chang model)]

Kim et al. (“Pain”, (USA), 1992, 50th, p. 355—36 A spinal nerve ligation model was prepared according to 3). In other words, rats were anesthetized by intraperitoneal administration of pentobarbital sodium 50 mg Zkg, skin incision was performed on the dorsal midline, incision was made along the spinous spinous process, and finally the fifth and sixth lumbar spinal nerves were detached. . The fifth and sixth lumbar spinal nerves were ligated with 6-0 silk thread, and the surgical site was sutured back to the breeding cage for breeding. In the sham operation group, the same treatment was performed until the spinal nerve was removed.

The pain reaction was performed according to the method of Seltzer et al. (“Pain”, (USA), 1990, 43rd, p. 205-218). In other words, the test was performed after a rat that had passed 2 weeks or more after the operation was placed on a stainless steel mesh floor, covered with a plastic cover, and fully accustomed. 1, 2, 3 and 4 hours after the oral administration of the compound of Example 12, von Frey filaments (Stoelting) of various strengths were pressed into the foot of the rat for 3 seconds at a frequency of 2 times per second in order from the weakest. Tactile stimulation was applied by applying. The pressure applied when the rat quickly pulled the hind limb was taken as the reaction threshold. The cut-off value was set at 28.84g.

[0043] Statistical analysis was performed by the following method, that is, the reaction threshold and the maximum reaction threshold were obtained. Statistical analysis was performed using Yukms StatLight (Yukms) and the non-parametric Dunnett's multiple comparison method for the difference in the average maximum response threshold. The results are shown in FIG. 1. As a result, the compound of Example 12 increased the threshold for nerve injury in a dose-dependent manner. In contrast, the threshold of normal limbs did not change.

The analgesic action of the compound of Example 12 shown in this experiment was abolished by the administration of Sigma 1 antagonist.

[0044] <Experimental example 3>

[Efficacy in rat STZ-induced diabetic pain model]

An STZ-induced diabetic pain model was created according to the method of Field et al. ("Pain", (USA), 1999, 80th, p. 391-398). That is, streptozocin (STZ) was intraperitoneally administered to rats at a dose of 50 mgZkg, and after 2 weeks, the blood glucose level was measured and rats with onset of 200 mgZdL or more were selected. The reaction threshold for mechanical stimulation was measured using von Frey filament in the same manner as in Experimental Example 2. 1, 2, 3, 4 hours after oral administration of the compound of Example 12 to diabetic rats, The filaments were pressed against the sole (center) in descending order of strength, and the strength that showed elevation reaction was taken as the reaction threshold. The cut-off value was 28.84 g. The compound of Example 12 increased the pain threshold of the hind limbs of STZ-induced diabetic rats in a dose-dependent manner, and the maximum response threshold of the injured limb by oral administration of 3, 10, and 30 mg Zkg was 1.90 g 3.70 g, 4 respectively 17g, 5. Raised to 03g.

Pregaparin used as a control substance increased the maximum reaction threshold of injured limbs from 2.21 g to 4.54 g by oral administration of lOmgZkg.

[0045] <Experimental example 4>

[Effectiveness in rat acetate rising test]

A rat rising test was performed to evaluate the effect on inflammatory pain. That is, a rat was given a 3% (v / v) acetic acid solution 1 hour after oral administration of the compound of Example 12.

The intraperitoneal administration was performed at a volume of 2 mLZkg, and the number of riding reactions that occurred during the 30-minute observation period was measured. As shown in FIG. 2, the compound of Example 12 suppressed the number of rising reactions by oral administration of lOmgZkg.

[0046] <Experimental example 5>

[Effectiveness in rat carrageen-induced pain test]

All experiments were performed in accordance with the ethical rules described in the International Association for the Study of Pain (Zimmermann, M., 1983. Pain 16 卷, p. 109). Five-week-old male Wistar rats were purchased from Japan SLC and bred in a room maintained at a room temperature of 21-25 ° C, a humidity of 45-55%, and a 12-hour day / night cycle. During the habituation period, they were allowed to feed and drink freely. The animals were tested at 6 weeks of age and fasted for at least 18 hours from the day before the measurement.

The test substance was dissolved or suspended in a 2% concentration of carboxymethylcellulose Na (Wako Pure Chemicals) solution, and orally administered to rats in a volume of lOmLZkg. One hour after administration of the compound of Example 12, 0.1 mL of force ragenin (Zushi Chemical) physiological saline suspended in lwZv% was subcutaneously administered to the right hind footpad of the animal to induce inflammation. The analgesic action of the test substance is the Randall-Selitto method (Randall, LO and Selitto, JJ, 1957. Arch. Int. Pharmacod yn, 111 卷, page 409). That is, pressure stimulation was applied to the right hind leg of rats 3 to 4 hours after administration of force-ragenin using an Analgesy meter (TK-201, Ucom), and the pressure when the animal caused the limbs to be pulled out was determined as the pain threshold. As measured. In this model animal, the compound of Example 12 increased pain threshold in a dose-dependent manner by oral administration of 10 to 100 mgZkg, and showed analgesic action. The results are shown in FIG.

[0047] <Experimental example 6>

[Brain migration test]

The following test was conducted in order to measure the migration of the compound of Example 12 into the brain. That is, the compound of Example 12 was orally administered to fasted SD rats (Japan SLC, OS, 6 weeks old) at a dose of 300 mgZkg, and rat plasma concentrations and brains at 30 minutes, 1 hour, and 2 hours after administration. The internal concentration was measured. The plasma concentration was measured as follows. In other words, abdominal aortic force was collected at each time point, plasma was obtained by centrifugation, diluted with a phosphate buffer containing an internal standard, extracted with ethyl acetate, and LC / MS / MS was used for internal standard method. It was measured. The brain concentration was as follows. That is, at each time point, after blood collection, the whole body was perfused with physiological saline containing heparin, the brain was removed, and the hippocampus was separated. These hippocampus were collected, methanol containing an internal standard substance was added to each, homogenized with Hiscotron (Nisshin Medical Science Instrument Co., Ltd.), and the centrifuged supernatant was analyzed by LC / MS / MS using the internal standard method. It was measured. As a result, the ratio of the brain concentration to the plasma concentration of the compound of Example 12 at each collection time was 1 to 2%. At the same time, the strength of the general symptom showed no abnormality, indicating the low toxicity of the compound of formula (I) of the present invention.

When the compound of formula (I) of the present invention is measured for its ability to migrate into the brain by the above method, the ratio of the brain concentration to the plasma concentration is 5% or less, more specifically 3% or less.

In addition, the measurement of intracerebral migration can also be performed using the in vitro test 1) or 2) described in the 29th aspect of the present invention or the in vivo test 3).

[0048] <Experimental example 7>

[Rota Rod test]

A rota-rod device (7750, for rat, with acceleration device) manufactured by Ugo- Basile was used. Rat Was placed on the bar of the apparatus, and the residence time was measured in the acceleration mode. The upper limit was set to 600 seconds. Two trials were conducted in the morning of the test day, and the groups were grouped based on the average residence time. Two trials were performed 3 hours after the oral administration of the drug, and the average value of the residence time was used as data.

Statistical analysis was performed by the following method. The average rota-rod residence time and standard error were determined for each group. Statistical analysis was performed using Yukms StatLight, and mean difference tests were performed using Dunnett's multiple comparison method. As a result, the compound of Example 12 was orally administered up to a dose of 3 OOmgZkg, but at any time, the effect on the residence time was not recognized. In contrast, pregaparin shortened the residence time at doses of 10 and 30 mg / kg.

[0049] <Experimental example 8>

[Measurement of hERG inhibitory activity]

(l) hERG inhibition test with Rb efflux

hERG (human ether-a-go-go) -expressing HEK cells were seeded in a 96-well plate and incubated for about 24 hours. After washing with the washing buffer and removing the medium, K + channel open buffer containing the test substance (the compound of the present invention) was added and incubated at 37 ° C for 3 hours. Next, it was replaced with Rb + Load buffer containing the test substance, and further incubated at 37 ° C for 3 hours to incorporate Rb + into the cells. Next, after washing with a washing buffer containing the test substance, K + channel open buffer containing the test substance was added and incubated at 37 ° C for 5 minutes to release intracellular Rb + out of the cell. . After collecting the supernatant on another plate, the cells were lysed, and the cell lysate was collected on another plate. The content of Rb + contained in the supernatant and cell lysate was measured, and the hERG inhibition rate was calculated. Table 1 shows the inhibition rate (%) of the test substance (100 M). In the results of this test, the compound of the formula (I) of the present invention had an inhibition rate of 50% or less at 100 μ μ.

[0050] [Table 1] table 1

[0051] (2) hERG inhibition test by whole cell patch clamp method

The effect of hERG (human ether—a—go—go related gene) against cheeks was measured by the whole cell patch clamp method. R to confirm the hERG I current in the cell

Periodic depolarization pulses were applied with the membrane potential held at -80 mV. After the generated current stabilized, the test substance was added to the perfusate. The effect of the test substance on the hERG channel was confirmed by a change in tail current induced by a +20 mV, 4.8 second depolarization pulse — a 50 mV, 5 second repolarization pulse. Stimulation was performed once every 15 seconds. The measurement was performed at room temperature. In comparison of hERG channel inhibitory activity, the reduction rate (inhibition rate) of tail current after application (10-15 minutes later) to tail current before test substance application was used as an index. As a result, the inhibitory activity of the compound of Example 12 was 50% or less even at a dose of 100 / zM.

[0052] Gu Experiment 9>

[Toxicity test]

When males of Wistar rats were orally administered the compounds of Examples 2, 4, 6, 8, and 12 with lOmgZKg, no abnormalities were observed in general symptoms, and no deaths were observed.

[0053] From the above results, the compound of the formula (I) of the present invention has an analgesic effect in a rat spinal nerve ligation model (Chan model), a rat STZ-induced diabetic pain model, a rat acetate rising test, and a force ragenin-induced pain model. Therefore, the compound of the formula (I) of the present invention can be used for various pains, especially chronic pain, more specifically, inflammatory pain including pain caused by rheumatoid arthritis and osteoarthritis, postoperative Pain or visceral pain, diabetic painNeuropathic pain including postherpetic neuralgia, prevention and Z or treatment of cancer pain It has been shown to be effective as a therapeutic agent or a therapeutic agent for symptoms such as alodysia.

In addition, the compound of the formula (I) of the present invention exhibits sigma 1 receptor binding activity in vitro, and the analgesic action in the neuropathic pain model of in vivo disappears with the sigma 1 receptor antagonist. Therefore, it shows an analgesic effect through the sigma 1 receptor.

Further, it has been clarified that the compound of the formula (I) of the present invention has a low ability to enter the brain and does not exhibit a central action unlike the conventional sigma 1 receptor ligand. From this result, it was shown that the compound of the formula (I) of the present invention is a sigma 1 receptor ligand acting on peripheral tissues, unlike the conventional centrally migrating sigma 1 receptor ligand.

Furthermore, since the compound of formula (I) of the present invention does not inhibit hERG inhibitory activity even at a dose of 100 / z M, QT prolongation by drugs and subsequent fatal side effects (ventricular tachycardia suddenly) Death etc.) is very unlikely to induce. Further, since no abnormality was observed in the toxicity test, the extremely low toxicity of the compound of the formula (I) of the present invention was shown.

Therefore, the compound of the formula (I) of the present invention is a sigma-1 ligand that acts on peripheral tissues with low ability to enter the brain, and has an excellent analgesic effect in animal models such as inflammatory pain and neuropathic pain. Excellent pain prevention and Z or therapeutic agent, especially chronic pain prevention and Z, because it has high safety and low risk of causing side effects on the heart. Or therapeutic agents, and more particularly, prevention and Z or treatment of inflammatory pain including pain associated with rheumatoid arthritis and osteoarthritis, or prevention and postoperative pain prevention and Z or treatment, prevention of visceral pain and Z or therapeutic agent, diabetic pain, prevention and treatment of neuropathic pain including postherpetic neuralgia, z or therapeutic agent, prophylactic and prevention of cancer pain, Z or therapeutic agent, or anti-alodial agent .

(1) Remarkably little ability to enter the brain of the present invention (2) A strong ligand of sigma 1 receptor (preferably a strong ligand of sigma 1 receptor), more specifically the above formula (I) The compounds represented by are not limited to those that can be used for pain associated with the following specific diseases. For example, acute pain includes pain associated with acute herpes zoster, cholelithiasis, urolithiasis, testicular torsion, ovarian torsion, dysmenorrhea (menstrual pain), and the like. Also nociceptive pain In recent years, as inflammatory pain included in chronic pain, breast pain, etc., shoulder periarthritis, stomach, duodenal ulcer, knee inflammation, appendicitis, prostatitis, osteoarthritis, arthritis , Rheumatoid arthritis, postoperative pain, sunburn, atopic dermatitis, etc .; neuropathic pain includes postherpetic neuralgia, spinal cord injury, trigeminal neuralgia, glossopharyngeal neuralgia, Atypical facial pain, etc., or peripheral neuropathy (e.g., reflex sympathetic dystrophy (RSD)), causalgia, reflex sympathetic neuropathy, genital herpes, low back pain-europathy, diabetic- Pain associated with europathy, etc .; in addition, pain associated with cancer pain, migraine, cluster headache, or irritable bowel syndrome, osteoporosis, herniated disc, gout, etc. Examples of psychogenic pain include pain associated with chronic fatigue syndrome, fibromyalgia and the like.

In addition, acute pain is also a pain with chronic pain therapy, lower limb pain, headache, facial pain, eye pain, ear pain, toothache, neck and shoulder pain, chest wall pain, chest pain, visceral pain, anal pain, low back pain, hand and foot pain, Pain associated with systemic pain, muscle 'fascia pain, hallux valgus, carpal tunnel syndrome, tender syndrome etc. can be mentioned. (1) Significantly less intracerebral transfer of the present invention (2) Sigma 1 receptor The body's strong ligand (preferably a strong sigma 1 receptor agonist), more specifically the compound of formula (I), can be used for these pains.

It can also be used for the purpose of preventing or inhibiting the worsening of symptoms over time in the above-mentioned diseases accompanied by chronic pain.

Furthermore, (1) the ability of the present invention to move into the brain is remarkably low (2) a strong ligand of sigma 1 receptor (preferably a strong agonist of sigma 1 receptor), more specifically, the above formula (I) The compound represented by can also be used for prophylactic treatment by administration before surgery. That is, if the propagation of nerve action potentials is blocked with a local anesthetic before surgery and acupuncture noxious stimuli are applied, pain will not increase even if continuous noxious stimuli such as surgery are applied. These pre-operative treatments are useful because they can reduce the dose of post-operative analgesics. (1) Significantly less intracerebral transfer (2) Strong sigma 1 receptor A ligand (preferably a strong ligand of the sigma 1 receptor), more particularly a compound of formula (I) The compound has symptoms such as hyperalgesia (a phenomenon that reacts excessively to noxious stimuli), alodynia (a state that feels just as if it is lightly touched), and spontaneous pain (nothing! It is also effective for the pain diseases shown.

Furthermore, (1) the ability of the present invention to move into the brain is remarkably low. (2) A strong ligand of sigma 1 receptor (preferably a strong ligand of sigma 1 receptor), more specifically the above formula (I) The compound represented by can be used not only for painful diseases but also for itchy diseases and irritable bowel syndrome. In addition, since the compound of the present invention does not pass through the blood-brain barrier, there is no fear of side effects in the center, but cerebral infarction acute phase, cerebral hemorrhage, transient cerebral ischemia, subarachnoid hemorrhage, head injury, brain When cerebrovascular disorders such as sequelae of surgery and sequelae of cerebral arteriosclerosis occur, the permeability of the blood-brain barrier is enhanced only in the affected area, so that the compound of the present invention does not affect other brain tissues. Since it can reach the affected area transiently, it can also be used for these diseases. (1) Remarkably little ability to enter the brain of the present invention (2) A strong ligand of sigma 1 receptor (preferably a strong ligand of sigma 1 receptor), more specifically the above formula (I) The compound represented by the formula (1) contains, as an active ingredient, a ligand of the sigma 1 receptor that has a low ability to enter the brain and acts specifically on peripheral tissues, and more specifically, a specific derivative having a pyrrolidine ring or a azetidine ring. The present invention relates to a preventive and Z or therapeutic agent for pain characterized by. At least a sigma-1 receptor ligand, particularly a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, which has a low ability to enter the brain and acts specifically on peripheral tissues. Prophylactic and Z or therapeutic agent for pain, characterized by containing as an active ingredient, in particular, prophylactic and Z or therapeutic agent for chronic pain, more particularly rheumatoid arthritis-pain caused by osteoarthritis Prevention and Z or treatment of inflammatory pain, including postoperative pain prevention and Z or treatment, diabetic pain and postherpetic neuralgia prevention and Z or treatment, cancerous It can be used as a prophylactic and Z or therapeutic agent for pain, or as an anti-allody agent.

The compound of the present invention can be used in combination with other drugs. For example, in addition to gabapentin, antidepressants such as pregaparin or amitriptyline; antidepressants such as carbamazepine and feutoine; antiarrhythmic drugs such as mexiletine, etc. Is mentioned. Gabapentin or pregaparin is preferable. When the compound of the present invention is used in combination with a drug used in combination, it may be a separate preparation or a combination. In separate preparations, both can be taken at the same time or can be administered at different times.

The medicament of the present invention is administered in the form of a pharmaceutical composition.

The pharmaceutical composition of the present invention comprises at least one of the compounds represented by the formula (1), the formula (Ila) or the formula (lib) of the present invention, and may be a pharmaceutically acceptable additive. It is made in combination with. More specifically, excipients (eg, lactose, sucrose, mannitol, crystalline cellulose, silicate, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polybulurpyrrolidone (PVP), macrogol, Polybulal alcohol (PVA)), lubricants (eg; magnesium stearate, calcium stearate, talc, carboxymethyl cellulose), disintegrants (eg; starches (corn starch, potato starch), strength ruboxymethyl starch natto Um, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer Ε, methacrylic acid) Copolymer LD), plasticizers (eg triethyl taenoate, macrogol), masking agents (eg acid titanium), colorants, flavoring agents, preservatives (eg salt benzalcoum, paraoxybenzoate) Acid esters), tonicity agents (eg; glycerin, sodium chloride, salt calcium, mannitol, glucose), rhodium regulators (eg, sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, Buffer solution such as sulfuric acid and phosphate buffer solution), stabilizer (eg, sugar, sugar alcohol, xanthan gum), dispersant, acid Antioxidation agents (eg, ascorbic acid, butyrylhydroxyl-sol (ΒΗΑ), propyl gallate, dl-a-tocopherol), buffering agents, preservatives (eg; paraben, benzyl alcohol, salt benzalkol) ), Fragrance (eg, vanillin, tomenthol, rose oil), solubilizer (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine, gelsia, hydroxypropyl methylcellulose ( HPMC)), absorption enhancers ( Examples; sodium glycolate, sodium edetate, strength sodium phosphate, acylcar-tins, limonene), gelling agents, suspending agents, or emulsifiers, commonly used suitable additives or solvents Thus, various dosage forms can be obtained by appropriately combining with the compound of the present invention.

[0058] Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, troches, liquids, spirits, suspensions Suspending agents, extract agents, elixirs and the like. Oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.

The dose of the compound of the present invention is usually 0.005 mg to 3. Og per day for an adult, preferably 0.05 mg to 2.5 g, more preferably 0.1 mg to 1.5 g depending on the symptoms or route of administration. It can be increased or decreased as appropriate.

The entire dose can be administered orally or parenterally in 1 or 2-6 doses, or it can be administered continuously, such as intravenous infusion.

Formulation example

[0059] The following are examples of the pharmaceutical composition of the present invention.

[Table 2] Formulation Example 1 Tablet

Compound of Example 2 1 0 0 g

Lactose 1 3 7 g

Crystalline cellulose 30 g

Hydroxypropinoresenorelose 1 5 g

Sodium carboxymethyl starch 15 g

Magnesium stearate Weigh the above ingredients and mix uniformly. This mixture is compressed into tablets with a weight of 150 mg.

[0060] [Table 3] Formulation Example 2 Film coating

Hydroxypropyl methylenocellulose 9 g

Macrogolf 6 0 0 0 1 g

Titanium oxide 2 g After weighing the above ingredients, dissolve hydroxypropylmethylcellulose and Macrogol 6000 in water and disperse the titanium oxide. This solution is film coated on 300 g of the tablets of Preparation Example 1 to obtain film-coated tablets.

[0061] [Table 4] Formulation Example 3 Capsule

Compound of Example 4 50 g

Lactose 4 3 5 g

Magnesium stearate 15 g The above ingredients are weighed and mixed uniformly. Fill the mixture into appropriate hard capsules with a weight of 300 mg in a capsule container to make capsules.

[0062] [Table 5] Formulation example 4 capsules

Example 2 Compound

Lactose

Tomorrow starch

Hydroxypropinoresenorelose

Talc After weighing the above components, the compound of Example 2, lactose, and corn starch are uniformly mixed, and an aqueous solution of hydroxypropylcellulose is prepared, and granules are produced by wet granulation. Talc is mixed uniformly into these granules, and 200 mg in weight is filled into appropriate hard capsules to make capsules.

[0063] [Table 6] Formulation Example 5 Powder

Example 1 0 Compound 2 0 0 g

Lactose 7 9 0 g

Magnesium stearate 10 g Weigh each of the above components and mix uniformly to make a 20% powder.

[0064] [Table 7]

Formulation Example 6 Granules, fine granules

Compound of Example 8 1 0 0 g

Lactose 2 0 0 g

Crystal Senor Mouth-1 0 0 g

Part c Hi starch 5 0 g

Hydroxypropylcellulose 5 0 g

After weighing the above components, the compound of Example 8, lactose, crystalline cellulose, and e mosquito卩part _α of Den Pung were uniformly mixed, Karoe an aqueous solution of hydroxypropyl cellulose (HPC), by a wet granulation granules Or produce fine granules. The granules or fine granules are dried to form granules or fine granules.

Example

Next, the power to give examples in order to describe the present invention in more detail. The present invention is not limited to this.

Nuclear magnetic resonance spectrum (NMR) is measured by Geol JNM—ΕΧ270 (JEOLJNM—ΕΧ270) FT-NMR (manufactured by JEOL Ltd.) or Giol JNM—LA300 (JEOLJNM-LA30 0) FT-NMR (manufactured by JEOL Ltd.) Infrared absorption spectrum (IR) using HORIBA FT-720 (manufactured by Horiba, Ltd.) and melting point using Mettler FP900 thermosystem (manufactured by METTLER TOLEDO) It was measured.

[0066] (Example 1)

4— ({1— [2— (4-Cyanophyl) ethyl)] 3-Synthesis of 3-Hydroxypyrrolidine-3-methylamino) benzoic acid

The title compound was obtained by the method described in Example 14 of WO 2004Z048326 pamphlet. The physical property values agreed with the values described in the pamphlet of the same issue.

[0067] (Example 2)

4— ({1— [2— (4-Cyanophyl) ethyl)] — 3-Hydroxypyrrolidine-1-3-methylmethyl) benzoic acid monohydrochloride synthesis

Example 1 in the same manner as Example 29 of the pamphlet of WO 2004Z048326 To give the title compound. The physical property values agreed with the values described in the pamphlet.

[Example 3]

4— ({1— [2— (4 Fluorophenyl) ethyl] 3 hydroxyazetidine 3 ylmethyl} methylamino) Synthesis of methyl benzoate

4-([3-Hydroxyzetidine 3-ylmethyl) methylamino] methyl benzoate monohydrochloride (550 mg) and 4-fluorophenylacetaldehyde (358 mg) were added with dichloromethane (15 mL), and triacetoxy hydrogen was cooled with ice water. After sodium boride (732 mg) was added, the mixture was stirred for 2 hours under a nitrogen atmosphere. Water (20 mL) and saturated aqueous sodium hydrogen carbonate solution were adjusted to a pH of 8 or more and separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate Z methanol) to give the title compound (421 mg). Obtained as colorless crystals.

NMR (CDC1, δ (ppm)): 7. 89 (2H, d, J = 9Hz), 7.2—6.9 (4H, m), 6.8

Three

2 (2H, d, J = 9Hz), 3.86 (3H, s), 3.71 (2H, s), 3.5—2.6 (8H, m), 3.10 (3H, s)

[0069] (Example 4)

4— ({1— [2— (4 Fluorophenyl) ethyl] 3 hydroxyazetidine 3 ylmethyl} methylamino) benzoic acid monohydrochloride synthesis

To a solution of the compound (380 mg) obtained in Example 3 in methanol (19 mL) was added 2N sodium hydroxide (2. OmL), and the mixture was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and ether and water were added to the residue for liquid separation. The aqueous layer was washed with ether and concentrated under reduced pressure. The remaining aqueous layer (about 4 mL) was adjusted to pH 5-7 with 3N hydrochloric acid. The deposited precipitate was collected by filtration, washed with water, and dried to give a white powder (346 mg). The obtained powder (330 mg) was dissolved in 0.2N hydrochloric acid and THF (15 mL), and concentrated under reduced pressure. The residue was powdered with ether and collected by filtration. The title compound (368 mg) was obtained by drying under reduced pressure.

NMR (CD OD, δ (ppm)): 8. 0—6.9 (8H, m), 4.4—2.7 (8H, m), 3.68 (

Three

2H, s), 3.14 (3H, s) [Example 5]

Synthesis of methyl 4-({l- [2- (4-methylthiophenyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoate

Using 4-[[(3-hydroxyazetidine 3-ylmethyl) methylamino] benzoic acid methyl monohydrochloride (500 mg) and 4-methylthiophenylacetaldehyde (392 mg), the title compound (474 mg ) Was obtained as colorless crystals.

NMR (CDC1, δ (ppm)): 7.89 (2H, d, J = 9Hz), 7.19 (2H, d, J = 8Hz), 7.

Three

10 (2H, d, J = 8Hz), 6.82 (2H, d, J = 9Hz), 3.86 (3H, s), 3.71 (2H, s), 3.5-2.6 (8H, m), 3.10 (3H , S), 2.47 (3H, s)

[0071] (Example 6)

4 ({1 [2- (4-Methylthiophenyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid monohydrochloride synthesis

Using the compound (440 mg) obtained in Example 5, the title compound (362 mg) was obtained as crystals in the same manner as in Example 4.

NMR (CD OD, δ (ppm)): 7.89 (2H, d, J = 9Hz), 7.3-6.8 (6H, m), 4.

Three

3—2.8 (8H, m), 4.0—3.9 (2H, m), 3.67 (2H, s), 3.13 (3H, s), 2.44 (3 H, s)

[Example 7]

4— ({1— [2— (4 Methylsulfuryl) ethyl) 3 hydroxyazetidine-3-ylmethyl} methylamino) Synthesis of methyl benzoate

4-([3-Hydroxyzetidine 3-ylmethyl) methylamino] methyl benzoate monohydrochloride (800 mg), 4-methylsulfurufuracetic acid (627 mg) and triethylamine (389 / zL) in dichloromethane (16 mL ) WSC'HCl (561 mg) was added to the solution and stirred at room temperature for 6 hours under a nitrogen atmosphere. The reaction solution was poured into ice water and separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was crystallized with methanol and collected by filtration to obtain 706 mg of a powder.

To a suspension of the obtained powder (690 mg) in tetrahydrofuran (7 mL), ice water was added under a nitrogen atmosphere. Borane-methyl sulfide complex salt (10M: 619 L) was added dropwise under cooling. The reaction was stirred at room temperature for 18 hours and then heated to reflux for 3 hours. Methanol was added to the reaction solution little by little under ice-water cooling, and then the pH was adjusted to 2 or less by adding a salt-hydrogen methanol solution, and the mixture was heated to reflux for 1.5 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the residue, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [Chromatolex NH ™; ChromatorexNH ™] (eluent; dichloromethane: methanol) to obtain the title compound (228 mg) as crystals. .

NMR (CDC1, δ (ppm)): 7. 9—7.8 (4H, m), 7.39 (2H, d, J = 8Hz), 6.8

Three

1 (2H, d, J = 9Hz), 3.87 (3H, s), 3.71 (2H, s), 3.5—2.7 (8H, m), 3.10 (3H, s) 3.06 (3H, s)

[0073] (Example 8)

4— ({1— [2— (4 Methylsulfuryl) ethyl] 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid monohydrochloride

Using the compound (198 mg) obtained in Example 7, the title compound (178 mg) was obtained in the same manner as in Example 4.

NMR (CD OD, δ (ppm)): 8.0-7.8 (4H, m), 7.53 (2H, d, J = 8Hz), 6.

Three

86 (2H, d, J = 9Hz), 4.3-3.2.9 (8H, m), 3.70 (2H, s), 3.14 (3H, s), 3.10 (3H, s )

[Example 9]

4— ({1— [2— (3,4 Dimethoxyphenyl) ethyl)]-3 Hydroxyzetidine-3-ylmethyl} methylamino) Synthesis of methyl benzoate

Methanesulfonic acid 2- (3,4 dimethoxyphenyl) ethyl (313mg) in acetonitrile (5mL) solution with 4-[[(3-hydroxyazetidine mono-3-ylmethyl) methylamino] benzoic acid methyl monohydrochloride (400mg ) And diisopropylethylamine (0.95 mL) were added and heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane and a saturated aqueous sodium hydrogen carbonate solution were added to the residue for liquid separation. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography. The title compound (178 mg) was obtained by purification with chromatography [Chromatolex NH; ChromatorexNH] (eluent; hexane: ethyl acetate).

NMR (CDC1, δ (ppm)): 7.90 (2H, d, J = 9Hz), 6.9—6.7 (5H, m), 3.8

Three

6 (9H, s), 3.71 (2H, s), 3.5-2.6 (8H, m), 3.10 (3H, s)

[0075] (Example 10)

4— ({1— [2— (3,4 Dimethoxyphenyl) ethyl)]-3 Hydroxyzetidine-3-ylmethyl} methylamino) benzoic acid monohydrochloride synthesis

Using the compound (150 mg) obtained in Example 9, the title compound (35 mg) was obtained in the same manner as in Example 4.

NMR (CD OD, δ (ppm)): 7.88 (2H, d, J = 9Hz), 6.9-6.7 (5H, m), 4.

Three

2-2.8 (8H, m), 3.79 (3H, s), 3.78 (3H, s), 3.65 (2H, s), 3.12 (3H, s) [0076] (Example 11)

4— ({1— [2— (4 Cyanophyl) ethyl) 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid synthesis

The title compound was obtained by the method described in Example 17 of WO 2004Z048326 pamphlet. The physical property values agreed with the values described in the pamphlet of the same issue.

[0077] (Example 12)

4— ({1— [2— (4 Cyanophyl) ethyl) 3 hydroxyazetidine 3-ylmethyl} methylamino) benzoic acid monohydrochloride synthesis

The title compound was obtained in the same manner as in Example 34 of International Publication No. 2004Z048326 using the compound described in Example 11. The physical property values agreed with the values described in the pamphlet.

[Example 13]

4— ({1— [2— (4 cyanophyl) ethyl) 3 hydroxyazetidine 3-ylmethyl} amino) Synthesis of tert butyl benzoate

<Step 1> 4-Synthesis of [(1-Diphenylmethyl-3-hydroxyazetidine-3-ylmethyl) amino] benzoate tert-butyl

Example of WO 2004Z048326 pamphlet Example 10 Magnesium trifluoromethanesulfonate (3.85 g) was added to a solution of the compound (3.00 g) and tert-butyl 4-aminobenzoate (2.31 g) in acetonitrile (30 mL), and the mixture was stirred at room temperature for 18 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; hexane Z ethyl acetate) to obtain the title compound (3.91 g) as an amorphous solid.

<Step 2> Synthesis of tert-Butyl 4-benzoate [(3 hydroxyazetidine 3-methyl) amino] benzoate

Using the compound (3.40 g) obtained in Step 1, the title compound (1.88 g) was obtained as a white powder in the same manner as in Example 11 <Step 4> of WO 2004Z048326 pamphlet.

<Step 3> Synthesis of tert-butyl 4-({1-[2- (4-cyanophyl) ethyl] 3 hydroxyazetidine 3-ylmethyl} amino) benzoate

Using the compound obtained in step 2 (0.80 g) and the WO 2004/048326 pamphlet in Example 1, the compound obtained in step 1> (0.50 g) was used for international publication. The title compound (0.83 g) was obtained as a white powder in the same manner as in Step 5> of Example 8 of the 2004 Z048326 pamphlet.

NMR (CDC1, δ (ppm)): 7.82 (2H, d, J = 9Hz), 7.58 (2H, d, J = 8Hz), 7

Three

29 (2H, d, J = 8Hz), 6.58 (2H, d, J = 9Hz), 4.59 (1H, t, J = 5Hz), 3.6-3.4 (4H, m) 2.97 (2H, d, J = 9Hz), 2. 8—2.6 (4H, m), 2.35 (1H, s), 1.57 (9H, s)

(Example 14)

4— ({1— [2— (4 Cyanophyl) ethyl) 3 hydroxyazetidine 3 yl methyl} amino) benzoic acid monohydrochloride synthesis

1N Hydrochloric acid-acetic acid solution (9.8 mL) was added to the compound obtained in Example 13 (0.40 g), and the mixture was stirred at room temperature for 22 hours. The reaction suspension was added to diisopropyl ether (50 mL), stirred for 30 minutes, and the precipitate was collected by filtration. Acetone (5 mL) was added to the filtrate and stirred for 30 minutes, and then the precipitate was collected by filtration and dried under reduced pressure to give the title compound (0.37 g) as colorless crystals. NMR (CD OD, δ (ppm)): 7.85 (2H, d, J = 9Hz), 7.72 (1H, d, J = 8Hz),

Three

7.67 (1H, d, J = 8Hz), 7.51 (1H, d, J = 8Hz), 7.40 (1H, d, J = 8Hz), 6.8 2 (1H, d, J = 9Hz), 6.75 (1H, d , J = 9Hz), 4.38 (1H, d, J = 12Hz), 4.09 (2H, s), 3.98 (1H, d, J = 12Hz), 3.7-3.5 (2H, m), 3.5- 3.4 (2H, m), 3.1-2.9 (2H, m)

Structural formulas of the compounds obtained in Examples 1 to 14 are shown below. Wherein, Me represents a methyl group, ^iota beta u is tert- butyl.

[Chemical 4]

Example 9 Example 10

Claims

Claims [1] Formula (I) below

[Chemical 1]

(Wherein A represents a group: L—W (L represents a bond or methylene, W represents a group: —NR ⁷ — (R ⁷ represents a hydrogen atom or a lower alkyl group)), and G represents ( CH) m (m is 0 or 1)

2

Y represents lower alkylene or a benzylidene group which may be substituted with R ⁴ , Z represents a bond or an oxygen atom, and when Z represents a bond, Y represents 5 to 5 carbon atoms on the benzene ring. It may form a 6-membered ring. R ¹ may be mono- or disubstituted with a -tro group, a lower alkoxycarbo group, or a lower alkyl group, or may be a protected rubermoyl group or protected. Hydroxyl group, optionally protected carboxyl group, protected V, may be N-hydroxycarbamoyl group, protected !, may! /, Lower alkyl group substituted with hydroxyl group, protected! Represents a lower alkyl group or a tetrazolyl group substituted with a carboxyl group, and R ² and R ³ are each independently substituted with a hydrogen atom, a halogen atom, or a halogen. Group, halogene ^May be substituted with a lower alkoxy group or a -tro group, and R ⁴ and R ⁵ may be independently substituted with a hydrogen atom, a halogen atom, or a halogen, and may be a lower alkyl group, (Substituted with a halogen may represent a lower alkoxy group, a cyano group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and R ⁶ represents a hydrogen atom or a lower alkyl group.) Or a pharmaceutically acceptable salt thereof, or at least one of solvates thereof as an active ingredient. [2] It contains at least one of the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Chronic pain prevention and Z or treatment.

[3] It contains at least one of the compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. A preventive and Z or therapeutic agent for inflammatory pain.

[4] The preventive and Z or therapeutic agent according to claim 3, wherein the inflammatory pain is pain caused by rheumatoid arthritis or osteoarthritis.

[5] It contains at least one of the compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Post-surgical pain prevention and Z or treatment.

[6] It contains at least one of the compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Neuropathic pain prevention and Z or treatment agent.

7. The preventive and Z or therapeutic agent according to claim 6, wherein the neuropathic pain is diabetic pain or postherpetic neuralgia.

[8] It contains at least one of the compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. , Prevention and Z or treatment of cancer pain.

[9] An effective amount of at least one of the compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof is administered to a patient. Be

, Pain prevention and Z or treatment methods.

[10] The compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvent thereof for the manufacture of a medicament for the prevention and Z or treatment of pain Use of Japanese.