WO2010010935A1

WO2010010935A1 - Optically active heterocyclidene-n-arylacetamide derivative

Info

Publication number: WO2010010935A1
Application number: PCT/JP2009/063221
Authority: WO
Inventors: 秀春内田
Original assignee: 持田製薬株式会社
Priority date: 2008-07-23
Filing date: 2009-07-23
Publication date: 2010-01-28
Also published as: JP2011201777A

Abstract

Disclosed are: a compound represented by formula (I) [wherein m represents a number of 1 or 2; n represents a number of 0 or 1; R¹ and R² independently represent H or a C_1-2 alkyl group or may, together with a carbon atom to which both R¹ and R² are attached, form a cyclo ring; the configuration of the hydroxyl group represents one of enantiomers; the dashed line, α, β, 1 and 2 independently represent the position at which each of –OH and –NH- and a carbon atom on the ring are bound to each other, provided that n represents 0 and the binding position for the hydroxyl group is β-position when the binding position for –NH- is position-1], a salt of the compound, or a solvate of the compound or the salt; and a pharmaceutical composition and a TRPV1 receptor antagonist each comprising the compound, the salt or the solvate as an active ingredient.

Description

Optically active heterocyclidene-N-arylacetamide derivatives

The present invention relates to a compound that modulates the function of a pharmaceutical, particularly a Transient Receptor Potential Vanilloid Type I receptor (hereinafter referred to as “TRPV1 receptor”), particularly an optically active heterocyclidene-N-arylacetamide derivative, The present invention relates to a TRPV1 receptor antagonist containing a derivative as an active ingredient, or a preventive or therapeutic agent for a disease involving a TRPV1 receptor including pain.

In the research on the mechanism of pain generation, the receptor (TRPV1 receptor) of capsaicin (8-methyl-N-vanillyl-6-nonanamide), the main pungent component of chili pepper, was cloned in 1997 (Caterina MJ , Schumacher MA, Tominaga M Ｒ Rosen TA, Levine JD, Julius D .: Nature, 389: 816-824, 1997). The TRPV1 receptor is a receptor that recognizes capsaicin, and is highly expressed in afferent sensory fibers including primary sensory neurons involved in pain sensation and C-fiber nerve terminals, and many TRP families have been cloned thereafter.

The TRP family is similar in structure, has a 6-transmembrane domain, and has an N-terminal side and a C-terminal side in the cell. The TRPV1 receptor causes cations such as calcium ions and sodium ions to flow into cells in response to capsaicin stimulation, acid (pH 6.0 or lower), or heat (43 ° C. or higher). Therefore, the expression site and the action of capsaicin assumed a large contribution to the neural excitation of the TRPV1 receptor. Furthermore, the contribution of TRPV1 receptor to the living body has been clarified from many reports of information, and in particular, mice lacking TRPV1 receptor (TRPV1 knockout mice) have increased heat sensitivity due to neuropathic pain. Incomplete, Freund's Adjuvant (CFA) -induced inflammatory pain model with suppressed edema (Szabo A, Hellies Z, Sandor K, Bite A, Pinter E, Nemeth J, BanVolk Ek, BV K, Szolcsanyi J .: Journal of Pharmacology And Experimental Therapeutics, 314: 111-119, 2005 ), Or the desensitization effect of a previously reported TRPV1 receptor agonist shows an analgesic effect in a neuropathic pain model or an inflammatory pain model, suggesting that the TRPV1 receptor is involved in pain (Rashid MH). , Inoue M, Kondo S, Kawashima T, Bakoshi S, Ueda H: Journal of Pharmacology And Experimental Therapeutics, 304: 940-948).

The application of capsaicin causes transient severe pain, but then induces desensitization and exerts an analgesic effect. Based on this property, many TRPV1 receptor agonists including capsaicin cream are used as analgesics. Under development (Super JR, Klapper J, Mathew NT, Raport A, Phillips SB, Bernstein JE, Archives of Neurology, 59: 990-994, 2002).

Recently, it has been reported that dorsal root ganglion cells induced by administration of streptozotocin have increased depolarization induced by capsaicin, that is, increased sensitivity to TRPV1 receptor. It has been suggested that the TRPV1 receptor is involved in diabetic pain (Hong S, Wiley JW: The Journal of Biological Chemistry, 280: 618-627, 2005). In addition, it has been reported that the desensitizing action of capsaicin, a TRPV1 receptor agonist, is promising for improving bladder function, and it has been suggested that it contributes to urination (Masayuki Takeda, Takeo Araki, Journal of Japanese Pharmacology, Vol. 121). 325-330, 2003). Furthermore, there are reports of bronchoconstriction induced by capsaicin and the inhibitory effect of TRPV1 receptor antagonists on this action, suggesting involvement in respiratory organs, etc. TRPV1 receptor is involved in various diseases Has been revealed. From such information, the usefulness of a so-called TRPV1 receptor modulator that regulates the function of the TRPV1 receptor is expected.

Of the TRPV1 modulators, agonists and antagonists that stimulate the TRPV1 receptor to induce desensitization are expected to be useful for various diseases, and among them, agonists are caused by transient intense stimulation. A TRPV1 receptor antagonist that does not induce excitement due to such stimulation has attracted attention because it induces pain. At present, compounds having TRPV1 receptor antagonistic activity are expected to have a wide range of usefulness such as analgesics, urinary incontinence drugs, and respiratory disease drugs.
“Pain includes unpleasant sensory and emotional experiences that occur based on substantial or potential injury to the tissue, as well as sensory and emotional experiences that are described using such expressions.” Yes. There are three major types of pain. Nociceptive pain, 2. 2. neuropathic pain; Classified as psychogenic pain.
Nociceptive pain is physiological pain caused by mechanical stimulation, temperature stimulation, and chemical stimulation, and is generally referred to as acute pain. Such pain serves as a biosensor based on an unpleasant sensory experience to protect yourself from danger. However, although pain such as rheumatism was certainly thought to be acute pain, it becomes chronic pain as the period from onset becomes longer and inflammation becomes chronic.
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 for hyperalgesia to thermal and mechanical stimuli. Inflammatory mediators appearing locally in inflammation and sensitization of pain receptors by lowering pH, inflammation Increased responsiveness to bradykinin and histamine due to local temperature rise, and further sensitization with nerve growth factor (NGF), etc. (Reference: Pain-Basics / Diagnosis / Treatment-Kazuo Hanaoka [edit] Asakura Shoten 2004) . Specific examples of diseases include rheumatoid arthritis and osteoarthritis of the knee. Non-steroidal anti-inflammatory analgesics (NSAIDs) have been used for a long time for inflammatory pain, including pain caused by chronic rheumatoid arthritis and knee osteoarthritis. There was limited use. Furthermore, in recent years, cyclooxygenase 2-selective inhibitors (COX2 inhibitors) developed to reduce the side effects of NSAIDs have developed into social problems 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.
Postoperative 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, and somatic pain is further divided into shallow pain and deep pain. Of these, leaving strong postoperative pain causes nerve sensitization and feels pain against non-noxious stimuli such as touch and pressure (allodynia). When such pain occurs, there are many intractable cases that cannot be controlled by administration of drugs such as nerve block therapy, NSAIDs, antiepileptic drugs and opioid agonists, and each drug used is, for example, NSAIDs If it is, side effects due to gastrointestinal disorders / renal disorders; if it is carbamazepine or phenytoin in anti-epileptic drugs, such as staggering, rash, gastrointestinal symptoms, cardiotoxicity, etc. If gabapentin, side effects such as somnolence or dizziness; opioid action Since drugs are associated with side effects such as constipation, there is a need for postoperative pain treatment agents that exhibit higher efficacy and fewer side effects.

Neuropathic pain is pain caused by primary damage to any part of the nerve transmission system from the periphery to the center or caused by dysfunction (illustration latest anesthesiology series 4, clinical clinic of pain 1 Akira, Kenjiro Dan, 1998, Medical View Inc.).
The nerve injury that causes neuropathic pain is typically trauma or injury to the peripheral nerve, plexus or perineural soft tissue, but the central somatosensory pathway (spinal cord, brainstem, It can also be caused by injury to the ascending somatosensory pathway at the thalamus or 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 onset, has not been fully clarified.
For example, allodynia is known as an abnormal skin reaction that characterizes neuropathic pain. Allodynia is a condition in which pain is felt by a stimulus that does not feel pain in normal humans. In allodynia, 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 allodynia. In postherpetic neuralgia, which is representative of neuropathic pain, allodynia has been confirmed in 87% of patients. The intensity of postherpetic neuralgia is proportional to the degree of allodynia. Allodynia is attracting attention as a treatment target for postherpetic neuralgia as a symptom that significantly limits patient freedom.

Herpes is a disease that develops when the herpes virus once infected is reactivated in the nerve, and 70% of herpes patients feel intense pain. Although this pain disappears with the healing of the disease, around 10% of patients suffer from so-called postherpetic neuralgia, with pain remaining for many years after healing. The onset mechanism is said to be that herpes virus re-growth occurs from the ganglia, and the nerve injury that occurs at this time promotes synaptic reorganization and causes allodynia, which is neuropathic pain. In clinical practice, older adults are more likely to develop postherpetic neuralgia, with more than 70% being 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-Basics / Diagnosis / Treatment-Kazuo Hanaoka [edit] Asakura Shoten 2004) .
Diabetic pain is broadly divided into acute pain that develops when hyperglycemia is corrected rapidly and chronic pain that develops due to factors such as demyelination and nerve regeneration. Among these diabetic pains, chronic pain is neuropathic pain in which dorsal root ganglion inflammation is caused by a decrease in blood flow due to diabetes, and subsequent nerve fiber regeneration causes spontaneous nerve firing and excitability. . Non-steroidal anti-inflammatory drugs, antidepressants, capsaicin cream, etc. are used as treatment methods, but there is no complete treatment for diabetic pain that can cure all diabetic pain with a single drug (Reference: Pharmaceuticals) Noyumi 211, No.5 2004, special issue "Pain Signal Control Mechanism and Latest Treatment Evidence").

In neuropathic pain, pain relief treatment for patients who complain of chronic pain symptoms and the pain itself interferes with daily life is directly related to quality of life (Quality of Life). ) Leads to improvement. However, central neuropathic drugs such as morphine, non-steroidal anti-inflammatory analgesics and steroids are considered to be ineffective for neuropathic pain. In actual drug therapy, prescription of antidepressants such as amitriptyline and In addition, anti-arrhythmic drugs such as gabapentin, pregabalin, carbamazepine, phenytoin, and mexiletine are diverted and prescribed. However, these drugs have side effects such as dry mouth, drowsiness, sedation, constipation, difficulty in urinating, etc. for amitriptyline, carbamazepine, phenytoin, rash, gastrointestinal symptoms, cardiotoxicity, and somnolence for gabapentin. Vertigo, but mexiletine is known for vertigo and digestive symptoms. These drugs, which are not specific neuropathic pain treatment drugs, have a poor difference between drug efficacy and side effects, and treatment satisfaction is low. Accordingly, there is a need for a therapeutic agent for neuropathic pain that exhibits higher efficacy by oral administration and has fewer side effects.

In recent years, research on compounds having an antagonistic action on TRPV1 receptor has been underway. Examples of the heterocyclic compound having an amide bond include, for example, International Publication No. 03/049702 pamphlet (Patent Document 1), International Publication No. 04/056774 pamphlet (Patent Document 2), International Publication No. 04/069792 pamphlet (Patent Document). 3) Pamphlet of International Publication No. 04/100985 (Patent Document 4), Pamphlet of International Publication No. 04/110986 (Patent Document 5), Pamphlet of International Publication No. 05/016922 (Patent Document 6), International Publication No. 05 / 030766 pamphlet (patent document 7), WO05 / 040121 pamphlet (patent document 8), WO05 / 046683 pamphlet (patent document 9), WO05 / 070885 pamphlet (patent document 10). , International Publication No. 05/095329 Pamphlet (Patent Document 11), International Publication No. 06/006741 pamphlet (Patent Document 12), International Publication No. 06/038871 pamphlet (Patent Document 13), International Publication No. 06/058338 (Patent Document 14), etc. It has been. However, none of these patent documents treats the relationship between a TRPV1 inhibitor and a change in body temperature as a problem to be solved. In addition, these patent documents do not disclose heterocyclidene-N- (aryl) acetamide derivatives.

As conventional techniques for disclosing compounds having a heterocyclidene skeleton, WO94 / 26692 pamphlet (Patent Document 15), WO95 / 06035 pamphlet (Patent Document 16), WO98 / 39325 pamphlet. (Patent Document 17), International Publication No. 03/042181 pamphlet (Patent Document 18), Japanese Patent Application Laid-Open No. 2001-213870 (Patent Document 19), International Publication No. 06/064075 pamphlet (Patent Document 20), International Publication No. 07/010383 pamphlet (Patent Document 21), Journal of Heterocyclic Chemistry, Vol. 22, No. 6, pp. 1511-18, 1985 (Non-Patent Document 1), Tetra Hedron Letta (Tetrahedron Letters), Vol. 42, No. 18, pp. 3227-3230, 2001 (Non-Patent Document 2), Chemical & Pharmaceutical Bulletin, Vol. 47, No. 3, 329 -339, 1999 (Non-Patent Document 3).
Patent Document 15 discloses that a muscle relaxant has a 1 (2H) -benzopyran-4-ylidene skeleton or a 1,2,3,4-tetrahydro-4-quinolidene skeleton, a hydrogen atom at the N atom of the acetamide structure, A compound having a structure in which an alkyl group or a cycloalkyl group is bonded is disclosed, but there is no disclosure of a compound in which a substituted aryl group or a heteroaryl group is bonded to an N atom. Patent Documents 16 to 18 have a 4,4-difluoro-2,3,4,5-tetrahydro-1 (1H) -benzodiazepine skeleton as an arginine vasopressin antagonist or oxytocin antagonist, A compound having a specific structure in which an arylcarbonyl group to which aryl is bonded to the N atom at the 1-position is disclosed.
In Patent Document 19, as a new charge control agent for an electrophotographic toner, 2- (1,2-benzisothiazole-3 (2H) -ylidene 1,1-dioxide) acetamide derivative is substituted with N atom of acetamide. Certain compounds having a phenyl group are disclosed.
Patent Document 20 discloses a compound having a specific structure having a sec-butyl group at the 3-position as an amide derivative of 2,3-dihydro-1-oxo-1H-isoquinoline-4-ylidene as a calpain inhibitor. ing.
Patent Document 21 discloses a novel heterocyclideneacetamide derivative as a TRPV1 receptor antagonist. However, this patent document does not disclose any relation between the heterocyclideneacetamide derivative and body temperature change.

Non-Patent Document 1 discloses 2- (1,2-dihydro-2-oxo-3H-indole-3-ylidene) -N, N-dimethyl-acetamide in a report on the synthesis of oxindole derivatives. However, a substituted aryl group or a heteroaryl group is not bonded to the N atom.
Non-Patent Document 2 discloses (1,2,3,4-tetrahydro-2-oxo-5H-1,4, -benzodiazepine-5-ylidene) acetamide derivatives as N-methyl-D-aspartate (NMDA) antagonists. As a compound having a specific structure in which a phenyl group is bonded to the N atom of acetamide.
Non-Patent Document 3 discloses a non-peptidic arginine vasopressin antagonist, (2,3,4,5-tetrahydro-1 (1H) -benzodiazepine-5-ylidene) acetamide derivative as 2-pyridylmethyl at the N atom of acetamide. A compound having a specific structure in which a group is bonded and the benzodiazepine skeleton does not have a substituent is disclosed.
None of the compounds having a heterocyclidene skeleton disclosed in Patent Documents 15 to 20 and Non-Patent Documents 1 to 3 disclose or suggest an antagonistic action of the TRPV1 receptor.
For reference, the applicant has also filed a TRPV1 receptor modulator represented by the following formula (A) (International Publication No. 08/091021; PCT / JP2008 / 051471). (Patent Document 22)).

It has been reported that administration of a TPRV1 receptor antagonist causes an increase in body temperature (Journal of Medicinal Chemistry, Vol. 48, No. 6, 1857-72, 2005 ( Non-patent document 4), Journal of Neuroscience, Vol. 27, No. 13, pages 3366-74, 2007 (non-patent document 5)). Recently, an example of a TRPV1 modulator that does not cause an increase in body temperature in rats is being reported (Journal of Pharmaceutical Therapy and Experimental Therapeutics, Vol. 326). 1, pp. 218-29, 2008 (Non-patent Document 6)). However, there is no suggestion about a compound having a cyclidene skeleton as in the present invention.

In drug development, not only intended pharmacological activity but also various criteria such as absorption, distribution, metabolism, and excretion are required to meet strict criteria. For example, drug interaction, desensitization or tolerance, digestive tract 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 clearance in the body Various application issues are required in the application method (application site, method, purpose) and the like, and it is difficult to find one that satisfies them.
As for TRPV1 receptor antagonists, there are always comprehensive problems in the development of these drugs, and they have not yet been put on the market. More specifically, for compounds having a TRPV1 receptor antagonistic activity, for example, hERG (human ether-a-go-go related) has low metabolic stability and is difficult to be administered orally, and has a risk of causing arrhythmia. gene) There are problems of usefulness and safety, such as exhibiting channel inhibitory activity or poor pharmacokinetics such as absorption and sustainability. There are also issues to be identified at the clinical trial stage. For example, although there is little change in body temperature associated with administration of a TRPV1 receptor antagonist, as a conventional technique that suggests the possibility of a compound that solves this problem, a non-patent document 6 describes a compound having a specific structure. There is no general suggestion about chemical structure. There is a need for compounds that solve these problems as much as possible and that are highly active.
In addition, there is a need for compounds that have fewer side effects than the conventional drugs currently used for the treatment of pain, including neuropathic pain as described above.

International Publication No. 03/049702 Pamphlet International Publication No. 04/056774 pamphlet International Publication No. 04/069792 Pamphlet International Publication No. 04/100865 Pamphlet International Publication No. 04/110986 Pamphlet International Publication No. 05/016922 Pamphlet International Publication No. 05/030766 Pamphlet International Publication No. 05/040121 Pamphlet International Publication No. 05/046683 Pamphlet International Publication No. 05/070885 Pamphlet International Publication No. 05/095329 Pamphlet WO 06/006741 pamphlet International Publication No. 06/038871 Pamphlet International Publication No. 06/058338 Pamphlet International Publication No. 94/26692 Pamphlet International Publication No. 95/06035 Pamphlet International Publication No. 98/39325 Pamphlet International Publication No. 03/042181 Pamphlet JP 2001-213870 A International Publication No. 06/064075 International Publication No. 07/010383 International Publication No. 08/091021 pamphlet; PCT application number: PCT / JP2008 / 051471

Under such circumstances, TRPV1 receptor modulators that can be administered orally, have high safety and are highly effective, especially TRPV1 receptor antagonists, or preventive or therapeutic agents for diseases involving TRPV1 receptors ( In particular, there is a demand for a preventive or therapeutic agent for pain. In particular, the problems in the prior art as described above, more specifically, amitriptyline side effects such as dry mouth, drowsiness, sedation, constipation, difficulty in urination, carbamazepine, phenytoin side effects rash, digestive symptoms, Cardiotoxicity and other side effects of gabapentin, such as somnolence and dizziness, such as dizziness and gastrointestinal symptoms that are side effects of mexiletine, gastrointestinal disorders that are side effects of non-steroidal anti-inflammatory analgesics, and heart failure that is a side effect of COX2 inhibitors Problems such as side effects such as reduction of hERG current inhibitory effect; improvement of metabolic stability and absorbability, oral administration possibility, improvement of pharmacokinetics and solubility, and problems to be addressed There is. And a drug that can be administered orally to mammals including humans that has overcome at least one of these problems, especially a clinically user-friendly preventive or therapeutic agent for a disease involving TRPV1 receptor with little body temperature change (In particular, a preventive or therapeutic agent for pain) is desired.

The present invention relates to a compound having an action of modulating the function of TRPV1 receptor, particularly an optically active heterocyclidene-N-arylacetamide derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, Those solvates, TRPV1 receptor modulators containing the derivatives as active ingredients, especially TRPV1 receptor antagonists, or preventive or therapeutic agents for pain, especially preventive or therapeutic agents for neuropathic pain, fibromyalgia It comprises a preventive or therapeutic agent for symptom and a preventive or therapeutic agent for inflammatory pain.

In order to solve the above-mentioned problems, the present inventors have conducted extensive research to obtain a compound having a function of regulating the function of TRPV1 receptor, which is highly safe and excellent in effectiveness. The optically active heterocyclidene-N-arylacetamide derivatives represented by the formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof has an effect of regulating the function of an excellent TRPV1 receptor. In addition, this compound group has at least one of high metabolic stability, excellent oral absorbability, good solubility, and no increase in body temperature (especially little change in body temperature). It has been found that it has the above characteristics. A pharmaceutical composition containing the compound as an active ingredient is a preventive or therapeutic agent for orally administrable pain, in particular, a prophylactic or therapeutic agent for neuropathic pain, a prophylactic or therapeutic agent for fibromyalgia, a prophylactic agent for inflammatory pain. Or it is expected as a therapeutic agent.

The present invention relates to an optically active heterocyclidene-N-arylacetamide derivative represented by the formula (I) shown in the following embodiments or a salt thereof, a pharmaceutical composition containing them as an active ingredient, and the derivative or a salt thereof. For medical use.
Hereinafter, each aspect of the present invention will be described. Incidentally, in the description of the invention compounds, for example, "C ₁ ~ _6", unless otherwise specified, the chain group refers to a "structure having a carbon number 1 to a straight or branched chain 6 '. For a cyclic group, it means “the number of carbon atoms constituting the ring”.
The molecular weight of the compound represented by the formula (I) of the present invention is not particularly limited, but is preferably 700 or less. More preferably, the molecular weight is 550 or less. Such molecular weight limitation is routinely used as another major limiting factor in addition to the basic skeleton with pharmacological characteristics when specifying the structure of a compound in recent drug designs.

[Aspect of the Invention]
[1] Aspect 1 of the present invention
A first aspect of the present invention is the following formula (I)

(Wherein, m represents an integer of 1 or 2, n represents an integer of 0 or 1, ^{R 1} and ^{R 2} each independently represent a hydrogen atom or a C ₁ ~ ₂ alkyl group, ^{R 1} And R ² may form a cyclo ring together with the carbon atom to which each is bonded, and the configuration of the hydroxyl group is one of the enantiomers, and the broken lines and α, β, 1 and 2 are , —OH or —NH— and the bonding position of each carbon atom on the ring, provided that the bonding position of —NH— is the 1st position, n is 0 and the bonding position of the hydroxyl group is the β position. Or a salt thereof or a solvate thereof.

Below, each group in the said formula (I) of the said aspect [1] is demonstrated concretely. In the following description, "C _{_1-6"} indicates that indicates from 1 to 6 carbon atoms, for example, C _{_1-6} alkyl group is an alkyl group of 1 to 6 carbon atoms.
In the compound represented by [1-1] Formula (I), ^{R 1} and ^{R 2} each independently represent a hydrogen atom or a C ₁ ~ ₂ alkyl group, for example, a hydrogen atom, a methyl group or an ethyl group Is mentioned. Further, “R ¹ and R ² may each form a cyclo ring together with the carbon atoms to which they are bonded” specifically means a 3- to 5-membered ring, for example, spirocyclopropane. Ring, spirocyclobutane ring, spirocyclopentane ring and the like.
[1-1-a] R ¹ and R ² are the same and more preferably a hydrogen atom, a methyl group, or an ethyl group. Further, when “R ¹ and R ² may each form a cyclo ring together with the carbon atoms to which they are bonded”, it is more preferably a spirocyclobutane ring.
[1-2] In the compound represented by the formula (I), m is an integer of 1 or 2.
When [1-2-a] m is 1, R ¹ and R ² are the same and are preferably a hydrogen atom, a methyl group, or an ethyl group. Further, it is preferable that together with the carbon atom to which R ¹ and R ² are each coupled to a spiro-cyclobutane ring.
When [1-2-b] m is 2, R ¹ and R ² are the same and are preferably a hydrogen atom.

[1-2-c] In the formula (I), preferred examples of the moiety of the following formula (II) include the following formulas (II-a) to (II-e).

[1-3] In the compound represented by the formula (I), n represents 0 or 1, the configuration of the hydroxyl group represents any enantiomer, and the broken line represents a bond to any carbon atom. , Α, β, 1 and 2 represent broken bond positions. When the —NH— bond position is position 1, n is 0 and the hydroxyl group bond position is the β position.
When the bonding position of [1-3-a] -NH— is at the 2-position and the bonding position of the hydroxyl group is at the α-position, n is preferably 0 or 1.
When the bonding position of [1-3-b] -NH— is at the 2-position and the bonding position of the hydroxyl group is at the β-position, n is preferably 1.
[1-3-1] In the above formula (I), examples of the moiety of the following formula (III) having a hydroxyl group include the following formulas (III-1) to (III-4): Preferably, a hydroxytetrahydronaphthylamino group or an indanolamino group having a different configuration of the hydroxyl group of the formula is represented by the following formula (III-1-A), formula (III-1-B), formula (III- Examples include 2-A), formula (III-2-B), formula (III-3-A), formula (III-3-B), and formula (III-4-B).

Expressed as a substituent, (2,3-dihydro-1-hydroxy-1H-inden-6-yl) amino group (A) (formula (III-1-A)), (2,3-dihydro-1- Hydroxy-1H-inden-6-yl) amino group (B) (formula (III-1-B)), (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) amino group (A ) (Formula (III-2-A)), (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) amino group (B) (formula (III-2-B)), (2 -Hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) amino group (A) (formula (III-3-A)), (2-hydroxy-1,2,3,4-tetrahydronaphthalene- 7-yl) amino group (B) (formula (III-3-B)), (2 3-dihydro-2-hydroxy -1H- inden-4-yl) amino group (B) (formula (III-4-B) is expressed as).

In the present specification, the hydroxyl group bonded to the carbon atom with * in the formula indicates any one of the configurations, for example, the formula (III-1-A) and the formula (III-1-B) represents an enantiomer of each other.
In the present specification, (A) and (B) are, for example, a compound of the formula (D-IV) which is a racemate of the compound of the formula (VI) in the following (Production Method D) <Step 4>. Are separated by an optical isomer separation column, the enantiomer obtained as the first fraction is represented as (A), and the enantiomer obtained as the second fraction is represented as (B). Therefore, in the case of formula (III-1-A), the first fraction obtained in the column for optical isomer separation is used, or in the case of formula (III-1-B), in the column for optical isomer separation. It means a part of the formula (III) obtained by using each of the obtained second fractions.

[1-4] In the compound of the formula (I) of the embodiment [1], a compound selected from the formulas (II-a) to (II-e) described in the embodiment [1-2-c], and Formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), formula (III) described in the above embodiment [1-3-1] It is more preferable that the compound is a combination of a formula selected from (III-3-B), formula (III-3-A) or formula (III-4-B).

[1-5] Examples of preferable compounds include the following.
(E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A) (Example 1) ;
(E) -2- (2,2-Dimethylchroman-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide ( A) (Example 2);
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A (Example 3);
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (B ) (Example 4);
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) acetamide (A) (Example 5);
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) acetamide (B) (Example 6);
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A ) (Example 7);
(E) -2- (2,2-diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (B ) (Example 8);
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) acetamide (A) (Example 9);
(E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (A) (Example 10);

(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (A) (Example 11);
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (B) (Example 12);
(E) -2- (3,4-Dihydro-8-trifluoromethyl-1-benzooxepin-5 (2H) -ylidene) -N- (2,3-dihydro-2-hydroxy-1H-indene-4- Yl) acetamide (B) (Example 13);
(E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) (Example 14);
(E) -2- (2,2-Dimethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) (Example 15);
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) (Example 16);
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl ) Acetamide (B) (Example 17).

[2] A second aspect of the present invention is characterized by containing the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. A pharmaceutical composition.
More specifically, the following embodiments are preferable.
[2-1]
According to a 2-1 aspect of the present invention, at least one of the compound according to the aspect [1-4] or the aspect [1-5], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a pharmaceutical composition characterized by containing one as an active ingredient.

[3] A third aspect of the present invention is characterized in that the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof is contained as an active ingredient. , A TRPV1 receptor antagonist.
More specifically, the following embodiments are preferable.
[3-1]
According to a 3-1 aspect of the present invention, at least one of the compound according to the aspect [1-4] or the aspect [1-5], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a TRPV1 receptor antagonist characterized by containing one as an active ingredient.
In the present specification, particularly in the third aspect of the present invention, the “TRPV1 receptor antagonist” is one aspect of the “TRPV1 receptor modulator”. The “TRPV1 receptor modulator” means an agent containing a compound that modulates the function of TRPV1 receptor, and more specifically, an agent containing a compound that suppresses activation of TRPV1 receptor. The compound includes a compound that binds to TRPV1 receptor and antagonizes an endogenous ligand to suppress TRPV1 receptor activation (TRPV1 receptor antagonist), and continuously activates TRPV1 receptor, There are compounds (TRPV1 receptor agonists) that desensitize the nerve in which the receptor is present, thereby inhibiting subsequent activation of the receptor. Therefore, TRPV1 modulator is a general term for TRPV1 receptor antagonists and TRPV1 receptor agonists. Antagonists include neutral antagonists and inverse agonists, and agonists include full and partial agonists. The partial agonist acts as an antagonist depending on conditions. The TRPV1 receptor modulator of the present invention is preferably a TRPV1 receptor antagonist. The TRPV1 receptor antagonists of the present invention include neutral antagonists, inverse agonists and partial agonists. The TRPV1 antagonist of the present invention is expected to show promising preventive or therapeutic effects for the following various diseases. Specifically, acute pain, chronic pain, neuropathic pain, fibromyalgia Post-herpetic neuralgia, trigeminal neuralgia, low back pain, pain after spinal cord injury, lower limb pain, causalgia, diabetic neuralgia, pain due to edema, burns, sprains, fractures, postoperative pain, shoulder periarthritis, osteoarthritis, arthritis , Rheumatoid arthritis pain, inflammatory pain, cancer pain, migraine, headache, toothache, neuralgia, myalgia, hyperalgesia, angina or menstrual pain, neuropathy, nerve damage, neurodegeneration, chronic obstructive lung Disease (COPD), asthma, airway hypersensitivity, wheezing, cough, rhinitis, inflammation of mucous membranes such as eyes, neurological skin diseases, inflammatory skin diseases such as psoriasis and eczema, edema, allergic diseases, gastroduodenal ulcer, ulcerative colon Flame, irritability Intestine, Crohn's disease, urinary incontinence, urge incontinence, overactive bladder, cystitis, nephritis, pancreatitis, uveitis, visceral disorder, ischemia, stroke, ataxia, obesity, sepsis, pruritus, diabetic Treatment and the like. In particular, promising therapeutic effects can be expected for neuropathic pain, fibromyalgia, inflammatory pain, and urinary incontinence.

[4] A fourth 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. A preventive and / or therapeutic agent for pain.
More specifically, the following embodiments are preferable.
[4-1]
A fourth aspect of the present invention provides at least one of the compound according to the aspect [1-4] or the aspect [1-5], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a preventive and / or therapeutic agent for pain, characterized by containing one as an active ingredient.
[5] A 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. Is a preventive and / or therapeutic agent for neuropathic pain.
More specifically, the following embodiments are preferable.
[5-1]
A fifth aspect of the present invention provides at least one of the compound according to the aspect [1-4] or the aspect [1-5], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a prophylactic and / or therapeutic agent for neuropathic pain characterized by containing one as an active ingredient.

[6] A sixth 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. Is a prophylactic and / or therapeutic agent for inflammatory pain.
More specifically, the following embodiments are preferable.
[6-1]
A sixth aspect of the present invention provides at least one of the compound according to the aspect [1-4] or the aspect [1-5], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a prophylactic and / or therapeutic agent for inflammatory pain characterized by containing one as an active ingredient.
In the second to sixth aspects and preferred aspects thereof, in the compound according to the aspect [1-4] or the aspect [1-5], a more preferable substituent or a combination thereof is the first aspect. It is described in.
In each of the embodiments described in [1] to [6] of the present invention, TRPV1 receptor antagonistic activity (for example, Experimental Example (1)-(b) described later: measurement of Ca inflow using FDSS-6000) ), It is preferable to use a compound having an IC ₅₀ value of 1 μM or less, preferably 100 nM or less, more preferably 30 nM or less.
In the above aspect of the present invention, the “therapeutic agent” is intended to include not only treatment of a disease or symptom but also improvement of the disease or symptom.

In all of the above embodiments, when the term “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. Isolation and purification of such stereoisomers can be carried out by those skilled in the art through conventional techniques through preferential crystallization, optical resolution using column chromatography or asymmetric synthesis.

The compound represented by the formula (I) of the present invention, or the compound described in the embodiment [1-4] or the embodiment [1-5] may form an acid addition salt. Depending on the type of substituent, a salt with a base may be formed. Such a salt 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, propionic acid, butyric acid, valeric acid, enanthic acid, capric 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 carboxylic acids such as aliphatic dicarboxylic acids such as carboxylic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid and tartaric acid, and aliphatic tricarboxylic acid such as citric acid; methanesulfonic acid and ethanesulfonic acid Organic sulfonic acids such as aliphatic sulfonic acids such as 2-hydroxyethanesulfonic acid, aromatic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid Acid addition salts with acidic amino acids such as aspartic acid and glutamic acid, and salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium and calcium, methylamine, ethylamine, ethanolamine, pyridine , Salts with organic bases such as lysine, arginine, ornithine, ammonium salts and the like.
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 desired acid or base, and collecting the desired salt by filtration or distilling off the solvent. Moreover, this invention compound or its salt can form solvates with solvents, such as water, ethanol, and glycerol.

Furthermore, the present invention relates to a compound represented by the formula (I) of the present invention, or a hydrate of the compound represented by the above embodiment [1-4] or the above embodiment [1-5], pharmaceutically acceptable Various possible solvates and crystalline polymorphs are also included. Of course, the present invention is not limited to the compounds described in the Examples below, but the compounds represented by the formula (I) of the present invention, or the above-mentioned embodiment [1-4] or the above-mentioned embodiment [1- 5] or any of the pharmaceutically acceptable salts thereof.

[Method for producing compound of the present invention]
The compound represented by the formula (I) used in the present invention, the compound described in the embodiment [1-4] or the embodiment [1-5], and related compounds can be obtained by the production method shown below. it can. Hereinafter, each reaction process will be described.
The compound represented by the formula (I) which is the compound of the present invention and a salt thereof can be easily produced from a commercially available compound or a commercially available compound by a method known in the literature, etc. and produced according to the production method shown below. Can do.
Further, the present invention is not limited to the manufacturing method described below.
Hereinafter, the production method will be described in detail.
In the following description, formula (I), formula (V), formula (Va), formula (Vb), formula (Vc), formula (VI), formula (VI-a), formula ( Unless otherwise specified, R ¹ , R ² , m, and n in the compounds represented by VI-b) and formula (VI-c) are the same as the previous definitions described in formula (I). R ^A is an alkyl group, R ^B is hydrogen or an alkyl group, P ¹ is a protecting group such as tert-butoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group, P ² is an alkyl group, M is Li, Na , K and Zn, and Y represents a leaving substituent such as halogen.

The compound represented by the formula (I) is obtained by a condensation reaction between a carboxylic acid represented by the formula (V) and an amine represented by the formula (VI).
(Reaction formula)

A method known in the literature using a compound of the formula (V) and a compound of the formula (VI), for example (Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen) 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), benzotriazole-1-yloxytris ( Dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate ( CIP), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) In the presence of a condensing agent such as 4-methylmorpholinium chloride (DMTMM), halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, N In a solvent that does not participate in the reaction, such as a polar solvent such as N, dimethylformamide, or an alcohol solvent such as methanol, ethanol, or 2-propanol, the solvent is added from 0 ° C. in the presence or absence of a base such as triethylamine or pyridine. By reacting at a refluxing temperature, the compound of formula (I) can be produced. Further, when the compound of the formula (V) is converted into an acid chloride (Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 144-146, 1992, Maruzen), etc. In the presence of a base such as triethylamine and pyridine, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, N, N-dimethylformamide and the like The compound of the formula (I) can be produced in the same manner by reacting at a temperature at which the solvent is refluxed from 0 ° C. in a solvent that does not participate in the reaction, such as a polar solvent.

The compound of the formula (V) in the above reaction formula is produced by the following (Production Method A) to (Production Method C), and the compound of the formula (VI) is produced by the following (Production Method D) to (Production Method G). Can do.

(Production method A)
<When m = 2 and R ¹ = R ² = H in Formula (V)>

<Step 1>
Using compounds of formula (AI) and compounds of formula (A-II), methods known in the literature, such as Journal of Medicinal Chemistry, 31 (1), 230-243, According to the method described in 1988, in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, methanol, ethanol, acetone, N, N -Using a solvent inert to the reaction, such as dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, or a mixed solvent thereof, the reaction is performed from room temperature to the temperature at which the solvent refluxes, and the compound of formula (A-III) Compounds can be made.

<Process 2>
Using compounds of formula (A-III), methods known in the literature, such as Synlett, No. 6, pp. 848-850, 2001, etc., in the presence of palladium catalyst such as palladium diacetate, tetrakistriphenylphosphine palladium, trisdibenzylideneacetone dipalladium, and silver carbonate, acetonitrile, Using a solvent inert to the reaction such as dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, N, N-dimethylformamide, or a mixed solvent thereof, the reaction is carried out at room temperature from which the solvent is refluxed. -IV) can be prepared.
<Step 3><R ^A = alkyl group such as methyl or ethyl>
A method described in the literature using a compound of the formula (A-IV), for example, a method described in (Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, page 1-33, 1992, Maruzen) In the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc., water and methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4 -Using a solvent inert to the reaction such as dioxane and tetrahydrofuran, or a mixed solvent thereof, the reaction can be carried out at a temperature at which the solvent is refluxed from 0 ° C to produce the compound of formula (Va).
<In the case of R ^A = tert-butyl group>
Using compounds of formula (A-IV), methods known in the literature, such as Greene et al., Protective Ve Group in Organic Synthesis, (USA), 3rd edition, 1999, etc., in the presence of an acid reagent such as formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, alcohol solvents such as methanol and ethanol, 1,4-dioxane, tetrahydrofuran. (THF) An ether solvent such as 1,2-dimethoxyethane, a solvent that does not participate in the reaction such as water, or a mixed solvent thereof is used to perform the reaction at a temperature at which the solvent is refluxed from 0 ° C. The compound of -a) can be produced.

Intermediate (A-III) can be produced according to the following method.
<Step 4>
Using the compound of formula (AI) and the compound of formula (AV), the compound of formula (A-VI) can be produced by the same method as in (Production Method A) <Step 1>. .
<Step 5>
A method known in the literature using a compound of formula (A-VI) and a compound of formula (A-VII), for example, tetrahedron, 60 (13), pages 3017-3035, 2004, etc. Benzylidenebistricyclohexylphosphine ruthenium dichloride, tricyclohexylphosphine-1,3-bis-2,4,6-trimethylphenyl-4,5-dihydroimidazol-2-ylidenebenzylidene ruthenium dichloride, ruthenium-1 1,4-bis-2,4,6-trimethylphenyl-2-imidazolidinylylidenedichloro-2--1-methylethoxyphenylmethylene and the like in the presence of a ruthenium catalyst, dichloromethane, chloroform and other halogenated solvents, 1,4- Dioxane, tetrahydrofuran, etc. Using a solvent inert to the reaction such as an ether solvent, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from the formula (A The compound of -III) can be prepared.
<Step 6>
Using the compound of formula (AI) and the compound of formula (A-VIII), the compound of formula (A-IX) can be produced by the same method as in (Production Method A) <Step 1>. .

<Step 7>
Methods known in the literature using compounds of the formula (A-IX), such as (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen), etc. A reducing agent such as diisobutylaluminum hydride (DIBAH), lithium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, Raney nickel (Raney-Ni) -formic acid, Reaction is performed at a temperature at which the solvent is refluxed from −78 ° C. using a solvent inert to the reaction such as diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, benzene, toluene, or a mixed solvent thereof. To produce a compound of formula (AX).
<Step 8>
Using compounds of the formula (AX), it is described in literature known methods such as (Experimental Chemistry Course 4th Edition 19, Organic Synthesis I, Hydrocarbon / Halogen Compounds, 53-298, 1992, Maruzen) In accordance with the above method, ethoxycarbonylmethyltriphenylphosphonium chloride, ethoxycarbonylmethyltriphenylphosphonium bromide, triphenylphosphoranylideneethyl acetate, bis-2,2,2-trifluoroethoxyphosphinyl acetate, diortolylphospho Wittig reagents such as Noethyl acetate, Dimethylphosphonoethyl acetate, Diethylphosphonoethyl acetate, 1-Trimethylsilylethyl acetate, Horner-Emmons reagent and Sodium hydride, Butyllithium, Piperazine, Morpholine, Triethyl In the presence of a base such as amine, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, phosphazene base-P4-tert-butyl, alcohol solvents such as methanol and ethanol, N , N-dimethylformamide and other polar solvents, 1,4-dioxane, tetrahydrofuran and other ether solvents, benzene, toluene, xylene and other aromatic hydrocarbon solvents and the like, or a mixed solvent thereof The compound of the formula (A-III) can be produced by reacting at a temperature at which the solvent refluxes from −78 ° C.

(Production Method B) <In the case where m = 1 and R ¹ = R ² = H in Formula (V)>

<Step 1><In the case of R ^B = H>
Using a compound of the formula (BI) and a compound of the formula (B-II), a method known in the literature, for example, Journal of Medicinal Chemistry, 31 (1), 230-243, According to the method described in 1988, in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, methanol, ethanol, acetone, N, N -Using a solvent inert to the reaction, such as dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, or a mixed solvent thereof, the reaction is performed from room temperature to the temperature at which the solvent is refluxed, and the compound of formula (B-IV) Compounds can be produced. Further, a method known in the literature using the compound of formula (BI) and the compound of formula (B-III), for example, the method described in International Publication No. 01/36381, pages 360-361, Reference Example 12 In the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc., methanol, ethanol, acetone, N, N-dimethylformamide, 1,4 -A compound of the formula (B-IV) can be produced by performing a reaction at a temperature at which the solvent is refluxed from room temperature using a solvent inert to the reaction such as dioxane, tetrahydrofuran, water, or a mixed solvent thereof. .

<Step 1><In the case of R ^B = alkyl group (for example, methyl, ethyl, etc.)>
Esters obtained by carrying out the reaction in the same manner as in the above <In the case of R ^B = H> can be prepared by methods known in the literature, for example (Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acids / Amino Acids / Peptides, pages 1-33, 1992, Maruzen) and the like in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water, methanol, ethanol, 2-propanol. , N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and the like, or a mixed solvent thereof, and the reaction is performed at a temperature from 0 ° C. to the reflux of the solvent. The compound of IV) can be prepared.
<Process 2>
In accordance with a method known in the literature using a compound of the formula (B-IV), for example, a method described in Journal of Medicinal Chemistry, 31 (1), 230-243, 1988. In cyclic dehydration reagents such as polyphosphoric acid (PPA), polyphosphoric acid ethyl ester (PPE), diphosphorus pentoxide (P ₂ O ₅ ), Eaton's reagent (mixture of methanesulfonic acid and diphosphorus pentoxide), or the like In the presence of water, the solvent is refluxed from 0 ° C. in a solvent that does not participate in the reaction, such as halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, and aromatic hydrocarbon solvents such as toluene and benzene. Producing a compound of formula (BV) by reacting at temperature Can do. Further, in the presence of a Lewis acid such as aluminum trichloride and tin tetrachloride, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. in a solvent that does not participate in the reaction such as halogen solvents such as dichloromethane and chloroform. The compound of -V) can be prepared analogously.

<Step 3>
Using compounds of the formula (BV), it is described in literature known methods such as (Experimental Chemistry Course 4th Edition 19, Organic Synthesis I, Hydrocarbon / Halogen Compounds, 53-298, 1992, Maruzen) In accordance with the above method, ethoxycarbonylmethyltriphenylphosphonium chloride, ethoxycarbonylmethyltriphenylphosphonium bromide, triphenylphosphoranylideneethyl acetate, bis-2,2,2-trifluoroethoxyphosphinyl acetate, diortolylphospho Wittig reagents such as Noethyl acetate, Dimethylphosphonoethyl acetate, Diethylphosphonoethyl acetate, 1-Trimethylsilylethyl acetate, Horner-Emmons reagent and Sodium hydride, Butyllithium, Piperazine, Morpholine, Triethyl In the presence of a base such as amine, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, phosphazene base-P4-tert-butyl, alcohol solvents such as methanol and ethanol, N , N-dimethylformamide and other polar solvents, ether solvents such as 1,4-dioxane and tetrahydrofuran, aromatic hydrocarbon solvents such as benzene, toluene and xylene, and the like, or a mixed solvent thereof. Can be used to carry out the reaction at a temperature at which the solvent is refluxed from −78 ° C. to produce a compound of the formula (B-VI).
<Step 4>
The compound of formula (Vb) can be produced by reacting the compound of formula (B-VI) in the same manner as in (Production Method A) <Step 3>.

<Step 5>
According to a method known in the literature using a compound of the formula (BV), for example, lithium diisopropylamide according to the method described in Synthetic Communications, 35 (3), 379-387, 2005 Reaction with an alkyl lithium reagent (formula (B-VII)) prepared from acetates, or reformatesky prepared from α-haloacetates such as ethyl bromoacetate and bromoacetate-tert-butyl in the presence of zinc A reaction with a reagent (formula (B-VII)) or a reaction in the presence of a silyl acetate such as ethyl trimethylsilyl acetate and a base such as phosphazene base-P4-tert-butyl is obtained by ether such as 1,4-dioxane or tetrahydrofuran. Solvents, benzene, true By using a solvent inert to the reaction, such as an aromatic hydrocarbon solvent such as xylene, or a mixed solvent thereof, at a temperature at which the solvent is refluxed from −78 ° C., the formula (B-VIII) Can be produced.
<Step 6>
Methods described in literatures using compounds of the formula (B-VIII), such as those described in literatures (for example, Experimental Chemistry Course 4th Edition 19, Organic Synthesis I, Hydrocarbons, 194-236, 1992, Maruzen) In the presence of an inorganic acid such as potassium hydrogen sulfate or concentrated sulfuric acid, an organic acid such as p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid, or a dehydrating agent such as thionyl chloride or phosphorus oxychloride. Using a solvent inert to the reaction, such as an ether solvent such as dioxane or tetrahydrofuran, an aromatic hydrocarbon solvent such as benzene, toluene or xylene, or a mixed solvent thereof, at a temperature at which the solvent is refluxed from −78 ° C. The reaction can be carried out to produce a compound of formula (B-VI).
<Step 7>
A compound of formula (B-IX) can be produced by reacting the compound of formula (B-VIII) in the same manner as in (Production Method A) <Step 3>.
<Step 8>
The compound of formula (Vb) can be produced by reacting the compound of formula (B-IX) in the same manner as in (Production Method B) <Step 6>.

(Production Method C) <In the case of formula (V), m = 1, R ¹ = R ² = alkyl group>

<Step 1>
According to a method known in the literature using a compound of formula (CI), for example, the method described in Journal of Medicinal Chemistry, 46 (13), 2683-2696, 2003 In the presence of methyllithium (MeLi), a solvent inert from the reaction such as diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, or a mixed solvent thereof, from −78 ° C. to the solvent Is allowed to react at a temperature at which is refluxed to produce a compound of formula (C-II).

<Process 2>
Using compounds of formula (C-II) and compounds of formula (C-III), methods known in the literature, for example Journal of Heterocyclic Chemistry, 32, 1393-1395, 1995 In the presence of a base such as pyrrolidine, piperazine, morpholine, triethylamine, N, N-diisopropylethylamine, pyridine, etc. The compound of the formula (C-IV) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C. in the middle or a mixed solvent thereof. Wherein ^R 1, ^{R 2} are each a straight-chain or branched alkyl group of _C 1 _{~ 5,} the alkyl group, a halogen atom, a hydroxyl _group, an alkyl group of _{_{_{C 1 ~ 2, C 1 ~}}} 2 alkoxyl group or from 1 to 1 to may be five substituted with two substituents are selected arbitrarily from an amino group optionally group with an alkyl group of C ₁ ~ _3, or, R ^1, R ² may form a cyclo ring group C ₃ ~ ₆ together with the carbon atom bonded to each said cyclic ring group is one carbon atom in the ring, oxygen atom or nitrogen atom <the nitrogen atom, a halogen atom, _-OH, -OCH 3, substituted with straight or branched chain alkyl group having one with 1-3 optionally substituted _C 1 _{to 3} -OCF ₃ May be replaced by>.
<Step 3>
Using the compound of formula (C-IV), the compound of formula (CV) can be produced by the same method as in (Production Method B) <Step 5>.
<Step 4>
Using the compound of formula (CV), the compound of formula (C-VI) can be produced by the same method as in (Production Method A) <Step 3>.
<Step 5>
Using the compound of formula (C-VI), the compound of formula (Vc) can be produced by the same method as in (Production Method B) <Step 6>.
<Step 6>
A compound of formula (C-VII) can be produced by using the compound of formula (CV) in the same manner as in (Production Method B) <Step 6>.
<Step 7>
Using the compound of formula (C-VII), the compound of formula (Vc) can be produced by the same method as in (Production Method A) <Step 3>.

(Production Method D) <In the case where n = 1 in Formula (VI)>

<Step 1>
In accordance with a method known in the literature using a compound of the formula (DI), for example, a method described in (Experimental Chemistry Course 4th Edition 20 Organic Synthesis II Alcohol Amine, 394-405, 1992, Maruzen) React with a nitrating agent such as nitric acid, nitric acid / sulfuric acid, nitric acid / acetic anhydride, potassium nitrate / sulfuric acid, sodium nitrate / sulfuric acid, potassium nitrate / acetic anhydride, nitric acid / trifluoromethanesulfonic acid at −40 ° C. to room temperature. The compound (D-II) can be produced.
<Process 2>
A method known in the literature using a compound of the formula (D-II), such as (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen) In the presence of a reducing agent such as sodium borohydride or lithium borohydride, an alcohol solvent such as methanol, ethanol or 2-propanol, or these and diethyl ether or 1,2-dimethoxyethane. Using a mixed solvent with a solvent inert to the reaction such as 1,4-dioxane, tetrahydrofuran, benzene, toluene, etc., the compound of formula (D-III) is reacted at a temperature from 0 ° C. to the reflux of the solvent. Can be manufactured. In addition, reducing agents such as diisobutylaluminum hydride (DIBAH), lithium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and the like, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane Using a solvent inert to the reaction, such as tetrahydrofuran, benzene, toluene, or a mixed solvent thereof, at a temperature at which the solvent refluxes from −78 ° C. to produce a compound of formula (D-III) You can also.

<Step 3>
A method known in the literature using a compound of the formula (D-III), such as (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen) In the presence of a catalyst such as palladium-carbon (Pd—C), Raney nickel (Raney-Ni), dichlorotristriphenylphosphine ruthenium, etc., in a hydrogen atmosphere, methanol, ethanol, 2-propanol Alcohol solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like, polar solvents such as ethyl acetate and methyl acetate, solvents not involved in the reaction, or mixed solvents thereof Is used to produce a compound of formula (D-IV) by reacting at a temperature from 0 ° C. to reflux of the solvent. Rukoto can. Alternatively, the compound of formula (D-IV) can be produced by reacting in concentrated hydrochloric acid or acetic acid in the presence of iron (Fe) or tin (Sn) at a temperature at which the solvent is refluxed from 0 ° C. Further, in the presence of Lewis acid such as nickel chloride (NiCl ₂ ) and tin chloride (SnCl ₂ ) and sodium borohydride, alcohol solvents such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran, 1,2-dimethoxy Using a solvent that does not participate in the reaction, such as an ether solvent such as ethane or 1,4-dioxane, or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C., and the compound of the formula (D-IV) is converted. It can also be manufactured.
<Step 4>
Using a compound of the formula (D-IV), an optical isomer separation column was prepared according to a method known in the literature, for example, the method described in Journal of Synthetic Organic Chemistry, 54 (5), 344-353, 1996. The compound of formula (VI-a) can be produced by optical resolution by preparative chromatography used.
Similar to the formula (VI), the configuration of the hydroxyl group in the formula (VI-a) represents any enantiomer. In the present specification, for any one of the amines represented by the formula (VI-a) obtained by separating the racemate using an optical isomer separation column, the first fraction of each enantiomer obtained is ( A), the second fraction is (B). In this production method, either one of the optically active substances is shown.

Furthermore, the intermediate formula (D-IV) can also be produced according to the following method.

<Step 5>
Using the compound of formula (D-II), the compound of formula (DV) can be produced by the same method as in (Production Method D) <Step 3>.
<Step 6>
The compound of formula (D-IV) can be produced by the same method as in (Production Method D) <Step 2>, using the compound of formula (DV).

Furthermore, the formula (VI-a) can also be produced according to the following method.
<Step 7>
Methods known in the literature using compounds of the formula (DV), such as (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 23-68, 1992, Maruzen) In the presence of a base reagent such as optically active dichloro [bis (diphenylphosphino) binaphthyl] [diphenylethylenediamine] ruthenium and potassium hydroxide, potassium tert-butoxide, in a hydrogen atmosphere, The compound of formula (VI-a) can be produced by carrying out the reaction using a 2-propanol solvent at a temperature at which the solvent is refluxed from room temperature. Alternatively, transition metal complexes such as dichlorotristriphenylphosphine ruthenium, benzene ruthenium (II) chloride (dimer), and optically active 2-amino-1,2-diphenylethanol, 1-amino-2-indanol, etc. In the presence of a reagent and a base reagent such as potassium hydroxide or potassium tert-butoxide, the reaction is carried out using 2-propanol solvent at a temperature at which the solvent refluxes to produce a compound of formula (VI-a) You can also Alternatively, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-in the presence of chlorodiisopinocinfeylborane (Ipc ₂ BCl), or optically active oxazaborolidine and borane (BH ₃ ) It is also possible to produce a compound of the formula (VI-a) by carrying out the reaction at a temperature at which the solvent is refluxed from 0 ° C using an ether solvent such as dioxane.

(Production Method E) <In the Formula (VI) where n = 1> (wherein P ¹ represents a protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, and the like) ² represents an alkyl group such as a methyl group or an ethyl group.)

<Step 1>
Using a compound of the formula (EI), protecting groups such as tert-butoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group and the like can be prepared by methods known in the literature, such as Greene et al. The compound of formula (E-II) can be produced by introducing by the method described in the book of Protective Groups in Organic Synthesis, (USA), 3rd edition, 1999, etc. it can.
<Process 2>
Using a compound of the formula (E-II), an alkyl group such as a methyl group or an ethyl group is converted into a known method, for example, Greene et al., Protective Groups in Organic Synthesis (Protective Groups in Organic). Synthesis), (USA), 3rd edition, 1999, etc., can be introduced by the method described in the textbook to produce a compound of formula (E-III).

<Step 3>
Using the compound of formula (E-III), the introduced protecting group can be converted to methods known in the literature such as Greene et al., Protective Groups in Organic Synthesis, ( The compound of the formula (E-IV) can be produced by the removal by the method described in the textbook of US), 3rd edition, 1999, etc.
<Step 4>
The compound of formula (E-IV) is converted to a method known in the literature, for example (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 165-167, 1992, Maruzen) According to the described method, for example, in the presence of a reagent containing a metal such as lithium, sodium, etc., in a solvent containing liquid ammonia and an alcohol such as methanol, ethanol, isopropanol, tert-butanol, etc. Can be reacted at room temperature (Birch reduction) to produce a compound of formula (EV).
<Step 5>
Compounds of formula (EV) can be prepared by methods known in the literature, such as those described in The Journal of Organic Chemistry, 51 (26), 5252-5258, 1986. In the presence of acid reagents such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, alcohol solvents such as methanol, ethanol, 1,4-dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane. The compound of the formula (E-VI) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction such as ether, acetone, water, or a mixed solvent thereof.
<Step 6>
Using the compound of formula (E-VI), the compound of formula (E-VII) can be produced by the same method as in (Production Method D) <Step 2>.
<Step 7>
Using the compound of formula (E-VII), the compound of formula (VI-a) can be produced by the same method as in (Production Method D) <Step 4>.
Similarly to the formula (VI), the configuration of the hydroxyl group in the formula (VI-a) represents any enantiomer, and any one of the formulas obtained by separating the racemate using an optical isomer separation column. For the amine represented by (VI), the first fraction of each enantiomer obtained is (A) and the second fraction is (B).

Furthermore, the intermediate formula (E-VII) can also be produced according to the following method.

<Step 8>
In accordance with a method known in the literature using a compound of the formula (EI), for example, according to the method described in (New Experimental Chemistry Course 15 Oxidation and Reduction II, 426-428, 1977, Maruzen) In the presence of a catalyst such as carbon (Pd—C), Raney nickel (Raney-Ni), platinum oxide or the like, in an atmosphere of hydrogen at 3 to 5 atmospheres, an alcohol solvent such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran, etc. The solvent is refluxed from 0 ° C. using an ether solvent such as 1,2-dimethoxyethane or 1,4-dioxane, a polar solvent such as ethyl acetate or methyl acetate, or a mixed solvent thereof. The compound of the formula (E-VII) can also be produced by carrying out the reaction at a temperature at which

Furthermore, the formula (VI-a) can also be produced according to the following method.
<Step 9>
Using the compound of formula (E-VI), the compound of formula (VI-a) can be produced by the same method as in (Production Method D) <Step 7>.

(Production Method F) <In the case where n = 0 in the formula (VI)>

<Step 1>
Using the compound of formula (FI), the compound of formula (F-II) can be produced by the same method as in (Production Method D) <Step 1>.
<Process 2>
Using the compound of formula (F-II), the compound of formula (F-III) can be produced by the same method as in (Production Method D) <Step 2>.
<Step 3>
In accordance with a method known in the literature using a compound of the formula (F-III), for example, the method described in Journal of Medicinal Chemistry, 46 (13), 2683-2696, 2003 In the presence of an acid catalyst such as p-toluenesulfonic acid and sulfuric acid, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, an ether solvent such as tetrahydrofuran and the like, or a solvent mixture thereof. The compound of formula (F-IV) can be produced by performing the reaction at a temperature at which the solvent is refluxed from room temperature.

<Step 4>
In accordance with a method known in the literature using a compound of the formula (F-IV), for example, the method described in Journal of Medicinal Chemistry, 46 (13), 2683-2696, 2003 In the presence of a reagent such as m-chloroperbenzoic acid, a halogen-based solvent such as dichloromethane or chloroform, an aromatic hydrocarbon-based solvent such as benzene, toluene or xylene, or a solvent mixture thereof. The compound of formula (FV) can be produced by performing the reaction at a temperature at which the solvent is refluxed from room temperature.
<Step 5>
In accordance with a method known in the literature using a compound of the formula (FV), for example, the method described in WO 97/45410 pamphlet, pages 47-50 (intermediate production method 3), magnesium bromide- In the presence of reagents such as diethyl ether complex and zinc iodide, halogen solvents such as dichloromethane and chloroform, ether solvents such as 1,4-dioxane and tetrahydrofuran, aromatic hydrocarbon solvents such as benzene, toluene and xylene, etc. The compound of the formula (F-VI) can be produced by performing the reaction using a solvent inert to the reaction or a mixed solvent thereof at a temperature at which the solvent is refluxed from room temperature.
<Step 6>
The compound of formula (F-VII) can be produced by the same method as in (Production method D) <Step 2>, using the compound of formula (F-VI).
<Step 7>
Using the compound of formula (F-VII), the compound of formula (F-VIII) can be produced by the same method as in (Production Method D) <Step 3>.
<Step 8>
Using the compound of formula (F-VIII), the compound of formula (VI-b) can be produced by the same method as in (Production Method D) <Step 4>.

In the formula (VI-b), the hydroxyl group bonded to the carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-b) obtained by separating the racemate using an optical isomer separation column, the first fraction of each enantiomer obtained is represented by (A), the second Let the fraction be (B).
Furthermore, the intermediate formula (F-VIII) can also be produced according to the following method.
<Step 9>
The compound of formula (F-IX) can be produced by using the compound of formula (F-VI) and the same method as in (Production Method D) <Step 3>.
<Step 10>
Using the compound of formula (F-IX), the compound of formula (F-VIII) can be produced by the same method as in (Production Method D) <Step 2>.

Furthermore, the formula (IV-b) can also be produced according to the following method.
<Step 11>
Using the compound of formula (F-IX), the compound of formula (VI-b) can be produced by the same method as in (Production Method D) <Step 7>.

(Production Method G) <In the above formula (VI), when n = 0>

<Step 1>
Using the compound of formula (F-II), the compound of formula (F-III) can be produced by the same method as in (Production Method D) <Step 2>.
<Process 2>
Using the compound of formula (F-III), the compound of formula (GI) can be produced by the same method as in (Production Method D) <Step 3>.
<Step 3>
Using the compound of formula (GI), the compound of formula (VI-c) can be produced by the same method as in (Production Method D) <Step 4>. In the formula (VI-c), the hydroxyl group bonded to the carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-c) obtained by separating the racemate using an optical isomer separation column, the first fraction of each enantiomer obtained is represented by (A), the second Let the fraction be (B).
Furthermore, the intermediate formula (GI) can also be produced according to the following method.
<Step 4>
Using the compound of formula (F-II), the compound of formula (G-II) can be produced by the same method as in (Production Method D) <Step 3>.
<Step 5>
Using the compound of formula (G-II), the compound of formula (GI) can be produced by the same method as in (Production Method D) <Step 2>.

Furthermore, the formula (VI-c) can also be produced according to the following method.
<Step 6>
Using the compound of formula (G-II), the compound of formula (VI-c) can be produced by the same method as in (Production Method D) <Step 7>.
In the formula (VI-c), the hydroxyl group bonded to the carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-c) obtained by separating the racemate using an optical isomer separation column, the first fraction of each enantiomer obtained is represented by (A), the second Let the fraction be (B).

When each compound synthesized by each of the above production methods has a reactive group such as a hydroxyl group, an amino group, or a carboxyl group as a substituent, these groups are appropriately protected in each production process, and the protection is performed at an appropriate stage. It can be produced by removing the group. Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the type of protecting group. For example, Green, et al., Protective Groups in Organic Synthesis, Protective Groups in Organic Synthesis. ), (USA), 3rd edition, 1999, and the like.

[Combination agent containing the compound of the present invention]
The compound of the present invention can be used in combination with other drugs.
Examples of analgesics include acetaminophen, opioid agonists such as aspirin and morphine, or gabapentin, antidepressants such as pregabalin, duloxetine, or amitriptyline; antidepressants such as carbamazepine and phenytoin; mexiletine, etc. Anti-inflammatory drugs such as NSAIDs represented by diclofenac, indomethacin, ibuprofen, naproxen, COX-2 inhibitors represented by Celebrex, NR2B antagonists, bradykinin antagonists, anti-migraine agents. Preferred are morphine, gabapentin or pregabalin, diclofenac, and Celebrex.
It is possible not only to be used in combination with other drugs, but also to be treated in combination with other treatment methods. Specific examples include acupuncture, laser treatment, and nerve block. Diseases involving TRPV1 other than pain can be used in combination with drugs used in each region. For example, it can be used in combination with NSAIDs, DMARDs, anti-TNFα antibodies, soluble TNFα receptors, steroids, immunosuppressants and the like that are commonly used in chronic rheumatoid arthritis. In addition, in COPD and allergic diseases, it can be used in combination with general therapeutic agents such as β2 receptor agonists and steroids. Furthermore, for overactive bladder and urinary incontinence, it can be combined with anticholinergic drugs.
By using in combination with existing drugs for the above-mentioned diseases, it is possible to reduce the dosage of existing drugs and reduce the side effects of existing drugs. Of course, the combination method using the drug is not limited to the above diseases, and the drug used in combination is not limited to the compounds exemplified above.
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. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.

[Formulation of the preventive / therapeutic agent of the present invention]
The medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention only needs to contain at least one compound represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable additive. More specifically, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, 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, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbo Cymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid) Copolymer LD), plasticizers (eg triethyl citrate, macrogol), masking agents (eg titanium oxide), colorants, flavoring agents, preservatives (eg benzalkonium chloride, paraoxybenzoic acid esters), isotonic Agents (eg, glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH regulators (eg, buffers such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stable Agent (eg, sugar, sugar a) (Alcohol, xanthan gum), dispersant, antioxidant (eg; ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffer, preservative (eg; paraben, benzyl alcohol, benzal chloride) Luconium), fragrance (eg, vanillin, l-menthol, rose oil), solubilizer (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancer (E.g., sodium glycolate, sodium edetate, sodium caprate, acylcarnitines, limonene), gelling agents, suspending agents or emulsifiers, commonly used suitable additives or solvents It can be combined with the compounds of the invention as appropriate to form various dosage forms. Come.

Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir. 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 3.0 g, preferably 0.05 mg to 2.5 g, more preferably 0.1 mg to 1.5 g per day for an adult. Can be increased or decreased as appropriate.
The total amount can be divided into 1 or 2-6 doses, orally or parenterally, or can be administered continuously by intravenous infusion.

[Examples of pharmacological experiments]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.
(1) Measurement of capsaicin-induced Ca influx in human and rat TRPV1-transformed CHO cell lines (a) Establishment of human and rat TRPV1-transformed CHO cell lines And cloned from rat dorsal root ganglia. The cloned TRPV1 cDNA was incorporated into a pCAGGS vector, which was introduced into a CHO-K1 cell line for transformation. Clones obtained by limiting dilution were stimulated with capsaicin, and clones with high response were selected using an increase in Ca concentration as an index. Selected clones were used for experiments.

(B) Measurement of Ca influx using FDSS-6000 Human or rat TRPV1-transformed CHO cells were seeded in a 96-well plate (black wall, transparent bottom / manufactured by Greiner) at a density of 40,000 cells per well. After overnight culture at 37 ° C. and 5% CO ₂ , the loading solution of FLIPR Calcium 3 assay kit (Molecular Devices) supplemented with 2.5 mmol / L probenecid was added to each well in the same amount as the medium. The cells were then incubated at 37 ° C. for 60 minutes. Capsaicin (10 nmol / L) Changes in intracellular Ca concentration were measured using FDSS-6000 (λex: 480 nm, λem: 540 nm, Hamamatsu Photonics) for 3 minutes after stimulation. After calculating the integrated value of the increase rate of intracellular Ca concentration in each of the compound treatment group and the vehicle group of the present invention, the concentration of the compound of the present invention (IC ₅₀₎ that suppresses the increase in intracellular Ca concentration induced by capsaicin by 50%. ) And the inhibitory effect of the test compound was compared using this value as an index. A case where the IC ₅₀ value in human TRPV1 is less than 100 nmol / L is shown in Table 1 as A. The compound of the present invention exhibits an intensity of at least 1 μmol / L or less when the IC ₅₀ value is measured by the above method.

(2) Effect of Compound on CFA-Induced Rat Inflammatory Pain Model A CFA-induced rat inflammatory pain model is prepared by a general method, for example, the method of Pomonis JD (The Journal of Pharmaceutical Therapy and Volume 306: 387- 393). Specifically, inflammation is induced by administering 50 μL of 100% CFA to the soles of rats.
Oral administration of the compound of the present invention to rats 2 days or 1 week after administration of CFA suppresses the decrease in pain threshold, that is, proves its effectiveness as a therapeutic agent for inflammatory pain.
(3) Effect of Compound on Neuropathic Pain Model Rat When the compound of the present invention is orally administered to any one of Chung model rat, Seltzer model rat and STZ-induced diabetic pain model rat, the decrease in pain threshold is suppressed. In other words, the effectiveness as a therapeutic agent for neuropathic pain is proved.
(4) Effect of Compound on Mouse PQ Rising Mouse PQ (Phenyl-p-quinone) rising is prepared by a method such as Mustafa AA (General Pharmacology, Vol. 23: 1177-1182). Specifically, after the administration of Phenyl-p-quinone diluted with physiological saline into the abdominal cavity of the mouse, the number of times that the mouse showed an action such as stretching, twisting or rolling is recorded for a certain period of time.
By administering the compound of the present invention to mice prior to administration of Phenyl-p-quinone, the number of times of behavior such as stretching, twisting, and rounding after administration of Phenyl-p-quinone is reduced, thereby showing the effectiveness.

(5) Safety test The compound of the present invention is orally administered to a rat at a dose of 30 mg / Kg once, and no deaths are observed and no remarkable behavioral abnormalities are observed. Indicated.

(6) hERG inhibition test by patch clamp method The effect on hERG (human ether-a-go-related gene) channel is measured using a fully automatic patch clamp system (PatchXpress 7000A; molecular device). In order to confirm the hERG I _Kr current of the cells, a depolarizing pulse is periodically applied while maintaining the membrane potential at −80 mV. After the generated current has stabilized, the test substance is added to the perfusate. The effect of the test substance on the hERG channel is confirmed by changes in tail current induced by -50 mV, 0.2 s and 20 mV, 5 s depolarization pulse followed by -50 mV, 5 s repolarization pulse. Stimulation was performed once every 12 seconds. The measurement is performed at room temperature. The hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 5 minutes after application with respect to the maximum tail current before application of the test substance.
By calculating this inhibition rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.

(7) Pharmacokinetics For example, by using male SD rats aged 5 to 6 weeks and examining the change in plasma concentration after single oral administration of the compound of the present invention, bioavailability is good, It is proved that the maximum plasma concentration (Cmax) and AUC both increase and keep linearity almost in proportion to the dose. In addition, by measuring the inhibitory action on human drug-metabolizing enzymes, the influence on it is proved. In addition, human, monkey, dog and rat liver microsomes are used to demonstrate whether they are less susceptible to metabolism and whether they are less susceptible to the first pass effect of liver metabolism.

(8) Effect on rectal temperature A test compound was administered to a rat once at a dose of 1 mg / Kg, and the rectal temperature was measured after 15 minutes, 30 minutes and 60 minutes. The results are shown in Table 2.
A test compound was orally administered to a rat once at a dose of 10 mg / Kg, and the rectal temperature at 30 minutes, 60 minutes, and 120 minutes was measured, and the rectal temperature was observed. The results are shown in Table 2. Indicated.
The effect on the rectal temperature can be observed using various animals as appropriate in addition to rats. For example, rodents (eg, hamsters, mice, guinea pigs, etc.), carnivores (eg, sunks), heavy teeth (eg, rabbits), carnivores (eg, dogs, ferrets, minks, cats, etc.) Ostracoda (for example, horses, etc.), cloven-hoofed eyes (for example, pigs, cows, goats, sheep, etc.), and primates (for example, various monkeys, chimpanzees, etc.). It is also possible to observe the effect on human body temperature.

Compound A: 4- (3-trifluoromethylpyridin-2-yl) -N- (5-trifluoromethylpyridin-2-yl) -1-piperazinecarboxamide Compound B: (E) -3- (4-t -Butylphenyl) -N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acrylamide

Compound C: N- (4- “6- (4-trifluoromethyl-phenyl) -pyrimidin-4-yloxy] -benzothiazol-2-yl” acetamide (*)
(*): NEUROSCIENCE 2007
Program # / Poster #: 400.9 / OO22
Title: The capsaicin receptor TRPV1: Is it a pain transducer or a regulator of body temperature?
Location: San Diego Convention Center: Halls BH
Presentation Start / End Time: Monday, Nov 05, 2007, 8:00 AM-9:00 AM
Authors: N. R. GAVVA;

Compound D: Compound of Example 68 described in WO2007 / 010383 / (E) -2- (8-trifluoromethyl-3,4-dihydrobenzo [b] oxepin-5 (2H) -ylidene) -N -(3-Hydroxy-1,2,3,4-tetrahydroquinolin-5-yl) acetamide

The difference between the average values of the test compound administration group and the vehicle administration group was calculated at each measurement time point, and the rat rectal temperature change was classified into the following three levels from the maximum absolute value of the difference.
-: Maximum value is less than 0.5 degrees Celsius +: Maximum value is 0.5 degrees Celsius or more and less than 1 degree ++: Maximum value is 1 degree Celsius or more

From the above results, it was shown that the compound of the present invention has an antagonistic action on the TRPV1 receptor. Moreover, it shows the analgesic effect of inflammatory pain model and neuropathic pain model of in ViVo, no abnormality is observed in the safety test, and the low toxicity of the present invention is shown.
Furthermore, preferred compounds of the present invention have high metabolic stability and good pharmacokinetics. Moreover, it has excellent solubility and does not cause an increase in body temperature at a dose that exhibits a medicinal effect (particularly, there is little change in body temperature).
Therefore, the compound of the present invention is expected as a TRPV1 receptor modulator, particularly as a TRPV1 receptor antagonist, as a prophylactic or therapeutic agent for pain, particularly as a prophylactic or therapeutic agent for inflammatory pain or neuropathic pain.

The compounds of the present invention are expected to show promising preventive or therapeutic effects for these various diseases. Specifically, acute pain, chronic pain, neuropathic pain, fibromyalgia, postherpetic neuralgia, trigeminal neuralgia, back pain, pain after spinal cord injury, lower limb pain, causalgia, diabetic neuralgia, edema, burns, sprains, Pain due to fracture, postoperative pain, periarthritis, osteoarthritis, arthritis, rheumatoid arthritis pain, inflammatory pain, cancer pain, migraine, headache, toothache, neuralgia, muscle pain, hyperalgesia, narrow Pain due to heart disease and menstruation, neuropathy, nerve damage, neurodegeneration, chronic obstructive pulmonary disease (COPD), asthma, airway hyperresponsiveness, wheezing, cough, rhinitis, inflammation of mucous membranes such as eyes, neurological skin disease, psoriasis and Inflammatory skin diseases such as eczema, edema, allergic diseases, gastroduodenal ulcer, ulcerative colitis, irritable colon, Crohn's disease, urinary incontinence, urge incontinence, overactive bladder, cystitis, nephritis, pancreatitis, grape Membrane inflammation, visceral injury, ischemia, Among, ataxia, obesity, sepsis, pruritus, it can be used for the treatment of diabetes. Promising therapeutic effects can be expected for neuropathic pain, fibromyalgia, inflammatory pain, and urinary incontinence.

[Formulation example]
The following are examples of the pharmaceutical composition of the present invention.
Formulation Example 1 Compound of Tablet Example 1 100 g
137g of lactose
Crystalline cellulose 30g
Hydroxypropylcellulose 15g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
Weigh the above ingredients and mix evenly. This mixture is compressed into tablets having a weight of 150 mg.
Formulation Example 2 Film-coated hydroxypropylmethylcellulose 9g
Macrogol 6000 1g
Titanium oxide 2g
After weighing the above components, hydroxypropylmethylcellulose and macrogol 6000 are dissolved in water and titanium oxide is dispersed. This liquid is film-coated on 300 g of the tablet of Preparation Example 1 to obtain film-coated tablets.

Formulation Example 3 Capsule Example 2 Compound 50g
Lactose 435g
Magnesium stearate 15g
The above ingredients are weighed and mixed uniformly. The mixture is filled into an appropriate hard capsule in an amount of 300 mg in a capsule encapsulator to obtain a capsule.
Formulation Example 4 Capsules Example 6 Compound 100g
Lactose 63g
Corn starch 25g
Hydroxypropylcellulose 10g
Talc 2g
After weighing the above components, the compound of Example 6, lactose and corn starch are uniformly mixed, an aqueous solution of hydroxypropylcellulose is added, and granules are produced by wet granulation. Talc is uniformly mixed into the granules, and 200 mg in weight is filled into suitable hard capsules to form capsules.

Formulation Example 5 Powder Example 10 Compound 200g
790 g of lactose
Magnesium stearate 10g
After weighing each of the above components, they are mixed uniformly to form a 20% powder.
Formulation Example 6 Granules, Fine Granules Compound of Example 12 100 g
Lactose 200g
Crystalline cellulose 100g
Partially pregelatinized starch 50g
Hydroxypropylcellulose 50g

After weighing the above components, the compound of Example 12, lactose, crystalline cellulose, and partially pregelatinized starch were added and mixed uniformly, an aqueous solution of hydroxypropylcellulose (HPC) was added, and granules or fine granules were obtained by wet granulation. Manufacturing. The granules or fine granules are dried to obtain granules or fine granules.
Formulation Example 7 Cream Compound of Example 1 0.5 g
0.1 g of dl-α-tocopherol acetate
Stearyl glycyrrhetinate 0.05g
Stearic acid 3g
Higher alcohol 1g
Squalane 10g
Octyldodecyl myristate 3g
7g of trimethylglycine
Preservative Appropriate amount Saponifying agent Appropriate amount After weighing the above components, the compound of Example 1 is mixed and dissolved. An appropriate amount of purified water is added to make 50 g to obtain a cream formulation.

Next, examples are given to describe the present invention in more detail, but the present invention is not limited thereto.
For the measurement of nuclear magnetic resonance spectrum (NMR), Geol JNM-EX270 (JEOL JNM-EX270) FT-NMR (manufactured by JEOL Ltd.), Geol JNM-ECX300 (JEOL JNM-ECX300) FT-NMR (JEOL) GEOL JNM-ECX400 (JEOL JNM-ECX400) FT-NMR (manufactured by JEOL Ltd.) was used. LC Mass is a Waters FractionLynx MS system (Waters), Waters column, SunFire column (4.6 mm × 5 cm, 5 μm), mobile phase acetonitrile, 0.05% acetic acid aqueous solution, acetonitrile. : 0.05% acetic acid aqueous solution = 1: 9 (0 minutes) to 9: 1 (5 minutes) to 9: 1 (6 minutes) Gradient conditions were used for analysis. A DIP-1000 type digital polarimeter (manufactured by JASCO Corporation) was used for the measurement of optical rotation ([α] _D ).

Reference Example 1 Synthesis of (E) -2- (3,4-dihydro-8-trifluoromethyl-1-benzooxepin-5 (2H) -ylidene) acetic acid <Step 1> 2-iodo-5-trifluoro Synthesis of methylphenol A solution of 3-trifluoromethylphenol (16.6 g) in toluene (200.0 mL) was added dropwise to a suspension of sodium hydride (7.1 g) in toluene (300.0 mL) under ice-cooling. did. After stirring at the same temperature for 30 minutes, iodine (26.0 g) was added. After stirring at room temperature for 12 hours, 3N hydrochloric acid aqueous solution was added to adjust to pH = 2. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (30.8 g) as a pale yellow oil.
<Step 2> Synthesis of 3- (3-cyanopropyloxy) -4-iodotrifluoromethylbenzene (Reference Example 1) Acetone (250.0 mL) solution of the compound (60.0 g) obtained in <Step 1> To the solution, potassium carbonate (31.7 g), 4-bromobutyronitrile (31.5 g) and potassium iodide (3.5 g) were added, and the mixture was heated to reflux for 4 hours. After standing to cool, the insoluble material was filtered off and washed with acetone. The filtrate and washings were concentrated, water was added, extracted with ethyl acetate, washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (72.4 g) as a pale yellow oil.

<Step 3> Synthesis of 3- (5-ethoxycarbonyl-4-pentene) oxy-4-iodotrifluoromethylbenzene (Reference Example 1) Toluene (600) of the compound (100.0 g) obtained in <Step 2> 0.0 mL), diisobutylaluminum hydride (toluene solution, 341.0 mL) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. A 0.5 N aqueous sulfuric acid solution (1.4 L) was added, the mixture was extracted with hexane, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an intermediate (aldehyde) as a pale yellow liquid. Ethyl diethylphosphonoacetate (25.8 g) was added to a solution of the obtained aldehyde in tetrahydrofuran (1.0 L), and a suspension of potassium hydroxide (7.9 g) in tetrahydrofuran (200.0 mL) was added under ice cooling. The mixture was further stirred at room temperature for 8 hours. Water was added, the mixture was extracted with hexane, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (111.6 g) as a pale yellow oil.
<Step 4> Synthesis of (E) -2- (3,4-dihydro-8-trifluoromethyl-1-benzooxepin-5 (2H) -ylidene) ethyl acetate (Reference Example 1) obtained in <Step 3> To a solution of the compound (48.4 g) in tetrahydrofuran (500.0 mL) were added palladium acetate (2.8 g), triphenylphosphine (5.9 g), and silver carbonate (31.2 g), and the mixture was stirred under a nitrogen stream for 15 hours. Heated to reflux. The reaction solution was filtered through celite, water was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (15.7 g) as a white solid.
<Step 5> Synthesis of (E) -2- (3,4-dihydro-8-trifluoromethyl-1-benzooxepin-5 (2H) -ylidene) acetic acid (Reference Example 1) obtained in <Step 4> A 2N aqueous sodium hydroxide solution (28.0 mL) was added to a solution of the compound (10.2 g) in methanol (56.0 mL), and the mixture was heated to reflux for 2 hours. After evaporating the solvent under reduced pressure, the reaction mixture was neutralized with 1N aqueous hydrochloric acid, and the resulting solid was collected by filtration and washed with n-hexane to give the title compound (8.2 g) as a white solid.

Reference Example 2 Synthesis of (E) -2- (7-trifluoromethylchroman-4-ylidene) acetic acid <Step 1-A> Synthesis of 3- (3-trifluoromethylphenoxy) propionic acid 3-trifluoro 3-Chloropropionic acid (25.0 g) was added dropwise to a 2N aqueous sodium hydroxide solution (120.0 mL) of methylphenol (25.0 g). While maintaining pH = 10 or higher with a 5N aqueous sodium hydroxide solution, the mixture was heated to reflux for 1 hour. After cooling to room temperature, the reaction solution was washed with diethyl ether. The mixture was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized by adding n-hexane to give the title compound (6.1 g) as colorless crystals.
<Step 1-B> Synthesis of 3- (3-trifluoromethylphenoxy) propionic acid To a solution of 3-trifluoromethylphenol (2.0 g) in N, N-dimethylformamide (20.0 mL), sodium hydride ( 0.6 g) was added and stirred at room temperature for 1 hour. β-propiolactone (1.0 mL) was added and stirred at room temperature for 2.5 hours. Water was added, pH was adjusted to 2 using 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized by adding n-hexane to give the title compound (2.2 g) as colorless crystals.

<Step 2> Synthesis of 7-trifluoromethylchroman-4-one Diphosphorus pentoxide (2.0 g) was added little by little to methanesulfonic acid (18.0 g), and the mixture was stirred at room temperature for 2.5 hours. The compound (2.0 g) obtained in (Reference Example 2) <Steps 1-A and B> was added over 10 minutes at an external temperature of 70 to 80 ° C. The mixture was stirred at the same temperature for 30 minutes, allowed to cool, and poured into ice water (100.0 mL). The mixture was extracted with ethyl acetate, and the combined organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 95: 5) to obtain the title compound (1.7 g) as a yellow solid.
<Step 3> Synthesis of ethyl 2- (4-hydroxy-7-trifluoromethylchroman-4-yl) acetate Zinc (0.3 g) was suspended in tetrahydrofuran (4.0 mL), and the external temperature was 70 ° C. ( Reference Example 2) A solution of the compound obtained in <Step 2> (0.5 g) and ethyl bromoacetate (0.6 g) in toluene (8.0 mL) was added dropwise. The mixture was heated to reflux for 30 minutes, and zinc (0.3 g) and ethyl bromoacetate (0.6 g) were added. The mixture was heated to reflux for 30 minutes, allowed to cool, and 1N aqueous hydrochloric acid solution was added to the reaction mixture. After liquid separation, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.7 g) as a brown oil.
<Step 4> Synthesis of 2- (4-hydroxy-7-trifluoromethylchroman-4-yl) acetic acid (Reference Example 1) In the same manner as in <Step 5>, (Reference Example 2) in <Step 3> From the obtained compound (0.7 g), the title compound (0.6 g) was obtained as a deep orange amorphous.
<Step 5> Synthesis of (E) -2- (7-trifluoromethylchroman-4-ylidene) acetic acid (Reference Example 2) The compound (120.0 mg) obtained in <Step 4> was dissolved in toluene (1.0 mL). ), Concentrated sulfuric acid (1 drop) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Trituration with diethyl ether / n-hexane was followed by filtration to obtain the title compound (22.0 mg) as a pale yellow powder.

Reference Example 3 Synthesis of (E) -2- (2,2-dimethyl-7-trifluoromethylchroman-4-ylidene) acetic acid <Step 1> Synthesis of 2-hydroxy-4-trifluoromethylacetophenone 4- To a solution of trifluoromethyl salicylic acid (80.0 g) in tetrahydrofuran (780.0 mL) was added methyllithium (1.6 M diethyl ether solution, 800.0 mL) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into ice water. Concentrated hydrochloric acid (135.0 mL) was added under ice cooling. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (68.0 g) as a pale yellow oil.
<Step 2> Synthesis of 7-trifluoromethyl-2,2-dimethylchroman-4-one (Reference Example 3) To a solution of the compound (50.0 g) obtained in <Step 1> in methanol (900.0 mL) , Acetone (28.8 mL) and pyrrolidine (32.7 mL) were added, and the mixture was stirred at room temperature for 12 hours. To the residue obtained by evaporating the solvent under reduced pressure, 10% aqueous citric acid solution (420.0 mL) and water (420.0 mL) were added, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. And dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (50.4 g) as a brown oil.

<Step 3> Synthesis of ethyl 2- (4-hydroxy-2,2-dimethyl-7-trifluoromethylchroman-4-yl) acetate N, N-diisopropylamine (45.0 mL) in tetrahydrofuran (600.0 mL) N-Butyllithium (1.6M n-hexane solution) (200.0 mL) was added dropwise to the solution at an external temperature of −78 ° C. over 30 minutes. After stirring at the same temperature for 30 minutes, ethyl acetate (31.5 mL) was added dropwise, and the mixture was further stirred for 30 minutes. Further, (Reference Example 3) A solution of the compound (40.0 g) obtained in <Step 2> in tetrahydrofuran (200.0 mL) was added dropwise over 20 minutes, and the mixture was stirred at −78 ° C. for 1.5 hours. The reaction solution was poured into water (1.0 L) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title crude compound (49.0 g) as an orange oil.
<Step 4> Synthesis of ethyl (E) -2- (2,2-dimethyl-7-trifluoromethylchroman-4-ylidene) (Reference Example 3) Compound (90.0 g) obtained in <Step 3> ) In dichloromethane (1.4 L) was added dropwise trifluoroacetic acid (101.0 mL) at 0 ° C. Stir at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract 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; n-hexane: ethyl acetate = 100: 0 to 99: 1 to 50:50) to give the title compound (46.5 g ) Was obtained as a pale yellow oil.
<Step 5> Synthesis of (E) -2- (2,2-dimethyl-7-trifluoromethylchroman-4-ylidene) acetic acid (Reference Example 3) Compound (46.2 g) obtained in <Step 4> 1N aqueous sodium hydroxide solution (293.0 mL) was added to an ethanol (590.0 mL) solution. Stir at room temperature for 5 hours. The reaction mixture was concentrated, 1N aqueous hydrochloric acid solution was added to the obtained residue to adjust to pH = 1, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was recrystallized from n-hexane to obtain the title compound (22.1 g) as colorless crystals.

Reference Example 4 Synthesis of (E) -2- (2,2-diethyl-7-trifluoromethylchroman-4-ylidene) acetic acid <Step 1> 2,2-diethyl-7-trifluoromethylchroman-4 Synthesis of —one (Reference Example 3) From the compound obtained in <Step 1> (44.5 g) and 3-pentanone (36.6 mL), (Reference Example 3) In the same manner as in <Step 2> The title compound (25.7 g) was obtained as a white solid.
<Step 2> Synthesis of ethyl 2- (2,2-diethyl-4-hydroxy-7-trifluoromethylchroman-4-yl) acetate (Reference Example 4) Compound (29.2 g) obtained in <Step 1> ) To give the title crude compound (36.3 g) as a white solid in the same manner as in (Reference Example 3) <Step 3>.
<Step 3> Synthesis of 2- (2,2-diethyl-4-hydroxy-7-trifluoromethylchroman-4-yl) acetic acid (Reference Example 4) Compound obtained in <Step 2> (36.0 g) (Reference Example 3) In the same manner as in <Step 5>, the title compound (31.1 g) was obtained as a pale yellow oil.
<Step 4> Synthesis of (E) -2- (2,2-diethyl-7-trifluoromethylchroman-4-ylidene) acetic acid (Reference Example 4) Compound obtained in <Step 3> (31.1 g) (Reference Example 3) In the same manner as in <Step 4>, the title compound (9.1 g) was obtained as a white solid.

Reference Example 5 Synthesis of (E) -2- (7-trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) acetic acid <Step 1> 7-trifluoromethyl-spiro [chroman Synthesis of -2,1′-cyclobutane] -4 (3H) -one (Reference Example 3) From the compound (90.0 g) obtained in <Step 1> and cyclobutanone (52.7 mL), (Reference Example 3 ) The title compound (134.0 g) was obtained as a brown oil in the same manner as in <Step 2>.
<Step 2> Synthesis of 2- (4-hydroxy-7-trifluoromethyl-spiro [chroman-2,1′-cyclobutane])-4-yl) ethyl acetate (Reference Example 5) obtained in <Step 1> The title crude compound (65.7 g) was obtained as a red-brown oil from the compound (55.0 g) in the same manner as in (Reference Example 3) <Step 3>.
<Step 3> Synthesis of 2- (4-hydroxy-7-trifluoromethyl-spiro [chroman-2,1'-cyclobutane])-4-yl) acetic acid (Reference Example 5) obtained in <Step 2> The title compound (149.2 g) was obtained as a reddish brown gum from the compound (158.0 g) in the same manner as in (Reference Example 3) <Step 5>.
<Step 4> Synthesis of (E) -2- (7-trifluoromethyl-spiro [chroman-2,1′-cyclobutane])-4-ylidene) acetic acid (Reference Example 5) obtained in <Step 3> The title compound (32.1 g) was obtained as a white solid from the compound (149.2 g) in the same manner as in (Reference Example 3) <Step 4>.

Reference Example 6 Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydro-1-naphthol <Step 1> (Rac) -1,2,3,4-tetrahydro-7-nitro- Synthesis of 1-naphthol Sodium borohydride (2.0 g) was added to an ethanol solution (100.0 mL) of 7-nitro-1-tetralone (10.1 g) under ice cooling, and the mixture was stirred at room temperature for 1 hour. . The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (11.0 g).
<Step 2> Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydro-1-naphthol (Reference Example 6) Methanol (100) of the compound (10.2 g) obtained in <Step 1> 0.0 mL) solution was added 10% palladium-carbon (Pd / C) (1.0 g), and the mixture was stirred under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 90: 10-50: 50-20: 80). The title compound (6.5 g) was obtained as a pink solid.

Reference Example 7 Optical resolution of (Rac) -7-amino-1,2,3,4-tetrahydro-1-naphthol Reference Example 6 The compound (5.0 g) obtained in <Step 2> was separated. Preparative chromatography (column: CHIRALPAK IC (5 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent: n-hexane: 2-propanol: methanol: diethylamine = 70: 20: 10: 0.1, flow rate: 32 mL / Min, UV: 295 nm detection) to give each enantiomer of the title compound the first fraction (2.3 g, white solid, 99.2% ee, retention time 6.7 min, [α ] ²⁷ _D = -76.6 ^(c0.1, ethanol) :( enantiomer A: reference example 7- (A)), and a second fraction (2.3 g, white solid, 98.9% ee, Ritenshi Ntaimu 8.1 min, [α] ²⁷ _D = + 89.4 ^(c0.1, Ethanol) :( enantiomer B:.. Obtained as Reference Example 7- (B)) The optical purity was determined by chiral column (column: CHIRALPAK IC (0.46 cm × 25.0 cm) manufactured by Daicel Chemical Industries, Ltd., eluent: n-hexane: 2-propanol: methanol: diethylamine = 70: 20: 10: 0.1, flow rate: 1.0 mL / Min, UV: 295 nm detection).

Reference Example 8 Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydro-2-naphthol <Step 1> (Rac) -7-nitro-1,2,3,4-tetrahydro- Synthesis of 2-naphthol 7-nitro-2-tetralone synthesized according to the method described in Journal of the American Chemical Society, 119, 12722-12726, 1997 To a solution of (9.8 g) in methanol (200.0 mL) and tetrahydrofuran (100.0 mL) was added sodium borohydride (2.9 g) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1N aqueous hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, triturated with ethyl acetate cooled to −60 ° C. and collected by filtration to obtain the title compound (7.2 g).
<Step 2> Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydro-2-naphthol (Reference Example 8) Methanol (120 g) of the compound (7.2 g) obtained in <Step 1> 0.0 mL) solution was added 10% palladium-carbon (Pd / C) (720.0 mg), and the mixture was stirred for 6 hours under a hydrogen gas atmosphere. The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was triturated with diethyl ether and collected by filtration to obtain the title compound (5.8 g) as a pink solid.

Reference Example 9 Optical resolution of (Rac) -7-amino-1,2,3,4-tetrahydro-2-naphthol (Reference Example 8) The compound (5.0 g) obtained in <Step 2> was separated. Preparative chromatography (Column: CHIRALPAK IC (5 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent; n-hexane: ethanol: diethylamine = 80: 20: 0.1, flow rate: 47 mL / min, UV: 295 nm detection ) To give each enantiomer of the title compound as the first fraction (2.3 g, white solid, 99.9% ee, retention time 7.9 minutes, [α] ^27.5 _D = +72.6 (c0.1, ethanol): (Enantiomer A: Reference Example 9- (A)), and the second fraction (2.3 g, white solid, 99.9% ee, retention time 9.9 minutes, α] ^27.5 _D = -89.7 ^(c0.1, ethanol)..: was obtained as a (enantiomer B Example 9-(B)) The optical purity was determined by chiral column (column: manufactured) Daicel Chemical CHIRALPAK IC (0.46 cm × 25.0 cm) manufactured by Kogyo Co., Ltd., eluent ;: n-hexane: ethanol: diethylamine = 80: 20: 0.1, flow rate: 1.0 mL / min, UV: 295 nm detection).

Reference Example 10 Synthesis of (Rac) -6-amino-2,3-dihydro-1H-inden-1-ol <Step 1> (Rac) -2,3-dihydro-6-nitro-1H-indene- Synthesis of 1-ol 2,3-Dihydro-6-nitro synthesized according to the method described in The Journal of Organic Chemistry, 54, 1354-1359, 1989 In the same manner as in (Reference Example 6) <Step 1>, the title crude compound (10.4 g) was obtained as a red-brown solid from -1H-inden-1-one (10.0 g).
<Step 2> Synthesis of (Rac) -6-amino-2,3-dihydro-1H-inden-1-ol (Reference Example 6) In the same manner as in <Step 2>, (Reference Example 10) <Step 1 The title compound (6.8 g) was obtained as a white solid from the compound (10.1 g) obtained in>.

Reference Example 11 Optical Resolution of (Rac) -6-Amino-2,3-dihydro-1H-inden-1-ol Reference Example 10 The compound (5.0 g) obtained in <Step 2> was separated. Optical resolution using preparative chromatography (column: CHIRALPAK IC (5 cm × 25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent; acetonitrile: diethylamine = 100: 0.1, flow rate: 47 mL / min, UV: 301 nm detection) To give each enantiomer of the title compound as the first fraction (2.2 g, white solid, 99.6% ee, retention time 4.2 minutes, [α] ²⁹ _D = −49.8 (c0.1 , Ethanol): (Enantiomer A: Reference Example 11- (A)), and second fraction (2.4 g, white solid, 99.6% ee, retention time 5.7 minutes, [α] ²⁹ _D = + 46.8 (c0.1, ethanol): (enantiomer B: Reference Example 11- (B)) Optical purity was determined with a chiral column (column: CHIRALPAK IC (0) manufactured by Daicel Chemical Industries, Ltd.) .46 cm × 25.0 cm), eluent: acetonitrile: diethylamine = 100: 0.1, flow rate: 1.0 mL / min, UV: 301 nm detection).

Reference Example 12 Synthesis of (Rac) -4-amino-2,3-dihydro-1H-inden-2-ol <Step 1> (Rac) -4-nitro-2,3-dihydro-1H-indene- Synthesis of 1-ol 2,3-dihydro-4-nitro synthesized according to the method described in The Journal of Organic Chemistry, 52, 1649-1655, 1987 In the same manner as in (Reference Example 6) <Step 1>, the title crude compound (15.0 g) was obtained as a red-brown solid from -1H-inden-1-one (14.0 g).
<Step 2> Synthesis of 7-nitro-1H-indene (Reference Example 12) p-Toluenesulfonic acid monohydrate in a toluene (500.0 mL) solution of the compound (14.2 g) obtained in <Step 1> (4.7 g) was added and heated to reflux for 13 hours. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude compound was triturated with n-hexane: diethyl ether = 1: 1 and collected by filtration to obtain the title compound (8.8 g) as a pale yellow solid.
<Step 3> Synthesis of 1a, 6a-dihydro-5-nitro-6H-indeno [1,2-b] oxylene (Reference Example 12) Compound (13.0 g) of dichloromethane (520) obtained in <Step 2> 0.0 mL) solution was added m-chloroperbenzoic acid (48.8 g) under ice-cooling and stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (14.7 g) as a white solid.

<Step 4> Synthesis of 2,3-dihydro-4-nitro-1H-inden-2-one (Reference Example 12) A solution of the compound (14.3 g) obtained in <Step 3> in toluene (260.0 mL) To the solution, zinc iodide (12.9 g) was added and heated under reflux for 1 hour. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate at room temperature, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was triturated with n-hexane: diethyl ether = 2: 1 and collected by filtration to obtain the title compound (12.3 g) as a pale red solid.
<Step 5> Synthesis of (Rac) -2,3-dihydro-4-nitro-1H-inden-2-ol (Reference Example 6) In the same manner as in <Step 1>, (Reference Example 12) <Step 4 > The title crude compound (9.0 g) was obtained as an orange solid from the compound obtained in (13.0 g).
<Step 6> Synthesis of (Rac) -4-amino-2,3-dihydro-1H-indene-2-ol (Reference Example 6) In the same manner as in <Step 2>, (Reference Example 12) < The title compound (2.3 g) was obtained as an orange solid from the compound (9.0 g) obtained in Step 5>.

Reference Example 13 Optical Resolution of (Rac) -4-Amino-2,3-dihydro-1H-inden-2-ol (Reference Example 12) The compound (4.8 g) obtained in <Step 6> was separated. Preparative chromatography (Column: CHIRALPAK AD-H (5 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent: n-hexane: 2-propanol: methanol: diethylamine = 80: 15: 5: 0.1, flow rate: Each enantiomer of the title compound was subjected to optical resolution using 47 mL / min, UV: 237 nm detection) to give the first fraction (2.1 g, white solid, 99.5% ee, retention time 8.6 min) [α] ²⁹ _D = -27.1 ^(c0.1, ethanol)) :( enantiomer A: reference example 13-(A)), and a second fraction (2.2 g, white solid, 98.2% ee Retention time 9.6 minutes, [α] ²⁹ _D = + 38.9 ^(c0.1, Ethanol) :( enantiomer B:.. Obtained as Reference Example 13-(B)) The optical purity was determined by chiral column (column : CHIRALPAK AD-H (0.46 cm × 25.0 cm), manufactured by Daicel Chemical Industries, Ltd., eluent; n-hexane: 2-propanol: methanol: diethylamine = 80: 15: 5: 0.1, flow rate: 1 0 mL / min, UV: 237 nm detection)

In this specification, in the above (Reference Example 7), (Reference Example 9), (Reference Example 11), and (Reference Example 13), the racemate is subjected to preparative chromatography using a column for optical isomer separation. The enantiomer obtained as the first fraction was represented by (A), and the enantiomer obtained as the second fraction was represented by (B).
When (A) and (B) are used in the names of the following examples, the compounds of the formula (I) obtained by using the enantiomeric amine compound (A) or (B) obtained by the fractionation are used. It represents an Example compound.

Example 1
Synthesis of (E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A) Reference Example 7 -(A): An optically active amine (40.0 mg) of the enantiomer (A) and (Reference Example 2) a solution of the carboxylic acid (77.0 mg) obtained in <Step 5> in methanol (4.0 mL) -(4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM) (101.1 mg) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water and dissolved in ethyl acetate, and then gradually added n-hexane, and the precipitated solid was collected by filtration and dried to give the title compound (61. 0 mg) was obtained as a white solid.

(Reference Example 1) <Step 5>, (Reference Example 2) <Step 5>, (Reference Example 3) <Step 5>, (Reference Example 4) <Step 4>, (Reference Example 5) <Step 4> The obtained carboxylic acid, and (Reference Example 7- (A)), (Reference Example 7- (B)), (Reference Example 9- (A)), (Reference Example 9- (B)), (Reference Example) 11- (A)), (Reference Example 11- (B)), and (Reference Example 13- (B)) were obtained from the optically active amines in the same manner as in Example 1 to obtain the following Example compounds. Example compounds obtained by using the optically active amines of (Reference Example 7- (A)), (Reference Example 9- (A)), and (Reference Example 11- (A)) used here were each Example compounds. (A) and the optically active amines of (Reference Example 7- (B)), (Reference Example 9- (B)), (Reference Example 11- (B)), and (Reference Example 13- (B)) were used. The Example compound obtained in this manner was used as Example compound (B).

(Example 2)
(E) -2- (2,2-Dimethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A The title compound was synthesized from the optically active amine of (Reference Example 7-A) and the carboxylic acid obtained in (Reference Example 3) <Step 5>.
(Example 3)
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A The title compound was synthesized from the optically active amine of (Reference Example 7-A) and the carboxylic acid obtained in (Reference Example 4) <Step 4>.
Example 4
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (B The title compound was synthesized from the optically active amine of (Reference Example 7-B) and the carboxylic acid obtained in (Reference Example 4) <Step 4>.
(Example 5)
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) Synthesis of Acetamide (A) The title compound was synthesized from the optically active amine of (Reference Example 7-A) and the carboxylic acid obtained in (Reference Example 5) <Step 4>.

(Example 6)
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) Synthesis of Acetamide (B) The title compound was synthesized from the amine obtained by the optical activity of (Reference Example 7-B) and the carboxylic acid obtained in (Reference Example 5) <Step 4>.
(Example 7)
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A The title compound was synthesized from the optically active amine of (Reference Example 9-A) and the carboxylic acid obtained in (Reference Example 4) <Step 4>.
(Example 8)
(E) -2- (2,2-diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (B The title compound was synthesized from the optically active amine of (Reference Example 9-B) and the carboxylic acid obtained in (Reference Example 4) <Step 4>.
Example 9
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) Synthesis of Acetamide (A) The title compound was synthesized from the optically active amine of Reference Example 9-A and the carboxylic acid obtained in Reference Example 5 <Step 4>.
(Example 10)
Synthesis of (E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (A) (Reference Example 11 The title compound was synthesized from the optically active amine of -A) and the carboxylic acid obtained in (Reference Example 2) <Step 5>.
Example 11
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (A) The title compound was synthesized from the optically active amine of (Reference Example 11-A) and the carboxylic acid obtained in (Reference Example 4) <Step 4>.

(Example 12)
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (B) The title compound was synthesized from the optically active amine of (Reference Example 11-B) and the carboxylic acid obtained in (Reference Example 4) <Step 4>.
(Example 13)
(E) -2- (3,4-Dihydro-8-trifluoromethyl-1-benzooxepin-5 (2H) -ylidene) -N- (2,3-dihydro-2-hydroxy-1H-indene-4- Yl) Synthesis of Acetamide (B) The title compound was synthesized from the optically active amine of Reference Example 13-B and the carboxylic acid obtained in Reference Example 1 <Step 5>.
(Example 14)
Synthesis of (E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) (Reference Example 13 The title compound was synthesized from the optically active amine of -B) and the carboxylic acid obtained in (Reference Example 2) <Step 5>.
(Example 15)
(E) -2- (2,2-Dimethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) The title compound was synthesized from the optically active amine of (Reference Example 13-B) and the carboxylic acid obtained in (Reference Example 3) <Step 5>.
(Example 16)
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) The title compound was synthesized from the optically active amine of (Reference Example 13-B) and the carboxylic acid obtained in (Reference Example 4) <Step 4>.
(Example 17)
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl ) Synthesis of Acetamide (B) The title compound was synthesized from the optically active amine of (Reference Example 13-B) and the carboxylic acid obtained in (Reference Example 5) <Step 4>.

The structures of the compounds synthesized in (Example 1) to (Example 17) above are [Compound List 1], intermediates synthesized in (Reference Example 1) to (Reference Example 5), and (Reference Example 6). The structure of the intermediate synthesized in (Reference Example 12) is shown in [Compound List 2]. LC Mass data is shown in Table 3. The NMR data of Examples and Reference Examples are shown in Tables 4 and 5 (400 MHz: no mark, 300 MHz: * mark, 270 MHz: ** mark).

[Compound List 1]

[List of compounds 2]

Claims

Formula (I)

(Wherein, m represents an integer of 1 or 2, n represents an integer of 0 or 1, R 1 and R 2 each independently represent a hydrogen atom or a C 1 ~ 2 alkyl group, R 1 And R 2 may form a cyclo ring together with the carbon atom to which each is bonded, and the configuration of the hydroxyl group is one of the enantiomers, and the broken lines and α, β, 1 and 2 are , —OH or —NH— and the bonding position of each carbon atom on the ring, provided that the bonding position of —NH— is the 1st position, n is 0 and the bonding position of the hydroxyl group is the β position. Or a salt thereof or a solvate thereof.
(E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A);
(E) -2- (2,2-Dimethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A );
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A );
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (B );
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) acetamide (A);
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) acetamide (B);
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (A );
(E) -2- (2,2-diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acetamide (B );
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-7- Yl) acetamide (A);
(E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (A);
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (A) ;
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acetamide (B) ;
(E) -2- (3,4-Dihydro-8-trifluoromethyl-1-benzooxepin-5 (2H) -ylidene) -N- (2,3-dihydro-2-hydroxy-1H-indene-4- Yl) acetamide (B);
(E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B);
(E) -2- (2,2-Dimethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) ;
(E) -2- (2,2-Diethyl-7-trifluoromethylchroman-4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acetamide (B) ;
(E) -2- (7-Trifluoromethyl-spiro [chroman-2,1′-cyclobutane] -4-ylidene) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl Acetamide (B)
The compound of Claim 1 selected from these, its salt, or those solvates.
A pharmaceutical composition comprising at least one of the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. .
TRPV1 (Transient), comprising as an active ingredient at least one of the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof. Receptor Potential Vanilloid Type I) receptor antagonist.