WO2010010935A1 - Dérivé de n-arylacétamide d’hétérocyclidène optiquement actif - Google Patents

Dérivé de n-arylacétamide d’hétérocyclidène optiquement actif Download PDF

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Publication number
WO2010010935A1
WO2010010935A1 PCT/JP2009/063221 JP2009063221W WO2010010935A1 WO 2010010935 A1 WO2010010935 A1 WO 2010010935A1 JP 2009063221 W JP2009063221 W JP 2009063221W WO 2010010935 A1 WO2010010935 A1 WO 2010010935A1
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compound
formula
ylidene
hydroxy
acetamide
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PCT/JP2009/063221
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English (en)
Japanese (ja)
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秀春 内田
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持田製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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,
  • TRPV1 receptor Transient Receptor Potential Vanilloid Type I receptor
  • 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.
  • TRPV1 receptor the receptor of capsaicin (8-methyl-N-vanillyl-6-nonanamide), the main pungent component of chili pepper.
  • capsaicin 8-methyl-N-vanillyl-6-nonanamide
  • 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.
  • 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).
  • TRPV1 receptor modulator that regulates the function of the TRPV1 receptor is expected.
  • 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.
  • 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. 2.
  • 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.
  • 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.
  • NGF nerve growth factor
  • 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.
  • 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).
  • NSAIDs nerve block therapy
  • opioid agonists drugs such as nerve block therapy, NSAIDs, antiepileptic drugs and opioid agonists
  • each drug used is, for example, NSAIDs
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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").
  • 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).
  • central neuropathic drugs such as morphine, non-steroidal anti-inflammatory analgesics and steroids are considered to be ineffective for neuropathic pain.
  • antidepressants such as amitriptyline
  • anti-arrhythmic drugs such as gabapentin, pregabalin, carbamazepine, phenytoin, and mexiletine are diverted and prescribed.
  • these drugs have side effects such as dry mouth, drowsiness, sedation, constipation, difficulty in urinating, etc.
  • heterocyclic compound having an amide bond examples 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.
  • Patent Document 15 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.
  • 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.
  • 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.
  • NMDA N-methyl-D-aspartate
  • 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.
  • Patent Documents 15 to 20 and Non-Patent Documents 1 to 3 disclose or suggest an antagonistic action of the TRPV1 receptor.
  • 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)).
  • hERG human ether-a-go-go related
  • hERG human ether-a-go-go related
  • problems of usefulness and safety such as exhibiting channel inhibitory activity or poor pharmacokinetics such as absorption and sustainability.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the chain group refers to a "structure having a carbon number 1 to a straight or branched chain 6 '.
  • 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.
  • 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 ⁇ , ⁇ , 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 ⁇ position. Or a salt thereof or a solvate thereof.
  • 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.
  • 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.
  • 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.
  • R 1 and R 2 are the same and more preferably a hydrogen atom, a methyl group, or an ethyl group.
  • 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.
  • m is an integer of 1 or 2.
  • 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.
  • R 1 and R 2 are the same and are preferably a hydrogen atom.
  • n 0 or 1
  • the configuration of the hydroxyl group represents any enantiomer
  • the broken line represents a bond to any carbon atom.
  • ⁇ , ⁇ , 1 and 2 represent broken bond positions.
  • n 0
  • the hydroxyl group bond position is the ⁇ position.
  • n is preferably 0 or 1.
  • the bonding position of [1-3-b] -NH— is at the 2-position and the bonding position of the hydroxyl group is at the ⁇ -position
  • n is preferably 1.
  • examples of the moiety of the following formula (III) having a hydroxyl group include the following formulas (III-1) to (III-4):
  • 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).
  • 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.
  • (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>.
  • the enantiomer obtained as the first fraction is represented as (A)
  • the enantiomer obtained as the second fraction is represented as (B).
  • 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.
  • Examples of preferable compounds include the following.
  • 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.
  • 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.
  • 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,
  • TRPV1 receptor agonists compounds 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.
  • COPD
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a more preferable substituent or a combination thereof is the first aspect. It is described in.
  • TRPV1 receptor antagonistic activity for example, Experimental Example (1)-(b) described later: measurement of Ca inflow using FDSS-6000
  • the “therapeutic agent” is intended to include not only treatment of a disease or symptom but also improvement of the disease or symptom.
  • the pharmaceutically acceptable salt is also referred to.
  • 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 may form an acid addition salt.
  • a salt with a base may be formed.
  • Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • 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-hydroxyethan
  • 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.
  • this invention compound or its salt can form solvates with solvents, such as water, ethanol, and glycerol.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention is not limited to the manufacturing method described below. Hereinafter, the production method will be described in detail.
  • 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
  • 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 he
  • 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.
  • 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.
  • 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.
  • the reaction is carried out at a temperature at which the solvent is refluxed from the formula (A).
  • a solvent inert 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.
  • DIBAH diisobutylaluminum hydride
  • Li triethoxyaluminum hydride lithium triethoxyaluminum hydride
  • sodium bis (2-methoxyethoxy) aluminum hydride Raney nickel (Raney-Ni) -formic acid
  • a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water, methanol, ethanol, 2-propanol.
  • 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
  • PPA polyphosphoric acid
  • PPE polyphosphoric acid ethyl ester
  • P 2 O 5 diphosphorus pentoxide
  • Eaton's reagent mixture of methanesulfonic acid and diphosphorus pentoxide
  • 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.
  • halogen solvents such as dichloromethane and chloroform
  • ether solvents
  • 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.
  • 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.
  • halogen solvents such as dichloromethane and chloroform.
  • 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 ⁇ -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.
  • a silyl acetate such as ethyl trimethylsilyl acetate and
  • 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).
  • 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>.
  • 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>.
  • 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>.
  • 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>.
  • 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>.
  • 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)
  • 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.
  • the compound of formula (D-III) is reacted at a temperature from 0 ° C. to the reflux of the solvent. Can be manufactured.
  • 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
  • DIBAH diisobutylaluminum hydride
  • 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.
  • 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.
  • alcohol solvents such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran, 1,2-dimethoxy
  • 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.
  • 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.
  • 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.
  • 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).
  • 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)
  • a base reagent such as optically active dichloro [bis (diphenylphosphino) binaphthyl] [diphenylethylenediamine] ruthenium and potassium hydroxide, potassium tert-butoxide
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of formula (E-VII) can be produced by the same method as in (Production Method D) ⁇ Step 2>.
  • the compound of formula (VI-a) can be produced by the same method as in (Production Method D) ⁇ Step 4>.
  • 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.
  • the first fraction of each enantiomer obtained is (A) and the second fraction is (B).
  • 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.
  • a catalyst such as carbon (Pd—C), Raney nickel (Raney-Ni), platinum oxide or the like
  • an alcohol solvent such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran, etc.
  • the solvent is refluxed from
  • the compound of the formula (E-VII) can also be produced by carrying out the reaction at a temperature at which
  • 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>.
  • 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.
  • 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.
  • 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>.
  • the hydroxyl group bonded to the carbon bond marked with * indicates any configuration.
  • the first fraction of each enantiomer obtained is represented by (A)
  • the intermediate formula (F-VIII) can also be produced according to the following method.
  • 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>.
  • 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>.
  • the first fraction of each enantiomer obtained is represented by (A), the second Let the fraction be (B).
  • 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>.
  • 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>.
  • the hydroxyl group bonded to the carbon bond marked with * indicates any configuration.
  • the first fraction of each enantiomer obtained is represented by (A), the second Let the fraction be (B).
  • 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 can be used in combination with other drugs.
  • 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.
  • TRPV1 other than pain
  • NSAIDs a drug used in each region
  • DMARDs a drug used in each region
  • anti-TNF ⁇ antibodies soluble TNF ⁇ receptors
  • steroids immunosuppressants and the like that are commonly used in chronic rheumatoid arthritis
  • COPD and allergic diseases it can be used in combination with general therapeutic agents such as ⁇ 2 receptor agonists and steroids.
  • overactive bladder and urinary incontinence it can be combined with anticholinergic drugs.
  • 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.
  • 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.
  • the compound of the present invention when 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.
  • 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.
  • 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; cellulose
  • Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir.
  • 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.
  • 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 ⁇ L 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.
  • 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).
  • 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.
  • 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.
  • primates for example, various monkeys, chimpanzees, etc.
  • 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
  • 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).
  • 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
  • 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.
  • HPC hydroxypropylcellulose
  • Example 7 Cream Compound of Example 1 0.5 g 0.1 g of dl- ⁇ -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.
  • ⁇ 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.
  • 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
  • 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 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.
  • ⁇ 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.
  • ⁇ 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 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>.
  • 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 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.
  • 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 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 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>.

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Abstract

Cette invention concerne un composé de formule (I) [m vaut 1 ou 2 ; n vaut 0 ou 1 ; R1 et R2 représentent indépendamment H ou un groupe alkyle en C1-2 ou peut avec un atome de carbone auquel R1 et R2 sont tous les deux attachés, former un cycle cyclo ; la configuration du groupe hydroxyle représente l’un des énantiomères ; les tirets, α, β, 1 et 2 représentent indépendamment la position à laquelle chacun de –OH et –NH- et un atome de carbone sur le cycle sont liés les uns aux autres, dans la mesure où n vaut 0 et la position de la liaison du groupe hydroxyle est la position β lorsque la position de liaison de –NH- est la position 1], un sel du composé, un solvate du composé ou le sel ; et une composition pharmaceutique et un antagoniste du récepteur TRPV1 comprenant chacun le composé, le sel ou le solvate comme principe actif.
PCT/JP2009/063221 2008-07-23 2009-07-23 Dérivé de n-arylacétamide d’hétérocyclidène optiquement actif WO2010010935A1 (fr)

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US7910751B2 (en) 2005-07-22 2011-03-22 Mochida Pharmaceutical Co., Ltd. Heterocyclidene acetamide derivative
WO2013096226A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
WO2013096223A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
US8796328B2 (en) 2012-06-20 2014-08-05 Abbvie Inc. TRPV1 antagonists
US8802711B2 (en) 2011-03-25 2014-08-12 Abbvie Inc. TRPV1 antagonists
CN110831930A (zh) * 2017-05-31 2020-02-21 持田制药株式会社 杂环亚基乙酰胺衍生物的晶体
CN114206847A (zh) * 2019-08-23 2022-03-18 持田制药株式会社 杂环亚基乙酰胺衍生物的制造方法

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7910751B2 (en) 2005-07-22 2011-03-22 Mochida Pharmaceutical Co., Ltd. Heterocyclidene acetamide derivative
US8383839B2 (en) 2005-07-22 2013-02-26 Mochida Pharmaceutical Co., Ltd. Heterocyclidene acetamide derivative
US8802711B2 (en) 2011-03-25 2014-08-12 Abbvie Inc. TRPV1 antagonists
WO2013096226A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
WO2013096223A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
US8859584B2 (en) 2011-12-19 2014-10-14 Abbvie, Inc. TRPV1 antagonists
US8969325B2 (en) 2011-12-19 2015-03-03 Abbvie Inc. TRPV1 antagonists
US8796328B2 (en) 2012-06-20 2014-08-05 Abbvie Inc. TRPV1 antagonists
CN110831930A (zh) * 2017-05-31 2020-02-21 持田制药株式会社 杂环亚基乙酰胺衍生物的晶体
CN110831930B (zh) * 2017-05-31 2023-04-28 持田制药株式会社 杂环亚基乙酰胺衍生物的晶体
CN114206847A (zh) * 2019-08-23 2022-03-18 持田制药株式会社 杂环亚基乙酰胺衍生物的制造方法

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