[go: up one dir, main page]

WO2010010933A1 - Dérivé d’acétamide d’hétérocyclidène-n-(3,4-dihydro-2(1h)-quinazolin-5-yl) - Google Patents

Dérivé d’acétamide d’hétérocyclidène-n-(3,4-dihydro-2(1h)-quinazolin-5-yl) Download PDF

Info

Publication number
WO2010010933A1
WO2010010933A1 PCT/JP2009/063215 JP2009063215W WO2010010933A1 WO 2010010933 A1 WO2010010933 A1 WO 2010010933A1 JP 2009063215 W JP2009063215 W JP 2009063215W WO 2010010933 A1 WO2010010933 A1 WO 2010010933A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
dihydro
ylidene
acetamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2009/063215
Other languages
English (en)
Japanese (ja)
Inventor
秀春 内田
真一 小川
宗義 真壁
能崇 前田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mochida Pharmaceutical Co Ltd
Original Assignee
Mochida Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mochida Pharmaceutical Co Ltd filed Critical Mochida Pharmaceutical Co Ltd
Publication of WO2010010933A1 publication Critical patent/WO2010010933A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

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 N- (3,4-dihydro having a heterocyclidene skeleton. -2 (1H) -quinazolinone-5-yl) acetamide derivative, a TRPV1 receptor antagonist containing the derivative as an active ingredient, or a prophylactic or therapeutic agent for diseases involving TRPV1 receptor including pain.
  • TRPV1 receptor Transient Receptor Potential Vanilloid Type I receptor
  • 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 the TRPV1 receptor to the living body has been clarified from many reports, and in particular, mice lacking the 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 present inventors have 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 showing channel inhibitory activity or poor pharmacokinetics.
  • problems 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.
  • 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.
  • the present invention relates to a compound having an action of regulating the function of TRPV1 receptor, particularly heterocyclidene-N- (3,4-dihydro-2 (1H) -quinazolinon-5-yl) represented by the formula (I)
  • An acetamide derivative or a pharmaceutically acceptable salt thereof or a solvate thereof, a TRPV1 receptor modulator containing the derivative as an active ingredient, in particular, a TRPV1 receptor antagonist, or a prophylactic or therapeutic agent for pain In particular, it comprises an agent for preventing or treating neuropathic pain, an agent for preventing or treating fibromyalgia, and an agent for preventing or treating inflammatory pain.
  • This compound group has an excellent function of regulating the function of TRPV1 receptor, and this compound group has high metabolic stability, excellent oral absorption, good solubility, or increased body temperature. It has been found that it has at least one or more characteristics such as absence (particularly, little body temperature change).
  • 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 provides a heterocyclidene-N- (3,4-dihydro-2 (1H) -quinazolinon-5-yl) acetamide derivative represented by the formula (I) shown in the following embodiment or a salt thereof, It is a pharmaceutical composition as an active ingredient, and a pharmaceutical use of the derivative or a salt thereof.
  • each aspect of the present invention will be described.
  • 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.
  • a first aspect of the present invention is the following formula (I) (Wherein, m represents an integer of 0 or 1, R 1 represents a C 1 ⁇ 2 alkyl group, R 2 and R 3 are each independently substituted with hydrogen atom or a hydroxyl or C 1 ⁇ 2 alkoxy group or is represent an C 1 ⁇ 4 alkyl group optionally, R 2 and R 3 may form a cycloalkyl ring of 4-6 membered together with the carbon atom to which each is attached, the cyclic ring May contain one oxygen atom and Z Represents a methylene group, an ethylene group or —NH—.
  • formula (I) wherein, m represents an integer of 0 or 1, R 1 represents a C 1 ⁇ 2 alkyl group, R 2 and R 3 are each independently substituted with hydrogen atom or a hydroxyl or C 1 ⁇ 2 alkoxy group or is represent an C 1 ⁇ 4 alkyl group optionally, R 2 and R 3 may form a cycloalkyl
  • 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 represents a C 1 ⁇ 2 alkyl group, methyl group or ethyl group.
  • R 2 and R 3 are each a hydrogen atom or a hydroxyl or C 1 ⁇ 2 alkoxy optionally substituted C 1 ⁇ 4 alkyl group with a group R 2 and R 3 may form a 4- to 6-membered cyclo ring together with the carbon atom to which each is bonded, and the cyclo ring may contain one oxygen atom Good.
  • the C 1 ⁇ 2 alkoxy groups include methoxy or ethoxy group.
  • the C 1 ⁇ 4 alkyl group e.g., methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- butyl group, etc.
  • R 2 and R 3 may form a 4- to 6-membered cyclo ring together with the carbon atom to which each is bonded, and the cyclo ring may contain one oxygen atom.”
  • a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring and the like can be mentioned.
  • R 2 and R 3 are each independently a hydrogen atom or a hydroxyl or C 1 - 2 optionally C 1 be alkoxy groups substituted 1-2 alkyl group, specifically Specific examples include a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.
  • “R 2 and R 3 may form a 4- to 6-membered cyclo ring together with the carbon atom to which each is bonded, and the cyclo ring may contain one oxygen atom.
  • R 2 and R 3 are identical, substituted with hydrogen atom or C 1 ⁇ 2 alkoxy group is also optionally C 1 ⁇ 2 alkyl group, specifically Includes a hydrogen atom, a methyl group, an ethyl group, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.
  • R 2 and R 3 may form a 4- to 6-membered cyclo ring together with the carbon atom to which each is bonded, and the cyclo ring may contain one oxygen atom.
  • a cyclobutane ring, a tetrahydropyran ring and the like are more preferable.
  • R 2 and R 3 are the same and are particularly preferably a hydrogen atom, a methyl group, an ethyl group, a methoxymethyl group, or a methoxyethyl group.
  • R 2 and R 3 together with the carbon atom to which each is bonded form a 4- to 6-membered cyclo ring, and the cyclo ring may particularly contain one oxygen atom,
  • An example is a tetrahydropyran ring.
  • Z I is a methylene group, an ethylene group or —NH—.
  • Z I is a methylene group, an ethylene group or —NH—.
  • 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.
  • the 2-1 aspect of the present invention includes the formula (Ia), the formula (Ib), the formula (Ic), the formula (Id), and the formula (Ie). At least one of the compound represented by the formula (If), the formula (Ig) or the formula (Ih), or a pharmaceutically acceptable salt thereof, or a solvate thereof. 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.
  • the 3-1 aspect of the present invention includes the formula (Ia), the formula (Ib), the formula (Ic), the formula (Id), and the formula (Ie). At least one of the compound represented by the formula (If), the formula (Ig) or the formula (Ih), or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a TRPV1 receptor antagonist characterized by containing 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, There are compounds (TRPV1 receptor agonists) that desensitize the nerve in which the receptor is present, thereby inhibiting subsequent activation of the receptor.
  • 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.
  • 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.
  • the 4-1 aspect of the present invention includes the formula (Ia), the formula (Ib), the formula (Ic), the formula (Id), and the formula (Ie). At least one of the compound represented by the formula (If), the formula (Ig) or the formula (Ih), or a pharmaceutically acceptable salt thereof, or a solvate thereof. Is an agent for preventing and / or treating pain.
  • a fifth aspect of the present invention contains at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the 5-1 aspect of the present invention includes the formula (Ia), the formula (Ib), the formula (Ic), the formula (Id), and the formula (Ie). At least one of the compound represented by the formula (If), the formula (Ig) or the formula (Ih), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Is a preventive and / or therapeutic agent for neuropathic pain characterized by comprising
  • 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 includes the formula (Ia), the formula (Ib), the formula (Ic), the formula (Id), and the formula (Ie). At least one of the compound represented by the formula (If), the formula (Ig) or the formula (Ih), or a pharmaceutically acceptable salt thereof, or a solvate thereof. Is a prophylactic and / or therapeutic agent for inflammatory pain, characterized by containing.
  • the formula (Ia), the formula (Ib), the formula (Ic), the formula (Id), the formula (Id), In the compound represented by Ie), the formula (If), the formula (Ig), or the formula (Ih), preferred substituents or combinations thereof are described in the first embodiment.
  • the TRPV1 receptor antagonistic activity for example, experimental examples (1) to (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.
  • Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Compounds of formula (Ig) or formula (Ih) may form acid addition salts.
  • 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-hydroxyethanesul
  • 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 the formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (I) It includes hydrates of compounds represented by If), formula (Ig) or formula (Ih), various pharmaceutically acceptable solvates and crystal polymorphs, and the like.
  • the present invention is not limited to the compounds described in the examples below, and the formula (I), formula (Ia), formula (Ib), formula (I- c), a compound represented by formula (Id), formula (Ie), formula (If), formula (Ig) or formula (Ih) or a pharmaceutically acceptable salt thereof Is included.
  • 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, it is represented by formula (I), formula (Ih), formula (V), formula (Va), formula (Vb), formula (Vc), or formula (VI). Unless otherwise specified, Z, R 1 , R 2 , R 3 , and m in the compound are the same as defined above in formula (I).
  • R A is an alkyl group
  • R B is hydrogen or an alkyl group
  • M is a metal such as Li, Na, K, and Zn
  • X and Y are leaving substituents such as halogen
  • Me is a methyl group.
  • 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 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
  • 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.
  • reaction formula B ⁇ Step 1>
  • a compound of formula (VIII) can be produced by a method according to (Reaction Scheme A) using a compound of formula (VII).
  • a dialkyl group such as a dimethyl group, a diethyl group, a cycloalkyl group or the like is converted into a method known in the literature, for example, Greene et al.
  • a compound of the formula (X) is produced by introducing R 2 and R 3 groups by the method described in the documents of Organic Groups (Protective Groups in Organic Synthesis), (USA), 3rd edition, 1999, etc. can do.
  • Step 3> In accordance with a method known in the literature using a compound of the formula (X), for example, a method described in Bullen Society Society Belgium (Bull. Soc. Chim. Belg.), 87, 229, 1978. (Toluene, benzene, xylene, 1,2-dimethoxyethane, dichloromethane in the presence of (2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide) , 1,2-dichloroethane, chloroform, hexamethylphosphoric triamide and the like, or a mixed solvent thereof, and the reaction is carried out at a temperature at which the solvent refluxes from 0 ° C.
  • Step 4> Using a compound of formula (XI) and a compound of formula (XII), methods known in the literature, for example, Synlett, No. 11, 1171-1118, 1996, etc., in the presence of a base such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, acetonitrile, 1,4-dioxane, tetrahydrofuran , Benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform and the like, or a mixed solvent thereof, and the reaction is carried out at a temperature from which the solvent is refluxed to obtain a compound of the formula (XIII) Can be manufactured.
  • a base such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, acetonitrile, 1,4-dio
  • phosphine reagents such as triphenylphosphine and tributylphosphine
  • phosphines such as trimethylphosphite, triethylphosphite, tripropylphosphite and tributylphosphite.
  • a compound of formula (Ih) is produced by reacting at a temperature at which the solvent is refluxed from room temperature in the presence of a base such as a phyto-based reagent, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine and the like. Can do.
  • a base such as a phyto-based reagent, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine and the like.
  • the compound of formula (V) in the above reaction formula is prepared by the following (Production Method A) to (Production Method C), and the compound of Formula (VI) is prepared by the following (Production Method D) to (Production Method E). Can do.
  • a compound of formula (AI) and a compound 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-dioxan
  • Step 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 a palladium catalyst such as palladium (II) acetate, tetrakistriphenylphosphine palladium, trisdibenzylideneacetone dipalladium, and silver carbonate, Reaction is performed at a temperature at which the solvent is refluxed using a solvent inert to the reaction such as acetonitrile, 1,4-dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, N, N-dimethylformamide, or a mixed solvent thereof. To produce a compound of formula (A-IV).
  • a palladium catalyst such as palladium (II) acetate, tetrakistriphenylphosphine palladium, trisdibenzylideneace
  • 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 refluxes 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 sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, methanol, ethanol, acetone, N, N-dimethylformamide
  • 1,4 -A compound of 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 the like, or a mixed solvent thereof.
  • a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water, methanol, ethanol, 2-propanol.
  • ⁇ Step 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.
  • 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
  • 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 such as diethyl ether and tetrahydrofuran
  • aromatic hydrocarbon solvents such as toluene and benzene.
  • Producing a compound of formula (BV) by reacting at temperature Kill. 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 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>.
  • a 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 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 May be substituted with 1 to 5 groups optionally selected from an alkoxyl group, an amino group optionally substituted with 1 to 2 alkyl groups of C 1 to 3 , or R 2 , R 3 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 is substituted with a C 1-3 straight or branched alkyl group which may be substituted with one to three halogen atoms, —OH, —OCH 3 , or —OCF 3.
  • Step 3> In accordance with a method known in the literature using a compound of formula (D-III), for example, the method described in Journal of Medicinal Chemistry, 25 (6), 735-742, 1982.
  • a carbonylating reagent such as urea, 1,1'-carbonylbis-1H-imidazole, triphosgene N, N-d
  • the compound of the formula (D-IV) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using these mixed solvents.
  • a catalyst such as palladium-carbon (Pd—C), Raney nickel (Raney-Ni), dichlorotristriphenylphosphine ruthenium, etc.
  • a catalyst such as palladium-carbon (Pd—C), Raney nickel (Raney-Ni), dichlorotristriphenylphosphine ruthenium, etc.
  • a catalyst such as palladium-carbon (Pd—C), Raney nickel (Raney-Ni), dichlorotristriphenylphosphine ruthenium, etc.
  • methanol ethanol
  • 2- Alcohol solvents such as propanol, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, polar solvent
  • the compound of formula (VI) can also be produced by reacting in concentrated hydrochloric acid or acetic acid in the presence of iron (Fe) and tin (Sn) at a temperature at which the solvent refluxes from 0 ° C.
  • Step 3> According to a method known in the literature using a compound of the compound of the formula (E-II), for example, a method described in Tetrahedron Letters, pages 36, 6373-6374, 1995, for example, 2
  • An aromatic hydrocarbon solvent such as benzene, toluene or xylene in the presence of a nosyl reagent (formula (E-III)) such as nitrobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride and a base reagent such as potassium carbonate;
  • a solvent inert to the reaction such as an ether solvent such as 4-dioxane or tetrahydrofuran, a halogen solvent such as methylene chloride, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C.
  • a compound of (E-IV) can be produced.
  • Step 4> A method known in the literature using a compound of the formula (E-IV) and benzyl alcohols such as veratryl alcohol (DMB-OH), for example, Tetrahedron Letters, 36, 6373-6374, 1995
  • benzyl alcohols such as veratryl alcohol (DMB-OH)
  • DMB-OH veratryl alcohol
  • DEAD diethyl azodicarboxylate
  • triphenylphosphine aromatic hydrocarbon solvents such as benzene, toluene and xylene, 1,4-dioxane, tetrahydrofuran
  • the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C.
  • a solvent inert to the reaction such as an ether solvent such as methylene chloride, a halogen solvent such as methylene chloride, or a mixture thereof.
  • a solvent inert to the reaction such as an ether solvent such as methylene chloride, a halogen solvent such as methylene chloride, or a mixture thereof.
  • a solvent inert to the reaction such as an ether solvent such as methylene chloride, a halogen solvent such as methylene chloride, or a mixture thereof.
  • a solvent inert to the reaction such as a halogen-based solvent such as methylene chloride, 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 3>.
  • Step 7> A method known in the literature using a compound of the formula (E-VII) and a compound of the formula (E-VIII), for example (Experimental Chemistry Course 4th Edition 20 Organic Synthesis II Alcohol Amines, 280-372, 1992, In the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc., diethyl ether, tetrahydrofuran, 1, 2 -Ether solvents such as dimethoxyethane and 1,4-dioxane, hydrocarbon solvents such as benzene and toluene, polar solvents such as acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide, or a mixed
  • Step 8> Using compounds of formula (E-IX) and described in literature known methods such as The Journal of Organic Chemistry, 62 (16), 5428-5431, 1997. According to the method, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a strong acid solvent such as trifluoroacetic acid or sulfuric acid in the presence or absence of anisole to produce a compound of formula (EX) be able to.
  • a strong acid solvent such as trifluoroacetic acid or sulfuric acid in the presence or absence of anisole to produce a compound of formula (EX) be able to.
  • ⁇ Step 9> Using the compound of formula (EX), the compound of formula (VI) can be produced by the same method as in (Production Method D) ⁇ Step 4>.
  • 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 comprises the formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) of the present invention. It may contain at least one of the compounds represented by formula (If), formula (Ig) or formula (Ih), and is made 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, the analgesic effect in an in vivo inflammatory pain model and a neuropathic pain model is shown, 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, fibromyalgia or neuropathic pain. Is done.
  • 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 3 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 with 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 11 100 g Lactose 200g Crystalline cellulose 100g Partially pregelatinized starch 50g Hydroxypropylcellulose 50g After weighing the above components, the compound of Example 11, lactose, crystalline cellulose, and partially pregelatinized starch were added and mixed uniformly, an aqueous solution of hydroxypropyl cellulose (HPC) was added, and granules or fine granules were obtained by wet granulation. Manufacturing.
  • HPC hydroxypropyl cellulose
  • 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.
  • a Discover S-class microwave synthesizer manufactured by SEM was used.
  • ⁇ 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 2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoic acid (Reference Example 2)
  • a solution of the compound (18.5 g) obtained in ⁇ Step 1> in tetrahydrofuran (190.0 mL) To the solution, tetramethylethylenediamine (32 mL) and n-butyllithium (131.0 mL) were added at -78 ° C. After raising the temperature to ⁇ 30 ° C. and stirring at the same temperature for 5 hours, the temperature was again set to ⁇ 78 ° C., and dry ice (32.0 g) was added. The mixture was warmed to room temperature and stirred for 12 hours.
  • ⁇ Step 3> Synthesis of 5-trifluoromethylanthranilic acid (Reference Example 2) To a solution of the compound (26.0 g) obtained in ⁇ Step 2> in ethanol (230.0 mL), 1N hydrochloric acid aqueous solution (60 mL) And heated to reflux for 3 hours. The mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (13.2 g) as yellow crystals.
  • ⁇ Step 4> Synthesis of 2-iodo-5-trifluoromethylbenzoic acid (Reference Example 2) Concentrated hydrochloric acid (15.0 mL) of compound (13.0 g) obtained in ⁇ Step 3>, water (80.0 mL) ) Sodium hypochlorite (5.3 g) dissolved in water (12.0 mL) was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, the mixture was added to an aqueous solution of potassium iodide (21.0 g) dissolved in water (30.0 mL) and concentrated sulfuric acid (5.0 mL), and stirred at 100 ° C. for 2 hours.
  • ⁇ Step 8> Synthesis of 2- [4-[(1,1-dimethylethyloxy) carbonyl] -3-buteneoxy] methyl-1-iodo-4-trifluoromethylbenzene (Reference Example 2)
  • ⁇ Step 7> To a solution of the obtained compound (12.8 g) and tert-butyl acrylate (52.7 mL) in dichloromethane (180.0 mL), tricyclohexylphosphine-1,3-bis-2,4,6-trimethylphenyl-4, 5-Dihydroimidazol-2-ylidenebenzylideneruthenium dichloride (Grubbs reagent second generation) (1.5 g) was added, and the mixture was stirred at 40 ° C.
  • ⁇ 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 3 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 3) 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 3) 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.
  • ⁇ Step 3> Synthesis of ethyl 2- (4-hydroxy-2,2-dimethyl-7-trifluoromethylchroman-4-yl) acetate
  • N, N-diisopropylamine (45 mL) in tetrahydrofuran (600.0 mL) n-Butyllithium (1.6M n-hexane solution) (200.0 mL) was added dropwise at an external temperature of ⁇ 78 ° C. over 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 5) 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 4) ⁇ Step 3>.
  • ⁇ Step 3> Synthesis of 2- (2,2-diethyl-4-hydroxy-7-trifluoromethylchroman-4-yl) acetic acid (Reference Example 5) Compound obtained in ⁇ Step 2> (36.0 g) (Reference Example 4) 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 ethyl 2- (4-hydroxy-7-trifluoromethyl-spiro [chroman-2,4'-tetrahydropyran] -4-yl) acetate (Reference Example 7) obtained in ⁇ Step 1>
  • the title crude compound (16.1 g) was obtained as a red oil from the compound (12.0 g) in the same manner as in (Reference Example 4) ⁇ Step 3>.
  • Step 3> Synthesis of 2- (4-hydroxy-7-trifluoromethyl-spiro [chroman-2,4'-tetrahydropyran] -4-yl) acetic acid (Reference Example 7) obtained in ⁇ Step 2>
  • the title compound (13.4 g) was obtained as a red solid from the compound (16.0 g) in the same manner as in (Reference Example 4) ⁇ Step 5>.
  • ⁇ Step 2> Synthesis of 2-amino-6-nitrobenzylamine
  • a suspension of sodium borohydride (10.9 g) in tetrahydrofuran (70.0 mL) was cooled with ice, trifluoroacetic acid (22.0 mL), ( Reference Example 9)
  • a solution of the compound (9.4 g) obtained in ⁇ Step 1> in tetrahydrofuran (140.0 mL) was sequentially added, and the mixture was stirred at room temperature for 12 hours.
  • the reaction mixture was poured into 1N aqueous sodium hydroxide solution (1.0 L), ethyl acetate (500.0 mL) was added, and the mixture was stirred for 1.5 hr.
  • ⁇ Step 4> Synthesis of N- (2-amino-6-nitrobenzyl) -N- (3,4-dimethoxybenzyl) -2-nitrobenzenesulfonamide (Reference Example 9)
  • ⁇ Step 5> Synthesis of 2-amino-N- (3,4-dimethoxybenzyl) -6-nitrobenzylamine (Reference Example 9)
  • N, N- of the compound (1.0 g) obtained in ⁇ Step 4> Lithium hydroxide monohydrate (0.4 g) and thioglycolic acid (0.3 mL) were sequentially added to a dimethylformamide (6.0 mL) solution, and the mixture was stirred at room temperature for 1 hour. 1N Aqueous sodium hydroxide solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (0.7 g) as a yellow solid.
  • Example 1 (E) -2- (3,4-Dihydro-8-trifluoromethyl-1-benzooxepin-5 (2H) -ylidene) -N- (3,4-dihydro-1-methyl-2 Synthesis of (1H) -quinazolinon-5-yl) acetamide (Reference Example 1) Oxalyl dichloride (50.0 ⁇ L) was added to a solution of the carboxylic acid (75.0 mg) obtained in ⁇ Step 5> in dichloromethane (3.0 mL). , N, N-dimethylformamide (1 drop) was added and stirred at room temperature for 30 minutes.
  • Example 2 (E) -2- (3,4-Dihydro-8-trifluoromethyl-2-benzooxepin-5 (1H) -ylidene) -N- (3,4-dihydro-1-methyl-2 (1H) -Quinazolinon-5-yl) acetamide (Example 3) (E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (3,4-dihydro-1-methyl-2 ( 1H) -Quinazolinon-5-yl) acetamide (Example 4) (E) -2- (2,2-dimethyl-7-trifluoromethylchroman-4-ylidene) -N- (3,4-dihydro-1 -Methyl-2 (1H) -quinazolinon-5-yl) acetamide (Example 5) (E) -2- (3,4-dihydro-8-trifluoromethyl-1-benzooxepin-5 (2
  • ⁇ Step 2> Synthesis of 2,3-dihydro-2,2-dimethyl-7-trifluoromethyl-4H-1,3-benzoxazin-4-one
  • Example 12 Compound (1) obtained in ⁇ Step 1> 0.8 g) in chloroform (20.0 mL) was added 2,2-dimethoxypropane (4.3 mL) and concentrated sulfuric acid (0.4 mL), and the mixture was heated to reflux for 8 hours. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • ⁇ Step 4> Synthesis of 2-bromo-N- (3,4-dihydro-1-methyl-2 (1H) -quinazolinon-5-yl) acetamide (Reference Example 8)
  • the amine obtained in ⁇ Step 4> 0.2 (g) and bromoacetic acid (0.2g) in methanol (5.0 mL) in 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium Chloride (DMTMM) (0.4 g) was added and stirred at room temperature for 14 hours. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with water, and azeotroped with ethanol.
  • DTMM 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium Chloride

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Cette invention concerne un composé permettant de réguler la fonction du récepteur TRPV1 (transient receptor potential vanilloid type I); un antagoniste du récepteur TRPV1; et un agent de prévention et/ou de traitement des maladies, y compris de la douleur, associées avec le récepteur TRPV1. L'invention concerne aussi un composé de formule (I), son sel, son solvate, et une composition pharmaceutique contenant le composé, le sel ou le solvate comme principe actif. (Dans la formule, m vaut 0 ou 1; R1 représente un groupe alkyle en C1-C2; R2 et R3 représentent indépendamment H, OH ou un groupe alkyle en C1-C4 qui peut être substitué par un groupe alcoxy en C1-C2, ou en variante R2 et R3 peuvent former un cycle cyclo avec un atome de carbone auquel R2 et R3 sont liés et le cycle cyclo peut former un groupe hétérocyclique non aromatique contenant O; et Z représente un groupe méthylène, un groupe éthylène ou -NH-.)
PCT/JP2009/063215 2008-07-23 2009-07-23 Dérivé d’acétamide d’hétérocyclidène-n-(3,4-dihydro-2(1h)-quinazolin-5-yl) Ceased WO2010010933A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008-190338 2008-07-23
JP2008190338A JP2011201776A (ja) 2008-07-23 2008-07-23 ヘテロシクリデン−ｎ−（３，４−ジヒドロ−２（１ｈ）−キナゾリノン−５−イル）アセトアミド誘導体

Publications (1)

Publication Number Publication Date
WO2010010933A1 true WO2010010933A1 (fr) 2010-01-28

Family

ID=41570393

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/063215 Ceased WO2010010933A1 (fr) 2008-07-23 2009-07-23 Dérivé d’acétamide d’hétérocyclidène-n-(3,4-dihydro-2(1h)-quinazolin-5-yl)

Country Status (2)

Country Link
JP (1) JP2011201776A (fr)
WO (1) WO2010010933A1 (fr)

Cited By (2)

* 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
WO2013183035A2 (fr) 2012-06-08 2013-12-12 Glenmark Pharmaceuticals S.A. Amides de composés de 2-amino-4-arylthiazole et leurs sels

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007010383A1 (fr) * 2005-07-22 2007-01-25 Mochida Pharmaceutical Co., Ltd. Nouveau dérivé d'acétamide d'hétérocyclidène
WO2008091021A1 (fr) * 2007-01-24 2008-07-31 Mochida Pharmaceutical Co., Ltd. Dérivé d'hétérocyclidène-n-(aryl)acétamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007010383A1 (fr) * 2005-07-22 2007-01-25 Mochida Pharmaceutical Co., Ltd. Nouveau dérivé d'acétamide d'hétérocyclidène
WO2008091021A1 (fr) * 2007-01-24 2008-07-31 Mochida Pharmaceutical Co., Ltd. Dérivé d'hétérocyclidène-n-(aryl)acétamide

Cited By (3)

* 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
WO2013183035A2 (fr) 2012-06-08 2013-12-12 Glenmark Pharmaceuticals S.A. Amides de composés de 2-amino-4-arylthiazole et leurs sels

Also Published As

Publication number Publication date
JP2011201776A (ja) 2011-10-13

Similar Documents

Publication Publication Date Title
JP5303590B2 (ja) 新規なヘテロシクリデンアセトアミド誘導体
EP3355889B1 (fr) Modulateurs des récepteurs p2x3 et p2x2/3 de diaminopyrimidine destinés à être utilisés dans le traitement de la toux
JP7530390B2 (ja) 新規ｅｇｆｒ阻害剤
JPWO2008091021A1 (ja) ヘテロシクリデン−ｎ−（アリール）アセトアミド誘導体
AU2017253937A1 (en) Compounds and compositions for treating conditions associated with NLRP activity
JP2010518080A (ja) 治療薬
BR122014012788A2 (pt) derivados de pirimidina fundidos, seus usos, e composição farmacêutica para inibição da atividade de tirosina quinase
JP7148500B2 (ja) 新規テトラヒドロナフチルウレア誘導体
WO2016155545A1 (fr) Dérivé de 1,2,5-oxadiazole contenant un groupe sulfamyle, son procédé de préparation et son utilisation dans des produits pharmaceutiques
WO2010010935A1 (fr) Dérivé de n-arylacétamide d’hétérocyclidène optiquement actif
WO2010010934A1 (fr) Dérivé d’hétérocyclidène ayant un arylacétamide p‑substitué
US20100016285A1 (en) Heterocyclidene-n-(aryl) acetamide derivative
KR20200139702A (ko) 칼페인 조정자 및 그 치료학적 용도
CN117580831A (zh) Grk2抑制剂及其用途
JP2017537957A (ja) 置換されたピリジル−シクロアルキル−カルボン酸類、それらを含む組成物およびそれらの医学的使用
WO2010010933A1 (fr) Dérivé d’acétamide d’hétérocyclidène-n-(3,4-dihydro-2(1h)-quinazolin-5-yl)
CN104487427A (zh) 新的四唑衍生物和它们作为钾通道调节剂的用途
IL286900B2 (en) Intracellular chloride concentration modulators
CN101228131B (zh) 新的杂环亚基乙酰胺衍生物
CA3018115A1 (fr) Derives d'indolizine, composition et methodes d'utilisation
AU2015201306B2 (en) Small molecule inhibitors of the pleckstrin homology domain and methods for using same
KR20200052938A (ko) 테트라히드로나프틸우레아 유도체의 결정
JPWO2006082822A1 (ja) アシクロビル耐性ヘルペスウイルスによる疾患の予防・治療剤
HK1114857A (en) Novel heterocyclidene acetamide derivative

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09800447

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09800447

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP