WO2007020935A1 - Therapeutic agent for pain comprising p2y12 receptor and/or p2y14 receptor blocker - Google Patents

Therapeutic agent for pain comprising p2y12 receptor and/or p2y14 receptor blocker Download PDF

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Publication number
WO2007020935A1
WO2007020935A1 PCT/JP2006/316081 JP2006316081W WO2007020935A1 WO 2007020935 A1 WO2007020935 A1 WO 2007020935A1 JP 2006316081 W JP2006316081 W JP 2006316081W WO 2007020935 A1 WO2007020935 A1 WO 2007020935A1
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receptor
group
pain
substituent
general formula
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PCT/JP2006/316081
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French (fr)
Japanese (ja)
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Koichi Noguchi
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Ono Pharmaceutical Co., Ltd.
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Priority to JP2007531005A priority Critical patent/JPWO2007020935A1/en
Publication of WO2007020935A1 publication Critical patent/WO2007020935A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 comprises a P2Y receptor and a P2Y receptor blocker
  • Pain mainly consists of (1) “nociceptive pain”, which is thought to be caused by persistent stimulation of nociceptors, and (2) abnormalities in the function of nerve fibers involved in pain transmission and inhibition mechanisms. “Neuropathic pain”, which is the result of the results, and (3) “Psychogenic pain” where emphasis is placed on emotions and emotions.
  • neuropathic pain is refractory pain resulting from dysfunction of the peripheral or central nervous system, such as pressure on the peripheral nerve, plexus or perineural soft tissue, trauma or injury, Caused by injury to central somatosensory pathways (eg, ascending somatosensory pathways at the spinal cord, brainstem, thalamus or cortical level).
  • central somatosensory pathways eg, ascending somatosensory pathways at the spinal cord, brainstem, thalamus or cortical level.
  • Specific examples include neurodegenerative diseases, bone degenerative diseases, metabolic disorders (for example, diabetes), cancer, infection, inflammation, ischemia, surgery, trauma, radiation therapy, administration of anticancer drugs, etc. sell.
  • neuropathic pain Although the mechanism of neuropathic pain is largely unknown, certain ion channels It is thought to include spontaneous firing of sensory nerves due to novel expression of mitochondrion, firing of sensory nerve fibers in various layers of the spinal cord, and changes in the expression of various neurotransmitters and receptors in the sensory nerve and spinal cord .
  • Typical symptoms of neuropathic pain include Allodynia, Hypergesia, or Hyperesthesia. These symptoms present characteristic pains such as “burning”, “stinging with a needle” or “like electric shock”.
  • neuropathic pain it is known that not only analgesics that are effective for normal nociceptive pain but also narcotic analgesics are not effective (The Lancet, 353, 1959-1966, 1999). .
  • morphine is known to have a powerful analgesic effect on nociceptive pain, but does not have a sufficient effect on neuropathic pain. Insufficient analgesic action by morphine is also a major feature of neuropathic pain, and it has been used for its diagnosis (Ayumi Medicine, 189 (10), 751-755, 1999). The reason why morphine is ineffective in neuropathic pain is thought to be due to neurological damage that caused functional and morphological changes in the nerve, resulting in degeneration of inhibitory neurons and a decrease in opioid receptors (latest Brain and Neuroscience Series, VI, “Pain Neuroscience”, Medical View, 97, 1997) o
  • alodya is one of the typical symptoms of neuropathic pain.
  • Alodya refers to a condition in which normal humans do not feel pain, but to feel a degree of stimulation as pain, and in alodynia, pain is caused by non-noxious stimuli such as light contact and pressure, moderate heat and cooling, etc. It is. In other words, there is a point that there is a qualitative change in sensory response, and that the threshold itself is lowered, which is considered to be a basic characteristic of alodiure.
  • post-herpetic pain which is a typical example of neuropathic pain, 87% of patients have had alodidia, and the intensity of post-herpetic pain is proportional to the degree of alodiure.
  • Alodia is attracting attention as a very important therapeutic target because it is a symptom that significantly lowers the patient's QOL in neuropathic pain including postherpetic pain.
  • neuropathic pain is treated by neurosurgical treatment such as nerve block and spinal epidural electrical stimulation (Ayumi of Medicine, 189 (10), 757-762, 1999), gabapentinya Gabapentinoids such as pregabalin, N-type calcium channel inhibitors such as ziconotide, Cyclic antidepressants (clinical and pharmacotherapy, 18 (7), 643-646, 1999), antiepileptics, local anesthetics, noclofen, etc. are used.
  • neurosurgical treatment such as nerve block and spinal epidural electrical stimulation (Ayumi of Medicine, 189 (10), 757-762, 1999), gabapentinya Gabapentinoids such as pregabalin, N-type calcium channel inhibitors such as ziconotide, Cyclic antidepressants (clinical and pharmacotherapy, 18 (7), 643-646, 1999), antiepileptics, local anesthetics, noclofen, etc.
  • purine receptors include a P1 receptor having adenosine as a ligand, adenosine 5,
  • P2 receptors with triphosphate (ATP) and adenosine 5'-diphosphate (ADP) as ligands.
  • P2 receptors are further classified into ion channel type (P2X receptor) in which the receptor protein itself constitutes an ion channel and metabolic control type (P2Y receptor) that functions by activating the G protein. Each is further classified into several subtypes.
  • receptors such as P2X, P2X, P2X, P2Y, and P2Y
  • TNP—ATP N-5-triphosphate
  • P2Y receptor subtype force conjugated to G such as P2Y and P2Y, vanilloy
  • R 1A represents a hydrogen atom, optionally substituted alkyl, cycloalkyl, aryl, aryl, alkyl, heteroaryl, heteroaryl, or alkanol; 2A represents aryl or heteroaryl.
  • Compound, its several isomers, its tautomers, its salts, its esters, or their prodrugs, is a P 2Y receptor antagonistic action, for example, peripheral vascular disease, cardiovascular disease, brain Vascular disease
  • Patent Document 1 International Publication No. 2005Z000281 pamphlet
  • R represents an optionally substituted Cl to 6 alkyl, C3 to 8 cycloalkyl, or a phenyl
  • R 2B represents an optionally substituted Cl to 8 Represents an alkyl or the like
  • one of R 3B and R 4B represents a hydrogen atom
  • the other represents hydroxy
  • X B represents ⁇ or NHR 5B or the like.
  • the compound, its salt, or its solvate shown by this is a P receptor (old name of P2Y receptor) antagonistic action.
  • Patent Document 2 it is described that it is useful for the treatment of platelet aggregation diseases (see, for example, International Publication No. 99Z05144 pamphlet (Patent Document 2)).
  • R represents OR or CH R and the like, and R 1 represents Cl to 6 alkyl or Cl to 6
  • R 3D represents an optionally substituted C 3-6 cycloalkyl or the like
  • R 4D represents Cl-6 alkyl.
  • a salt thereof, or a solvate thereof, exhibits P receptor antagonism.
  • R is optionally substituted, Cl to 6 alkyl, 2 to 6 alkyl, C2 to 6 alkyl, C3 to 8 cycloalkyl, aryl, or chale, etc.
  • R 2F represents an optionally substituted Cl-8 alkyl, C2-87 ketone, C2-8 alkyl, C3-8 cycloalkyl, etc.
  • R 3F and R 4F Both represent hydroxy
  • R 5F represents a hydrogen atom or Cl- 6 alkyl
  • R 6F represents an optionally substituted Cl-6 alkyl, and the like.
  • P receptor antagonist activity such as angina pectoris
  • Patent Document 6 It is described that it is useful for prevention and Z or treatment of myocardial infarction or the like (for example, see International Publication No. 99Z41254 (Patent Document 6)).
  • R 1 l represents an optionally substituted C3-5 alkyl, etc.
  • IT G represents a phenyl optionally substituted with a fluorine atom
  • R 3G and R 4G are Both represent hydroxy
  • R G represents X G OH
  • X G represents CH, OCH CH, or a bond.
  • R lh represents a hydrogen atom, an optionally substituted Cl-6 alkyl group, a C3-6 cycloalkyl group, a Cl-6 alkoxy group, a C6-10 aryl group, or the like
  • R 2H is a hydrogen atom, Cl to 7 alkanoyl group, C7 to: L 1 aryl hydrocarbon group, C 6 to 10 aryl sulfo group, C 7 to 16 alkyl aryl sulfo group, Cl to 6 alkyl sulfur
  • R 3H represents an optionally substituted C6-10 aryl group, heteroaryl group, etc.
  • x 1H , x 2H , x 3H , x 4H , and x 5H are independently hydrogen atoms Represents a halogen atom or the like
  • n H represents an integer of 0 to 2.
  • R 1 represents an amino optionally substituted with lower alkyl
  • R 1 represents a hydrogen atom, or lower alkyl or aryl each optionally substituted
  • R 1U and R 1 represent an adjacent nitrogen atom and Together, R may form an optionally substituted cyclic amino, each independently represents an optionally substituted lower alkyl, cycloalkyl, aryl or heterocycle, wherein R is halogen, Represents lower alkyl, or —O-lower alkyl, represents a lower alkyl substituted with cycloalkyl or non-aromatic heterocyclic ring, or cycloalkyl, each optionally substituted; Substituted with hydrogen atom, halogen, cyano, nitro, lower alkyl, halogeno lower alkyl, cycloalkyl, each optionally substituted; Substituted with hydrogen atom, halogen, cyano, nitro, lower alkyl, halogeno lower alkyl, cycloalkyl
  • Receptor subtypes conjugated with 12 14 i are associated with the development of pain, particularly neuropathic pain, and there is no mention that these receptor blockers are useful for the treatment of pain.
  • Patent Document 1 Pamphlet of International Publication No. 2005Z000281
  • Patent Document 2 Pamphlet of International Publication No.99Z05144
  • Patent Document 3 Pamphlet of International Publication No. 01Z19826
  • Patent Document 4 International Publication No. 01Z36421 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 01Z36438
  • Patent Document 6 International Publication No.99Z41254 Pamphlet
  • Patent Document 7 International Publication No. 00Z34283 Pamphlet
  • Patent Document 8 JP-A-2005-179350
  • Patent Document 9 Japanese Patent Application Laid-Open No. 2005-053903
  • An object of the present invention is to provide a preventive, therapeutic and Z or symptom progression inhibitor for pain, particularly neuropathic pain.
  • neuropathic pain is cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia. ;
  • a) a low molecular compound (b) an antibody, (c) an antisense, (d) a short interfering RNA, (e) a decoy, (D ribozyme, or (g) an aptamer Agent;
  • Low molecular weight compounds are (1) P2Y receptor antagonists, (2) ⁇ 2 ⁇ receptor antagonists
  • the low molecular weight compound is represented by the general formula (I)
  • R 1_1 represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or a cyclic group which may have a substituent
  • R 2_1 represents a substituent. It represents a cyclic group which may have a group.
  • ring A represents an optionally substituted 5- to 7-membered heterocyclic ring
  • Q represents a substituent, and may be! / An aliphatic hydrocarbon group. !! or an substituted / ⁇ I be ⁇ cyclic group
  • R 1 "2 represents an amino group which may be substituted
  • R 2 - 2 are shown and represented] a substituent.
  • R 1 — ° has a hydrogen atom, an alkoxy group which may have a substituent, an aliphatic hydrocarbon group which may have a substituent, or a substituent. represent also cyclic group
  • R 2 _ 3 represents a hydrogen atom or a substituent
  • R 3 - 3 represents a cyclic group which may have a substituent
  • X 1 - 3 is a hydrogen atom or Represents a substituent
  • n 3 represents 0 or an integer of 1 to 2
  • ring D represents a phenyl group which may further have a substituent.
  • X 4 and Y 4 each independently represent CH, C-halogen atom, C-alkyl group optionally having substituent (s), or nitrogen atom
  • E represents a substituent group.
  • the represents an amino group which is also cyclic group, or a substituted have
  • R 2 - 4 are have an aliphatic hydrocarbon group, or a substituent not good may have a substituent
  • R 3 — 4 represents a halogen atom, an aliphatic hydrocarbon group which may have a substituent, or an alkoxy group which may have a substituent, R 4 — 4, have a which may have an aliphatic hydrocarbon group or an optionally substituted a substituent represent also cyclic group
  • R 5 - 4 represents a substituent.
  • the agent of the above-mentioned [7] which is a compound represented by the formula:
  • the low molecular weight compound is clopidogrel, ticlovidin, cangrelor, prasdarrel, A ZD-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, oral xyfiban, MRS2395 or those
  • opioid analgesics non-aged pioid analgesics, neuropathic pain analgesics, non-steroidal anti-inflammatory drugs, sedatives, antidepressants, antiepileptics, central muscle relaxants, antiemetics, [11]
  • a P2Y receptor characterized by administering an effective dose
  • ⁇ 2 ⁇ receptor and ⁇ 2 or ⁇ 2 ⁇ receptor positive cell inhibitor is ⁇ 2 ⁇ ⁇ receptor
  • ⁇ 2 ⁇ receptor and ⁇ or ⁇ 2 ⁇ receptor blocker means ⁇ In at least one of 2Y receptor and P2Y receptor,
  • Any substance may be used as long as a receptor suppresses a signal that is also transmitted to cells when a host (eg, cocoon, ADP, etc.) is bound. That is, it may be a substance that decreases the binding between a receptor and an in vivo ligand, such as a so-called receptor antagonist (antagonist), and it is coupled to these receptors to produce a G protein ( G) or later
  • a receptor suppresses a signal that is also transmitted to cells when a host (eg, cocoon, ADP, etc.) is bound. That is, it may be a substance that decreases the binding between a receptor and an in vivo ligand, such as a so-called receptor antagonist (antagonist), and it is coupled to these receptors to produce a G protein ( G) or later
  • P2Y receptor and Z or P2Y receptor may be a substance that suppresses signal. It may also be one that reduces the expression level of the receptor itself. Such substances, i.e. P2Y receptor and Z or P2Y receptor
  • Container blockers include, for example, (a) low molecular weight compounds, (b) antibodies, (c) antisense, (d) short interfering RNAs, (e) decoys, (D ribozymes, (g) Abutamas, etc. The thing which has the form of is mentioned.
  • Antibodies include, for example, anti-2 receptor antibodies and anti-2 receptor antibodies. This
  • These antibodies should be ⁇ 2 ⁇ receptors or antibodies that can recognize ⁇ 2 ⁇ receptors, respectively.
  • Either a polyclonal antibody or a monoclonal antibody may be used.
  • the site that recognizes the ⁇ 2 ⁇ receptor and the site that recognizes the ⁇ 2 ⁇ receptor in one antibody molecule may be used.
  • bispecific antibody it is possible to obtain a bispecific antibody by providing.
  • antibodies that can be safely administered to humans such as human antibodies (eg, human monoclonal antibodies) or humanized antibodies. These antibodies are (1) ⁇ 2 ⁇ 2 ⁇
  • Antigens for producing anti-P2Y receptor antibodies or anti-P2Y receptor antibodies are:
  • a mammal alone or together with a carrier or diluent.
  • complete Freund's adjuvant or incomplete Freund's adjuvant is used. It may be administered. Dosing is usually performed once every 2 to 6 weeks, 2 to 10 times in total.
  • a power mouse and a rat including a monkey, a rabbit, a dog, a guinea pig, a mouse, a rat, a hedge, a goat and the like are preferably used.
  • the administration site is not particularly limited, as long as the antibody can be produced.
  • Monoclonal antibody-producing cells are prepared by selecting a warm-blooded animal that has been immunized with an antigen, for example, an individual with an antibody titer, such as a mouse, and collecting the spleen or lymph nodes 2 to 5 days after the final immunization.
  • Monoclonal antibody-producing hyperpridoma can be prepared by fusing the antibody-producing cells contained therein with myeloma cells. The antibody titer in the antiserum can be measured, for example, by reacting the labeled P2Y receptor or the P2Y receptor with the antiserum.
  • the fusion operation with myeloma cells can be performed according to a known method, for example, the method of Kohler and Milstein (Nature, 256, 495, 1975).
  • PEG polyethylene glycol
  • Sendai virus or the like preferably PEG or the like
  • myeloma cells include NS-1, P3U1, SP2Z0, etc., and P3U1 is preferred.
  • the preferred ratio between the number of antibody-producing cells (spleen cells) and the number of myeloma cells used is about 1: 1 to 20: 1, and PEG (preferably PEG1000 to PE)
  • G6000 is added at a concentration of about 10% to 80% and is efficiently incubated by incubation at about 20 ° C to about 40 ° C, preferably about 30 ° C to about 37 ° C for about 1 minute to about 10 minutes. Cell fusion can be performed.
  • antigens such as P2Y receptor and P2Y receptor can be used directly or with a carrier.
  • Anti-immunoglobulin antibody labeled with radioactive substance or enzyme etc. is added to the solid phase (for example, microplate) adsorbed together, and then labeled with radioactive substances or enzymes (if the cells used for cell fusion are mice, (Anti-mouse immunoglobulin antibody is used) or protein A is added to detect monoclonal antibody bound to the solid phase.
  • Hypridoma culture supernatant is added to the solid phase adsorbed with anti-immunoglobulin antibody or protein A.
  • a method of detecting a monoclonal antibody bound to a solid phase by adding a receptor protein labeled with a radioactive substance or an enzyme.
  • Monoclonal antibody selection is well known or Is a force that can be performed according to a similar method. Usually, it can be performed in a medium for animal cells to which HAT (hypoxanthine, aminopterin, thymidine) is added. Any medium can be used as a selection and breeding medium as long as it is capable of growing Hypridoma.
  • HAT hyperxanthine, aminopterin, thymidine
  • Any medium can be used as a selection and breeding medium as long as it is capable of growing Hypridoma.
  • RPMI-1640 medium containing 1% to 20%, preferably 10% to 20% fetal bovine serum, GIT medium (made by Wako Pure Chemical Industries) containing 1% to 10% fetal bovine serum, or hybridoma culture Serum-free medium (SFM-101, manufactured by Nissui Pharmaceutical) etc.
  • SFM-101 hybridoma culture Serum-free medium
  • the culture temperature is usually 20 ° C to 40 ° C, preferably about 37 ° C.
  • the culture time is usually 5 days to 3 weeks, preferably 1 week to 2 weeks. Cultivation can usually be performed under 5% carbon dioxide gas.
  • the antibody titer of the cell culture supernatant can be determined in the same manner as the measurement of the antibody titer in the antiserum.
  • the separation and purification of the monoclonal antibody can be carried out according to the method of separating and purifying immunoglobulin in the same manner as the separation and purification of ordinary polyclonal antibodies.
  • purification methods include salting out, alcohol precipitation, isoelectric precipitation, electrophoresis, adsorption / desorption using ion exchangers (eg DEAE), ultracentrifugation, gel filtration And a specific purification method in which the antibody is obtained by collecting only the antibody using an antigen-binding solid phase or an active adsorbent such as protein A or protein G, and dissociating the binding.
  • the polyclonal antibody can be produced according to a known method or a method analogous thereto.
  • P2Y receptor or P2Y receptor that is an immunizing antigen and carrier protein are known methods or a method analogous thereto.
  • P2Y receptor or P2Y receptor that is an immunizing antigen and carrier protein are known methods or a method analogous thereto.
  • the type of carrier protein and the mixing ratio of carrier and hapten are the same as those of immunized knotten cross-linked with carrier.
  • Ratio to hapten 1 On the other hand, a method of coupling at a ratio of about 0.1 to about 20, preferably about 1 to about 5, is used.
  • various condensing agents can be used for coupling the hapten and the carrier, but an active ester reagent containing glutaraldehyde, carbodiimide, maleimide active ester, thiol group, or dithiopyridyl group is preferably used.
  • the condensation product is administered to a mammal alone or together with a carrier or diluent.
  • the administration site is not particularly limited as long as the antibody can be produced.
  • complete Freund's adjuvant or incomplete Freund's adjuvant may be administered. The administration is usually performed once every 2 to 6 weeks, for a total of 2 to 10 times.
  • the polyclonal antibody can also collect blood, ascites, etc., preferably blood power of the immunized mammal.
  • the polyclonal antibody titer in the antiserum can be measured in the same manner as the above-described measurement of the antibody titer in the serum. Separation and purification of the polyclonal antibody can be performed according to the same immunoglobulin separation and purification method as the above-described monoclonal antibody separation and purification.
  • Human monoclonal antibodies can be produced according to a known method or a method analogous thereto. For example, using a transformed or transchromosomal mouse (eg, HuMAb mouse (registered trademark), KM mouse (registered trademark), etc.) containing the human immune system, or phage display for screening a human immunoglobulin gene library It can be produced by using a method or using an SCID mouse in which human immune cells are reconstituted so that a human antibody response is generated by immunization.
  • a transformed or transchromosomal mouse eg, HuMAb mouse (registered trademark), KM mouse (registered trademark), etc.
  • SCID mouse an SCID mouse in which human immune cells are reconstituted so that a human antibody response is generated by immunization.
  • HuMAb mice registered trademark (Medarex) have non-rearranged human heavy chains ( ⁇ and ⁇ ) and ⁇ light chain immunoglobulins with target mutations that inactivate endogenous ⁇ and ⁇ chain loci. Since it contains a human immunoglobulin gene minilocus that encodes a sequence, it is a mouse that can produce a high-affinity human IgG ⁇ monoclonal antibody by an immune response (Handbook of Experimental Pharmacology, 1 ⁇ ⁇ 3, 49— 101, 1994; Intern. Rev. Immunol., 13, 6 5-93, 1995; Ann. NY Acad. Sci., 764, 536-546, 1995). By eliciting an immune response in the mouse using the antigen described above, the “P2Y receptor and
  • HuMAb mouse (Register (Trademark) instead of KM mouse (registered trademark) (WO02 / 043478)
  • Xenomouse (Abgenix)
  • Tc mouse Proc. Natl. Acad. Sci USA, 97, 722-727, 2000
  • Ushi National Biotechnology, 20, 889-894, 2002
  • a method for obtaining a human monoclonal antibody using a phage display method for screening a human immunoglobulin gene library has been established by a known technique. For example, it can be carried out according to the methods described in US Pat.
  • Antisense refers to, for example, the ⁇ ⁇ 2 ⁇ receptor or the DNA sequence of the ⁇ 2 ⁇ receptor.
  • nucleotide sequence may be used as long as it contains a complementary or substantially complementary nucleotide sequence or a part thereof, and has an action capable of suppressing the expression of the DNA.
  • A, DNA, or a modified nucleic acid may be used.
  • Specific examples of the modified nucleic acid include, for example, nucleic acid sulfur derivatives, thiophosphate derivatives, and those that are resistant to degradation of oligonucleotides or oligonucleoside amides.
  • the nucleotide sequence substantially complementary to the DNA of 12 receptor or P2Y receptor is, for example, P2
  • Examples thereof include base sequences having homology of 70% or more, preferably about 80% or more, more preferably about 90% or more, and particularly preferably about 95% or more.
  • the N-terminal site of the P2Y receptor or P2Y receptor protein is about 70% or more, preferably about 80% or more, more preferably about 90% or more, particularly preferably about 95% or more.
  • Antisense with homology (B) In the case of antisense directed to RNA degradation by RNaseH, the entire P2Y receptor or P2Y receptor DNA containing introns
  • Antisense having about 70% or more, preferably about 80% or more, more preferably about 90% or more, particularly preferably about 95% or more of homology with the complementary strand of the base sequence is suitable.
  • Antisense is usually composed of about 10 to 40, preferably about 15 to 30 basic forces.
  • the antisense used in the present invention is, for example, a phosphate residue (phosphate) of each nucleotide constituting the antisense in order to prevent degradation by a hydrolytic enzyme such as nuclease. It may be substituted with a chemically modified phosphate residue such as phosphonate or phosphorodithionate.
  • the sugar (deoxyribose) of each nucleotide may be substituted with a chemically modified sugar structure such as 2′-O-methyli ⁇ , and the base part (pyrimidine, purine) is also chemically modified. Also good.
  • antisense in the cell is made more stable, the cell permeability of the antisense is increased, the affinity for the target sense strand is increased, and if it is toxic
  • various modifications may be made for the purpose of reducing the toxicity of the antisense. Many such modifications have been reported, for example, in Pharm Tech Japan, 8 ⁇ , 247 or 395, 1992, Antisense Research and Applications, CRC Pres, 1993, and the like. These antisenses can be produced using a known DNA synthesizer or the like.
  • Short interfering RNA includes, for example, RNA encoding ⁇ 2 ⁇ receptor or P2Y receptor
  • a double-stranded RNA containing a part of RNA and RNA complementary thereto can be obtained according to a known method (Nature, 411, 494, 2001) etc.
  • ⁇ Decoy '' includes, for example, ⁇ 2 ⁇ receptor or a gene that regulates gene expression of ⁇ 2 ⁇ receptor
  • ⁇ 2 ⁇ receptor or a gene that regulates gene expression of ⁇ 2 ⁇ receptor
  • a short, double-stranded nucleic acid that mimics a site on a nucleic acid to which a factor such as a protein (eg, transcription factor) binds (single-stranded nucleic acid designed to “fall back” on itself)
  • a factor such as a protein (eg, transcription factor) binds
  • Such a decoy competitively inhibits the protein (for example, a transcription factor, etc.), so that the gene expression of P2Y receptor or P2Y receptor can be suppressed.
  • Ribozyme includes, for example, ⁇ 2 ⁇ receptor or ⁇ 2 ⁇ receptor mRNA
  • Synthetic RNA molecules that catalyze endoribonuclease activity specific to and derivatives thereof.
  • a ribozyme can be obtained by using a known method (TRENDS in Molecular Medicine, 7, 22 21, 2001) or the like, and a sequence of RNA encoding P2Y receptor or P2Y receptor.
  • RNA encoding the P2Y receptor or P2Y receptor can be built. As part of the RNA encoding the P2Y receptor or P2Y receptor
  • Examples include sequences in the vicinity of a consensus sequence NUX (wherein N represents all bases and X represents a base other than G) that can be cleaved by a known ribozyme.
  • ⁇ ⁇ 2 ⁇ receptor or ⁇ 2 ⁇ receptor or its signal
  • Examples include single-stranded oligonucleotides that specifically bind to protein molecules involved in transmission.
  • Low molecular weight compounds include, for example, ⁇ 2 ⁇ and ⁇ 2 ⁇ receptors.
  • low molecular weight compounds that exhibit antagonism and signal transduction of strong receptor power (for example, receptor clustering, protein phosphorylation and dephosphorylation, second messenger generation, target gene expression, etc.)
  • strong receptor power for example, receptor clustering, protein phosphorylation and dephosphorylation, second messenger generation, target gene expression, etc.
  • Low molecular weight compounds are included.
  • ⁇ 2 ⁇ receptor and ⁇ or ⁇ 2 ⁇ receptor directly bind to and antagonize
  • the low molecular weight compound means an organic compound having a molecular weight of 1000 or less (preferably a molecular weight of 100 to 700, etc., more preferably a molecular weight of 150 to 500).
  • Dual antagonist refers to a compound that exhibits antagonistic action on both P2Y receptor and P2Y receptor.
  • Low molecular weight compounds can be obtained by known methods, such as, for example, the Comprehensive 'Organic' Transformation: A Guide ⁇ To ⁇ ⁇ ⁇ Functional ⁇ Group ⁇ Preparations, Second Edition (Richard C. Larock, John Wiley and Sons Inc, 1999) [Comprehensive urganic iransformations: A Guiae to junctional roup Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)].
  • the product of the reaction can be obtained by usual purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization, etc. It can refine
  • These low molecular weight compounds are the P2Y receptor and
  • whether or not the signal through the receptor is suppressed depends on whether the receptor binds to the receptor or the low molecular weight compound is a receptor force signal due to ligand stimulation (for example, ATP stimulation or ADP stimulation). This can be done by using an assembly that evaluates whether or not to suppress transmission.
  • ligand stimulation for example, ATP stimulation or ADP stimulation
  • P2Y receptor and ⁇ or ⁇ 2 ⁇ receptor blocker are used in the present invention.
  • a compound represented by the general formula (I), a geometric isomer, a tautomer, a salt, a solvate thereof, or a prodrug thereof, a compound represented by the general formula ( ⁇ ), Its salt, its ⁇ -xoxide, its solvate, or their prodrugs are preferred.
  • a compound represented by the general formula (III), a salt thereof, or a prodrug thereof, a compound represented by the general formula (IV), or a salt thereof is also preferable.
  • the “cyclic group” in the “cyclic group optionally having substituent (s)” is arbitrarily selected from, for example, “carbocycle” or “heterocycle” And a monovalent group formed by removing one hydrogen atom.
  • Examples of the "carbocycle” include “C3-15 carbocycle”.
  • C3-15 charcoal "Prime ring” includes “C3-15 monocyclic, bicyclic or tricyclic carbocycle” and “C3-15 spiro-linked bicyclic carbocycle and bridged bicyclic carbocycle”. .
  • Examples of the ⁇ C3-15 monocyclic, bicyclic or tricyclic carbocycle '' include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclo Dodecane, Cyclotridecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclopentene, Cyclopentagen, Cyclohexagen, Cyclohexadiene, Cyclooctagen, Benzene, Pentalene, Perhydropentalene , Azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalen
  • C3-15 spiro-bonded bicyclic carbocycles and bridged bicyclic carbocycles include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] Ndecane, bicyclo [2. 2. 1] heptane, bicyclo [2. 2. 1] hepter 2-ene, bicyclo [3. 1. 1] heptane, bicyclo [3. 1. 1] hepter 2-en Bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, bicyclo [2.2.2] octane 2-adamantane, noradamantane ring and the like.
  • heterocycle examples include “a 3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom”. “3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom” includes “1 to 5 nitrogen atoms, 1 to 2 3-15 membered monocyclic, bicyclic or tricyclic heterocycle containing 1 oxygen atom and Z or 1 sulfur atom "and" 1-5 nitrogen atom, 1-2 oxygen atom and Z Or a 3 to 15-membered spiro-linked bicyclic heterocycle and a bridged bicyclic heterocycle containing one sulfur atom.
  • “3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom” includes, for example, pyrrole Imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, fura , Pyran, oxepin, thiophene, thiopyran, chepine, oxazonole, isoxazole, thiazole, isothiazole, furazane, oxazine, oxazine, oxazazine, oxazepine, oxadiazepine, thiadiazonole, thiazine, thiadiazine, thiazepine, indhiazole Indole, indolizine, benzofuran
  • spiro-bonded bicyclic heterocycles and bridged bicyclic heterocycles containing 1-5 nitrogen atoms, 1-2 oxygen atoms and Z or 1 sulfur atom Is
  • the “substituent” in the “cyclic group optionally having substituent (s)” is not particularly limited as long as it is a substituent.
  • the “substituent” includes, for example, (1) substituted or C1-20 alkyl group, (2) substituted !, C2-20 alkyl group, (3 ) An optionally substituted C2-20 alkyl group, (4) an optionally substituted Cl-20 alkylidene group, (5) an optionally substituted cyclic group, (6) an oxo group, ( 7) Hydroxyl group, (8) Cl-20 alkyloxy group optionally substituted, (9) Optionally substituted
  • V C2-20 alkyloxy group, (10) substituted !, C2-20 alkyloxy group, (11) hydroxyl group protected with an optionally substituted cyclic group, (12 ) Optionally substituted Cl-20 acyloxy group, (13) thixo group, (14) mercapto group, (15) substituted! C1-20 alkylthio group, (16) substituted !, C2-20 alkylthio group, (17) C2-20 alkylthio group optionally substituted, (18 Replaced)
  • V may be a mercapto group substituted with a cyclic group, (19) substituted !, may be a C1-20 alkylsulfyl group, (20) substituted !, may be C2 ⁇ 20 alkenylsulfier groups, (21) optionally substituted C2-20 alkynylsulfier groups, (22) substituted V, or sulfier groups substituted with cyclic groups (eg phenylsulfinyl groups) etc)
  • Sulfonyl groups substituted with cyclic groups eg phenylsulfonyl groups, etc.
  • substituents sulfino group, (28) substituted may be sulfo group, (29) substituted !, may be sulfamoyl group (eg For example, an unsubstituted sulfamoyl group, N-mono or di (optionally substituted Cl-20 alkyl) sulfamoyl group (eg, N-mono-C 1-6 alkylsulfamoyl group (eg, N-methylsulfayl group) Moyl group, N-ethylsulfamoyl group, N-propylsulfamoyl group, N-isopropylsulfamoyl group, N-butylsulfamoyl group, N-isobutylsulfamoyl group, N- (tert
  • acyl groups eg formyl, acetyl, propanol, bivaloyl, etc.
  • Carbamoyl eg, unsubstituted Force ruby N-mono or di (optionally substituted Cl-20 alkyl) force rubamoyl group
  • N-mono-Cl-6 alkyl force rubamoyl group for example, N-methylcarbamoyl group, N ethylcarbamoyl group
  • N-propyl rubamoyl group N isopropyl rubamoyl group, N butyl carbamoyl group, N isobutyl carbamoyl group, N— (tert butyl) force rubamoyl group, N pentyl carbamoyl group, N hexyl carbamoyl group, etc.
  • N-Mono Cl-6 alkyl group rubamoyl group (eg, N hydroxymethylcarbamoyl group, N— (2-hydroxyethyl) group rubamoyl group, N— (3-hydroxypropyl) group rubamoyl group, N— (4-hydroxy Butyl) carbamoyl group), amino group or dimethylamino group substituted N mono Cl-6 alkyl strength Luba Moyl group (eg N aminomethylcarbamoyl group, N— (2-aminoethyl) force Rubamoyl group, N— (3-Aminopropyl) force rubamoyl group, N— (4-Aminobutyl) force Rubamoyl group, N- (dimethylamino) methylcarbamoyl group, N— (2-dimethylaminoethyl) force rubamoyl group, N— ( 3) -dimethylaminopropyl) strong rubamoyl group, N— (4-di
  • Borhydrazino group (for example, methylcarbohydrazino group, ethylcarbohydrazino group, etc.), (44)
  • it may have a substituent such as benzaldehyde hydrazone group, p-methoxybenzaldehyde hydrazone group, etc.
  • C6 ⁇ : L0 arylhydrazone group and the like can be mentioned, and these optional substituents may be substituted by any number that can be substituted at any substitutable position.
  • cyclic group means a monovalent group formed by removing any one hydrogen atom from the “carbocycle” or “heterocycle”.
  • examples of the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” include “C1-20 alkyl group”. ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.
  • the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent.
  • Examples of such a “substituent” include those similar to those exemplified above as the “substituent” in the “cyclic group optionally having substituent (s)”.
  • the “5- to 7-membered heterocycle” in the “optionally substituted 5- to 7-membered heterocycle” includes, for example, “oxygen” Atoms, nitrogen atoms and sulfur atomic forces, including 5 to 7-membered monocyclic heterocycles containing 1 to 3 selected heteroatoms.
  • Examples of the “5- to 7-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom” include pyrrole, imidazole, pyrazole, pyridine, pyrazine and pyrimidine.
  • the “substituent” in the “optionally substituted 5- to 7-membered heterocycle” is not particularly limited as long as it is a substituent.
  • Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). It is done.
  • the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” includes, for example, “C1-20 alkyl group” ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.
  • the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent.
  • Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). .
  • examples of the “cyclic group optionally having a substituent” include, for example, “having a substituent” in the general formula (I). Examples include those similar to those exemplified as “cyclic group”.
  • the “optionally substituted amino group” is an unsubstituted one, so-called an amino group, or one or two groups depending on an arbitrary substituent. Examples thereof include a substituted amino group.
  • Such amino groups include, for example, (Cl-8 alkyl) sulfo-lumamino groups (eg, methylsulfo-amino-substituted ethyl sulfo-amino-containing propylsulfonyl-containing butylsulfonylamino, pentylsulfonylamino-containing hexylsulfonylamino, heptyl sulfone).
  • 3 to 6 membered cyclic amino group which may contain 1 to 3 selected heteroatoms (eg, acetylidyl, azetidyl, pyrrolidyl, pyrrolinyl, pyrrolyl, imidazolyl, Virazolyl, imidazolidinyl, piperidinated morpholino, dihydropyridyl, pyridyl, N-methylbiperazi- And N-ethylbiperazyl group).
  • heteroatoms eg, acetylidyl, azetidyl, pyrrolidyl, pyrrolinyl, pyrrolyl, imidazolyl, Virazolyl, imidazolidinyl, piperidinated morpholino, dihydropyridyl, pyridyl, N-methylbiperazi- And N-ethylbiperazyl group).
  • R 2 - 2 "substituent" represented by is not particularly limited as long as it is a substituent.
  • substituents include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I).
  • the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group optionally having a substituent” includes, for example, “C1-20 alkyl group” ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.
  • the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent.
  • Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). Can be mentioned.
  • examples of the “alkoxy group” in the “optionally substituted alkoxy group” include “C1-20 alkoxy group” and the like. .
  • the “substituent” in the “alkoxy group which may have a substituent” is not particularly limited as long as it is a substituent.
  • Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). It is done.
  • R 1 — 3 and R 3 — 3 represent “having a substituent.
  • optional cyclic group include those similar to those exemplified as the “cyclic group optionally having substituent (s)” in the general formula (I).
  • the" substituent "in the” optionally substituted phenyl group "represented by ring D is not particularly limited as long as it is a substituent.
  • substituents include those similar to those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). .
  • R 2 - 3 and X 1 - 3 represent "substituent” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those represented by the general formula (I).
  • Examples thereof include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent.
  • examples of the “alkyl group” in the “optionally substituted alkyl group” include “C1-20 alkyl group” and the like. It is done.
  • the “substituent” in the “alkyl group optionally having substituent (s)” is not particularly limited as long as it is a substituent.
  • Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). Can be mentioned.
  • the “cyclic group optionally having substituent (s)” represented by E, R 2 — 4 and R 4 — 4 includes, for example, the above general formula ( Examples thereof include those similar to those exemplified as the “optionally substituted cyclic group” in I).
  • R 3 - 4 and R 4 - 4 "aliphatic hydrocarbon group" of the "aliphatic optionally substituted hydrocarbon group" represented by, for example, "Cl ⁇ 20 alkyl group", “C2 -20 alkyl group “or” C2-20 alkyl group ".
  • the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent.
  • examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). Can be mentioned.
  • alkoxy group examples include “C1-20 alkoxy group” and the like.
  • the “substituent” in the “optionally substituted alkoxy group” is not particularly limited as long as it is a substituent.
  • examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). It is done.
  • the “optionally substituted amino group” is an unsubstituted one, that is, a so-called amino group, or one or two substituents by an arbitrary substituent.
  • Amino groups and the like examples include those similar to those exemplified as the “optionally substituted amino group” in the general formula (IV).
  • R 5 - 4 represent "substituent” is not limited especially if it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). I can get lost.
  • halogen atom means a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom.
  • C1-20 alkyl group means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Noel, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl Hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl groups and their isomer groups.
  • C1-8 alkyl group means a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.
  • C2-20 alkyl group refers to ethyl, probe, butenyl, pentyl, hexyl, heptul, otatur, nonel, decel, It means undecyl, dodecyl, tridecenyl, tetradecyl, pentadecyl, hexadecyl, heptadecenyl, octadecenyl, nonadecenyl, icosyl groups and their isomeric groups.
  • C2-20 alkyl group means ethynyl, probule, butur, pentininore, hexnore, hept-nore, octinore, no-nore, decinore, Undeshi Nore, It means dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecynyl, icosinyl groups and their isomeric groups.
  • C1-20 alkylidene group means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, otatilidene, no-lidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentade It means a silidene, hexadecylidene, heptadecylidene, octadecidylidene, nonadecylidene, icosilidene group and isomer groups thereof.
  • C1-20 alkyloxy group means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, It means pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy groups and their isomer groups.
  • C2-20 alkoxy group refers to ethuroxy, propyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, none-loxy, dec-loxy, undec It means -loxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecenyloxy, heptadecyloxy, octadecyloxy, nonadeceroxy, icocenyloxy and their isomeric groups.
  • C2-20 alkyloxy group means ethuroxy, propoxy, butynyloxy, pentynyloxy, hexyloxy, heptynyloxy, octyloxy, nitro-oxy, decoxyloxy.
  • C1-20 alkylthio group means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, no It means diruthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadecylthio, octadecylthio, nonadecylthio, icosylthio groups and isomeric groups thereof.
  • C2-20 alkthio group refers to etyrthio, probethio, butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio, nonethylthio, decthiolthio.
  • Undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecenylthio, hexadecenylthio, heptadecylthio, octadecenylthio, nonadecenylthio, icosenylthio and their isomeric groups means.
  • C2-20 alkylthio group refers to ethylthio, propylthio, butynylthio, pentynylthio, hexylthio, heptynylthio, octynylthio, no-- Ruthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadesurio, octadedecylthio, nonadecylthio, icosylthio groups and their It means an alien group.
  • C1-20 alkyl sulfier group means methyl sulfier, ethyl snorefi-nore, propinoles norefi-nore, butinoles norefi-nore, pentinores norefi -Nore, Hexinoles Norefi-Nore, Heptinoles Norefi-Nore, Otacinores Norefi-Nore, Noninoles Norefirl, Decyl Sulfiel, Undecyl Sulfiel, Dodecyl Sulfiel, Tridecyl Means sulfiel, tetradecylsulfur, pentadecylsulfyl, hexadecylsulfinyl, heptadecylsulfuryl, octadecylsulfuryl, nonadecylsulf
  • C2-20 alkenylsulfier group refers to etulsulfier, propenonolesnorefininore, buteninoresnorefininore, penteninoresnorefininore, hexenoresnorefininore, Hepteninolesnorefininole, otateninoresnorefininore, noneninoresnorefinil, decenylsulfier, undecenylsulfier, dodecenylsulfier, tridecenylsulfuryl, tetradecenyls Luffyol, pentadecenylsulfuric acid, hexadecenylsulfuric acid, heptadecenylsulfuric acid, octadecenylsulfuric acid , Nonadecyl sulfier, icos
  • C2-20 alkylsulfier group refers to ethylsulfier, propyninoresnorefininore, butyninoresnorefininore, pentinoinoresnorefininore, hekisnoresnorefi-nore, Heptyl Noles Nore, Otachi Noles Nore Nore, Non-Ninoles Nore, Decyl Sulfyl, Undecyl Sulfyl, Dodecyl Sulfyl, Tridecyl Sulfyl, Tetradecyl Rusulfil, It means pentadesulfuryl, hexadecylsulfil, heptadesulfuryl, octadecylsulfil, nonadecylsulfuryl, icosinylsulfiel groups and their isomeric groups.
  • the "C1-20 alkylsulfonyl group” means methylsulfol, ethyls norehoninole, propinolesnorehoninore, butinoresnorehoninore, pentinoresnorehoninore, Xinore, senorehoninore, heptinolesnorehoninore, octinoresnorehoninore, noninoresnorehoninore, decinolesol, undecylsulfol, dodecylsulfol, tridecylsulfol, tetradecylsulfol, It means pentadecylsulfol, hexadecylsulfol, heptadecinolesnorehoninore, octadecinoresnorehoninor
  • C2-20 alkenylsulfol group refers to etulsulfol, propenolesnorenore, buteresnorenore, pentenorenorenoinole, hexe- Noresnorejo Ninore, Hefteninoresnorehoninore, Taittenenoresnorehoninore, Nono Ninoresnorehoninore, Ninoreno, Undesenorejo-nore, Dodesenorenorenore, Toridese Nolesnoleol, tetradecylsulfol, pentadecenylsulfol, hexadecylsulfol, heptadecenylsulfol, octadecylsulfol, nonadecylsulfol, icocenylsulfur and These
  • C2-20 alkylsulfol group means ethylsulfol, propyninoresnorehoninore, butyninoresnorehoninore, pentyninoresnorehoninore, hexyl Ninoles Nore Ninore, Heptininoles Norehoninore, Kuchininores Norehoninore, Nonininores Norehoninore, Tenninore Sunorehoninore, Undeshi Noresnore Nore, Dodeci Nolesnorenore Nore , Tetradecyl sulfol, pentadecyl sulfol, hexadecyl sulfol, heptadecyl sulfol, octadecyl sulfol, nonadecyl sulfol,
  • the "C1-20 acyl group” means methanol, ethanol, propanoyl, butanol, pentanoyl, hexanoyl, heptanoyl, otatanyl, nonanoyl, decanol, undecanol, tetradecanol, tridecanol, Hexadecanol, heptadecanol, octadecanol, nonadecanol, icosanol and their isomers.
  • the “C1-20 acyloxy group” means methanoyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanooxy, hexanoyloxy, heptanoyloxy, otanoyloxy, nonanoyloxy, decanoxy, Undeoxy, dodecanoxy, tridecanoxy, tetradecanoxy, pentadecanoxy, hexadecanoyloxy, heptadecanoxy, octadecanoyloxy, nonadecanoxy, Means icosanoyloxy group and isomers thereof.
  • the geometric isomer of the compound represented by the general formula (I) is the general formula (Ig).
  • R 1_lg and R 2_lg represent the same meaning as R 1_1 and R 2_1 in general formula (I), respectively. ] Means.
  • R 1_lgt and R 2_lgt are R 1 _1 and R 2 in general formula (I), respectively.
  • R 1 — 1A and R 2 — 1A represent the same meaning as R 1 and R 2 described in International Publication No. 2005/000281, respectively. ] Can be represented.
  • examples of preferable groups and preferable compounds in general formula (IA) include those similar to those described in International Publication No. 2005/000281 and those described in Examples. Can be mentioned.
  • ring A z represents the same meaning as ring A above, represents a 5- to 6-membered saturated ring optionally having a ring or a substituent, and R 1_2Z represents R 1 — 2 above. R 2 — 2Z represents an optionally protected mercapto group. ] Can be represented.
  • Examples of the “5- to 6-membered saturated heterocyclic ring” include pyrrolidine, imidazolidine, triazolidine, tetrazolidine, virazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene.
  • Tetrahydrothipyran tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrosazazonole ( Oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydro Ajiajin, morpholine, thiomorpholine, Okisachian and the like.
  • Ring B z "substituent" in the "substituted, also O, 5-6 membered saturated heterocyclic ring” is not particularly limited as long as it is a substituent.
  • substituents include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). Can be mentioned.
  • the " optionally protected mercapto group" represented by R 2_2Z includes, in addition to mercapto groups, for example, mercapto groups protected with aliphatic hydrocarbon groups which may have substituents, substituted And a mercapto group protected with a cyclic group which may have a group.
  • “having a substituent may be an aliphatic hydrocarbon group” or “having a substituent, may be a cyclic group” used for protecting a mercapto group is the above general formula.
  • Examples of “substituent” in (I) “having a substituent, may be an aliphatic hydrocarbon group” or “having a substituent, but may be a cyclic group” And the like.
  • R 1_2G R 2_2G R 3 R 4 and R 2G have the same meaning as R 1 R 2 R 3 R 4 and R described in WO 00/34283, respectively. Represents meaning. ] Can be represented.
  • XX 2 X 3 X 4 X 5 represents the same meaning as n. ] Can be represented.
  • the preferred, group, preferred, and compound are, for example, the same as those described in JP 2005-179350 A, and those described in the examples. Can be mentioned.
  • preferred compounds in the general formula (IV) are represented by the general formula (IVJ).
  • R 2_4J , R 3_4J , R 4_4J , R 5_4J , R 11_4J , R 12_4J The meanings of the groups represented by and are respectively R 2 , R 3 , R 4 , R 5 , described in JP-A-2005-053903, It has the same meaning as R 12 , X, and ⁇ . ] Can be represented.
  • ⁇ low molecular weight compound as a cker '' include, for example, clopidogrel, titaropidine, cangrelor, prasdarrel, AZD-6140, INS-50589, INS-49266, AR-C 66096, ARL-67085, GR-144043, Roxifiban, MRS2395 or their salts can be mentioned.
  • the details of these compounds (for example, structure, pharmacological activity, production method, etc.) have been developed or developed as antagonists of P2Y receptors. It was a compound
  • [0162] indicates binding to the other side of the page (ie OC placement)
  • [0164] represents binding to the front side of the page (ie, ⁇ configuration)
  • [0166] represents a mixture of the a configuration and the j8-configuration in an arbitrary ratio.
  • a compound represented by the general formula (I), a compound represented by the general formula (II), a compound represented by the general formula (III), a compound represented by the general formula (IV) (Hereinafter, these may be collectively abbreviated as the compounds represented by the general formulas (I) to (IV).), Or clopidodarrel, ticlopidine, cangrelor, plusdarrel, AZD-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, Roxyfiban, MRS2395, P2Y
  • Salts such as antagonists include all pharmacologically acceptable salts.
  • the pharmacologically acceptable salt is preferably low-toxic and water-soluble. Suitable salts include, for example, alkali metal (eg, potassium, sodium, lithium, etc.) salts, alkaline earth metal (eg, calcium, magnesium, etc.) salts, ammonium salts (eg, tetramethylammonium ⁇ Salts, tetraptylammonium salts, etc.), organic amines (eg, triethylamine, methylamine, ethylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Salts of tris (hydroxymethyl) methylamine, lysine, arginine, orthine, N-methyl D-glucamine, etc., acid adduct salts (eg, inorganic acid salts (eg, hydrochloride, hydro
  • examples of the solvate of the compounds represented by the general formulas (I) to (IV) include solvates such as water and alcohol solvents (for example, ethanol and the like). Solvates preferably have low toxicity and water solubility.
  • the solvates of the compounds represented by the general formulas (I) to (IV) include solvates of the above salts.
  • the N-oxide form of the compound represented by the general formula ( ⁇ ) represents an oxidized nitrogen atom of the compound represented by the general formula (II). Further, the N-oxide form of the compound represented by the general formula (II) may further be an alkali (earth) metal salt, an ammonium salt, an organic amine salt, or an acid adduct salt. .
  • a compound represented by the general formula (I), a compound represented by the general formula ( ⁇ ), or a compound represented by the general formula (III) (hereinafter collectively referred to as general formulas (I) to (III)
  • the prodrug is a compound that can be converted into a compound represented by the general formulas (I) to ( ⁇ ) by a reaction with an enzyme, gastric acid, or the like in a living body.
  • prodrugs of the compounds represented by the general formulas (I) to ( ⁇ ) for example, when the compounds represented by the general formulas ( ⁇ ) to ( ⁇ ) have an amino group, the amino group is acylated or alkylated. , Phosphorylated compounds
  • Prodrugs of these compounds are represented by general formulas ( ⁇ ) to ( ⁇ ) under physiological conditions as described in Yodogawa Shoten 1990, “Development of Pharmaceuticals”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to a compound.
  • the prodrugs of the compounds represented by the general formulas ( ⁇ ) to ( ⁇ ), or the compound represented by the general formula ( ⁇ ) are the salts or solvates described above (for example, water, alcohol solvents (for example, A solvate such as ethanol) or the like, or may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 1251, etc.).
  • the product of the reaction can be purified by conventional purification means such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization. It can refine
  • the compound represented by the general formula (I) used in the present invention its geometric isomer, its tautomer, its salt, its solvate, or their prodrug, represented by the general formula ( ⁇ ) Compound, its salt, its N-oxide, its solvate, or prodrug thereof, A compound represented by the general formula (m), a salt thereof, or a prodrug thereof, and a compound represented by the general formula (IV), or a salt thereof, and ticlovidin, mandarelol, plasdarrel, AZD-6140, INS-50589 Compounds such as INS-49266, AR-C66096, ARL-67085, GR-144043, roxifiban, MRS2395, etc.
  • impurities e.g. Derived by-products, solvents, raw materials, etc., or decomposed products
  • the content of impurities acceptable as an active pharmaceutical ingredient varies depending on which compound is used, and also differs depending on the dosage form as a pharmaceutical (eg, intravenous administration, oral administration, transdermal administration, etc.). It is preferable to determine the amount while assessing efficacy and toxicity as appropriate.
  • an effective amount of the above-mentioned "P2Y receptor and Z or P2Y receptor blocker” for example, pain prevention, treatment and suppression of Z or symptom progression
  • a mammal eg, a human non-human animal, preferably a human, particularly preferably a patient.
  • prevention means that pain does not occur or only mild pain occurs, and “treatment” means that pain is relieved, "symptom progression suppression”
  • treatment means that pain is relieved
  • symptom progression suppression means that alleviatement of pain” (for example, expansion of pain range, increase of pain level, increase of pain frequency, etc.)
  • prevention includes the meaning of suppressing the occurrence of the next pain in periodic pains, and the meaning of preventing the pain threshold from being lowered. The meaning of returning to is also included.
  • the pain may be any sensation that is generally recognized as pain.
  • the disease itself may be the disease itself, such as trigeminal neuralgia, for example, a disease that shows pain as one of the symptoms, such as rheumatoid arthritis, so-called painful disease It may be one symptom.
  • the present invention is to be used as a prevention, treatment and Z or symptom progression suppression method for any of these pains.
  • pain is classified into various categories according to its characteristics. For example, pain Depending on the cause of, for example, nociceptive pain, neuro genie pain, psychogenic pain, etc. Pain [visceral pain], somatic pain [eg superficial pain], deep pain [deep pain], orofacial pain [orofacial pain], related pain [refferred pain ] May be classified.
  • the pain in the present invention includes a sensation recognized as “numbness”. That is, the pain in the present invention refers to a mammal that can be administered with (2R) -2-propyloctanoic acid, a salt thereof, or a prodrug thereof (eg, a human or a non-human animal, preferably a human, particularly preferably a patient). ) Is anything that feels “pain” or “numbness”! /.
  • Nociceptive pain is pain caused by tissue injury or the addition of a stimulus with the risk of tissue injury.
  • Nociceptive pain is pain through nociceptors, depending on the cause of pain from external stimuli (e.g., nociceptive mechanical, thermal, chemical, etc.) and endogenous stimuli (e.g., organic It can also be classified into pain due to disease, inflammatory pain) and the like.
  • external stimuli e.g., nociceptive mechanical, thermal, chemical, etc.
  • endogenous stimuli e.g., organic It can also be classified into pain due to disease, inflammatory pain
  • Nociceptive pain in the present invention includes pain resulting from injuries to living tissues such as cuts, bruises, fractures, fractures, burns, surgery, and cancer.
  • Neurogenic pain is pathological pain caused by dysfunction of the peripheral nerve or the central nervous system itself (brain, spinal cord, etc.), and pain pathways not via Z or nociceptors. Pain caused by the occurrence of abnormal excitement in the 1994, as proposed in the International Association for the Study of Pain [1994] Pain due to transient dysfunction of the nervous system ”And“ pathological pain (central pain) due to damage or dysfunction of the peripheral and Z or central nerves ”, so-called neuropathic pain. .
  • the type of neuropathy may be single neuropathy or multiple neuropathy. Specifically, nerve damage that causes damage or degeneration of nerves, nerve plexus, or surrounding nerve soft tissue due to trauma, compression, infection, cancer, ischemia, or metabolic disorders such as diabetes, etc. It means an abnormal state of persistent pain perception, such as a decrease in pain threshold due to some abnormal function caused by neuropathy.
  • these disease names may be names representing pain itself or names of painful diseases.
  • the same disease name may be exemplified multiple times in several categories.
  • pain includes, for example, headache (for example, migraine, myotonic headache, cluster headache, other symptomatic headaches), orofacial pain (for example, toothache, glossodynia, temporomandibular joint) , Cervical disc herniation, degenerative cervical spondylosis, cervical shoulder arm syndrome, shoulder periarthritis (fifty shoulders), cervical spinal canal stenosis, thoracic outlet syndrome, brachial nerve Plexus withdrawal injury, shoulder-hand syndrome, traumatic neck syndrome (whiplash), chest pain, abdominal pain (e.g. acute abdomen, cholelithiasis, acute splenitis, urinary calculus etc.), back pain (e.g.
  • headache for example, migraine, myotonic headache, cluster headache, other symptomatic headaches
  • orofacial pain for example, toothache, glossodynia, temporomandibular joint
  • Cervical disc herniation for example, toothache, glossodynia, temporomandi
  • neuralgia e.g. trigeminal neuralgia, intercostal neuralgia, sensory dysfunctional femoral neuralgia, inguinal neuralgia, saphenous neuralgia, median neuralgia, ulnar neuralgia, sciatica, nerve root pain, etc.
  • herpes zoster pain (E.g., acute herpes zoster pain, postherpetic pain (chronic), etc.)
  • diabetic pain e.g., diabetic-europathy, large-diameter fiber-europathy, small-diameter fiber neuropathy, proximal muscle dominant exercise-europathy, acute Mononeuropathy, paralysis due to compression, etc.
  • strangulation neuropathy e.g., thoracic outlet syndrome, suprascapular nerve strangulation disorder, scapulodorsal nerve strangulation disorder, quadrilateral gap syndrome, circumflex muscle syndrome, anterior Interosseous nerve syndrome, elbow canal syndrome, slow Onset ulnar nerve
  • the preferred pain is neuropathic pain (especially cancer pain, after herpes zoster) Pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, or orofacial pain.
  • neuropathic pain in addition to the above-mentioned diseases, hypersensitivity (particularly hyperalgesia etc.), spontaneous pain and the like are also preferable.
  • P2Y receptor and ⁇ ⁇ ⁇ or ⁇ 2 ⁇ receptor blocker
  • the “prevention and treatment of pain, and an epilepsy or symptom progression inhibitor” is preferably targeted to neuropathic pain among the above pains.
  • it is preferably used for cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia. Pain can be prevented, treated, and / or symptom-progressed, even with alodyya pain.
  • the present invention also aims at inhibiting P2Y receptor and / or P2Y receptor positive cells.
  • a mammal eg, a non-human animal, preferably a human, particularly preferably a patient.
  • ⁇ 2 ⁇ receptor and ⁇ or ⁇ 2 ⁇ receptor positive cell means ⁇ 2 ⁇ receptor and
  • ⁇ or ⁇ 2 ⁇ means a cell expressing the receptor, even a single molecule
  • the cell is included in the positive cell. ⁇ 2 ⁇
  • the action described in (1) or (2) may be caused by any regulation of cell differentiation, proliferation, life span, or the like.
  • the cell function described in (3) may be a function universally possessed by the cell. Among them, the cell function related to ⁇ 2 ⁇ receptor and ⁇ or ⁇ 2 ⁇ receptor, particularly any
  • a cell function that leads to a pain or a medical condition, particularly pain described later, is preferably mentioned.
  • the action described in (1) or (2) may be caused by any regulation such as protein synthesis, proteolysis, internalization, or shedding.
  • the receptor function described in (3) include binding of an in vivo ligand to the receptor, signal transduction when the in vivo ligand binds to the receptor (for example, receptor clustering, protein phosphorylation). (Oxidation, dephosphorylation, generation of second messenger, gene expression, etc.) are preferred.
  • a low molecular weight compound for example, (a) a low molecular weight compound, (b) an antibody, (c) an antisense, (d) a short interfering RNA, (e) a decoy, (£) a ribozyme, (g) an abutama Exists.
  • These substances may be used for the purpose of preventing or treating pain and suppressing Z or symptom progression, or P2Y
  • P2Y receptor For the purpose of Z- or P2Y receptor-positive cell suppression, P2Y receptor and
  • the form of the pharmaceutical composition when a low molecular weight compound is administered to a mammal, includes, for example, a preparation for oral administration (for example, a solid preparation for internal use, a liquid preparation for internal use, etc.) or for parenteral administration.
  • a preparation for oral administration for example, a solid preparation for internal use, a liquid preparation for internal use, etc.
  • parenteral administration for parenteral administration.
  • Formulations for example, injections, liquids for external use, ointments, coating agents, inhalants, sprays, suppositories, vaginal suppositories, etc.
  • solid preparations for internal use include tablets, pills, capsules (node capsules, soft capsules), powders, granules and the like.
  • These solid preparations for internal use consist of an active ingredient and various additives (for example, excipients (eg, ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (eg, hydroxypropylcellulose, polypyrrolopyrrolidone, Magnesium aluminate metasilicate, etc.), disintegrating agents (eg, calcium cellulose glycolate), lubricants (eg: magnesium stearate), stabilizers, solubilizers (eg: glutamic acid, aspartic acid) Etc.)) and the like, and can be produced using a known method.
  • coating agents eg, sucrose, gelatin, hydroxypropinolecellulose, hydroxypropenolemethinolecellulose phthalate, etc.
  • liquids for internal use include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. These liquid preparations for internal use can be produced by dissolving, suspending or emulsifying the active ingredient in a diluent generally used (for example, purified water, ethanol or a mixture thereof).
  • a diluent generally used for example, purified water, ethanol or a mixture thereof.
  • liquids for internal use may contain various additives (eg, wetting agents (eg, glycerin, propylene glycol, etc.), suspending agents (eg, carmellose, agar, gelatin, methylcellulose, etc.), emulsifiers (eg, : Arabic gum, popidone, glyceryl monostearate, etc.), sweeteners (eg, fructose, glucose, etc.), flavoring agents (eg, coffee, tea, cocoa, etc.), fragrances (eg, orange oil, thymol, etc.) ), Preservatives (eg, benzoic acid, sodium benzoate, ethyl parabenzoate, propyl parabenzoate), buffers (eg, citrate, disodium hydrogen phosphate, sodium citrate, sodium hydrogen carbonate, acetic acid) , Lactic acid, etc.) may be added.
  • wetting agents eg, glycerin, propylene glycol, etc.
  • injections may be, for example, suspension injections or emulsion injections, and solid injections that are dissolved or suspended at the time of use.
  • An agent for example, freeze-dried product
  • These injections are administered, for example, intramuscularly, subcutaneously, intradermally, intraarterially, intravenously, intraperitoneally, intrathecally.
  • injectables may also be administered by infusion.
  • These injections contain active ingredients as solvents (for example, distilled water for injection, physiological saline). , Vegetable oils, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof).
  • these injections may contain various additives (eg, stabilizers, solubilizers (eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), suspending agents (eg, methylcellulose, Carboxymethylcellulose, etc.), emulsifier (eg, polysorbate 80 (registered trademark), etc.), soothing agent (eg, pro-powered in, lidocaine hydrochloride, etc.), buffer (eg: sodium chloride, salted potassium, Disodium hydrogen phosphate, citrate, sodium citrate, etc.) and preservatives (eg, benzyl alcohol, etc.) may be added.
  • additives eg, stabilizers, solubilizers (eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), suspending agents (eg, methylcellulose, Carboxymethylcellulose, etc.), emulsifier (eg, polysorbate 80 (registered trademark), etc.), soothing agent (eg,
  • compositions for parenteral administration for example, preparations for external use, ointments, coatings, inhalants, sprays, suppositories, vaginal suppositories, etc. should be manufactured according to known formulations. You can.
  • the form of the pharmaceutical composition includes, for example, an injection (including infusion), a suppository, a nasal agent, a sublingual agent, a transdermal absorption agent, and the like.
  • an injection including infusion
  • a suppository a nasal agent, a sublingual agent, a transdermal absorption agent, and the like.
  • Monoclonal antibodies and polyclonal antibodies are high molecular weight proteins, so they are extremely unstable and unstable in adsorption to glass containers such as vials and syringes, and various physical and physical factors such as heat, It is expected to be easily deactivated due to pH and humidity.
  • a stabilizer in order to formulate in a stable form.
  • the stabilizer include amino acids such as glycine and alanine, saccharides such as dextran 40 and mannose, sugar alcohols such as sorbitol, mannitol and xylitol, and combinations of two or more of these are used. May be.
  • the added amount of these stabilizers is preferably about 0.01 to 100 times, particularly about 0.1 to 10 times the weight of the antibody. By adding these stabilizers, the storage stability of the liquid preparation or lyophilized preparation can be improved.
  • the buffer examples include a phosphate buffer and a citrate buffer.
  • the buffer is prepared by adjusting the pH of the aqueous solution after re-dissolution of the liquid preparation or lyophilized preparation. Stability and solubility can be improved.
  • the addition amount of the buffering agent is preferably about ImM to 10 mM, for example, with respect to the liquid amount after redissolving the liquid preparation or lyophilized preparation.
  • the surfactant for example, polysorbate 20, pull nick F-68, polyethylene glycol or the like is preferred, and polysorbate 80 or the like is particularly preferred. Moreover, you may use combining these 2 or more types.
  • a high molecular protein such as an antibody is easily adsorbed to glass resin or the like which is a material of a container. Therefore, by adding a surfactant, it is possible to prevent adsorption of the antibody after re-dissolution of the liquid preparation or lyophilized preparation into the container.
  • the amount of the surfactant added is preferably about 0.001% to 1.0% with respect to the weight of the liquid after redissolving the liquid preparation or lyophilized preparation, for example.
  • the antibody preparation can be prepared by adding a stabilizer, a buffer, or an adsorption inhibitor as described above, but it is acceptable as an osmotic pressure, particularly when used as a medical or animal injection.
  • the osmotic pressure ratio is preferably 1 to 2.
  • the osmotic pressure ratio can be adjusted by increasing / decreasing sodium chloride at the time of formulation.
  • the antibody content in the preparation can be appropriately adjusted according to the disease to be applied, the route of administration and the like. For example, when the antibody is administered to a human, about O.lmg Zkg to lOOmgZkg may be administered once every 1 to 30 days.
  • nucleic acid molecule such as antisense, short interfering RNA, decoy, ribozyme, aptamer, etc.
  • a pharmaceutical composition it is described in various known literatures in order to obtain a desired medicinal effect. It is preferable to use such a pharmaceutical composition.
  • RNA molecules are described in detail in WO94 / 02595 pamphlet. These documents are related to ribosome encapsulation, iontophoresis, or incorporation into other media (eg hydrogels, cyclodextrins, biodegradable nanocapsules, bioadhesive spherules, etc.)!
  • the method for administering the nucleic acid molecule used in the present invention is not limited to these.
  • a combination of a nucleic acid molecule and these media, or the nucleic acid molecule itself can be administered ex vivo to a cell or tissue, or can be directly injected into a vein or catheter. It can also be administered using a tellurium, an infusion pump, a stent or the like.
  • Neuroscience Letters, 257, 135-138, 1998; Mol. Brain Research, 55, 151-164, 1998; J. Endocri nol., 157, 169-175, 1998; Neuroscience Letters, 247, 21-24, 1998 Describes a method of administering oligonucleotides to the central nervous system using osmotic pumps, for example, Neurosurg. Focus, 3, article 4, 1997 by direct injection.
  • the administration to the central nervous system is described in detail in Drug Delivery systems: Technologies and Commercial Opportunities, Decision Resources, 1998, etc.
  • compositions used therefor are, for example, WO 93/23569 pamphlet, WO 99/05094 pamphlet, WO 99/04819 pamphlet. Since these are described in detail in the pamphlet of International Publication No. 94/02595, etc., these can be applied mutatis mutandis.
  • the dosing period of the pharmaceutical composition is expected to have a prophylactic effect, for example. If it is expected to have a therapeutic effect, for example, if the therapeutic effect is expected to be substantially completed, for example if it is expected to have a symptom progression suppressing effect, the symptom progression is substantially It may be any period until it is suppressed. If desired, it may be administered intermittently with an appropriate drug holiday.
  • the drug withdrawal period is 1 day or more and 30 days or less, for example, intermittent administration every other day, administration for 2 days, administration of intermittent treatment for 1 day, 2 days after continuous administration for 5 days It may be intermittent administration such as intermittent administration, etc., or a calendar system (for example, a tablet is called a calendar tablet).
  • the specific dosing period in the agent of the present invention is, for example, for oral administration, 1 day to 5 years, preferably 1 day to 1 year, more preferably 1 day to 6 months. Especially preferred is a period of 1 day to 2 months. Further, for example, in the case of intravenous administration, 1 day to 100 days, etc., preferably 1 day to 10 days, etc., more preferably 1 day to 7 days, etc., most preferably 7 days, etc. are mentioned.
  • the number of doses per day during these dosing periods is, for example, 1 to 5 times, preferably 1 to 3 times, etc. in the oral administration and intravenous administration forms. Good Preferably, it is once or twice, most preferably once.
  • transdermal administration can be expected to have a local action, it is possible to obtain superior effects by administering to the site when pain is felt.
  • the contained pharmaceutical composition may be used alone or in combination with other drugs or treatment methods used for pain treatment.
  • opioid analgesics eg morphine, codin, fentanyl, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxycodone, oxymorphone, pentazocine
  • Painkillers eg, N-type calcium channel inhibitors (eg, Ziconotide, ONO-2921, etc.), ABS-17, AC-262271, ACP-102, ADX-1, AV-333, AZD-6538, CGP -35024, CPI-1714, DP-236, EN-3215, Galantamine, JO-1614, M-58996, Neublastin, RWJ-38116, VX-409, YT-1006, Fental patch [ fent
  • auxiliary analgesics e.g., sedatives (e.g., Benzojiazepin anxiolytics (eg E.g., diazepam, flurazepam, etc.), antidepressants (e.g., amitriptyline, desipramine, etc.), antiepileptics (e.g., gabapentinoids (e.g., gabapentin, pregabalin, etc.), carbamazepine, phenytoin, clonazepam, divalpro X, lamotrigine, topiramate, oxcarbazepine etc.), central muscle relaxants (eg baclofen etc.), local anesthetics (eg mexiletine, lidocaine etc.
  • compositions containing ⁇ 12 ⁇ or ⁇ 2 ⁇ ⁇ ⁇ ⁇ receptor blocker '' and other treatment methods include
  • nerve blocks eg, trigger point block, stellate ganglion block, brachial plexus block, suprascapular nerve block, epidural block, nerve root block, facet joint block, isolation Block, sciatic nerve block, intercostal nerve block, etc.
  • spinal cord stimulation therapy nonconvulsive energization, iontophoresis, acupuncture (eg, electric acupuncture, placement, acupuncture, etc.), acupressure, massage, electrotherapy
  • transcutaneous electrical nerve stimulation TESS
  • low frequency low frequency
  • hyperthermia for example, hot pack, cooling therapy, diathermy, ultra high frequency, etc.
  • phototherapy for example, low power laser, polarized near infrared
  • Hot spring (water) treatment e.g., hot springs, drinking springs, mud baths, underwater function training, etc.
  • hyperbaric oxygen therapy e.g., aromatherapy, biofeedback and other cognitive techniques (e.g. relaxation training, hypnosis, Distraction techniques), psychological counseling, etc.
  • composition comprising a ⁇ 2 ⁇ receptor and a Z or P2Y receptor blocker
  • the aforementioned drugs that can be used in combination with products are merely examples, and are not limited thereto.
  • the administration method of these drugs used in combination is not particularly limited, and may be oral administration or parenteral administration.
  • these drugs may be administered in combination of any two or more.
  • These drugs include not only those that have been found so far, but also those that will be found in the future, based on the mechanism described above.
  • the present invention aims to prevent and treat pain and to suppress Z or symptom progression, or to suppress P 2Y receptor and Z or P2Y receptor positive cells, and further to P2Y.
  • ⁇ 2 ⁇ receptor and Z For the purpose of receptor and Z or P2Y receptor inhibition, ⁇ 2 ⁇ receptor and Z
  • the pharmaceutical composition is used for the above purpose in mammals (eg, humans, non-human animals, eg, monkeys, hidges, mice, horses, dogs, cats, rabbits, rats, mice, etc.) be able to.
  • mammals eg, humans, non-human animals, eg, monkeys, hidges, mice, horses, dogs, cats, rabbits, rats, mice, etc.
  • ⁇ 2 ⁇ receptor and ⁇ or ⁇ 2 ⁇ receptor blocker is treated as pain.
  • the present invention is an effective treatment method for patients who exhibit symptoms such as pain, such as alodynia, which cannot be improved by existing treatment methods.
  • Pain on the cell by expressing it on the cell and antagonizing or suppressing the expression of the receptor The ability to suppress was proved, for example, by the following experiment.
  • the following measurement methods have been improved as follows in order to improve measurement accuracy and Z or measurement sensitivity.
  • the detailed experimental method is shown below.
  • P2Y receptor (GenBank accession: # AF313450) Se 587-606, As 1013-994
  • P2Y receptor (GenBank accession: # U76206) Se 282-301, As 781-762
  • RNA extracted from rat spinal cord as a template to prepare cDNA.
  • the obtained cDNA was transformed into p-GEM T-easy vector to confirm the sequence, and this was used as a template for cRNA probe.
  • a radioisotope labeled cRNA probe was prepared, and in situ hybridization was performed. Furthermore, for identification of expressed cells, micrologria marker Ibal, astrocyte marker GFAP, and neuronal marker Neu N were combined with anti-Ibal antibody (anti-Ibal IgG) and anti-GFAP antibody (anti-GFAP antibody, respectively). Double staining of immunohistochemistry and in situ hybridization was performed by staining with IgG) and anti-NeuN antibody.
  • P2Y receptor mRNA is expressed in Neu N positive cells and GFAP in the naive spinal cord.
  • Vesicles can be seen and increase up to at least 30 days peaking at 3 days after sciatic nerve cutting (shown in Figure 1) It was.
  • P2Y receptor mRNA is hardly expressed in naive but is sciatic
  • the rat sciatic nerve partial ligation model was prepared according to the report of Seltzer et al. (Pain, 43, 205-218, 1990). Specifically, it was produced by the following procedure.
  • BIOGNOSTIK Used and designed and manufactured by BIOGNOSTIK (Germany).
  • MRS2395 purchased from Sigma (# M5942) was used.
  • P2Y receptor antisense and its missense are known as osmotic pump
  • the tip of the catheter connected to the osmotic pump was placed at the L4Z5 level of the lumbar vertebra, and it was continuously administered (50 pmolZhr) into the medullary canal for 2 days before partial sciatic nerve ligation.
  • P2Y receptor antisense and its missense were detected by the same method as described above.
  • the P2Y receptor antagonist MRS2395 is a dimethyl sulfoxide (DMSO) 20
  • Table 1 shows the changes over time in the escape threshold (hypersensitivity response) to mechanical stimulation when 2 days of sciatic nerve ligation was continuously administered intrathecally for 1 week.
  • n means the number of cases
  • pre means the escape threshold when no drug administration or partial ligation of the sciatic nerve is performed. The change over time was described as Day 0 on the day when the partial sciatic nerve ligation was performed, Day -1 on the previous day, and Day 1 on the next day.
  • Table 2 shows the changes over time of the escape threshold (hypersensitivity reaction) to mechanical stimulation when the sciatic nerve partial ligation force was also administered intrathecally for 1 week.
  • MRS2395 a P2Y receptor antagonist
  • Table 3 shows the changes over time in the escape threshold (hypersensitivity response) to mechanical stimulation when 2 days of force before partial ligation of the sciatic nerve was continuously administered intrathecally for 1 week.
  • saline is the physiological saline administration group
  • MRS2395 is the P2Y receptor antagonist
  • a pain comprising the P2Y receptor of the present invention and a Z or P2Y receptor blocker
  • Pain prevention, treatment and Z or symptom progression inhibitors are safe and pain, especially neuropathic pain, eg cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain
  • neuropathic pain eg cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain
  • pain in diseases such as neuralgia, orofacial pain, or hyperalgesia can be markedly improved, so that the degree of freedom of life of patients can be improved and QOL can be improved, which is useful as a medicine.

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Abstract

[PROBLEMS] To provide a therapeutic agent for pain. [MEANS FOR SOLVING PROBLEMS] A preventive agent, a therapeutic agent and/or an agent for inhibiting symptom development for pain comprising a P2Y12 receptor and/or P2Y14 receptor blocker. By administering the P2Y12 receptor and/or P2Y14 receptor blocker, pain, particularly neuropathic pain, for example, cancer pain, postherpetic pain, diabetic pain, HIV related neuropathic pain, pain caused by stone, neuralgia, orofacial pain or pain in disease such as hyperalgesia can be significantly improved.

Description

P2Y 受容体および Zまたは P2Y 受容体ブロッカーを含有してなる疼 Pain comprising P2Y receptor and Z or P2Y receptor blocker
12 14 12 14
痛治療剤 Pain treatment
技術分野  Technical field
[0001] 本発明は、 P2Y 受容体および たは P2Y 受容体ブロッカーを含有してなる、  [0001] The present invention comprises a P2Y receptor and a P2Y receptor blocker,
12 Zま  12 Z
14  14
(1)疼痛の予防、治療および Zまたは症状進展抑制剤、（2) Ρ2Υ  (1) pain prevention, treatment and Z or symptom progression inhibitor, (2) Ρ2Υ
12受容体および Ζ または Ρ2Υ 受容体陽性細胞抑制剤、および（3) Ρ2Υ 受容体および  12 receptors and Ζ or Ρ2Υ receptor positive cell inhibitors, and (3) Ρ2Υ receptors and
14 12 Ζまたは Ρ2Υ  14 12 or 2
14受容体抑制剤等に関する。 14 Receptor inhibitor and the like.
背景技術  Background art
[0002] 1994年の国際疼痛学会（IASP： International Association for the Study of Pain)に おいて発表された「慢性疼痛の分類（Classification of Chronic Pain)」によれば、「痛 み (疼痛)」とは、「組織の損傷を惹き起こす、或いは損傷を惹き起こす可能性のある 時に生じる不快な感覚や不快な情動を伴う体験、或いはそのような損傷が生じている ように表現される不快な感覚や不快な情動を伴う体験 (An unpleasant sensory and e motional experience associated with actual or potential tissue damage, or described i n terms such damage)」と定義 れて 、る。  According to the “Classification of Chronic Pain” published at the International Association for the Study of Pain (IASP) in 1994, “Pain” Is an unpleasant sensation or an experience with unpleasant emotions that occurs when there is or is likely to cause tissue damage, or an unpleasant sensation expressed as such damage or An unpleasant sensory and e motional experience associated with actual or potential tissue damage, or described in terms such damage.
[0003] 疼痛は主に、（1)侵害受容器が持続的に刺激されて生じると考えられる「侵害受容 性疼痛」、（2)疼痛伝達 ·抑制機構に力かわる神経線維の働きに異常をきたした結果 である「神経因性疼痛」、および（3)感情 ·情動面に重きがおかれる「心因性疼痛」に 分類される。  [0003] Pain mainly consists of (1) "nociceptive pain", which is thought to be caused by persistent stimulation of nociceptors, and (2) abnormalities in the function of nerve fibers involved in pain transmission and inhibition mechanisms. “Neuropathic pain”, which is the result of the results, and (3) “Psychogenic pain” where emphasis is placed on emotions and emotions.
[0004] このうち、神経因性疼痛は、末梢または中枢神経系の機能異常の結果として生じる 難治性の疼痛であり、例えば、末梢神経、神経叢または神経周囲軟組織への圧迫、 外傷または傷害、中枢性の体性感覚経路 (例えば、脊髄、脳幹、視床または皮質レ ベルでの上行体性感覚経路等)への傷害等が原因と考えられている。具体的には、 神経変性疾患、骨変性疾患、代謝異常疾患 (例えば、糖尿病等)、癌、感染、炎症、 虚血、外科的手術、外傷、放射線治療、抗ガン剤の投与等によっても起こりうる。  [0004] Of these, neuropathic pain is refractory pain resulting from dysfunction of the peripheral or central nervous system, such as pressure on the peripheral nerve, plexus or perineural soft tissue, trauma or injury, Caused by injury to central somatosensory pathways (eg, ascending somatosensory pathways at the spinal cord, brainstem, thalamus or cortical level). Specific examples include neurodegenerative diseases, bone degenerative diseases, metabolic disorders (for example, diabetes), cancer, infection, inflammation, ischemia, surgery, trauma, radiation therapy, administration of anticancer drugs, etc. sell.
[0005] 神経因性疼痛の発症のメカニズムは不明な点が多いが、ある種のイオンチャネル の新規発現に起因する知覚神経の自然発火、脊髄の種々の層への知覚神経線維 の発出、および知覚神経および脊髄における様々な神経伝達物質および受容体の 発現の変化を含むと考えられている。神経因性疼痛の代表的な症状には、ァロディ 二了 (Allodynia)、痛覚過敏（Hyperalgesia)または感覚過敏 (Hyperesthesia)等がある 。これらの症状は、「焼け付くような」、「針で刺されるような」または「電気ショックのよう な」等と表現される特徴的な痛みを呈する。神経因性疼痛には通常の侵害受容性疼 痛に有効である鎮痛薬はもとより、麻薬性鎮痛薬等でさえも効きにくいことが知られて いる（The Lancet, 353, 1959-1966, 1999)。例えば、モルヒネは侵害性疼痛に対して 強力な鎮痛作用を有するが、神経因性疼痛に対しては充分な効果を示さないことが 知られている。また、このモルヒネによる不十分な鎮痛作用が神経因性疼痛の大きな 特徴となることから、その診断にも用いられている（医学のあゆみ， 189 (10), 751-755, 1999)。モルヒネが神経因性疼痛に効果が無い理由としては、神経障害により神経 の機能的 ·形態的な変化が起こって抑制性ニューロンが変性したり、ォピオイド受容 体が減少したためと考えられている（最新脳と神経科学シリーズ，第 6卷，「痛みの 神経科学」，メジカルビユー社， 97, 1997) o [0005] Although the mechanism of neuropathic pain is largely unknown, certain ion channels It is thought to include spontaneous firing of sensory nerves due to novel expression of mitochondrion, firing of sensory nerve fibers in various layers of the spinal cord, and changes in the expression of various neurotransmitters and receptors in the sensory nerve and spinal cord . Typical symptoms of neuropathic pain include Allodynia, Hypergesia, or Hyperesthesia. These symptoms present characteristic pains such as “burning”, “stinging with a needle” or “like electric shock”. For neuropathic pain, it is known that not only analgesics that are effective for normal nociceptive pain but also narcotic analgesics are not effective (The Lancet, 353, 1959-1966, 1999). . For example, morphine is known to have a powerful analgesic effect on nociceptive pain, but does not have a sufficient effect on neuropathic pain. Insufficient analgesic action by morphine is also a major feature of neuropathic pain, and it has been used for its diagnosis (Ayumi Medicine, 189 (10), 751-755, 1999). The reason why morphine is ineffective in neuropathic pain is thought to be due to neurological damage that caused functional and morphological changes in the nerve, resulting in degeneration of inhibitory neurons and a decrease in opioid receptors (latest Brain and Neuroscience Series, VI, “Pain Neuroscience”, Medical View, 97, 1997) o
[0006] 前記したように、ァロディ-ァは、神経因性疼痛の代表的な症状の一つである。ァロ ディユアとは、正常なヒトでは痛みと感じな 、程度の刺激を痛みとして感じる状態を ヽ い、ァロディニァでは軽い接触や圧迫、適度の温熱や冷却等の非侵害刺激により痛 みが惹き起こされる。すなわち、感覚反応の質的な転換がある点、および、その閾値 自体が低下して 、る点がァロディユアの基本的な特性と考えられて 、る。神経因性 疼痛の代表例である帯状疱疹後疼痛では、 87%の患者にァロディ-ァが確認され ており、また、帯状疱疹後疼痛の痛みの強さはァロディユアの度合いに比例している とされている。ァロディ-ァは、帯状疱疹後疼痛をはじめとする神経因性疼痛におい て、患者の QOLを著しく低下させる症状であることから、極めて重要な治療対象であ るとして注目されている。  [0006] As described above, alodya is one of the typical symptoms of neuropathic pain. Alodya refers to a condition in which normal humans do not feel pain, but to feel a degree of stimulation as pain, and in alodynia, pain is caused by non-noxious stimuli such as light contact and pressure, moderate heat and cooling, etc. It is. In other words, there is a point that there is a qualitative change in sensory response, and that the threshold itself is lowered, which is considered to be a basic characteristic of alodiure. In post-herpetic pain, which is a typical example of neuropathic pain, 87% of patients have had alodidia, and the intensity of post-herpetic pain is proportional to the degree of alodiure. Has been. Alodia is attracting attention as a very important therapeutic target because it is a symptom that significantly lowers the patient's QOL in neuropathic pain including postherpetic pain.
[0007] 現在、神経因性疼痛の治療法としては、神経ブロックや、脊髄硬膜外電気刺激等 の神経外科的治療（医学のあゆみ， 189 (10), 757-762, 1999)、ガバペンチンゃプレ ガバリン等のガバペンチノイド、ジコノタイド等の N型カルシウムチャネル阻害薬、三 環系抗うつ薬（臨床と薬物治療， 18 (7), 643-646, 1999)、抗てんかん薬、局所麻酔 薬、ノクロフェン等が用いられている。し力しながら、安全で有効な治療法は未だ確 立しておらず、神経因性疼痛に有効な治療剤の開発が切望されている。 [0007] Currently, neuropathic pain is treated by neurosurgical treatment such as nerve block and spinal epidural electrical stimulation (Ayumi of Medicine, 189 (10), 757-762, 1999), gabapentinya Gabapentinoids such as pregabalin, N-type calcium channel inhibitors such as ziconotide, Cyclic antidepressants (clinical and pharmacotherapy, 18 (7), 643-646, 1999), antiepileptics, local anesthetics, noclofen, etc. are used. However, a safe and effective treatment has not yet been established, and the development of an effective treatment for neuropathic pain is eagerly desired.
[0008] 一方、プリン受容体には、アデノシンをリガンドとする P1受容体と、アデノシン 5， On the other hand, purine receptors include a P1 receptor having adenosine as a ligand, adenosine 5,
三リン酸 (ATP)やアデノシン 5 '—二リン酸 (ADP)をリガンドとする P2受容体が あることが知られている。 P2受容体はさらに、受容体蛋白質自体がイオンチャネルを 構成するイオンチャネル型のもの（P2X受容体）と、 G蛋白質を活性ィヒして機能する 代謝調節型 (P2Y受容体)とに分類され、それぞれがさらに数種類のサブタイプに分 類される。  There are known P2 receptors with triphosphate (ATP) and adenosine 5'-diphosphate (ADP) as ligands. P2 receptors are further classified into ion channel type (P2X receptor) in which the receptor protein itself constitutes an ion channel and metabolic control type (P2Y receptor) that functions by activating the G protein. Each is further classified into several subtypes.
[0009] P2受容体のなかでも、 P2X、 P2X、 P2X、 P2Y、および P2Yといった受容体  [0009] Among the P2 receptors, receptors such as P2X, P2X, P2X, P2Y, and P2Y
2 3 4 1 2  2 3 4 1 2
は、痛みと関連があることが示唆されている。例えば、ラットの第 5腰髄神経を結紮後 切断した神経因性疼痛モデルにおいては、脊髄後角のミクログリアに P2X受容体が  Has been suggested to be associated with pain. For example, in a neuropathic pain model in which the fifth lumbar spinal nerve of a rat is cut after ligation, P2X receptors are present in the microglia in the dorsal horn of the spinal cord.
4 発現するが、 P2Xを阻害する 2，— 3，— O— (2， 4， 6 トリニトロフエニル）アデノシ  4 Expresses but inhibits P2X 2, —3, — O— (2,4,6 trinitrophenyl) adenosine
4  Four
ン— 5—三リン酸 (TNP— ATP)を投与して、その受容体への刺激を遮断するとァロ ディ-ァをほぼ完全に抑制することができること、また、 TNP—ATPのかわりに P2X  N-5-triphosphate (TNP—ATP) to block the stimulation to its receptor can almost completely suppress alodysia, and instead of TNP—ATP, P2X
4 を阻害しないピリドキサールフォスフェイト一 6 ァゾフエ-ル一 2，， 4，一ジスルフォ ン酸 (PPADS)を投与するとァロディユアの抑制効果は見られな 、ことが報告されて いる（Nature, 242, 778-783, 2003)。  It has been reported that administration of pyridoxal phosphate 1-6, azophenol 1, 2, 4, 1-disulfonic acid (PPADS), which does not inhibit 4 is not effective in inhibiting alodiurea (Nature, 242, 778-). 783, 2003).
[0010] また、 P2Yや P2Yといった、 G と共役した P2Y受容体サブタイプ力 バニロイ [0010] Also, P2Y receptor subtype force conjugated to G, such as P2Y and P2Y, vanilloy
1 2 q/11  1 2 q / 11
ド受容体 TRPV1による痛みを増強すること（Proc. Natl. Acad. Sci. USA, 98, 6951-6 956, 2001； J. Neurosci., 23, 6058-6062, 2003)、さらに、 C—繊維に発現する P2Y  To enhance pain caused by the receptor TRPV1 (Proc. Natl. Acad. Sci. USA, 98, 6951-6 956, 2001; J. Neurosci., 23, 6058-6062, 2003), and further to C-fiber Expressed P2Y
2 受容体刺激によりァロディユアが発症すること（Folia Pharmacol.Jpn., 124, 228-233, 2004)が報告されている。  2 It has been reported that alodiure develops upon receptor stimulation (Folia Pharmacol. Jpn., 124, 228-233, 2004).
[0011] 一方、幾つかの化合物が P2Y 受容体拮抗作用を有していることが報告されてい [0011] On the other hand, some compounds have been reported to have P2Y receptor antagonism.
12  12
る。例えば、一般式 (A)  The For example, the general formula (A)
[0012] [化 1] [0012] [Chemical 1]
Figure imgf000005_0001
[0013] [式中、式 R1Aは、水素原子、置換されていてもよい、アルキル、シクロアルキル、ァリ ール、ァリールアルキル、ヘテロァリール、ヘテロァリールアルキル、またはアルカノィ ルを表し、 R2Aは、ァリールまたはへテロアリールを表す。 ]で示される化合物、その幾 何異性体、その互変異性体、その塩、そのエステル、またはそのプロドラッグ等力 P 2Y 受容体拮抗作用を示し、例えば、末梢血管疾患、心血管疾患、脳血管疾患、ま
Figure imgf000005_0001
[Wherein the formula R 1A represents a hydrogen atom, optionally substituted alkyl, cycloalkyl, aryl, aryl, alkyl, heteroaryl, heteroaryl, or alkanol; 2A represents aryl or heteroaryl. Compound, its several isomers, its tautomers, its salts, its esters, or their prodrugs, is a P 2Y receptor antagonistic action, for example, peripheral vascular disease, cardiovascular disease, brain Vascular disease
12 12
たは血小板凝集が関与する状態等の予防および Zまたは治療に有用である旨が記 載されている（例えば、国際公開第 2005Z000281号パンフレット (特許文献 1)参 照)。  It is also described that it is useful for prevention and Z or treatment of conditions involving platelet aggregation (see, for example, International Publication No. 2005Z000281 pamphlet (Patent Document 1)).
[0014] また、一般式 (B)  [0014] Further, the general formula (B)
[0015] [化 2] [0015] [Chemical 2]
Figure imgf000006_0001
Figure imgf000006_0001
[0016] [式中、 R は、置換されていてもよい、 Cl〜6アルキル、 C3〜8シクロアルキル、また はフエ-ル等を表し、 R2Bは、置換されていてもよい Cl〜8アルキル等を表し、 R3Bお よび R4Bの何れか一方は、水素原子を表し、他方はヒドロキシを表し、 XBは、 ΟΗまた は NHR5B等を表す。ただし、式中の記号は必要な部分のみ抜粋した。 ]で示される 化合物、その塩、またはその溶媒和物が、 P 受容体 (P2Y 受容体の旧名）拮抗作 [Wherein R represents an optionally substituted Cl to 6 alkyl, C3 to 8 cycloalkyl, or a phenyl, and R 2B represents an optionally substituted Cl to 8 Represents an alkyl or the like, one of R 3B and R 4B represents a hydrogen atom, the other represents hydroxy, and X B represents ΟΗ or NHR 5B or the like. However, only the necessary parts were extracted from the symbols in the formula. ] The compound, its salt, or its solvate shown by this is a P receptor (old name of P2Y receptor) antagonistic action.
2T 12  2T 12
用を示し、例えば、血小板凝集疾患等の治療に有用である旨が記載されている（例 えば、国際公開第 99Z05144号パンフレット (特許文献 2)参照)。  For example, it is described that it is useful for the treatment of platelet aggregation diseases (see, for example, International Publication No. 99Z05144 pamphlet (Patent Document 2)).
[0017] また、一般式 (C)  [0017] Further, the general formula (C)
[0018] [化 3]  [0018] [Chemical 3]
Figure imgf000006_0002
Figure imgf000006_0002
[0019] [式中、 は、 H、 CH R5 または CORb等を表し、 は、置換されていてもよい Cl〜6アルキルまたは CI〜6ァルケ-ル等を表し、 R3Cは、置換されていてもよい C3 〜8シクロアルキルを表し、 R4Gは、 Hまたはハロゲン原子で置換されていてもよい C1 〜6アルキル等を表す。ただし、式中の記号は必要な部分のみ抜粋した。 ]で示され る化合物、その塩、またはそれらの溶媒和物が、 P 受容体拮抗作用を示し、例えば [In the formula, represents H, CH R 5, COR b or the like, and may be substituted. Cl-6 alkyl or CI-6 alkyl etc., R 3C represents an optionally substituted C3-8 cycloalkyl, R 4G is optionally substituted with H or a halogen atom C1- 6 represents alkyl or the like. However, only the necessary parts were extracted from the symbols in the formula. Or a salt thereof, or a solvate thereof, exhibits P receptor antagonism, for example,
2T  2T
、心筋梗塞、血栓性脳卒中、一過性虚血発作、または末梢血管疾患等の予防およ び Zまたは治療に有用である旨が記載されている（例えば、国際公開第 01Z1982 6号パンフレット (特許文献 3)参照)。  , Myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, etc. are described as being useful for prevention and Z or treatment (for example, WO 01Z1982 6 pamphlet (patent Reference 3)).
[0020] また、一般式 (D)  [0020] Further, the general formula (D)
[0021] [化 4]  [0021] [Chemical 4]
Figure imgf000007_0001
Figure imgf000007_0001
[0022] [式中、 R は、 OR または CH R 等を表し、 R は、 Cl〜6アルキルまたは Cl〜6  [In the formula, R represents OR or CH R and the like, and R 1 represents Cl to 6 alkyl or Cl to 6
2  2
ハロアルキルを表し、 R3Dは、置換されていてもよい C3〜6シクロアルキル等を表し、 R4Dは、 Cl〜6アルキルを表す。ただし、式中の記号は必要な部分のみ抜粋した。 ] で示される化合物、その塩、またはそれらの溶媒和物が、 P 受容体拮抗作用を示し Represents haloalkyl, R 3D represents an optionally substituted C 3-6 cycloalkyl or the like, and R 4D represents Cl-6 alkyl. However, only the necessary parts were extracted from the symbols in the formula. ], A salt thereof, or a solvate thereof, exhibits P receptor antagonism.
2T  2T
、例えば、心筋梗塞、血栓性脳卒中、一過性虚血発作、または末梢血管疾患等の予 防および Zまたは治療に有用である旨が記載されている（例えば、国際公開第 oiZ It is described that it is useful for prevention and Z or treatment of, for example, myocardial infarction, thrombotic stroke, transient ischemic attack, or peripheral vascular disease (for example, International Publication No. oiZ
36421号パンフレット（特許文献 4)参照)。 36421 pamphlet (see Patent Document 4)).
[0023] また、一般式 (E) [0023] Further, the general formula (E)
[0024] [化 5] [0024] [Chemical 5]
Figure imgf000007_0002
Figure imgf000007_0002
[式中、 ま、 OHまたは COR で置換された Cl〜6アルキル等を表し、 R2tは、 C1 〜6アルキルまたは Cl〜6ハロアルキルを表し、 R3Eは、置換されていてもよい C3〜 6シクロアルキル等を表す。ただし、式中の記号は必要な部分のみ抜粋した。 ]で示さ れる化合物、その塩、またはそれらの溶媒和物が、 P 受容体拮抗作用を示し、例え [Wherein, it represents Cl to 6 alkyl or the like substituted with OH or COR, R 2t represents C1 to 6 alkyl or Cl to 6 haloalkyl, and R 3E represents an optionally substituted C3 to 6 Represents cycloalkyl and the like. However, only the necessary parts were extracted from the symbols in the formula. ] Compounds, salts thereof, or solvates thereof, exhibit P receptor antagonism, for example
2T  2T
ば、心筋梗塞、血栓性脳卒中、一過性虚血発作、または末梢血管疾患等の予防お よび Zまたは治療に有用である旨が記載されている（例えば、国際公開第 01Z364 38号パンフレット (特許文献 5)参照)。  For example, it is described that it is useful for prevention and Z or treatment of myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, etc. (for example, WO 01Z364 38 pamphlet (patent Reference 5)).
[0026] また、一般式 (F)  [0026] Further, the general formula (F)
[0027] [化 6]  [0027] [Chemical 6]
Figure imgf000008_0001
Figure imgf000008_0001
[0028] [式中、 R は、置換されていてもよい、 Cl〜6アルキル、じ2〜6ァルケ-ル、 C2〜6 アルキ -ル、 C3〜8シクロアルキル、ァリール、またはチェ-ル等を表し、 R2Fは、置 換されていてもよい、 Cl〜8アルキル、 C2〜87ルケ-ル、 C2〜8アルキ -ル、また は C3〜8シクロアルキル等を表し、 R3Fおよび R4Fは、ともにヒドロキシを表し、 R5Fは、 水素原子または Cl〜6アルキルを表し、 R6Fは、置換されていてもよい Cl〜6アルキ ル等を表す。ただし、式中の記号は必要な部分のみ抜粋した。 ]で示される化合物、 その塩、またはそれらの溶媒和物が、 P 受容体拮抗作用を示し、例えば、狭心症、 [Wherein R is optionally substituted, Cl to 6 alkyl, 2 to 6 alkyl, C2 to 6 alkyl, C3 to 8 cycloalkyl, aryl, or chale, etc. R 2F represents an optionally substituted Cl-8 alkyl, C2-87 ketone, C2-8 alkyl, C3-8 cycloalkyl, etc., R 3F and R 4F Both represent hydroxy, R 5F represents a hydrogen atom or Cl- 6 alkyl, R 6F represents an optionally substituted Cl-6 alkyl, and the like. However, only the necessary parts were extracted from the symbols in the formula. Or a salt thereof, or a solvate thereof, exhibits P receptor antagonist activity, such as angina pectoris,
2T  2T
心筋梗塞等の予防および Zまたは治療に有用である旨が記載されている (例えば、 国際公開第 99Z41254号パンフレット (特許文献 6)参照)。  It is described that it is useful for prevention and Z or treatment of myocardial infarction or the like (for example, see International Publication No. 99Z41254 (Patent Document 6)).
[0029] また、一般式 (G) [0029] Further, the general formula (G)
[0030] [化 7] [0030] [Chemical 7]
Figure imgf000008_0002
Figure imgf000008_0002
[式中、 Rl lま、置換されていてもよい C3〜5アルキル等を表し、 ITGは、フッ素原子 で置換されていてもよいフエ二ル等を表し、 R3Gおよび R4Gは、ともにヒドロキシを表し、 RGは、 XGOHを表し、 XGは CH、 OCH CH、または結合手等を表す。ただし、式中 [In the formula, R 1 l represents an optionally substituted C3-5 alkyl, etc., IT G represents a phenyl optionally substituted with a fluorine atom, R 3G and R 4G are Both represent hydroxy, R G represents X G OH, X G represents CH, OCH CH, or a bond. However, in the formula
2 2 2  2 2 2
の記号は必要な部分のみ抜粋した。 ]で示される化合物、その塩、またはそれらの溶 媒和物が、 P Only the necessary parts were extracted from the symbol. Or a salt thereof, or a solution thereof. The solvate is P
2T受容体拮抗作用を示し、例えば、心筋梗塞、血栓性脳卒中、一過性 虚血発作、または末梢血管疾患等の予防および Zまたは治療に有用である旨が記 載されて!、る (例えば、国際公開第 00Z34283号パンフレット (特許文献 7)参照)。  It shows 2T receptor antagonistic action and is described as being useful for prevention and Z or treatment of, for example, myocardial infarction, thrombotic stroke, transient ischemic attack, or peripheral vascular disease! , International Publication No. 00Z34283 pamphlet (Patent Document 7)).
[0032] また、一般式 (H) [0032] Further, the general formula (H)
[0033] [化 8] [0033] [Chemical 8]
Figure imgf000009_0001
Figure imgf000009_0001
[0034] [式中、 Rlhは、水素原子、置換されていてもよい、 Cl〜6アルキル基、 C3〜6シクロ アルキル基、 Cl〜6アルコキシ基、または C6〜10ァリール基等を表し、 R2Hは、水素 原子、 Cl〜7アルカノィル基、 C7〜： L 1ァリールカルボ-ル基、 C6〜10ァリールスル ホ-ル基、 C7〜 16アルキルァリールスルホ-ル基、 Cl〜6アルキルスルファ-ル基 等を表し、 R3Hは、置換されていてもよい C6〜10ァリール基、ヘテロァリール基等を 表し、 x1H、 x2H、 x3H、 x4H、および x5Hは、独立して水素原子、ハロゲン原子等を表 し、 nHは 0乃至 2の整数を表す。ただし、式中の記号は必要な部分のみ抜粋した。 ] で示される化合物、その薬理学上許容される塩、およびそのプロドラッグ力 ADP受 容体拮抗作用を有し、血栓塞栓形成疾患等の予防または治療に有用である旨が記 載されて!ヽる（例えば、特開 2005— 179350号公報 (特許文献 8)参照)。 [Wherein R lh represents a hydrogen atom, an optionally substituted Cl-6 alkyl group, a C3-6 cycloalkyl group, a Cl-6 alkoxy group, a C6-10 aryl group, or the like, R 2H is a hydrogen atom, Cl to 7 alkanoyl group, C7 to: L 1 aryl hydrocarbon group, C 6 to 10 aryl sulfo group, C 7 to 16 alkyl aryl sulfo group, Cl to 6 alkyl sulfur R 3H represents an optionally substituted C6-10 aryl group, heteroaryl group, etc., x 1H , x 2H , x 3H , x 4H , and x 5H are independently hydrogen atoms Represents a halogen atom or the like, and n H represents an integer of 0 to 2. However, only the necessary parts were extracted from the symbols in the formula. ], A pharmacologically acceptable salt thereof, and a prodrug thereof. It has an ADP receptor antagonism and is useful for the prevention or treatment of thromboembolic diseases and the like! (See, for example, JP-A-2005-179350 (Patent Document 8)).
[0035] また、一般式 (J)  [0035] Further, the general formula (J)
[0036] [化 9]  [0036] [Chemical 9]
Figure imgf000009_0002
Figure imgf000009_0002
[式中、 は、 C— R "または Nを表し、 は、 C— RWまたは Nを表し、 R1Uは、水素原 子、置換されていてもよい低級アルキル、または置換されていてもよい低級アルキル で置換されていてもよいアミノを表し、 R1 は、水素原子、またはそれぞれ置換されて いてもよい、低級アルキルもしくはァリールを表し、 R1Uと R1 は、隣接する窒素原子と 一体となって、置換されていてもよい環状アミノを形成してもよぐ R は、それぞれ置 換されていてもよい、低級アルキル、シクロアルキル、ァリールもしくはヘテロ環を表し 、 R は、ハロゲン、低級アルキル、または— O—低級アルキルを表し、 は、それぞ れ置換されていてもよい、シクロアルキルもしくは非芳香族へテロ環、またはシクロア ルキルで置換されている低級アルキルを表し、 R は、水素原子、ハロゲン、シァノ、 ニトロ、低級アルキル、ハロゲノ低級アルキル、シクロアルキル、ァリール、ヘテロ環、 O 低級アルキル、 OH、 一 NHCO 低級アルキル、 N (低級アルキル） CO —低級アルキル、低級アルキルで置換されていてもよいアミ入または置換されてい てもよい環状アミノを表し、 RWは、水素原子、ハロゲン、低級アルキルまたはハロゲノ 低級アルキルを表し、 R"は、水素原子、ハロゲン、低級アルキルまたはハロゲノ低級 アルキルを表す。ただし、式中の記号は必要な部分のみ抜粋した。 ]で示されるキノ ロン誘導体またはその製薬学的に許容される塩が、 P2Y 阻害作用を有し、血小板 [Wherein, represents C—R ”or N, represents C—R W or N, and R 1U represents a hydrogen atom, an optionally substituted lower alkyl, or an optionally substituted. R 1 represents an amino optionally substituted with lower alkyl, R 1 represents a hydrogen atom, or lower alkyl or aryl each optionally substituted, R 1U and R 1 represent an adjacent nitrogen atom and Together, R may form an optionally substituted cyclic amino, each independently represents an optionally substituted lower alkyl, cycloalkyl, aryl or heterocycle, wherein R is halogen, Represents lower alkyl, or —O-lower alkyl, represents a lower alkyl substituted with cycloalkyl or non-aromatic heterocyclic ring, or cycloalkyl, each optionally substituted; Substituted with hydrogen atom, halogen, cyano, nitro, lower alkyl, halogeno lower alkyl, cycloalkyl, aryl, heterocycle, O lower alkyl, OH, mono NHCO lower alkyl, N (lower alkyl) CO —lower alkyl, lower alkyl Represents an optionally substituted or substituted cyclic amino, and R W represents a hydrogen atom, halogen, lower alkyl Or halogeno lower alkyl, and R ″ represents a hydrogen atom, halogen, lower alkyl or halogeno lower alkyl. However, the symbols in the formula are extracted only as necessary.] The quinolone derivative represented by Acceptable salt has P2Y inhibitory action, and platelets
12  12
凝集阻害剤として有用である旨が記載されている（例えば、特開 2005— 053903号 公報 (特許文献 9)参照)。  It is described that it is useful as an aggregation inhibitor (see, for example, JP-A-2005-053903 (Patent Document 9)).
[0038] しかしながらこれまで、 P2Y受容体のなかでも、特に P2Y および P2Y といった G [0038] However, so far, among P2Y receptors, especially G such as P2Y and P2Y.
12 14 i と共役した受容体サブタイプが疼痛、とりわけ神経因性疼痛の発症に関連しており 、それらの受容体ブロッカーが疼痛の治療に有用である旨の記載はどこにもない。  Receptor subtypes conjugated with 12 14 i are associated with the development of pain, particularly neuropathic pain, and there is no mention that these receptor blockers are useful for the treatment of pain.
[0039] 特許文献 1：国際公開第 2005Z000281号パンフレット  [0039] Patent Document 1: Pamphlet of International Publication No. 2005Z000281
特許文献 2 :国際公開第 99Z05144号パンフレット  Patent Document 2: Pamphlet of International Publication No.99Z05144
特許文献 3 :国際公開第 01Z19826号パンフレット  Patent Document 3: Pamphlet of International Publication No. 01Z19826
特許文献 4:国際公開第 01Z36421号パンフレット  Patent Document 4: International Publication No. 01Z36421 Pamphlet
特許文献 5：国際公開第 01Z36438号パンフレット  Patent Document 5: Pamphlet of International Publication No. 01Z36438
特許文献 6 :国際公開第 99Z41254号パンフレット  Patent Document 6: International Publication No.99Z41254 Pamphlet
特許文献 7：国際公開第 00Z34283号パンフレット  Patent Document 7: International Publication No. 00Z34283 Pamphlet
特許文献 8：特開 2005— 179350号公報  Patent Document 8: JP-A-2005-179350
特許文献 9：特開 2005— 053903号公報  Patent Document 9: Japanese Patent Application Laid-Open No. 2005-053903
発明の開示  Disclosure of the invention
発明が解決しょうとする課題 [0040] 本発明の課題は、疼痛、とりわけ神経因性疼痛の予防、治療および Zまたは症状 進展抑制剤を提供することにある。 Problems to be solved by the invention [0040] An object of the present invention is to provide a preventive, therapeutic and Z or symptom progression inhibitor for pain, particularly neuropathic pain.
課題を解決するための手段  Means for solving the problem
[0041] 本発明者らは、ラット坐骨神経切断モデルを用いて検討を行なった結果、神経切 断後 3日をピークに、脊髄マイクログリアでの P2Y 受容体および P2Y 受容体の発 [0041] As a result of study using the rat sciatic nerve cutting model, the present inventors have found that P2Y receptor and P2Y receptor development in spinal microglia peaked at 3 days after nerve cutting.
12 14  12 14
現が選択的に増加するという驚くべき現象を見出した。本発明者らは、この知見をも とにさらに検討を加え、本発明を完成した。  I found the surprising phenomenon that the present increases selectively. The present inventors made further studies based on this finding and completed the present invention.
[0042] すなわち本発明は、 [0042] That is, the present invention provides
[1]P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカーを含有してなる Ρ2Υ 受 [1] P2Y receptor and Ζ or Ρ2Υ receptor blocker containing Ρ2Υ receptor
12 14 12 容体および Ζまたは Ρ2Υ 受容体陽性細胞抑制剤； 12 14 12 volume and Ζ or Ρ2Υ receptor positive cell inhibitor;
14  14
[2]Ρ2Υ 受容体および Ζまたは Ρ2Υ 受容体抑制剤である前記 [1]記載の剤； [2] The agent according to [1], which is a Ρ2Υ receptor and a Ζ or Ρ2Υ receptor inhibitor;
12 14 12 14
[3]疼痛の予防、治療および Ζまたは症状進展抑制剤である前記 [1]記載の剤； [4]疼痛が神経因性疼痛である前記 [3]記載の剤；  [3] The prevention and treatment of pain and the agent according to the above [1], which is an agent for suppressing epilepsy or symptom progression; [4] the agent according to the above [3], wherein the pain is neuropathic pain;
[5]神経因性疼痛が癌性疼痛、帯状疱疹後疼痛、糖尿病性疼痛、 HIV関連神経因 性疼痛、結石誘発疼痛、神経痛、口腔顔面痛、または痛覚過敏である前記 [4]記載 の剤；  [5] The agent according to [4], wherein the neuropathic pain is cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia. ;
[6]Ρ2Υ 受容体および Ζまたは Ρ2Υ 受容体ブロッカー力 （  [6] Ρ2Υ receptor and Ζ or Ρ2Υ receptor blocker force (
12 14 a)低分子化合物、（b) 抗体、（c)アンチセンス、（d)短鎖干渉 RNA、（e)デコイ、（Dリボザィム、または (g)ァプタ マーである前記 [ 1 ]記載の剤；  12 14 a) a low molecular compound, (b) an antibody, (c) an antisense, (d) a short interfering RNA, (e) a decoy, (D ribozyme, or (g) an aptamer Agent;
[7]低分子化合物が、（1)P2Y 受容体アンタゴニスト、 (2)Ρ2Υ 受容体アンタゴニス  [7] Low molecular weight compounds are (1) P2Y receptor antagonists, (2) Ρ2Υ receptor antagonists
12 14  12 14
ト、または (3)Ρ2Υ 受容体と Ρ2Υ 受容体のデュアルアンタゴ-ストである前記 [6]記  Or (3) the dual antagonist of the 記 2 デ ュ ア ル receptor and the Ρ2 受 容 receptor [6] above
12 14  12 14
載の剤；  Listed agents;
[8]低分子化合物が、一般式 (I)  [8] The low molecular weight compound is represented by the general formula (I)
[0043] [化 10] [0043] [Chemical 10]
Figure imgf000011_0001
[0044] [式中、 R1_1は、水素原子、置換基を有していてもよい脂肪族炭化水素基、または置 換基を有していてもよい環状基を表し、 R2_1は、置換基を有していてもよい環状基を 表す。 ]で示される化合物、その幾何異性体、その互変異性体、その塩、その溶媒和 物、またはそれらのプロドラッグ、一般式 (II)
Figure imgf000011_0001
[Wherein R 1_1 represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or a cyclic group which may have a substituent, and R 2_1 represents a substituent. It represents a cyclic group which may have a group. , Geometric isomers, tautomers, salts, solvates thereof, or prodrugs thereof, represented by the general formula (II)
[0045] [化 11]
Figure imgf000012_0001
[0045] [Chemical 11]
Figure imgf000012_0001
[0046] [式中、環 Aは置換基を有していてもよい 5〜7員の複素環を表し、 Qは置換基を有し て!ヽてもよ!/ヽ脂肪族炭化水素基または置換基を有して!/ヽてもよ!ヽ環状基を表し、 R1" 2は置換されていてもよいアミノ基を表し、 R2—2は置換基を表す。 ]で示される化合物 、その塩、その N—才キシド体、その溶媒和物、またはそれらのプロドラッグ、一般式 ( III) [In the formula, ring A represents an optionally substituted 5- to 7-membered heterocyclic ring, Q represents a substituent, and may be! / An aliphatic hydrocarbon group. !! or an substituted /ヽI beヽcyclic group, R 1 "2 represents an amino group which may be substituted, R 2 - 2 are shown and represented] a substituent. Compound, salt, N-xide, solvate, or prodrug thereof, general formula (III)
[0047] [化 12]  [0047] [Chemical 12]
Figure imgf000012_0002
Figure imgf000012_0002
[0048] [式中、 R1_°は、水素原子、置換基を有していてもよいアルコキシ基、置換基を有し ていてもよい脂肪族炭化水素基、または置換基を有していてもよい環状基を表し、 R2 _3は、水素原子または置換基を表し、 R3—3は、置換基を有していてもよい環状基を 表し、 X1—3は、水素原子または置換基を表し、 n3は 0または 1〜2の整数を表し、環 D はさらに置換基を有していてもよいフエ-ル基を表す。 ]で示される化合物、その塩、 またはそれらのプロドラッグ、もしくは一般式 (IV) [In the formula, R 1 — ° has a hydrogen atom, an alkoxy group which may have a substituent, an aliphatic hydrocarbon group which may have a substituent, or a substituent. represent also cyclic group, R 2 _ 3 represents a hydrogen atom or a substituent, R 3 - 3 represents a cyclic group which may have a substituent, X 1 - 3 is a hydrogen atom or Represents a substituent, n 3 represents 0 or an integer of 1 to 2, and ring D represents a phenyl group which may further have a substituent. Or a salt thereof, or a prodrug thereof, or a compound represented by the general formula (IV)
[0049] [化 13]  [0049] [Chemical 13]
Figure imgf000012_0003
[0050] [式中、 X4および Y4は、それぞれ独立して CH、 C—ハロゲン原子、 C—置換基を有 していてもよいアルキル基、または窒素原子を表し、 Eは、置換基を有していてもよい 環状基または置換されていてもよいアミノ基を表し、 R2—4は、置換基を有していてもよ い脂肪族炭化水素基または置換基を有していてもよい環状基を表し、 R3—4は、ハロ ゲン原子、置換基を有していてもよい脂肪族炭化水素基、または置換基を有してい てもよいアルコキシ基を表し、 R4—4は、置換基を有していてもよい脂肪族炭化水素基 または置換基を有していてもよい環状基を表し、 R5—4は、置換基を表す。 ]で示され る化合物、またはその塩である前記 [7]記載の剤；
Figure imgf000012_0003
[Wherein, X 4 and Y 4 each independently represent CH, C-halogen atom, C-alkyl group optionally having substituent (s), or nitrogen atom, and E represents a substituent group. the represents an amino group which is also cyclic group, or a substituted have, R 2 - 4 are have an aliphatic hydrocarbon group, or a substituent not good may have a substituent R 3 — 4 represents a halogen atom, an aliphatic hydrocarbon group which may have a substituent, or an alkoxy group which may have a substituent, R 4 — 4, have a which may have an aliphatic hydrocarbon group or an optionally substituted a substituent represent also cyclic group, R 5 - 4 represents a substituent. The agent of the above-mentioned [7], which is a compound represented by the formula:
[9]低分子化合物が、クロピドグレル、チクロビジン、カングレロール、プラスダレル、 A ZD-6140、 INS-50589、 INS-49266、 AR-C66096、 ARL-67085、 GR-144043,口キシフ ィバン、 MRS2395またはそれらの塩である前記 [7]記載の剤；  [9] The low molecular weight compound is clopidogrel, ticlovidin, cangrelor, prasdarrel, A ZD-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, oral xyfiban, MRS2395 or those The agent according to the above [7], which is a salt;
[10]さらに、ォピオイド鎮痛薬、非才ピオイド鎮痛薬、神経因性疼痛鎮痛薬、非ステ ロイド系抗炎症薬、鎮静薬、抗うつ薬、抗てんかん薬、中枢性筋弛緩薬、制吐薬、お よび局所麻酔薬力 選択される一種以上を組み合わせてなる前記 [3]記載の剤； [11]哺乳動物に対し、 P2Y 受容体および たは P2Y 受容体ブロッカーの有  [10] In addition, opioid analgesics, non-aged pioid analgesics, neuropathic pain analgesics, non-steroidal anti-inflammatory drugs, sedatives, antidepressants, antiepileptics, central muscle relaxants, antiemetics, [11] The agent according to the above [3], comprising a combination of at least one selected from local anesthetic powers; and [11] having a P2Y receptor or a P2Y receptor blocker for a mammal.
12 Zま  12 Z
14  14
効量を投与することを特徴とする、 P2Y 受容体および  A P2Y receptor characterized by administering an effective dose and
12 Zまたは P2Y 受容体陽性  12 Z or P2Y receptor positive
14  14
細胞抑制方法；  Cell suppression method;
[12]P2Y 受容体および Ζまたは Ρ2Υ 受容体抑制方法である前記 [11]記載の  [12] The method according to [11] above, wherein the method is a method for inhibiting P2Y receptor and Ζ or Ρ2Υ receptor
12 14  12 14
方法；  Method;
[ 13]疼痛の予防、治療および Ζまたは症状進展抑制方法である前記 [11]記載の 方法；  [13] The method according to [11] above, which is a method for preventing, treating and suppressing epilepsy or symptom progression;
[14]Ρ2Υ 受容体および Ζまたは Ρ2Υ 受容体陽性細胞抑制剤を製造するための  [14] For producing Ρ2Υ receptor and Ζ or Ρ2Υ receptor positive cell inhibitor
12 14  12 14
Ρ2Υ 受容体および  Ρ2Υ receptors and
12 Ζまたは Ρ2Υ 受容体ブロッカーの使用；  12 Ζ or Ρ2Υ use of receptor blockers;
14  14
[15]Ρ2Υ 受容体および Ζまたは Ρ2Υ 受容体陽性細胞抑制剤が Ρ2Υ 受容体  [15] Ρ2Υ receptor and Ζ2 or Ρ2Υ receptor positive cell inhibitor is Ρ2 受 容 receptor
12 14 12 および Ζまたは Ρ2Υ 受容体抑制剤である前記 [14]記載の使用；および  12 14 12 and use according to [14] above, which is a Ζ or Ρ2Υ receptor inhibitor; and
14  14
[16]Ρ2Υ 受容体および Ζまたは Ρ2Υ 受容体陽性細胞抑制剤が疼痛の予防、治  [16] Ρ2Υ receptor and Ζ or Ρ2Υ receptor-positive cell inhibitor prevent or treat pain
12 14  12 14
療および Ζまたは症状進展抑制剤である前記 [14]記載の使用等に関する。  And the use according to [14] above, which is an acupuncture or symptom progression inhibitor.
[0051] 本発明において、「Ρ2Υ 受容体および Ζまたは Ρ2Υ 受容体ブロッカー」とは、 Ρ 2Y 受容体および P2Y 受容体の少なくとも何れか一方において、その生体内リガ[0051] In the present invention, "体 2Υ receptor and Ζ or Ρ2Υ receptor blocker" means Ρ In at least one of 2Y receptor and P2Y receptor,
12 14 12 14
ンド (例えば、 ΑΤΡや ADP等）が結合した際に受容体力も細胞内に伝達されるシグ ナルを抑制する物質であればどのようなものであってもよい。すなわち、いわゆる受 容体拮抗薬 (アンタゴニスト）のような、受容体と生体内リガンドの結合を減少させる物 質であってもよ 、し、また、これら受容体とカップリングして 、る G蛋白（G )以降の  Any substance may be used as long as a receptor suppresses a signal that is also transmitted to cells when a host (eg, cocoon, ADP, etc.) is bound. That is, it may be a substance that decreases the binding between a receptor and an in vivo ligand, such as a so-called receptor antagonist (antagonist), and it is coupled to these receptors to produce a G protein ( G) or later
i/o  i / o
シグナルを抑制する物質であってもよい。また、受容体自体の発現量を低下させるも のであってもよい。このような物質、すなわち P2Y 受容体および Zまたは P2Y 受  It may be a substance that suppresses signal. It may also be one that reduces the expression level of the receptor itself. Such substances, i.e. P2Y receptor and Z or P2Y receptor
12 14 容体ブロッカーとしては、例えば、（a)低分子化合物、（b)抗体、（c)アンチセンス、（d)短 鎖干渉 RNA、（e)デコイ、（Dリボザィム、（g)アブタマ一等の形態を有するものが挙げら れる。  12 14 Container blockers include, for example, (a) low molecular weight compounds, (b) antibodies, (c) antisense, (d) short interfering RNAs, (e) decoys, (D ribozymes, (g) Abutamas, etc. The thing which has the form of is mentioned.
[0052] 本発明において、「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカーとしての  [0052] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"
12 14  12 14
抗体」には、例えば、抗 Ρ2Υ 受容体抗体ゃ抗 Ρ2Υ 受容体抗体等が含まれる。こ  “Antibodies” include, for example, anti-2 receptor antibodies and anti-2 receptor antibodies. This
12 14  12 14
れらの抗体は、 Ρ2Υ 受容体または Ρ2Υ 受容体をそれぞれ認識し得る抗体であれ  These antibodies should be Ρ2Υ receptors or antibodies that can recognize Ρ2Υ receptors, respectively.
12 14  12 14
ばよぐポリクローナル抗体またはモノクローナル抗体の何れであってもよい。また、 一つの抗体分子に、 Ρ2Υ 受容体を認識する部位と Ρ2Υ 受容体を認識する部位  Either a polyclonal antibody or a monoclonal antibody may be used. In addition, the site that recognizes the Ρ2Υ receptor and the site that recognizes the Ρ2Υ receptor in one antibody molecule
12 14  12 14
をもたせることにより、バイスぺシフィック抗体とすることもできる。特に、ヒト抗体 (例え ば、ヒトモノクローナル抗体等)またはヒト化抗体と称されるような、ヒトに対して安全に 投与できる抗体が好ましい。これらの抗体は、（1) Ρ2Υ 2Υ  It is possible to obtain a bispecific antibody by providing. Particularly preferred are antibodies that can be safely administered to humans, such as human antibodies (eg, human monoclonal antibodies) or humanized antibodies. These antibodies are (1) Ρ2Υ 2Υ
12受容体または Ρ  12 receptors or Ρ
14受容体 14 receptors
、（2) Ρ2Υ 受容体または Ρ2Υ 受容体とキャリアー蛋白質との複合体、或いは（3) , (2) Ρ2Υ receptor or Ρ2Υ complex of receptor and carrier protein, or (3)
12 14  12 14
アミノ基ゃカルボキシル基を Ρ2Υ 受容体または Ρ2Υ 受容体の側鎖に有する誘導  Induction with amino group or carboxyl group in Ρ2Υ receptor or 鎖 2Υ receptor side chain
12 14  12 14
体とキャリアー蛋白質との複合体等を抗原として用いて、公知の抗体もしくは抗血清 の製造法に従って製造することができる。具体的な方法について、以下に一例を示 す。  It can be produced according to a known antibody or antiserum production method using a complex of the antibody and carrier protein as an antigen. An example of the specific method is shown below.
[0053] 〔モノクローナル抗体の作製〕  [Preparation of monoclonal antibody]
(a)モノクローナル抗体産生細胞の作製  (a) Preparation of monoclonal antibody-producing cells
抗 P2Y 受容体抗体または抗 P2Y 受容体抗体を製造するための上記の抗原は、  Antigens for producing anti-P2Y receptor antibodies or anti-P2Y receptor antibodies are:
12 14  12 14
単独で、または担体や希釈剤とともに哺乳動物に対して投与される。投与に際して抗 体産生能を高めるため、完全フロイントアジュバントや不完全フロイントアジュバントを 投与してもよい。投与は通常 2週乃至 6週毎に 1回ずつ、計 2回乃至 10回程度行な われる。用いられる哺乳動物としては、例えば、サル、ゥサギ、ィヌ、モルモット、マウ ス、ラット、ヒッジ、ャギ等が挙げられる力 マウスおよびラットが好ましく用いられる。ま た、投与部位は特に限定されず、抗体産生が可能な部位であればよい。モノクロ一 ナル抗体産生細胞の作製は、抗原を免疫された温血動物、例えば、マウスカゝら抗体 価の認められた個体を選択し、最終免疫の 2日乃至 5日後に脾臓またはリンパ節を 採取し、それらに含まれる抗体産生細胞を骨髄腫細胞と融合させることにより、モノク ローナル抗体産生ハイプリドーマを調製することができる。抗血清中の抗体価の測定 は、例えば、前記の標識された P2Y 受容体または P2Y 受容体と抗血清とを反応 It is administered to a mammal alone or together with a carrier or diluent. In order to enhance antibody production during administration, complete Freund's adjuvant or incomplete Freund's adjuvant is used. It may be administered. Dosing is usually performed once every 2 to 6 weeks, 2 to 10 times in total. As the mammal to be used, for example, a power mouse and a rat including a monkey, a rabbit, a dog, a guinea pig, a mouse, a rat, a hedge, a goat and the like are preferably used. In addition, the administration site is not particularly limited, as long as the antibody can be produced. Monoclonal antibody-producing cells are prepared by selecting a warm-blooded animal that has been immunized with an antigen, for example, an individual with an antibody titer, such as a mouse, and collecting the spleen or lymph nodes 2 to 5 days after the final immunization. Monoclonal antibody-producing hyperpridoma can be prepared by fusing the antibody-producing cells contained therein with myeloma cells. The antibody titer in the antiserum can be measured, for example, by reacting the labeled P2Y receptor or the P2Y receptor with the antiserum.
12 14  12 14
させたのち、抗体に結合した標識物質の活性を測定することにより行なうことができるCan be performed by measuring the activity of the labeling substance bound to the antibody.
。骨髄腫細胞との融合操作は公知の方法、例えば、ケーラーとミルスタインの方法 (N ature, 256, 495, 1975)に従って行うことができる。融合を促進するために、例えば、 ポリエチレングリコール (PEG)やセンダイウィルス等 (好ましくは、 PEG等）が用いら れる。ここで、骨髄腫細胞としては、例えば、 NS— 1、 P3U1、 SP2Z0等が挙げられ るが、 P3U1が好ましい。用いられる抗体産生細胞 (脾臓細胞)数と骨髄腫細胞数と の好ましい比率は 1 : 1乃至 20 : 1程度であり、 PEG (好ましくは、 PEG1000乃至 PE. The fusion operation with myeloma cells can be performed according to a known method, for example, the method of Kohler and Milstein (Nature, 256, 495, 1975). In order to promote fusion, for example, polyethylene glycol (PEG), Sendai virus or the like (preferably PEG or the like) is used. Here, examples of myeloma cells include NS-1, P3U1, SP2Z0, etc., and P3U1 is preferred. The preferred ratio between the number of antibody-producing cells (spleen cells) and the number of myeloma cells used is about 1: 1 to 20: 1, and PEG (preferably PEG1000 to PE)
G6000)が 10%乃至 80%程度の濃度で添加され、約 20°C乃至約 40°C、好ましくは 約 30°C乃至約 37°Cで約 1分乃至約 10分間インキュベートすることにより効率よく細 胞融合を実施できる。 G6000) is added at a concentration of about 10% to 80% and is efficiently incubated by incubation at about 20 ° C to about 40 ° C, preferably about 30 ° C to about 37 ° C for about 1 minute to about 10 minutes. Cell fusion can be performed.
モノクローナル抗体産生ハイブリドーマのスクリーニングには種々の方法が使用で きるが、例えば、抗原、すなわち P2Y 受容体や P2Y 受容体を直接或いは担体と  Various methods can be used to screen for monoclonal antibody-producing hybridomas. For example, antigens such as P2Y receptor and P2Y receptor can be used directly or with a carrier.
12 14  12 14
ともに吸着させた固相（例えば、マイクロプレート等）にハイプリドーマ培養上清を添 加し、次に放射性物質や酵素等で標識した抗免疫グロブリン抗体 (細胞融合に用い られる細胞がマウスの場合、抗マウス免疫グロブリン抗体が用いられる）またはプロテ イン Aを加え、固相に結合したモノクローナル抗体を検出する方法、抗免疫グロプリ ン抗体またはプロテイン Aを吸着させた固相にハイプリドーマ培養上清を添加し、放 射性物質や酵素等で標識したレセプター蛋白質を加え、固相に結合したモノクロ一 ナル抗体を検出する方法等が挙げられる。モノクローナル抗体の選別は、公知或い はそれに準じる方法に従って行なうことができる力 通常は HAT (ヒポキサンチン、ァ ミノプテリン、チミジン)を添加した動物細胞用培地等で行なうことができる。選別およ び育種用培地としては、ハイプリドーマが生育できるものならばどのような培地を用い てもよい。例えば、 1%乃至 20%、好ましくは 10%乃至 20%の牛胎児血清を含む R PMI— 1640培地、 1%乃至 10%の牛胎児血清を含む GIT培地 (和光純薬製)また はハイブリドーマ培養用無血清培地 (SFM— 101、 日水製薬製)等を用いることがで きる。培養温度は、通常 20°C乃至 40°C、好ましくは約 37°Cである。培養時間は、通 常 5日乃至 3週間、好ましくは 1週間乃至 2週間である。培養は、通常 5%炭酸ガス下 で行なうことができる。ノ、イブリドーマ培養上清の抗体価は、上記の抗血清中の抗体 価の測定と同様に行うことができる。 Anti-immunoglobulin antibody labeled with radioactive substance or enzyme etc. is added to the solid phase (for example, microplate) adsorbed together, and then labeled with radioactive substances or enzymes (if the cells used for cell fusion are mice, (Anti-mouse immunoglobulin antibody is used) or protein A is added to detect monoclonal antibody bound to the solid phase. Hypridoma culture supernatant is added to the solid phase adsorbed with anti-immunoglobulin antibody or protein A. And a method of detecting a monoclonal antibody bound to a solid phase by adding a receptor protein labeled with a radioactive substance or an enzyme. Monoclonal antibody selection is well known or Is a force that can be performed according to a similar method. Usually, it can be performed in a medium for animal cells to which HAT (hypoxanthine, aminopterin, thymidine) is added. Any medium can be used as a selection and breeding medium as long as it is capable of growing Hypridoma. For example, RPMI-1640 medium containing 1% to 20%, preferably 10% to 20% fetal bovine serum, GIT medium (made by Wako Pure Chemical Industries) containing 1% to 10% fetal bovine serum, or hybridoma culture Serum-free medium (SFM-101, manufactured by Nissui Pharmaceutical) etc. can be used. The culture temperature is usually 20 ° C to 40 ° C, preferably about 37 ° C. The culture time is usually 5 days to 3 weeks, preferably 1 week to 2 weeks. Cultivation can usually be performed under 5% carbon dioxide gas. The antibody titer of the cell culture supernatant can be determined in the same manner as the measurement of the antibody titer in the antiserum.
(b)モノクローナル抗体の精製 (b) Purification of monoclonal antibody
モノクローナル抗体の分離精製は、通常のポリクローナル抗体の分離精製と同様に 免疫グロブリンの分離精製法に従って行なうことができる。このような精製法としては、 例えば、塩析法、アルコール沈殿法、等電点沈殿法、電気泳動法、イオン交換体 (例 えば、 DEAE等）による吸脱着法、超遠心法、ゲルろ過法、抗原結合固相、またはプ 口ティン A或いはプロテイン G等の活性吸着剤により抗体のみを採取し、結合を解離 させて抗体を得る特異的精製法等が挙げられる。 The separation and purification of the monoclonal antibody can be carried out according to the method of separating and purifying immunoglobulin in the same manner as the separation and purification of ordinary polyclonal antibodies. Examples of such purification methods include salting out, alcohol precipitation, isoelectric precipitation, electrophoresis, adsorption / desorption using ion exchangers (eg DEAE), ultracentrifugation, gel filtration And a specific purification method in which the antibody is obtained by collecting only the antibody using an antigen-binding solid phase or an active adsorbent such as protein A or protein G, and dissociating the binding.
〔ポリクローナル抗体の作製〕  [Preparation of polyclonal antibody]
ポリクローナル抗体は、公知の方法或いはそれに準じる方法に従って製造することが できる。例えば、免疫抗原である P2Y 受容体または P2Y 受容体とキャリアー蛋白 The polyclonal antibody can be produced according to a known method or a method analogous thereto. For example, P2Y receptor or P2Y receptor that is an immunizing antigen and carrier protein
12 14  12 14
質との複合体を作成し、前記のモノクローナル抗体の製造法と同様に哺乳動物に免 疫を行ない、かかる免疫動物から P2Y 受容体または P2Y 受容体に対する抗体を And then immunize mammals in the same manner as the monoclonal antibody production method described above. From such immunized animals, antibodies against P2Y receptor or P2Y receptor are obtained.
12 14  12 14
含有するものを採取して、抗体の分離精製を行なうことによって製造することができる 。哺乳動物を免疫するために用いられる免疫抗原とキャリアー蛋白質との複合体に おいて、キャリアー蛋白質の種類およびキャリアーとハプテンとの混合比は、キャリア 一に架橋させて免疫したノヽプテンに対して抗体が効率良く作成できるものであれば、 どの様なものをどの様な比率で架橋させてもよいが、例えば、ゥシ血清アルブミン、ゥ シサイログロブリン、キーホール ·リンペット ·へモシァニン等を、重量比でハプテン 1に 対し、約 0.1乃至約 20、好ましくは約 1乃至約 5の割合でカップルさせる方法が用いら れる。また、ハプテンとキャリアーのカップリングには、種々の縮合剤を用いることがで きるが、グルタルアルデヒドやカルボジイミド、マレイミド活性エステル、チオール基、 ジチォピリジル基を含有する活性エステル試薬等が好適に用いられる。縮合生成物 は、単独で、または担体や希釈剤とともに哺乳動物に対して投与される。また、投与 部位は特に限定されず、抗体産生が可能な部位であればよい。投与に際して抗体 産生能を高めるため、完全フロイントアジュバントや不完全フロイントアジュバントを投 与してもよい。投与は通常 2週乃至 6週毎に 1回ずつ、計 2回乃至 10回程度行なわ れる。ポリクローナル抗体は、前記の免疫された哺乳動物の血液、腹水等、好ましく は血液力も採取することができる。抗血清中のポリクローナル抗体価の測定は、上記 の血清中の抗体価の測定と同様にして測定することができる。ポリクローナル抗体の 分離精製は、上記のモノクローナル抗体の分離精製と同様の免疫グロブリンの分離 精製法に従って行なうことができる。 It can be produced by collecting the contained material and performing separation and purification of the antibody. In the complex of immunizing antigen and carrier protein used to immunize mammals, the type of carrier protein and the mixing ratio of carrier and hapten are the same as those of immunized knotten cross-linked with carrier. Can be cross-linked at any ratio. For example, urine serum albumin, cythyroglobulin, keyhole limpet hemocyanin, etc. Ratio to hapten 1 On the other hand, a method of coupling at a ratio of about 0.1 to about 20, preferably about 1 to about 5, is used. In addition, various condensing agents can be used for coupling the hapten and the carrier, but an active ester reagent containing glutaraldehyde, carbodiimide, maleimide active ester, thiol group, or dithiopyridyl group is preferably used. The condensation product is administered to a mammal alone or together with a carrier or diluent. In addition, the administration site is not particularly limited as long as the antibody can be produced. In order to enhance antibody production ability upon administration, complete Freund's adjuvant or incomplete Freund's adjuvant may be administered. The administration is usually performed once every 2 to 6 weeks, for a total of 2 to 10 times. The polyclonal antibody can also collect blood, ascites, etc., preferably blood power of the immunized mammal. The polyclonal antibody titer in the antiserum can be measured in the same manner as the above-described measurement of the antibody titer in the serum. Separation and purification of the polyclonal antibody can be performed according to the same immunoglobulin separation and purification method as the above-described monoclonal antibody separation and purification.
[0056] 〔ヒトモノクローナル抗体の作製〕 [Production of human monoclonal antibody]
ヒトモノクローナル抗体は、公知の方法或いはそれに準じる方法に従って製造するこ とができる。例えば、ヒト免疫系部分を含む形質転換またはトランス染色体マウス (例 えば、 HuMAbマウス (登録商標）、 KMマウス (登録商標）等）を用いたり、ヒトイムノ グロブリン遺伝子ライブラリ一スクリ一ユングのためのファージディスプレイ方法を用 ヽ たり、或いは免疫によりヒト抗体応答が起こるようにヒト免疫細胞を再構築した SCIDマ ウスを用いたりすることによって製造することができる。  Human monoclonal antibodies can be produced according to a known method or a method analogous thereto. For example, using a transformed or transchromosomal mouse (eg, HuMAb mouse (registered trademark), KM mouse (registered trademark), etc.) containing the human immune system, or phage display for screening a human immunoglobulin gene library It can be produced by using a method or using an SCID mouse in which human immune cells are reconstituted so that a human antibody response is generated by immunization.
[0057] HuMAbマウス（登録商標）（Medarex社）は、内因性 μおよび κ鎖座を不活性化す る標的変異とともに、非再配置ヒト重鎖（ μおよび κ )および κ軽鎖ィムノグロブリン配 列をコードするヒトイムノグロブリン遺伝子ミニ遺伝子座を含むため、免疫応答により 高親和性のヒト IgG κモノクローナル抗体を産生することができるマウスである（Handb ook of Experimental Pharmacology, 1丄《3, 49—101 , 1994； Intern. Rev. Immunol., 13, 6 5-93, 1995; Ann. N. Y. Acad. Sci. , 764, 536-546, 1995)。前記の抗原を用いて該マ ウスに免疫応答を起こさせることによって、容易に「P2Y 受容体および [0057] HuMAb mice (registered trademark) (Medarex) have non-rearranged human heavy chains (μ and κ) and κ light chain immunoglobulins with target mutations that inactivate endogenous μ and κ chain loci. Since it contains a human immunoglobulin gene minilocus that encodes a sequence, it is a mouse that can produce a high-affinity human IgG κ monoclonal antibody by an immune response (Handbook of Experimental Pharmacology, 1 丄 << 3, 49— 101, 1994; Intern. Rev. Immunol., 13, 6 5-93, 1995; Ann. NY Acad. Sci., 764, 536-546, 1995). By eliciting an immune response in the mouse using the antigen described above, the “P2Y receptor and
12 Ζまたは Ρ2 12 Ζ or Ρ2
Υ 受容体ブロッカーとしての抗体」を得ることができる。また、 HuMAbマウス（登録 商標）の代わりに KMマウス（登録商標）（WO02/043478)ゃゼノマウス（Xenomouse) ( Abgenix社）（米国特許 5939598、 6075181、 6114598、 6150584、および 6162963)、 Tc マウス（Proc. Natl. Acad. Sci. USA, 97, 722-727, 2000)、ヒト重鎖および軽鎖トランス 染色体を有するゥシ（Nature Biotechnology, 20, 889-894, 2002)等を用いることもで きる。 “Antibodies as receptor blockers” can be obtained. Also, HuMAb mouse (Register (Trademark) instead of KM mouse (registered trademark) (WO02 / 043478) Xenomouse (Abgenix) (US Patents 5939598, 6075181, 6114598, 6150584, and 6162963), Tc mouse (Proc. Natl. Acad. Sci USA, 97, 722-727, 2000), and Ushi (Nature Biotechnology, 20, 889-894, 2002) having human heavy and light chain transchromosomes can also be used.
[0058] ヒトイムノグロブリン遺伝子ライブラリースクリーニングのためのファージディスプレイ 方法を用いてヒトモノクローナル抗体を得る方法は、公知技術にお!、て確立されて ヽ る。例えば、米国特許 5223409、 5403484、 5571698、 5427908、 5580717、 5969108、 6 172197、 5885793、 6521404、 6544731、 6555313、 6582915、および 6593081等に記載 の方法に従って行うことができる。  [0058] A method for obtaining a human monoclonal antibody using a phage display method for screening a human immunoglobulin gene library has been established by a known technique. For example, it can be carried out according to the methods described in US Pat.
[0059] また、免疫によりヒト抗体応答が起こるようにヒト免疫細胞を再構築した SCIDマウス を用いてヒトモノクローナル抗体を得る方法は、公知技術にお 、て確立されて 、る。 例えば、米国特許 5476996、および 5698767等に記載の方法に従って行うことができ る。  [0059] In addition, a method for obtaining a human monoclonal antibody using SCID mice in which human immune cells have been reconstructed so that a human antibody response occurs by immunization has been established in the publicly known art. For example, it can be performed according to the methods described in US Pat. Nos. 5,476,996 and 5,698,767.
[0060] 本発明において、「P2Y 受容体および  [0060] In the present invention, "P2Y receptor and
12 Ζまたは Ρ2Υ 受容体ブロッカーとしての  12 Ζ or Ρ2Υ as a receptor blocker
14  14
アンチセンス」は、例えば、 Ρ2Υ 受容体または Ρ2Υ 受容体の DNA塩基配列に相  Antisense refers to, for example, the 塩 基 2Υ receptor or the DNA sequence of the Υ2Υ receptor.
12 14  12 14
補的な、または実質的に相補的な塩基配列またはその一部を含有し、該 DNAの発 現を抑制し得る作用を有するものであればどのようなものであってもよぐ例えば、 RN A、 DNA、または修飾された核酸 (RNA、 DNA)等であってもよい。修飾された核酸 の具体例としては、例えば、核酸の硫黄誘導体、チォホスフェート誘導体、ポリヌクレ オシドアミドゃオリゴヌクレオシドアミドの分解に抵抗性のもの等が挙げられる。 P2Y  Any nucleotide sequence may be used as long as it contains a complementary or substantially complementary nucleotide sequence or a part thereof, and has an action capable of suppressing the expression of the DNA. A, DNA, or a modified nucleic acid (RNA, DNA) may be used. Specific examples of the modified nucleic acid include, for example, nucleic acid sulfur derivatives, thiophosphate derivatives, and those that are resistant to degradation of oligonucleotides or oligonucleoside amides. P2Y
12 受容体または P2Y 受容体の DNAに実質的に相補的な塩基配列とは、例えば、 P2  The nucleotide sequence substantially complementary to the DNA of 12 receptor or P2Y receptor is, for example, P2
14  14
Y 受容体または P2Y 受容体の DNAに相補的な塩基配列（すなわち、 P2Y 受 Base sequence complementary to DNA of Y receptor or P2Y receptor (ie P2Y acceptor)
12 14 12 容体または P2Y 受容体の DNAの相補鎖）の全塩基配列或いは部分塩基配列と約 The total base sequence or partial base sequence of 12 14 12 container or complementary strand of P2Y receptor DNA) and about
14  14
70%以上、好ましくは約 80%以上、より好ましくは約 90%以上、特に好ましくは約 9 5%以上の相同性を有する塩基配列等が挙げられる。特に、 P2Y 受容体または P2  Examples thereof include base sequences having homology of 70% or more, preferably about 80% or more, more preferably about 90% or more, and particularly preferably about 95% or more. In particular, the P2Y receptor or P2
12  12
Y 受容体の DNAの相補鎖の全塩基配列のうち、（A)翻訳阻害を指向したアンチセ Of the entire nucleotide sequence of the complementary strand of the Y receptor DNA, (A) an antisense directed to translation inhibition
14 14
ンスの場合は、 P2Y 受容体または P2Y 受容体のタンパク質の N末端部位をコー ドする部分の塩基配列 (例えば、開始コドン付近の塩基配列等)の相補鎖と約 70% 以上、好ましくは約 80%以上、より好ましくは約 90%以上、特に好ましくは約 95%以 上の相同性を有するアンチセンス力 （B)RNaseHによる RNA分解を指向するアン チセンスの場合は、イントロンを含む P2Y 受容体または P2Y 受容体の DNAの全 The N-terminal site of the P2Y receptor or P2Y receptor protein. About 70% or more, preferably about 80% or more, more preferably about 90% or more, particularly preferably about 95% or more. Antisense with homology (B) In the case of antisense directed to RNA degradation by RNaseH, the entire P2Y receptor or P2Y receptor DNA containing introns
12 14  12 14
塩基配列の相補鎖と約 70%以上、好ましくは約 80%以上、より好ましくは約 90%以 上、特に好ましくは約 95%以上の相同性を有するアンチセンスがそれぞれ好適であ る。  Antisense having about 70% or more, preferably about 80% or more, more preferably about 90% or more, particularly preferably about 95% or more of homology with the complementary strand of the base sequence is suitable.
[0061] アンチセンスは通常、 10個乃至 40個程度、好ましくは 15個乃至 30個程度の塩基 力も構成される。本発明で用いられるアンチセンスは、例えば、ヌクレアーゼ等の加 水分解酵素による分解を防ぐために、アンチセンスを構成する各ヌクレオチドのリン 酸残基（ホスフェート）は、例えば、ホスホロチォエート、メチノレホスホネート、ホスホロ ジチォネート等の化学修飾リン酸残基に置換されていてもよい。また、各ヌクレオチド の糖 (デォキシリボース）は、 2'—O—メチルイ匕等の化学修飾糖構造に置換されてい てもよいし、塩基部分 (ピリミジン、プリン)も化学修飾を受けたものであってもよい。勿 論これら以外にも、細胞内でのアンチセンスをより安定なものにする、アンチセンスの 細胞透過性をより高める、目標とするセンス鎖に対する親和性をより大きなものにする 、また、もし毒性があるような場合はアンチセンスの毒性をより小さなものにする、等の 目的のために種々の修飾を施してもよい。このような修飾は、例えば、 Pharm Tech Ja pan, 8卷， 247頁または 395頁， 1992年、 Antisense Research and Applications, CRC P ress, 1993年等で数多く報告されている。これらのアンチセンスは、公知の DNA合成 装置等を用いて製造することができる。  [0061] Antisense is usually composed of about 10 to 40, preferably about 15 to 30 basic forces. The antisense used in the present invention is, for example, a phosphate residue (phosphate) of each nucleotide constituting the antisense in order to prevent degradation by a hydrolytic enzyme such as nuclease. It may be substituted with a chemically modified phosphate residue such as phosphonate or phosphorodithionate. In addition, the sugar (deoxyribose) of each nucleotide may be substituted with a chemically modified sugar structure such as 2′-O-methyli 匕, and the base part (pyrimidine, purine) is also chemically modified. Also good. Of course, in addition to these, antisense in the cell is made more stable, the cell permeability of the antisense is increased, the affinity for the target sense strand is increased, and if it is toxic In some cases, various modifications may be made for the purpose of reducing the toxicity of the antisense. Many such modifications have been reported, for example, in Pharm Tech Japan, 8 卷, 247 or 395, 1992, Antisense Research and Applications, CRC Pres, 1993, and the like. These antisenses can be produced using a known DNA synthesizer or the like.
[0062] 本発明において、「P2Y 受容体および  [0062] In the present invention, "P2Y receptor and
12 Ζまたは Ρ2Υ 受容体ブロッカーとしての  12 Ζ or Ρ2Υ as a receptor blocker
14  14
短鎖干渉 RNA」には、例えば、 Ρ2Υ 受容体または P2Y 受容体をコードする RNA  “Short interfering RNA” includes, for example, RNA encoding Ρ2Υ receptor or P2Y receptor
12 14  12 14
の一部とそれに相補的な RNAとを含有する二重鎖 RNA等が含まれる。かかる短鎖 干渉 RNAは、公知の方法（Nature, 411, 494, 2001)等に準じて、 P2Y 受容体また  A double-stranded RNA containing a part of RNA and RNA complementary thereto. Such a short interfering RNA can be obtained according to a known method (Nature, 411, 494, 2001) etc.
12  12
は P2Y 受容体をコードする RNAの配列を基に設計して製造することができる。  Can be designed and produced based on the RNA sequence encoding the P2Y receptor.
14  14
[0063] 本発明において、「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカーとしての  [0063] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"
12 14  12 14
デコイ」には、例えば、 Ρ2Υ 受容体または Ρ2Υ 受容体の遺伝子発現を調節するタ ンパク質 (例えば、転写因子等)のような因子が結合する、核酸上の部位を模倣する 短 、二本鎖核酸 (それ自体上に"フォールバッグ'するように設計された一本鎖核酸 を含む)等が含まれる。このようなデコイは該タンパク質 (例えば、転写因子等)を競合 的に阻害するので、 P2Y 受容体または P2Y 受容体の遺伝子発現を抑えることが `` Decoy '' includes, for example, Ρ2Ρ receptor or a gene that regulates gene expression of Ρ2Υ receptor A short, double-stranded nucleic acid that mimics a site on a nucleic acid to which a factor such as a protein (eg, transcription factor) binds (single-stranded nucleic acid designed to “fall back” on itself) Such a decoy competitively inhibits the protein (for example, a transcription factor, etc.), so that the gene expression of P2Y receptor or P2Y receptor can be suppressed.
12 14  12 14
できる。デコイを同定し、構築する方法は、例えば、米国特許第 5716780号等に記載 されている。  it can. A method for identifying and constructing decoys is described, for example, in US Pat. No. 5,716,780.
[0064] 本発明において、「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカーとしての  [0064] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"
12 14  12 14
リボザィム」には、例えば、 Ρ2Υ 受容体または Ρ2Υ 受容体の mRNAに対し、高度  Ribozyme includes, for example, 高度 2Υ receptor or Ρ2Υ receptor mRNA
12 14  12 14
に特異的なエンドリボヌクレアーゼ活性を触媒する合成 RNA分子とその誘導体等が 含まれる。このようなリボザィムは、公知の方法（TRENDS in Molecular Medicine, 7, 2 21, 2001)等に準じて、 P2Y 受容体または P2Y 受容体をコードする RNAの配列  Synthetic RNA molecules that catalyze endoribonuclease activity specific to and derivatives thereof. Such a ribozyme can be obtained by using a known method (TRENDS in Molecular Medicine, 7, 22 21, 2001) or the like, and a sequence of RNA encoding P2Y receptor or P2Y receptor.
12 14  12 14
を基に設計して製造することができる。例えば、公知のリボザィムの配列の一部を、 P 2Y 受容体または P2Y 受容体をコードする RNAの一部に置換することによって製 It can be designed and manufactured based on this. For example, by replacing a part of the known ribozyme sequence with a part of RNA encoding P2Y receptor or P2Y receptor.
12 14 12 14
造することができる。 P2Y 受容体または P2Y 受容体をコードする RNAの一部とし  Can be built. As part of the RNA encoding the P2Y receptor or P2Y receptor
12 14  12 14
ては、公知のリボザィムによって切断され得るコンセンサス配列 NUX (式中、 Nはす ベての塩基を、 Xは G以外の塩基を示す。）の近傍の配列等が挙げられる。  Examples include sequences in the vicinity of a consensus sequence NUX (wherein N represents all bases and X represents a base other than G) that can be cleaved by a known ribozyme.
[0065] 本発明において、「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカーとしての [0065] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"
12 14  12 14
ァプタマ一」には、例えば、 Ρ2Υ 受容体または Ρ2Υ 受容体、或いはそのシグナル  For example, プ タ 2Υ receptor or Ρ2Υ receptor, or its signal
12 14  12 14
伝達に関係するタンパク質分子に対し、特異的に結合する一本鎖オリゴヌクレオチド 等が含まれる。  Examples include single-stranded oligonucleotides that specifically bind to protein molecules involved in transmission.
[0066] 本発明において、「Ρ2Υ 受容体および  [0066] In the present invention, "Ρ2Υ receptor and
12 Ζまたは Ρ2Υ 受容体ブロッカーとしての  12 Ζ or Ρ2Υ as a receptor blocker
14  14
低分子化合物」には、例えば、 Ρ2Υ 受容体および Ρ2Υ 受容体に直接結  Low molecular weight compounds include, for example, Ρ2Ρ and Ρ2Υ receptors.
12 Ζまたは  12 Ζ or
14  14
合し、拮抗作用を示す低分子化合物や、力かる受容体力 のシグナル伝達 (例えば 、受容体のクラスタリング、蛋白質のリン酸化や脱リン酸化、セカンドメッセンジャーの 生成、標的遺伝子の発現等)を調節する低分子化合物等が含まれる。なかでも、 Ρ2 Υ 受容体および Ζまたは Ρ2Υ 受容体に直接結合し、拮抗作用を示す低分子化 In combination, it regulates low molecular weight compounds that exhibit antagonism and signal transduction of strong receptor power (for example, receptor clustering, protein phosphorylation and dephosphorylation, second messenger generation, target gene expression, etc.) Low molecular weight compounds are included. Among them, 低 2 体 receptor and Ζ or Ρ2Υ receptor directly bind to and antagonize
12 14 12 14
合物、すなわち、 (a)P2Y 受容体アンタゴ-スト、 (b)P2Y 受容体アンタゴ-スト、ま  (A) P2Y receptor antagonist, (b) P2Y receptor antagonist
12 14  12 14
たは (c)P2Y 受容体と P2Y 受容体のデュアルアンタゴニスト等が好ましい。ここで、 低分子化合物とは、分子量が 1000以下 (好ましくは分子量 100乃至 700等、より好まし くは分子量 150乃至 500等）の有機化合物を意味する。また、デュアルアンタゴ-ストと は、 P2Y 受容体と P2Y 受容体の両方に拮抗作用を示すィ匕合物をいう。これらの Or (c) a dual antagonist of P2Y receptor and P2Y receptor, etc. are preferred. here, The low molecular weight compound means an organic compound having a molecular weight of 1000 or less (preferably a molecular weight of 100 to 700, etc., more preferably a molecular weight of 150 to 500). Dual antagonist refers to a compound that exhibits antagonistic action on both P2Y receptor and P2Y receptor. these
12 14  12 14
低分子化合物は、公知の方法、例えば、コンプリへンシヴ 'オーガニック 'トランスフォ 一メーシヨンズ：ァ ·ガイド ·トゥ^ ~ ·ファンクショナル ·グループ ·プレパレーシヨンズ、セ カンド.エディション（リチャード C.ラロック、ジョンワイリーアンドサンズ Inc, 1999) [C omprehensive urganic iransformations： A Guiae to junctional roup Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)]に記載された方法 等に従って製造することができる。反応の生成物は通常の精製手段、例えば、常圧 下または減圧下における蒸留、シリカゲルまたはケィ酸マグネシウムを用いた高速液 体クロマトグラフィー、薄層クロマトグラフィー、或いはカラムクロマトグラフィーまたは 洗浄、再結晶等の方法により精製することができる。また所望によって、凍結乾燥等 の処理に付してもよい。これらの低分子化合物が、 P2Y 受容体および  Low molecular weight compounds can be obtained by known methods, such as, for example, the Comprehensive 'Organic' Transformation: A Guide · To ^ · · Functional · Group · Preparations, Second Edition (Richard C. Larock, John Wiley and Sons Inc, 1999) [Comprehensive urganic iransformations: A Guiae to junctional roup Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)]. The product of the reaction can be obtained by usual purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization, etc. It can refine | purify by the method of. If desired, it may be subjected to a treatment such as freeze-drying. These low molecular weight compounds are the P2Y receptor and
12 Zまたは P2 12 Z or P2
Y Y
14受容体を介するシグナルを抑制するものであるか否かは、例えば、受容体との結 合アツセィや、その低分子化合物がリガンド刺激 (例えば、 ATP刺激や ADP刺激等 )による受容体力ものシグナル伝達を抑制するかどうかを評価するアツセィ等を用い て行うことができる。  14For example, whether or not the signal through the receptor is suppressed depends on whether the receptor binds to the receptor or the low molecular weight compound is a receptor force signal due to ligand stimulation (for example, ATP stimulation or ADP stimulation). This can be done by using an assembly that evaluates whether or not to suppress transmission.
[0067] 本発明において「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカー」は、低分  [0067] In the present invention, "P2Y receptor and Ζ or Ρ2Υ receptor blocker"
12 14  12 14
子化合物の形態をとるものであることが好ましい。例えば、前記一般式 (I)で示される 化合物、その幾何異性体、その互変異性体、その塩、その溶媒和物、またはそれら のプロドラッグや、前記一般式 (Π)で示される化合物、その塩、その Ν—才キシド体、 その溶媒和物、またはそれらのプロドラッグ等が好ましい。また、前記一般式 (III)で 示される化合物、その塩、またはそれらのプロドラッグや、前記一般式 (IV)で示され る化合物、またはその塩等も好ましい。  It is preferable that it takes the form of a child compound. For example, a compound represented by the general formula (I), a geometric isomer, a tautomer, a salt, a solvate thereof, or a prodrug thereof, a compound represented by the general formula (Π), Its salt, its 才 -xoxide, its solvate, or their prodrugs are preferred. Further, a compound represented by the general formula (III), a salt thereof, or a prodrug thereof, a compound represented by the general formula (IV), or a salt thereof is also preferable.
[0068] 本明細書中、一般式 (I)において、「置換基を有していてもよい環状基」における「 環状基」としては、例えば、「炭素環」または「複素環」等から任意の一個の水素原子 を除 、てできる一価基等が挙げられる。  In the present specification, in the general formula (I), the “cyclic group” in the “cyclic group optionally having substituent (s)” is arbitrarily selected from, for example, “carbocycle” or “heterocycle” And a monovalent group formed by removing one hydrogen atom.
[0069] 「炭素環」としては、例えば、「C3〜15の炭素環」等が挙げられる。「C3〜15の炭 素環」には、「C3〜15の単環、二環または三環式炭素環」および「C3〜15のスピロ 結合した二環式炭素環および架橋した二環式炭素環」等が含まれる。「C3〜15の単 環、二環または三環式炭素環」としては、例えば、シクロプロパン、シクロブタン、シク 口ペンタン、シクロへキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカ ン、シクロウンデカン、シクロドデカン、シクロトリデカン、シクロテトラデカン、シクロべ ンタデカン、シクロペンテン、シクロへキセン、シクロヘプテン、シクロ才クテン、シクロ ペンタジェン、シクロへキサジェン、シクロへブタジエン、シクロォクタジェン、ベンゼ ン、ペンタレン、パーヒドロペンタレン、ァズレン、パーヒドロアズレン、インデン、パーヒ ドロインデン、インダン、ナフタレン、ジヒドロナフタレン、テトラヒドロナフタレン、パーヒ ドロナフタレン、 6, 7—ジヒドロ一 5H—ベンゾ [7]ァヌレン、 5H—ベンゾ [7]ァヌレン 、ヘプタレン、パーヒドロヘプタレン、ビフエ二レン、 as—インダセン、 s—インダセン、 ァセナフチレン、ァセナフテン、フルオレン、フエナレン、フエナントレン、アントラセン 環等が挙げられる。「C3〜 15のスピロ結合した二環式炭素環および架橋した二環式 炭素環」としては、例えば、スピロ [4. 4]ノナン、スピロ [4. 5]デカン、スピロ [5. 5]ゥ ンデカン、ビシクロ [2. 2. 1]ヘプタン、ビシクロ [2. 2. 1]ヘプター 2—ェン、ビシクロ [3. 1. 1]ヘプタン、ビシクロ [3. 1. 1]ヘプター 2—ェン、ビシクロ [3. 2. 1]オクタン 、ビシクロ [2. 2. 2]オクタン、ビシクロ [2. 2. 2]ォクタ一 2—ェン、ァダマンタン、ノル ァダマンタン環等が挙げられる。 [0069] Examples of the "carbocycle" include "C3-15 carbocycle". "C3-15 charcoal "Prime ring" includes "C3-15 monocyclic, bicyclic or tricyclic carbocycle" and "C3-15 spiro-linked bicyclic carbocycle and bridged bicyclic carbocycle". . Examples of the `` C3-15 monocyclic, bicyclic or tricyclic carbocycle '' include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclo Dodecane, Cyclotridecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclopentene, Cyclopentagen, Cyclohexagen, Cyclohexadiene, Cyclooctagen, Benzene, Pentalene, Perhydropentalene , Azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, 6, 7-dihydro-5H-benzo [7] anulene, 5H-benzo [7] anu Len, heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene, acenenaphthylene, acenenaphthene, fluorene, phenalene, phenanthrene, anthracene ring and the like. “C3-15 spiro-bonded bicyclic carbocycles and bridged bicyclic carbocycles” include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] Ndecane, bicyclo [2. 2. 1] heptane, bicyclo [2. 2. 1] hepter 2-ene, bicyclo [3. 1. 1] heptane, bicyclo [3. 1. 1] hepter 2-en Bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, bicyclo [2.2.2] octane 2-adamantane, noradamantane ring and the like.
「複素環」としては、例えば、「1〜5個の窒素原子、 1〜2個の酸素原子および Zま たは 1個の硫黄原子を含む 3〜15員の複素環」等が挙げられる。「1〜5個の窒素原 子、 1〜2個の酸素原子および Zまたは 1個の硫黄原子を含む 3〜15員の複素環」 には、「1〜5個の窒素原子、 1〜2個の酸素原子および Zまたは 1個の硫黄原子を 含む 3〜15員の単環、二環または三環式複素環」および「1〜5個の窒素原子、 1〜 2個の酸素原子および Zまたは 1個の硫黄原子を含む 3〜15員のスピロ結合した二 環式複素環および架橋した二環式複素環」等が含まれる。「1〜5個の窒素原子、 1 〜2個の酸素原子および Zまたは 1個の硫黄原子を含む 3〜15員の単環、二環また は三環式複素環」としては、例えば、ピロール、イミダゾール、トリァゾール、テトラゾー ル、ピラゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、ァゼピン、ジァゼピン、フラ ン、ピラン、ォキセピン、チォフェン、チォピラン、チェピン、ォキサゾーノレ、イソォキサ ゾール、チアゾール、イソチアゾール、フラザン、ォキサジァゾール、ォキサジン、ォキ サジァジン、ォキサゼピン、ォキサジァゼピン、チアジアゾーノレ、チアジン、チアジア ジン、チアゼピン、チアジアゼピン、インドール、イソインドール、インドリジン、ベンゾ フラン、イソべンゾフラン、ベンゾチォフェン、イソベンゾチォフェン、ジチアナフタレン 、インダゾール、キノリン、イソキノリン、キノリジン、プリン、フタラジン、プテリジン、ナフ チリジン、キノキサリン、キナゾリン、シンノリン、ベンゾォキサゾール、ベンゾチアゾー ル、ベンゾイミダゾール、クロメン、ベンゾォキセピン、ベンゾォキサゼピン、ベンゾォ キサジァゼピン、ベンゾチェピン、ベンゾチアゼピン、ベンゾチアジアゼピン、ベンゾ ァゼピン、ベンゾジァゼピン、ベンゾフラザン、ベンゾチアジアゾーノレ、ベンゾトリァゾ ール、カルバゾール、 13 カルボリン、アタリジン、フエナジン、ジベンゾフラン、キサ ンテン、ジベンゾチォフェン、フエノチアジン、フエノキサジン、フエノキサチイン、チア ンスレン、フエナントリジン、フエナント口リン、ペリミジン、アジリジン、ァゼチジン、ピロ リン、ピロリジン、イミダゾリン、イミダゾリジン、トリァゾリン、トリァゾリジン、テトラゾリン、 テトラゾリジン、ピラゾリン、ビラゾリジン、ジヒドロピリジン、テトラヒドロピリジン、ピベリジ ン、ジヒドロビラジン、テトラヒドロビラジン、ピぺラジン、ジヒドロピリミジン、テトラヒドロピ リミジン、パーヒドロピリミジン、ジヒドロピリダジン、テトラヒドロピリダジン、ノ ーヒドロピリ ダジン、ジヒドロアゼピン、テトラヒドロアゼピン、パーヒドロアゼピン、ジヒドロジァゼピ ン、テトラヒドロジァゼピン、パーヒドロジァゼピン、ォキシラン、ォキセタン、ジヒドロフ ラン、テトラヒドロフラン、ジヒドロピラン、テトラヒドロピラン、ジヒドロォキセピン、テトラヒ ドロォキセピン、パーヒドロォキセピン、チイラン、チェタン、ジヒドロチォフェン、テトラ ヒドロチオフ ン、ジヒドロチォピラン、テトラヒドロチォピラン、ジヒドロチェピン、テトラ ヒドロチェピン、パーヒドロチェピン、ジヒドロォキサゾール、テトラヒドロォキサゾール（ ォキサゾリジン）、ジヒドロイソォキサゾール、テトラヒドロイソォキサゾール (イソォキサ ゾリジン）、ジヒドロチアゾール、テトラヒドロチアゾール（チアゾリジン）、ジヒドロイソチ ァゾール、テトラヒドロイソチアゾール (イソチアゾリジン）、ジヒドロフラザン、テトラヒドロ フラザン、ジヒドロォキサジァゾール、テトラヒドロォキサジァゾール（ォキサジァゾリジ ン）、ジヒドロォキサジン、テトラヒドロォキサジン、ジヒドロォキサジァジン、テトラヒドロ ォキサジァジン、ジヒドロォキサゼピン、テトラヒドロォキサゼピン、パーヒドロォキサゼ ピン、ジヒドロォキサジァゼピン、テトラヒドロォキサジァゼピン、パーヒドロォキサジァ ゼピン、ジヒドロチアジアゾール、テトラヒドロチアジアゾール（チアジアゾリジン）、ジヒ ドロチアジン、テトラヒドロチアジン、ジヒドロチアジアジン、テトラヒドロチアジアジン、 ジヒドロチアゼピン、テトラヒドロチアゼピン、パーヒドロチアゼピン、ジヒドロチアジアゼ ピン、テトラヒドロチアジアゼピン、パーヒドロチアジアゼピン、モノレホリン、チオモルホ リン、ォキサチアン、インドリン、イソインドリン、ジヒドロべンゾフラン、パーヒドロべンゾ フラン、ジヒドロイソべンゾフラン、パーヒドロイソべンゾフラン、ジヒドロベンゾチォフエ ン、パーヒドロベンゾチォフェン、ジヒドロイソベンゾチォフェン、パーヒドロイソべンゾ チォフェン、ジヒドロインダゾール、パーヒドロインダゾール、ジヒドロキノリン、テトラヒド 口キノリン、パーヒドロキノリン、ジヒドロイソキノリン、テトラヒドロイソキノリン、パーヒドロ イソキノリン、ジヒドロフタラジン、テトラヒドロフタラジン、パーヒドロフタラジン、ジヒドロ ナフチリジン、テトラヒドロナフチリジン、パーヒドロナフチリジン、ジヒドロキノキサリン、 テトラヒドロキノキサリン、パーヒドロキノキサリン、ジヒドロキナゾリン、テトラヒドロキナゾ リン、パーヒドロキナゾリン、ジヒドロシンノリン、テトラヒドロシンノリン、パーヒドロシンノリ ン、ベンゾォキサチアン、ジヒドロべンゾォキサジン、ジヒドロべンゾチアジン、ピラジノ モノレホリン、ジヒドロベンゾォキサゾーノレ、パーヒドロベンゾォキサゾーノレ、ジヒドロべ ンゾチアゾーノレ、ノ ーヒドロべンゾチアゾーノレ、ジヒドロべンゾイミダゾーノレ、ノ ーヒドロ ベンゾイミダゾール、ジヒドロベンゾァゼピン、テトラヒドロベンゾァゼピン、ジヒドロベン ゾジァゼピン、テトラヒドロべンゾジァゼピン、ベンゾジ才キセパン、ジヒドロベンゾ才キ サゼピン、テトラヒドロべンゾォキサゼピン、ジヒドロカルバゾール、テトラヒドロカルバ ゾール、パーヒドロカルバゾール、ジヒドロアクリジン、テトラヒドロアクリジン、ノ ーヒドロ アタリジン、ジヒドロジべンゾフラン、ジヒドロジべンゾチオフ ン、テトラヒドロジべンゾ フラン、テトラヒドロジベンゾチォフェン、パーヒドロジべンゾフラン、パーヒドロジべンゾ チォフェン、ジォキソラン、ジォキサン、ジチオラン、ジチアン、ジォキサインダン、ベ ンゾジォキサン、クロメン、クロマン、ベンゾジチオラン、ベンゾジチアン環等が挙げら れる。「1〜5個の窒素原子、 1〜2個の酸素原子および Zまたは 1個の硫黄原子を含 む 3〜 15員のスピロ結合した二環式複素環および架橋した二環式複素環」としては、 例えば、ァザスピロ [4. 4]ノナン、ォキサザスピロ [4. 4]ノナン、ォキサァザスピロ [2 . 5]オクタン、ァザスピロ [4. 5]デカン、 1, 3, 8—トリァザスピロ [4. 5]デカン、 2, 7 —ジァザスピロ [4. 5]デカン、 1, 4, 9—トリァザスピロ [5. 5]ゥンデカン、ォキサザス ピロ [4. 5]デカン、ァザスピロ [5. 5]ゥンデカン、ァザビシクロ [2. 2. 1]ヘプタン、ァ ザビシクロ [3. 1. 1]ヘプタン、ァザビシクロ [3. 2. 1]オクタン（8—ァザビシクロ [3. 2. 1]オクタン環等）、ァザビシクロ [2. 2. 2]オクタン（2—ァザビシクロ [2. 2. 2]オタ タン環等）、ァザビシクロ [2. 1. 1]へキサン（5—ァザビシクロ [2. 1. 1]へキサン環 等)環等が挙げられる。 Examples of the “heterocycle” include “a 3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom”. “3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom” includes “1 to 5 nitrogen atoms, 1 to 2 3-15 membered monocyclic, bicyclic or tricyclic heterocycle containing 1 oxygen atom and Z or 1 sulfur atom "and" 1-5 nitrogen atom, 1-2 oxygen atom and Z Or a 3 to 15-membered spiro-linked bicyclic heterocycle and a bridged bicyclic heterocycle containing one sulfur atom. “3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom” includes, for example, pyrrole Imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, fura , Pyran, oxepin, thiophene, thiopyran, chepine, oxazonole, isoxazole, thiazole, isothiazole, furazane, oxazine, oxazine, oxazazine, oxazepine, oxadiazepine, thiadiazonole, thiazine, thiadiazine, thiazepine, indhiazole Indole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole , Benzothiazole, benzimidazole, chromene, benzoxepin, benzoxazepine, benzox Diazepine, benzochepine, benzothiazepine, benzothiadiazepine, benzodiazepine, benzodiazepine, benzofurazan, benzothiadiazonole, benzotriazole, carbazole, 13 carboline, atalidine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothiazine, Phenoxazine, phenoxathiin, thianthrene, phenanthridine, phenanthorin, perimidine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, virazolidine, dihydropyridine, dihydropyridine, dihydropyridine , Dihydrovirazine, tetrahydrovirazine, piperazine, dihydropyrimidine, Toluhydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, nohydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxsilane, oxetane, dihydrofuran, Tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydroxepin, perhydrooxepin, thiirane, chetan, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrochepin, tetrahydrochepin, par Hydrochepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, te Lahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadi Azol (oxaziazolidin), Dihydrooxazine, Tetrahydrooxazine, Dihydrooxadiazine, Tetrahydro Oxaziazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (Thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiazine Asian Zepin, Monorephorin, Thiomorpholine, Oxathian, Indoline, Isoindoline, Dihydrobenzofuran, Perhydrobenzofuran, Dihydroisobenzofuran, Perhydroisobenzofuran, Dihydrobenzo Thiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthal Razine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline , Perhydrocinnoline, benzoxanthian, dihydrobenzox Gin, dihydrobenzothiazine, pyrazino monoreforin, dihydrobenzoxazonole, perhydrobenzoxazonole, dihydrobenzothiazonore, nohydrobenzozozonole, dihydrobenzimidazole, nohydrobenzimidazole, dihydrobenzase Pin, tetrahydrobenzozepine, dihydrobenzazodiapine, tetrahydrobenzodiazepine, benzodi-aged xepane, dihydrobenzo-aged xazezepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, nohydroataridin, Dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothi And phosphene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane, dioxaidane, benzodioxane, chromene, chromane, benzodithiolane, and benzodithian ring. As "3- to 15-membered spiro-bonded bicyclic heterocycles and bridged bicyclic heterocycles containing 1-5 nitrogen atoms, 1-2 oxygen atoms and Z or 1 sulfur atom" Is For example, azaspiro [4. 4] nonane, oxazaspiro [4. 4] nonane, oxazaspiro [2.5] octane, azaspiro [4.5] decane, 1, 3, 8—triazaspiro [4.5] decane, 2, 7—Jazaspiro [4. 5] decane, 1, 4, 9—Triazaspiro [5.5] Undecane, Oxazas Piro [4.5] Decane, Azaspiro [5.5] Undecane, Azabicyclo [2. 2. 1] heptane , Azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane (8-azabicyclo [3.2.1] octane ring, etc.), azabicyclo [2.2.2] octane (2-azabicyclo) [2. 2. 2] Otane ring, etc.) and azabicyclo [2.1.1] hexane (5-azabicyclo [2. 1. 1] hexane ring, etc.) ring.
本明細書中、一般式 (I)において、「置換基を有していてもよい環状基」における「 置換基」は、置換基であれば特に限定されない。該「置換基」としては、例えば、（1) 置換されて 、てもよ 、C1〜20アルキル基、（2)置換されて!、てもよ 、C2〜20アル ケ-ル基、（3)置換されていてもよい C2〜20アルキ-ル基、（4)置換されていてもよ い Cl〜20アルキリデン基、（5)置換されていてもよい環状基、（6)ォキソ基、（7)水 酸基、（8)置換されていてもよい Cl〜20アルキルォキシ基、（9)置換されていてもよ In the present specification, in the general formula (I), the “substituent” in the “cyclic group optionally having substituent (s)” is not particularly limited as long as it is a substituent. The “substituent” includes, for example, (1) substituted or C1-20 alkyl group, (2) substituted !, C2-20 alkyl group, (3 ) An optionally substituted C2-20 alkyl group, (4) an optionally substituted Cl-20 alkylidene group, (5) an optionally substituted cyclic group, (6) an oxo group, ( 7) Hydroxyl group, (8) Cl-20 alkyloxy group optionally substituted, (9) Optionally substituted
V、C2〜20アルケ-ルォキシ基、（10)置換されて!、てもよ 、C2〜20アルキ-ルォキ シ基、（11)置換されていてもよい環状基で保護された水酸基、（12)置換されていて もよい Cl〜20ァシルォキシ基、（13)チォキソ基、（14)メルカプト基、（15)置換され て！、てもよ 、C1〜20アルキルチオ基、（16)置換されて!、てもよ 、C2〜20ァルケ- ルチオ基、（17)置換されていてもよい C2〜20アルキ-ルチオ基、（18)置換されてV, C2-20 alkyloxy group, (10) substituted !, C2-20 alkyloxy group, (11) hydroxyl group protected with an optionally substituted cyclic group, (12 ) Optionally substituted Cl-20 acyloxy group, (13) thixo group, (14) mercapto group, (15) substituted! C1-20 alkylthio group, (16) substituted !, C2-20 alkylthio group, (17) C2-20 alkylthio group optionally substituted, (18 Replaced)
V、てもよ 、環状基で置換されたメルカプト基、 ( 19)置換されて!、てもよ 、C1〜20ァ ルキルスルフィ-ル基、（20)置換されて!、てもよ 、C2〜20アルケ-ルスルフィエル 基、（21)置換されていてもよい C2〜20アルキニルスルフィエル基、（22)置換されて V、てもよ 、環状基で置換されたスルフィエル基（例えば、フエニルスルフィニル基等）V, may be a mercapto group substituted with a cyclic group, (19) substituted !, may be a C1-20 alkylsulfyl group, (20) substituted !, may be C2 ~ 20 alkenylsulfier groups, (21) optionally substituted C2-20 alkynylsulfier groups, (22) substituted V, or sulfier groups substituted with cyclic groups (eg phenylsulfinyl groups) etc)
、（23)置換されていてもよい Cl〜20アルキルスルホ-ル基、（24)置換されていて もよ!/ヽ C2〜20アルケニルスルホ -ル基、（25)置換されて!、てもよ ヽ C2〜20アルキ ニルスルホ-ル基、（26)置換されて!、てもよ!/、環状基で置換されたスルホ -ル基（ 例えば、フエニルスルホニル基等）、（27)置換されていてもよいスルフィノ基、（28) 置換されて 、てもよ 、スルホ基、（29)置換されて!、てもよ 、スルファモイル基（例え ば、無置換のスルファモイル基、 N—モノまたはジー（置換されていてもよい Cl〜20 アルキル）スルファモイル基（例えば、 N—モノー C 1〜6アルキルスルファモイル基（ 例えば、 N—メチルスルファモイル基、 N ェチルスルファモイル基、 N—プロピルス ルファモイル基、 N—イソプロピルスルファモイル基、 N ブチルスルファモイル基、 N イソブチルスルファモイル基、 N— (tert ブチル）スルファモイル基、 N—ペンチ ルスルファモイル基、 N へキシルスルファモイル基等）、 N, N ジ Cl〜6アルキル スルファモイル基（例えば、 N, N ジメチルスルファモイル基、 N, N ジェチルスル ファモイル基、 N, N ジプロピルスルファモイル基、 N, N—ジブチルスルファモイル 基、 N, N ジペンチルスルファモイル基、 N, N ジへキシルスルファモイル基、 N —メチルー N ェチルスルファモイル基等）等）等）、（30)置換されて!、てもよ 、カル ボ-ル基（例えば、メトキシカルボ-ル基、エトキシカルボ-ル基、 t ブトキシカルボ -ル基等の C1 6アルコキシカルボ-ル基等、例えば、シクロペンチルカルボ-ル 基、シクロへキシルカルボ-ル基等の C3〜8シクロアルカノィル基、例えば、ベンゾィ ル基等の C6〜 10ァリールカルボ-ル基、例えば、モルホリンー4ーィルカルボ-ル 基、ピぺリジン 1ーィルカルボ-ル基、 1ーメチルピペラジン 4ーィルカルボ-ル 基等の置換基を有していてもよい複素環カルボニル基等）、（31)置換されていてもよ い Cl〜20ァシル基（例えば、ホルミル基、ァセチル基、プロパノィル基、ビバロイル 基等）、（32)置換されて!ヽてもよ ヽカルバモイル基 (例えば、無置換の力ルバモイル 基、 N—モノまたはジー（置換されていてもよい Cl〜20アルキル)力ルバモイル基（ 例えば、 N—モノー Cl〜6アルキル力ルバモイル基（例えば、 N—メチルカルバモイ ル基、 N ェチルカルバモイル基、 N プロピル力ルバモイル基、 N イソプロピル力 ルバモイル基、 N ブチルカルバモイル基、 N イソブチルカルバモイル基、 N—（t ert ブチル）力ルバモイル基、 N ペンチルカルバモイル基、 N へキシルカルバ モイル基等）、水酸基が置換した N モノー Cl〜6アルキル力ルバモイル基 (例えば 、 N ヒドロキシメチルカルバモイル基、 N— (2—ヒドロキシェチル）力ルバモイル基、 N— (3—ヒドロキシプロピル）力ルバモイル基、 N— (4—ヒドロキシブチル）カルバモ ィル基等）、アミノ基またはジメチルァミノ基が置換した N モノ Cl〜6アルキル力 ルバモイル基（例えば、 N アミノメチルカルバモイル基、 N—（2—アミノエチル）力 ルバモイル基、 N— (3—ァミノプロピル）力ルバモイル基、 N— (4—アミノブチル）力 ルバモイル基、 N- (ジメチルァミノ）メチルカルバモイル基、 N— (2—ジメチルァミノ ェチル）力ルバモイル基、 N— (3—ジメチルァミノプロピル）力ルバモイル基、 N— (4 ージメチルアミノブチル）力ルバモイル基等）、 N, N—ジ Cl〜6アルキル力ルバモイ ル基（例えば、 N, N—ジメチルカルバモイル基、 N, N—ジェチルカルバモイル基、 N, N—ジプロピル力ルバモイル基、 N, N—ジブチルカルバモイル基、 N, N—ジぺ ンチルカルバモイル基、 N, N—ジへキシルカルバモイル基、 N—メチルー N—ェチ ルカルバモイル基等)等）、 N—モノまたはジー（置換されていてもよい炭素環または 複素環)力ルバモイル基 (例えば、 N—モノ (置換されて 、てもよ 、炭素環)カルバモ ィル基（例えば、 N—シクロプロピル力ルバモイル基、 N—シクロペンチルカルバモイ ル基、 N—シクロへキシルカルバモイル基、 N—フエ-ルカルバモイル基等）等）等）、 (33)シァノ基、（34)置換されていてもよいアミジノ基、（35)ニトロ基、（36)ニトロソ基 、（37)置換されていてもよいイミノ基 (例えば、無置換のイミノ基、 Cl〜6アルキル基 が置換したイミノ基 (例えば、メチルイミノ基、ェチルイミノ基等）、置換基を有していて もよい C6〜10ァリール基が置換したイミノ基（例えば、フエ-ルイミノ基、 p—フルォロ フエ二ルイミノ基、 p—クロ口フエ二ルイミノ基等）、ヒドロキシィミノ基等の水酸基が置換 したイミノ基等）、（38)置換されていてもよいアミノ基 (例えば、モノ—またはジ— C1 〜6アルキルアミノ基 (例えば、メチルァミノ基、ェチルァミノ基、プロピルアミノ基、ジメ チルァミノ基、ジェチルァミノ基等）、モノ—またはジ— C6〜10ァリールァミノ基 (例え ば、フエ-ルァミノ基、ジフエ-ルァミノ基等）、モノ一 Cl〜6アルキル一モノ一 C6〜l 0ァリールアミノ基（例えば、 N—フエ-ルー N—メチルァミノ基、 N—フエ-ルー N— ェチルァミノ基等)等）、（39)ハロゲン原子、（40)カルボキシ基、（41)ホスホノ基（一 PO (OH) )、（42)ジヒドロキシボリル基（—B (OH) )、（43) C1〜20アルキルカル , (23) optionally substituted Cl-20 alkyl sulfonyl group, (24) optionally substituted! / ヽ C2-20 alkenyl sulfonyl group, (25) substituted!ヽ C2-20 alkynylsulfol group, (26) substituted !, may! /, Sulfonyl groups substituted with cyclic groups (eg phenylsulfonyl groups, etc.), (27) substituted Optionally substituted sulfino group, (28) substituted, may be sulfo group, (29) substituted !, may be sulfamoyl group (eg For example, an unsubstituted sulfamoyl group, N-mono or di (optionally substituted Cl-20 alkyl) sulfamoyl group (eg, N-mono-C 1-6 alkylsulfamoyl group (eg, N-methylsulfayl group) Moyl group, N-ethylsulfamoyl group, N-propylsulfamoyl group, N-isopropylsulfamoyl group, N-butylsulfamoyl group, N-isobutylsulfamoyl group, N- (tert-butyl) sulfamoyl group, N-penty Rusulfamoyl group, N-hexylsulfamoyl group, etc.), N, N DiCl-6 alkyl sulfamoyl group (eg, N, N dimethylsulfamoyl group, N, N Jetylsulfamoyl group, N, N Dipropylsulfamoyl group) N, N-dibutylsulfamoyl group, N, N dipentylsulfamoyl group, N, N dihexylsulfamoyl group, N Methyl) -Nethylsulfamoyl group, etc.)))), (30) substituted !, or carbo group (eg methoxy carbo ol group, ethoxy carbo ol group, t-butoxy carbo- C16 alkoxy carbonyl group such as thiol group, etc., for example, C3-8 cycloalkanoyl group such as cyclopentyl carbo yl group, cyclohexyl carbo yl group, etc., for example, C6-10 aryl carbonate such as benzoyl group, etc. (E.g., a heterocyclic carbonyl group which may have a substituent such as morpholine-4-ylcarbol group, piperidine 1-ylcarbol group, 1-methylpiperazine 4-ylcarbol group, etc.), (31 ) May be substituted Cl to 20 acyl groups (eg formyl, acetyl, propanol, bivaloyl, etc.), (32) may be substituted! Carbamoyl (eg, unsubstituted) Force ruby N-mono or di (optionally substituted Cl-20 alkyl) force rubamoyl group (for example, N-mono-Cl-6 alkyl force rubamoyl group (for example, N-methylcarbamoyl group, N ethylcarbamoyl group) N-propyl rubamoyl group, N isopropyl rubamoyl group, N butyl carbamoyl group, N isobutyl carbamoyl group, N— (tert butyl) force rubamoyl group, N pentyl carbamoyl group, N hexyl carbamoyl group, etc. N-Mono Cl-6 alkyl group rubamoyl group (eg, N hydroxymethylcarbamoyl group, N— (2-hydroxyethyl) group rubamoyl group, N— (3-hydroxypropyl) group rubamoyl group, N— (4-hydroxy Butyl) carbamoyl group), amino group or dimethylamino group substituted N mono Cl-6 alkyl strength Luba Moyl group (eg N aminomethylcarbamoyl group, N— (2-aminoethyl) force Rubamoyl group, N— (3-Aminopropyl) force rubamoyl group, N— (4-Aminobutyl) force Rubamoyl group, N- (dimethylamino) methylcarbamoyl group, N— (2-dimethylaminoethyl) force rubamoyl group, N— ( 3) -dimethylaminopropyl) strong rubamoyl group, N— (4-dimethylaminobutyl) strong rubamoyl group, etc.), N, N—diCl-6 alkyl rubamoyl group (for example, N, N-dimethylcarbamoyl group, N, N-Jetylcarbamoyl group, N, N-Dipropyl-carbamoyl group, N, N-dibutylcarbamoyl group, N, N-dipentylcarbamoyl group, N, N-dihexylcarbamoyl group, N-methyl-N -Ethylcarbamoyl group, etc.), N-mono or di (optionally substituted carbocycle or heterocycle) force rubamoyl group (eg N-mono (substituted, optionally carbocycle)) Rubamoyl group (eg, N-cyclopropyl-powered rubamoyl group, N-cyclopentylcarbamoyl group, N-cyclohexylcarbamoyl group, N-phenylcarbamoyl group, etc.))), (33) cyano group, (34) optionally substituted amidino group, (35) nitro group, (36) nitroso group, (37) optionally substituted imino group (for example, unsubstituted imino group, Cl-6 alkyl group) A substituted imino group (for example, methylimino group, ethylimino group, etc.), an optionally substituted C6-10 aryl group substituted with an imino group (for example, a feu-rimino group, a p-fluorofluoroimino group, p-chlorophenimino group, etc.), an imino group substituted with a hydroxyl group such as a hydroxyimino group), (38) an optionally substituted amino group (eg mono- or di-C1-6 alkylamino) Group (for example, Methylamino group, ethylamino group, propylamino group, dimethylamino group, jetylamino group, etc.), mono- or di-C6-10 allylamamino group (eg, phenolamino group, diphenylamino group, etc.), mono-Cl-6 Alkyl mono mono C6-l 0 arylamino group (eg, N-ferro-N-methylamino group, N-ferro-N-ethylamino group, etc.), (39) halogen atom, (40) carboxy group, ( 41) Phosphono group (one PO (OH)), (42) Dihydroxyboryl group (—B (OH)), (43) C1-20 alkyl carb
2 2  twenty two
ボ-ルヒドラジノ基（例えば、メチルカルボ-ルヒドラジノ基、ェチルカルボ-ルヒドラジ ノ基等）、（44)例えば、ベンゾアルデヒド ヒドラゾン基、 p—メトキシベンゾアルデヒド ヒドラゾン基等の置換基を有して 、てもよ 、C6〜： L0ァリールヒドラゾン基等が挙げ られ、これら任意の置換基は、置換可能な任意の位置に置換可能な任意の数だけ 置換していてもよい。尚、 (29)、 (32)、（34)、（38)で例示した「置換されていてもよ ヽスルファモイル基」、「置換されて 、てもよ 、力ルバモイル基」、「置換されて 、てもよ いアミジノ基」および「置換されていてもよいアミノ基」は、置換基が 2個のとき、それら が結合する窒素原子と一緒になつて、 1〜5個の窒素原子、 1個の酸素原子および Z または 1個の硫黄原子を含む 5〜7員の単環複素環を形成してもよぐ形成されたこ の複素環は、 Cl〜8アルキル基、水酸基またはアミノ基によって置換されていてもよ い。 Borhydrazino group (for example, methylcarbohydrazino group, ethylcarbohydrazino group, etc.), (44) For example, it may have a substituent such as benzaldehyde hydrazone group, p-methoxybenzaldehyde hydrazone group, etc. C6˜: L0 arylhydrazone group and the like can be mentioned, and these optional substituents may be substituted by any number that can be substituted at any substitutable position. (29), (32), (34), (38) “Sulphamoyl group”, “substituted, or rubamoyl group”, “substituted and optionally amidino group” and “optionally substituted amino group” have two substituents. Sometimes together with the nitrogen atom to which they are attached, form a 5-7 membered monocyclic heterocycle containing 1-5 nitrogen atoms, 1 oxygen atom and Z or 1 sulfur atom. This hetero ring formed may be substituted with a Cl-8 alkyl group, a hydroxyl group or an amino group.
[0072] 本明細書中、一般式 (I)において、「置換基を有していてもよい環状基」における「 置換基」として（1)〜 (44)に例示した置換基中、「環状基」とは、前記「炭素環」また は「複素環」から任意の一個の水素原子を除!、てできる一価基等を意味する。  In the present specification, in the general formula (I), among the substituents exemplified in (1) to (44) as the “substituent” in the “cyclic group optionally having substituent (s)”, “cyclic The “group” means a monovalent group formed by removing any one hydrogen atom from the “carbocycle” or “heterocycle”.
[0073] 本明細書中、一般式 (I)において、「置換基を有していてもよい環状基」における「 置換基」として（1)〜 (44)に例示した置換基中、「置換されて 、てもよ 、」 、う記載 は、例えば、（1) C1〜20アルキル基、（2) C2〜20アルケ-ル基、（3) C2〜20アル キニル基、（4) C1〜20アルキリデン基、（5)環状基、（6)環状基で置換された Cl〜 20アルキル基、（7)ォキソ基、（8)水酸基、（9) C1〜20アルキルォキシ基、（10) C2 〜20アルケ-ルォキシ基、（11) C2〜20アルキ-ルォキシ基、（12)環状基で保護 された水酸基、（13) C1〜20ァシルォキシ基、（14)チォキソ基、（15)メルカプト基、 (16) C1〜20アルキルチオ基、（17) C2〜20アルケ-ルチオ基、（18) C2〜20ァ ルキ-ルチオ基、（19)環状基で置換されたメルカプト基、（20) C1〜20アルキルス ルフィ-ル基、（21) C2〜20アルケ-ルスルフィエル基、（22) C2〜20アルキ-ルス ルフィ-ル基、（23)環状基で置換されたスルフィエル基、（24) C1〜20アルキルス ルホ-ル基、（25) C2〜20アルケ-ルスルホ -ル基、（26) C2〜20アルキ-ルスル ホニル基、（27)環状基で置換されたスルホニル基、（28)環状基で置換された Cl〜 20アルキルスルホ-ル基、（29)スルフィノ基、（30)スルホ基、（31)スルファモイル 基、（32) C1〜20ァシル基、（33)環状基で置換された Cl〜20ァシル基、（34)環 状基で置換されたカルボニル基、（35)力ルバモイル基、（36)シァノ基、（37)アミジ ノ基、（38) -トロ基、（39) -トロソ基、（40)イミノ基、（41)アミノ基、（42)ハロゲン原 子、（43)カルボキシ基等の置換基で置換されていてもよいということを意味する。こ れら任意の置換基は、置換可能な任意の位置に置換可能な任意の数だけ置換して いてもよい。尚、これらの置換基中、「環状基」とは、前記「炭素環」または「複素環」か ら任意の一個の水素原子を除!、てできる一価基等を意味する。 [0073] In the present specification, in the general formula (I), among the substituents exemplified in (1) to (44) as "substituents" in the "optionally substituted cyclic group", The description may be, for example, (1) C1-20 alkyl group, (2) C2-20 alkenyl group, (3) C2-20 alkynyl group, (4) C1 ~ 20 alkylidene groups, (5) cyclic groups, (6) Cl-20 alkyl groups substituted with cyclic groups, (7) oxo groups, (8) hydroxyl groups, (9) C1-20 alkyloxy groups, (10) C2- 20 alkyloxy groups, (11) C2-20 alkyloxy groups, (12) hydroxyl groups protected with cyclic groups, (13) C1-20 acyloxy groups, (14) thixo groups, (15) mercapto groups, 16) C1-20 alkylthio group, (17) C2-20 alkylthio group, (18) C2-20 alkylthio group, (19) mercapto group substituted with cyclic group, (20) C1-20 alkyls group Rufyl group, (21) C2-20a Kellsulfiel group, (22) C2-20 alkylsulfur group, (23) Sulfiel group substituted with cyclic group, (24) C1-20 alkylsulfur group, (25) C2-20 alkene -Sulfol group, (26) C2-20 alkylsulfonyl group, (27) sulfonyl group substituted with cyclic group, (28) Cl-20 alkylsulfol group substituted with cyclic group, (29 ) Sulfino group, (30) sulfo group, (31) sulfamoyl group, (32) C1-20 acyl group, (33) Cl-20 substituted with cyclic group, (34) substituted with cyclic group Carbonyl group, (35) force rumoyl group, (36) cyano group, (37) amidino group, (38) -tro group, (39) -troso group, (40) imino group, (41) amino group, ( 42) It means that it may be substituted with a substituent such as a halogen atom and (43) a carboxy group. These optional substituents are substituted by any number that can be substituted at any substitutable position. May be. Of these substituents, “cyclic group” means a monovalent group formed by removing any one hydrogen atom from the “carbocycle” or “heterocycle”.
[0074] 本明細書中、一般式 (I)において、「置換基を有していてもよい脂肪族炭化水素基 」における「脂肪族炭化水素基」としては、例えば、「C1〜20アルキル基」、「C2〜20 ァルケ-ル基」、または「C2〜20アルキ-ル基」等が挙げられる。  In the present specification, in the general formula (I), examples of the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” include “C1-20 alkyl group”. ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.
[0075] 本明細書中、一般式 (I)において、「置換基を有していてもよい脂肪族炭化水素基 」における「置換基」は、置換基であれば特に限定されない。このような「置換基」とし ては、例えば、前記「置換基を有していてもよい環状基」における「置換基」として、前 記に例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (I), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified above as the “substituent” in the “cyclic group optionally having substituent (s)”.
[0076] 本明細書中、一般式 (Π)において、「置換基を有していてもよい 5〜7員の複素環」 における「5〜7員の複素環」としては、例えば、「酸素原子、窒素原子および硫黄原 子力 選択される 1〜3個のへテロ原子を含む、 5〜7員の単環複素環」等が挙げら れる。「酸素原子、窒素原子および硫黄原子から選択される 1〜3個のへテロ原子を 含む、 5〜7員の単環複素環」としては、例えば、ピロール、イミダゾール、ピラゾール 、ピリジン、ピラジン、ピリミジン、ピリダジン、ァゼピン、ジァゼピン、フラン、ピラン、才 キセピン、チォフェン、チォピラン、チェピン、ォキサゾーノレ、イソォキサゾーノレ、チア ゾール、イソチアゾール、フラザン、ォキサジン、ォキサゼピン、ォキサジァゼピン、チ ァジン、チアゼピン、チアジアゼピン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン 、ピラゾリン、ビラゾリジン、ジヒドロピリジン、テトラヒドロピリジン、ピぺリジン、ジヒドロピ ラジン、テトラヒドロビラジン、ピぺラジン、ジヒドロピリミジン、テトラヒドロピリミジン、ノ ーヒドロピリミジン、ジヒドロピリダジン、テトラヒドロピリダジン、パーヒドロピリダジン、ジ ヒドロアゼピン、テトラヒドロアゼピン、パーヒドロアゼピン、ジヒドロジァゼピン、テトラヒ ドロジァゼピン、パーヒドロジァゼピン、ジヒドロフラン、テトラヒドロフラン、ジヒドロビラ ン、テトラヒドロピラン、ジヒドロォキセピン、テトラヒドロォキセピン、パーヒドロォキセピ ン、ジヒドロチオフ ン、テトラヒドロチオフ ン、ジヒドロチォピラン、テトラヒドロチォピ ラン、ジヒドロチェピン、テトラヒドロチェピン、パーヒドロチェピン、ジヒドロォキサゾー ル、テトラヒドロォキサゾール（ォキサゾリジン）、ジヒドロイソォキサゾール、テトラヒドロ イソォキサゾール (イソォキサゾリジン）、ジヒドロチアゾール、テトラヒドロチアゾール（ チアゾリジン）、ジヒドロイソチアゾール、テトラヒドロイソチアゾール (イソチアゾリジン） 、ジヒドロフラザン、テトラヒドロフラザン、ジヒドロォキサジン、テトラヒドロォキサジン、 ジヒドロォキサゼピン、テトラヒドロォキサゼピン、パーヒドロォキサゼピン、ジヒドロォキ サジァゼピン、テトラヒドロォキサジァゼピン、パーヒドロォキサジァゼピン、ジヒドロチ ァジン、テトラヒドロチアジン、ジヒドロチアゼピン、テトラヒドロチアゼピン、パーヒドロチ ァゼピン、ジヒドロチアジアゼピン、テトラヒドロチアジアゼピン、パーヒドロチアジアゼ ピン、モルホリン、チオモルホリン、ォキサチアン、ジォキソラン、ジォキサン、ジチオラ ン、ジチアン等が挙げられる。 In the present specification, in the general formula (Π), the “5- to 7-membered heterocycle” in the “optionally substituted 5- to 7-membered heterocycle” includes, for example, “oxygen” Atoms, nitrogen atoms and sulfur atomic forces, including 5 to 7-membered monocyclic heterocycles containing 1 to 3 selected heteroatoms. Examples of the “5- to 7-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom” include pyrrole, imidazole, pyrazole, pyridine, pyrazine and pyrimidine. , Pyridazine, azepine, diazepine, furan, pyran, age xepin, thiophene, thiopiran, chepin, oxazonole, isoxazolene, thiazole, isothiazole, furazane, oxazine, oxazepine, oxadiazepine, thiazine, thiazepine, thiazepine, pyrroline , Pyrrolidine, imidazoline, imidazolidine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydrobiazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, no Hydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydroviran, tetrahydropyran , Dihydrooxepin, tetrahydroxepin, perhydroxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrochepin, tetrahydrochepin, perhydrochepin, dihydrox Xazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tet Hydro thiazole ( Thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxazine, tetrahydrooxazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine , Dihydroxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazine, tetrahydrothiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiazepine, perhydrothiazepine And hydrothiadiazepine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane and the like.
[0077] 本明細書中、一般式 (Π)において、「置換基を有していてもよい 5〜7員の複素環」 における「置換基」は、置換基であれば特に限定されない。このような「置換基」として は、例えば、前記一般式 (I)の「置換基を有して 、てもよ 、環状基」における「置換基 」として例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (基), the “substituent” in the “optionally substituted 5- to 7-membered heterocycle” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). It is done.
[0078] 本明細書中、一般式 (Π)において、「置換基を有していてもよい脂肪族炭化水素基 」における「脂肪族炭化水素基」としては、例えば、「C1〜20アルキル基」、「C2〜20 ァルケ-ル基」、または「C2〜20アルキ-ル基」等が挙げられる。  In the present specification, in the general formula (Π), the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” includes, for example, “C1-20 alkyl group” ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.
[0079] 本明細書中、一般式 (Π)において、「置換基を有していてもよい脂肪族炭化水素基 」における「置換基」は、置換基であれば特に限定されない。このような「置換基」とし ては、例えば、前記一般式 (I)の「置換基を有していてもよい環状基」における「置換 基」として例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (ii), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). .
[0080] 本明細書中、一般式 (Π)において、「置換基を有していてもよい環状基」としては、 例えば、前記一般式 (I)の「置換基を有して 、てもよ 、環状基」として例示したものと 同様のもの等が挙げられる。  In the present specification, in the general formula (Π), examples of the “cyclic group optionally having a substituent” include, for example, “having a substituent” in the general formula (I). Examples include those similar to those exemplified as “cyclic group”.
[0081] 本明細書中、一般式 (Π)において、「置換されていてもよいアミノ基」としては、無置 換のもの、いわゆるァミノ基の他、任意の置換基によって 1個または 2個置換されたァ ミノ基等が挙げられる。このようなアミノ基としては、例えば、（Cl〜8アルキル)スルホ -ルァミノ基（例えば、メチルスルホ -ルアミ入ェチルスルホ -ルアミ入プロピルスル ホニルアミ入ブチルスルホニルァミノ、ペンチルスルホニルアミ入へキシルスルホニ ルァミノ、へプチルスルホ -ルアミ入ォクチルスルホ -ルァミノ基およびその異性体 等）、 5〜7員複素環 (Cl〜6アルカノィル)アミノ基 (例えば、ピリジルメチルカルボ- ルァミノ基等）、 5〜7員複素環カルボ-ルァミノ基 (例えば、フロイル、テノィル、ニコ チノィル基等）、 C5〜7炭素環（Cl〜6アルカノィル）アミノ基（例えば、ベンジルカル ボ-ルァミノ基等）、 C5〜7炭素環カルボ-ルァミノ基 (例えば、ベンゾィルアミノ基等 ) , N, N—ジ— Cl〜4アルキル力ルバモイルァミノ基（例えば、 N, N—ジメチルカル バモイルアミ入 N, N—ジェチルカルバモイルアミ入 N, N—ジプロピル力ルバモイ ルァミノ、 N, N—ジブチルカルバモイルァミノ基等）、 N— C1〜4アルキルカルバモ ィルァミノ基（例えば、 N—メチルカルバモイルアミ入 N—ェチルカルバモイルァミノ 、 N—プロピル力ルバモイルアミ入 N—イソプロピル力ルバモイルアミ入 N—ブチル 力ルバモイルァミノ基等）、 N—ァシル—N— (じ1〜6ァルキル）ァミノ基（基中のじ1 〜6アルキルとしては例えば、メチル、ェチル、プロピル、ブチル、ペンチル、へキシ ル等）、 N—ァリール— N— (Cl〜6アルキル）アミノ基（例えば、 N—フエ-ル— N— メチルアミ入 N—フエ二ルー N—ェチルアミ入 N—フエ二ルー N—プロピルアミ入 N —フエ-ルー N—ブチルアミ入 N—フエ-ルー N—ペンチルアミ入 N—フエ-ルー N—へキシルァミノ基等）、 N—炭素環ァミノ基 (例えば、シクロへキシルアミ入フエ二 ルアミ入ジフヱ-ルアミ入ブトキシフヱ-ルァミノ基等）、 N—複素環ァミノ基 (例えば 、 N—ピリジルアミ入 N—キノリルアミノ基等）、ァシルァミノ基（例えば、 Cl〜8アル力 ノィルァミノ基（例えば、ァセチルアミ入プロパノィルアミ入ブチリルアミ入バレリル アミ入へキサノィルアミ入ヘプタノィルアミ入オタタノィルアミ入ビバロイルァミノ基 およびその異性体等）等）、アミノ基、ァリールスルホニルァミノ基 (例えば、フ ニルス ルホ -ルァミノ、 p—トルエンスルホ -ルァミノ基等）、アルキルスルホ -ルァミノ基（例 えば、メチルスルホ -ルアミ入ェチルスルホ -ルアミ入ベンジルスルホ -ルァミノ基 等）、力ルバモイル（Cl〜10アルキル）アミノ基（例えば、 1—力ルバモイル—（2—シ クロへキシル）ェチルァミノ基等）、力ルバモイルァミノ基、モノ—またはジ—（ci〜10 アルキル）アミノ基（例えば、メチルァミノ、ェチルァミノ、 n—プロピルアミ入イソプロピ ルァミノ、 n—ブチルアミ入イソブチルアミ入 tert—ブチルアミ入 n—ペンチルァミノ 、イソペンチルアミ入ネオペンチルアミ入 n—へキシルアミ入ヘプチルアミ入オタ チルァミノ、ジメチルアミ入ジェチルアミ入ジプロピルアミ入ジイソプロピルアミ入ジ ブチルアミ入ジペンチルアミ入ジへキシルァミノ、ジヘプチルァミノ、ジォクチルアミ 入ェチルメチルアミ入メチルプロピルアミ入ェチルプロピルアミ入 N—ブチルー N —シクロへキシルメチルァミノ基等）、モノ—またはジ—（C6〜10ァリール)アミノ基（ 例えば、フエニルァミノ、ジフヱ-ルァミノ基等）、炭化水素基で置換されたスルホ-ル アミノ基 (例えば、メチルスルホニルァミノ基等）、炭素原子と 1個の窒素原子以外に 酸素原子、硫黄原子、窒素原子等力 選ばれたヘテロ原子を 1〜3個含んでいても よい 3〜6員の環状アミノ基（例えば、ァチリジ -ル、ァゼチジュル、ピロリジ -ル、ピロ リニル、ピロリル、イミダゾリル、ビラゾリル、イミダゾリジニル、ピペリジ入モルホリノ、ジ ヒドロピリジル、ピリジル、 N—メチルビペラジ-ル、 N—ェチルビペラジ-ル基等）等 が挙げられる。 In the present specification, in the general formula (Π), the “optionally substituted amino group” is an unsubstituted one, so-called an amino group, or one or two groups depending on an arbitrary substituent. Examples thereof include a substituted amino group. Such amino groups include, for example, (Cl-8 alkyl) sulfo-lumamino groups (eg, methylsulfo-amino-substituted ethyl sulfo-amino-containing propylsulfonyl-containing butylsulfonylamino, pentylsulfonylamino-containing hexylsulfonylamino, heptyl sulfone). -Luamine-octylsulfo-luamino group and its isomers Etc.), 5- to 7-membered heterocyclic (Cl-6 alkanoyl) amino group (for example, pyridylmethylcarbolamino group), 5- to 7-membered heterocyclic carboamino group (for example, furoyl, tenol, nicotinol group, etc.) ), C5-7 carbocyclic (Cl-6 alkanoyl) amino groups (eg, benzylcarboamino groups, etc.), C5-7 carbocyclic carboamino groups (eg, benzoylamino groups, etc.), N, N-di-Cl ~ 4 alkyl strength ruberamoylamino groups (for example, N, N-dimethylcarbamoylami group N, N-jetylcarbamoylami group N, N-dipropyl power ruberamoylamino, N, N-dibutylcarbamoylamino group, etc.), N- C1 ~ 4 alkyl carbamoylamino groups (for example, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propyl, rubamoylami, N-isopropyl, rubamoylami) N-butyl-powered ruberamoylamino group, etc.), N-acyl-N- (1-6 alkyl) amino groups (1-6 alkyl in the group include, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl) Etc.), N-aryl-N— (Cl-6 alkyl) amino group (for example, N-phenyl-N-methylamino N-phenyl N-ethylamino N-phenyl N-propylamino N — Phenyl-N-butylamino N-Fellow N-Pentylami-containing N-Fellow-N-Hexylamino group, etc., N-Carbocyclic amino group (eg, Cyclohexylami-modified phenyl-containing diphenylamine) Butoxyphen-lamino group, etc.), N-heterocyclic amino group (eg, N-pyridylamino-containing N-quinolylamino group, etc.), islamamino group (eg, Cl-8 alkyl group, such as acetylamino-containing propanolamine group) Butylylamino valeryl amide hexanol amide heptanoyl amide otatanyl amide bivalylamino groups and isomers thereof, etc.), amino groups, aryl sulfonylamino groups (eg, phenylsulfolamino, p-toluenesulfo-lumino groups, etc.) ), Alkylsulfo-ramino groups (for example, methylsulfo-l-amino-substituted ethylsulfo-l-amino-containing benzylsulfo-lamino groups, etc.), rubamoyl (Cl-10 alkyl) amino groups (for example, 1-force rubamoyl- (2-cyclo) (Hexyl) ethylamino group, etc.), strong ruberamoylamino group, mono- or di- (ci-10 alkyl) amino group (eg methylamino, ethylamino, n-propylamino-containing isopropylamino, n-butylamido-isobutylamido tert-butylamido-containing) n-pentylamino, isopen Ruami input Neopenchiruami input n- to Kishiruami input Hepuchiruami input OTA Chiruamino, dimethylaminopyridine input Jechiruami input Jipuropiruami input diisopropyl amino Nyuji Dibutylamino, diheptylamino, dioctylamino, dioctylami, methylpropylami, methylpropylami, and ethylpropylamino, N-butyl-N—cyclohexylmethylamino, etc.), mono- or di- (C6-10 aryl) An amino group (eg, phenylamino, diphenyl-lumino group, etc.), a sulfolamino group substituted with a hydrocarbon group (eg, methylsulfonylamino group, etc.), an oxygen atom in addition to a carbon atom and one nitrogen atom, Sulfur atom, nitrogen atom, etc. 3 to 6 membered cyclic amino group which may contain 1 to 3 selected heteroatoms (eg, acetylidyl, azetidyl, pyrrolidyl, pyrrolinyl, pyrrolyl, imidazolyl, Virazolyl, imidazolidinyl, piperidinated morpholino, dihydropyridyl, pyridyl, N-methylbiperazi- And N-ethylbiperazyl group).
[0082] 本明細書中、一般式 (Π)において、 R2—2が表す「置換基」は、置換基であれば特に 限定されない。このような「置換基」としては、例えば、前記一般式 (I)の「置換基を有 していてもよい環状基」における「置換基」として例示したものと同様のもの等が挙げ られる。 During [0082] this specification, in the general formula (Π), R 2 - 2 "substituent" represented by is not particularly limited as long as it is a substituent. Examples of such “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I).
[0083] 本明細書中、一般式 (ΠΙ)において、「置換基を有していてもよい脂肪族炭化水素 基」における「脂肪族炭化水素基」としては、例えば、「C1〜20アルキル基」、「C2〜 20ァルケ-ル基」、または「C2〜20アルキ-ル基」等が挙げられる。  In the present specification, in the general formula (ΠΙ), the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group optionally having a substituent” includes, for example, “C1-20 alkyl group” ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.
[0084] 本明細書中、一般式 (ΠΙ)において、「置換基を有していてもよい脂肪族炭化水素 基」における「置換基」は、置換基であれば特に限定されない。このような「置換基」と しては、例えば、前記一般式 (I)の「置換基を有していてもよい環状基」における「置 換基」として例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (ii), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). Can be mentioned.
[0085] 本明細書中、一般式 (ΠΙ)において、「置換基を有していてもよいアルコキシ基」に おける「アルコキシ基」としては、例えば、「C1〜20アルコキシ基」等が挙げられる。  In the present specification, in the general formula (基), examples of the “alkoxy group” in the “optionally substituted alkoxy group” include “C1-20 alkoxy group” and the like. .
[0086] 本明細書中、一般式 (ΠΙ)において、「置換基を有していてもよいアルコキシ基」に おける「置換基」は、置換基であれば特に限定されない。このような「置換基」としては 、例えば、前記一般式 (I)の「置換基を有していてもよい環状基」における「置換基」と して例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (基), the “substituent” in the “alkoxy group which may have a substituent” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). It is done.
[0087] 本明細書中、一般式 (III)において、 R1—3および R3—3が表す「置換基を有していて もよい環状基」としては、例えば、前記一般式 (I)の「置換基を有していてもよい環状 基」として例示したものと同様のもの等が挙げられる。 In this specification, in the general formula (III), R 1 — 3 and R 3 — 3 represent “having a substituent. Examples of the “optional cyclic group” include those similar to those exemplified as the “cyclic group optionally having substituent (s)” in the general formula (I).
[0088] 本明細書中、一般式 (ΠΙ)において、環 Dが表す「置換基を有していてもよいフエ- ル基」における「置換基」は、置換基であれば特に限定されない。このような「置換基」 としては、例えば、前記一般式 (I)の「置換基を有していてもよい環状基」における「置 換基」として例示したものと同様のもの等が挙げられる。  [0088] In the present specification, in the general formula (「), the" substituent "in the" optionally substituted phenyl group "represented by ring D is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). .
[0089] 本明細書中、一般式 (III)において、 R2—3および X1—3が表す「置換基」は、置換基 であれば特に限定されない。このような「置換基」としては、例えば、前記一般式 (I)のDuring [0089] this specification, in the general formula (III), R 2 - 3 and X 1 - 3 represent "substituent" is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those represented by the general formula (I).
「置換基を有して 、てもよ 、環状基」における「置換基」として例示したものと同様のも の等が挙げられる。 Examples thereof include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent.
[0090] 本明細書中、一般式 (IV)において、「置換基を有していてもよいアルキル基」にお ける「アルキル基」としては、例えば、「C1〜20アルキル基」等が挙げられる。  In the present specification, in the general formula (IV), examples of the “alkyl group” in the “optionally substituted alkyl group” include “C1-20 alkyl group” and the like. It is done.
[0091] 本明細書中、一般式 (IV)において、「置換基を有していてもよいアルキル基」にお ける「置換基」は、置換基であれば特に限定されない。このような「置換基」としては、 例えば、前記一般式 (I)の「置換基を有して 、てもよ 、環状基」における「置換基」とし て例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (IV), the “substituent” in the “alkyl group optionally having substituent (s)” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). Can be mentioned.
[0092] 本明細書中、一般式 (IV)において、 E、 R2—4および R4—4が表す「置換基を有して いてもよい環状基」としては、例えば、前記一般式 (I)の「置換基を有していてもよい 環状基」として例示したものと同様のもの等が挙げられる。 In the present specification, in the general formula (IV), the “cyclic group optionally having substituent (s)” represented by E, R 2 — 4 and R 4 — 4 includes, for example, the above general formula ( Examples thereof include those similar to those exemplified as the “optionally substituted cyclic group” in I).
[0093] 本明細書中、一般式 (IV)において、
Figure imgf000033_0001
R3—4および R4—4が表す「置換基を有し ていてもよい脂肪族炭化水素基」における「脂肪族炭化水素基」としては、例えば、「 Cl〜20アルキル基」、「C2〜20アルケ-ル基」、または「C2〜20アルキ-ル基」等 が挙げられる。 [0093] In the present specification, in the general formula (IV),
Figure imgf000033_0001
R 3 - 4 and R 4 - 4 "aliphatic hydrocarbon group" of the "aliphatic optionally substituted hydrocarbon group" represented by, for example, "Cl~20 alkyl group", "C2 -20 alkyl group "or" C2-20 alkyl group ".
[0094] 本明細書中、一般式 (IV)において、「置換基を有していてもよい脂肪族炭化水素 基」における「置換基」は、置換基であれば特に限定されない。このような「置換基」と しては、例えば、前記一般式 (I)の「置換基を有していてもよい環状基」における「置 換基」として例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (IV), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). Can be mentioned.
[0095] 本明細書中、一般式 (IV)において、「置換基を有していてもよいアルコキシ基」に おける「アルコキシ基」としては、例えば、「C1〜20アルコキシ基」等が挙げられる。 [0095] In the present specification, in the general formula (IV), "optionally substituted alkoxy group" Examples of the “alkoxy group” include “C1-20 alkoxy group” and the like.
[0096] 本明細書中、一般式 (IV)において、「置換基を有していてもよいアルコキシ基」に おける「置換基」は、置換基であれば特に限定されない。このような「置換基」としては 、例えば、前記一般式 (I)の「置換基を有していてもよい環状基」における「置換基」と して例示したものと同様のもの等が挙げられる。 In the present specification, in the general formula (IV), the “substituent” in the “optionally substituted alkoxy group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). It is done.
[0097] 本明細書中、一般式 (IV)において、「置換されていてもよいアミノ基」としては、無 置換のもの、いわゆるァミノ基の他、任意の置換基によって 1個または 2個置換された アミノ基等が挙げられる。このようなアミノ基としては、例えば、前記一般式 (Π)の「置 換されていてもよいアミノ基」として例示したものと同様のもの等が挙げられる。  In the present specification, in the general formula (IV), the “optionally substituted amino group” is an unsubstituted one, that is, a so-called amino group, or one or two substituents by an arbitrary substituent. Amino groups and the like. Examples of such an amino group include those similar to those exemplified as the “optionally substituted amino group” in the general formula (IV).
[0098] 本明細書中、一般式 (IV)において、 R5—4が表す「置換基」は、置換基であれば特 に限定されない。このような「置換基」としては、例えば、前記一般式 (I)の「置換基を 有して 、てもよ 、環状基」における「置換基」として例示したものと同様のもの等が挙 げられる。 During [0098] this specification, in the general formula (IV), R 5 - 4 represent "substituent" is not limited especially if it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). I can get lost.
[0099] 本明細書中、「ハロゲン原子」とは、塩素原子、臭素原子、フッ素原子、ヨウ素原子 を意味する。  In this specification, “halogen atom” means a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom.
[0100] 本明細書中、「C1〜20アルキル基」とは、メチル、ェチル、プロピル、ブチル、ペン チル、へキシル、ヘプチル、ォクチル、ノエル、デシル、ゥンデシル、ドデシル、トリデ シル、テトラデシル、ペンタデシル、へキサデシル、ヘプタデシル、ォクタデシル、ノナ デシル、ィコシル基およびそれらの異性体基を意味する。  In the present specification, “C1-20 alkyl group” means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Noel, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl Hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl groups and their isomer groups.
[0101] 本明細書中、「C1〜8アルキル基」とは、メチル、ェチル、プロピル、ブチル、ペンチ ル、へキシル、ヘプチル、ォクチル基およびそれらの異性体基を意味する。  [0101] In the present specification, the "C1-8 alkyl group" means a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.
[0102] 本明細書中、「C2〜20アルケ-ル基」とは、ェテュル、プロべ-ル、ブテニル、ペン テュル、へキセ -ル、ヘプテュル、オタテュル、ノネ-ル、デセ -ル、ゥンデセ -ル、ド デセ -ル、トリデセニル、テトラデセ-ル、ペンタデセ -ル、へキサデセ -ル、ヘプタ デセニル、ォクタデセニル、ノナデセニル、ィコセ-ル基およびそれらの異性体基を 意味する。  [0102] In the present specification, "C2-20 alkyl group" refers to ethyl, probe, butenyl, pentyl, hexyl, heptul, otatur, nonel, decel, It means undecyl, dodecyl, tridecenyl, tetradecyl, pentadecyl, hexadecyl, heptadecenyl, octadecenyl, nonadecenyl, icosyl groups and their isomeric groups.
[0103] 本明細書中、「C2〜20アルキ-ル基」とは、ェチニル、プロビュル、ブチュル、ペン チニノレ、へキシュノレ、へプチ-ノレ、ォクチ-ノレ、ノ--ノレ、デシ-ノレ、ゥンデシ-ノレ、 ドデシ-ル、トリデシニル、テトラデシ-ル、ペンタデシュル、へキサデシ-ル、ヘプタ デシニル、ォクタデシ-ル、ノナデシニル、ィコシニル基およびそれらの異性体基を 意味する。 [0103] In the present specification, the "C2-20 alkyl group" means ethynyl, probule, butur, pentininore, hexnore, hept-nore, octinore, no-nore, decinore, Undeshi Nore, It means dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecynyl, icosinyl groups and their isomeric groups.
[0104] 本明細書中、「C1〜20アルキリデン基」とは、メチリデン、ェチリデン、プロピリデン 、ブチリデン、ペンチリデン、へキシリデン、ヘプチリデン、オタチリデン、ノ-リデン、 デシリデン、ゥンデシリデン、ドデシリデン、トリデシリデン、テトラデシリデン、ペンタデ シリデン、へキサデシリデン、ヘプタデシリデン、ォクタデシリデン、ノナデシリデン、ィ コシリデン基およびこれらの異性体基を意味する。  In the present specification, the “C1-20 alkylidene group” means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, otatilidene, no-lidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentade It means a silidene, hexadecylidene, heptadecylidene, octadecidylidene, nonadecylidene, icosilidene group and isomer groups thereof.
[0105] 本明細書中、「C1〜20アルキルォキシ基」とは、メトキシ、エトキシ、プロポキシ、ブ トキシ、ペンチルォキシ、へキシルォキシ、ヘプチルォキシ、ォクチルォキシ、ノニル ォキシ、デシルォキシ、ゥンデシルォキシ、ドデシルォキシ、トリデシルォキシ、テトラ デシルォキシ、ペンタデシルォキシ、へキサデシルォキシ、ヘプタデシルォキシ、ォ クタデシルォキシ、ノナデシルォキシ、ィコシルォキシ基およびそれらの異性体基を 意味する。  [0105] In the present specification, the "C1-20 alkyloxy group" means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, It means pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy groups and their isomer groups.
[0106] 本明細書中、「C2〜20アルケ-ルォキシ基」とは、ェテュルォキシ、プロべ-ルォ キシ、ブテニルォキシ、ペンテニルォキシ、へキセニルォキシ、ヘプテニルォキシ、ォ クテニルォキシ、ノネ-ルォキシ、デセ -ルォキシ、ゥンデセ -ルォキシ、ドデセ-ル ォキシ、トリデセ -ルォキシ、テトラデセ -ルォキシ、ペンタデセ -ルォキシ、へキサ デセニルォキシ、ヘプタデセ -ルォキシ、ォクタデセ -ルォキシ、ノナデセ-ルォキ シ、ィコセニルォキシ基およびそれらの異性体基を意味する。  [0106] In the present specification, the "C2-20 alkoxy group" refers to ethuroxy, propyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, none-loxy, dec-loxy, undec It means -loxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecenyloxy, heptadecyloxy, octadecyloxy, nonadeceroxy, icocenyloxy and their isomeric groups.
[0107] 本明細書中、「C2〜20アルキ-ルォキシ基」とは、ェチュルォキシ、プロピ -ルォ キシ、ブチニルォキシ、ペンチニルォキシ、へキシュルォキシ、へプチニルォキシ、ォ クチ-ルォキシ、ノ- -ルォキシ、デシ-ルォキシ、ゥンデシ-ルォキシ、ドデシ-ル ォキシ、トリデシ-ルォキシ、テトラデシニルォキシ、ペンタデシュルォキシ、へキサデ シニルォキシ、ヘプタデシュルォキシ、ォクタデシ-ルォキシ、ノナデシ-ルォキシ、 ィコシ-ルォキシ基およびそれらの異性体基を意味する。  [0107] In the present specification, the "C2-20 alkyloxy group" means ethuroxy, propoxy, butynyloxy, pentynyloxy, hexyloxy, heptynyloxy, octyloxy, nitro-oxy, decoxyloxy. , Undecyloxy, dodecyloxy, tridecyloxy, tetradecynyloxy, pentadecyloxy, hexadecinyloxy, heptadesuloxy, octadecyloxy, nonadecyloxy, icosyloxy and their isomerism It means body group.
[0108] 本明細書中、「C1〜20アルキルチオ基」とは、メチルチオ、ェチルチオ、プロピル チォ、ブチルチオ、ペンチルチオ、へキシルチオ、へプチルチオ、ォクチルチオ、ノ 二ルチオ、デシルチオ、ゥンデシルチオ、ドデシルチオ、トリデシルチオ、テトラデシ ルチオ、ペンタデシルチオ、へキサデシルチオ、ヘプタデシルチオ、ォクタデシルチ ォ、ノナデシルチオ、ィコシルチオ基およびそれらの異性体基を意味する。 In the present specification, the “C1-20 alkylthio group” means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, no It means diruthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadecylthio, octadecylthio, nonadecylthio, icosylthio groups and isomeric groups thereof.
[0109] 本明細書中、「C2〜20アルケ-ルチオ基」とは、エテュルチオ、プロべ-ルチオ、 ブテニルチオ、ペンテ二ルチオ、へキセニルチオ、ヘプテニルチオ、ォクテ二ルチオ 、ノネ-ルチオ、デセ-ルチオ、ゥンデセ-ルチオ、ドデセ-ルチオ、トリデセ -ルチ ォ、テトラデセ-ルチオ、ペンタデセ二ルチオ、へキサデセ-ルチオ、ヘプタデセ二 ルチオ、ォクタデセニルチオ、ノナデセニルチオ、ィコセ二ルチオ基およびそれらの 異性体基を意味する。  [0109] In the present specification, the "C2-20 alkthio group" refers to etyrthio, probethio, butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio, nonethylthio, decthiolthio. , Undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecenylthio, hexadecenylthio, heptadecylthio, octadecenylthio, nonadecenylthio, icosenylthio and their isomeric groups means.
[0110] 本明細書中、「C2〜20アルキ-ルチオ基」とは、ェチ-ルチオ、プロピ-ルチオ、 ブチニルチオ、ペンチ二ルチオ、へキシュルチオ、へプチ二ルチオ、ォクチ二ルチオ 、ノ--ルチオ、デシ-ルチオ、ゥンデシ-ルチオ、ドデシ-ルチオ、トリデシ-ルチ ォ、テトラデシ-ルチオ、ペンタデシュルチオ、へキサデシ-ルチオ、ヘプタデシュル チォ、ォクタデシ二ルチオ、ノナデシ二ルチオ、ィコシ二ルチオ基およびそれらの異 性体基を意味する。  [0110] In the present specification, "C2-20 alkylthio group" refers to ethylthio, propylthio, butynylthio, pentynylthio, hexylthio, heptynylthio, octynylthio, no-- Ruthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadesurio, octadedecylthio, nonadecylthio, icosylthio groups and their It means an alien group.
[0111] 本明細書中、「C1〜 20アルキルスルフィエル基」とは、メチルスルフィエル、ェチル スノレフィ-ノレ、プロピノレスノレフィ-ノレ、ブチノレスノレフィ-ノレ、ペンチノレスノレフィ-ノレ、へ キシノレスノレフィ-ノレ、ヘプチノレスノレフィ-ノレ、オタチノレスノレフィ-ノレ、ノニノレスノレフィ- ル、デシルスルフィエル、ゥンデシルスルフィエル、ドデシルスルフィエル、トリデシル スルフィエル、テトラデシルスルフィ -ル、ペンタデシルスルフィ -ル、へキサデシルス ルフィニル、ヘプタデシルスルフィ -ル、ォクタデシルスルフィ -ル、ノナデシルスルフ ィニル、ィコシルスルフィ-ル基およびそれらの異性体基を意味する。  [0111] In the present specification, "C1-20 alkyl sulfier group" means methyl sulfier, ethyl snorefi-nore, propinoles norefi-nore, butinoles norefi-nore, pentinores norefi -Nore, Hexinoles Norefi-Nore, Heptinoles Norefi-Nore, Otacinores Norefi-Nore, Noninoles Norefirl, Decyl Sulfiel, Undecyl Sulfiel, Dodecyl Sulfiel, Tridecyl Means sulfiel, tetradecylsulfur, pentadecylsulfyl, hexadecylsulfinyl, heptadecylsulfuryl, octadecylsulfuryl, nonadecylsulfinyl, icosylsulfyl groups and their isomeric groups To do.
[0112] 本明細書中、「C2〜20アルケ-ルスルフィエル基」とは、エテュルスルフィエル、プ ロぺニノレスノレフィニノレ、ブテニノレスノレフィニノレ、ペンテニノレスノレフィニノレ、へキセニノレ スノレフィニノレ、ヘプテニノレスノレフィニノレ、オタテニノレスノレフィニノレ、ノネニノレスノレフィニ ル、デセニルスルフィエル、ゥンデセニルスルフィエル、ドデセニルスルフィエル、トリ デセニルスルフィ -ル、テトラデセニルスルフィ -ル、ペンタデセニルスルフィ -ル、へ キサデセニルスルフィ -ル、ヘプタデセニルスルフィ -ル、ォクタデセニルスルフィ二 ル、ノナデセ-ルスルフィエル、ィコセニルスルフィエル基およびそれらの異性体基を 意味する。 [0112] In the present specification, "C2-20 alkenylsulfier group" refers to etulsulfier, propenonolesnorefininore, buteninoresnorefininore, penteninoresnorefininore, hexenoresnorefininore, Hepteninolesnorefininole, otateninoresnorefininore, noneninoresnorefinil, decenylsulfier, undecenylsulfier, dodecenylsulfier, tridecenylsulfuryl, tetradecenyls Luffyol, pentadecenylsulfuric acid, hexadecenylsulfuric acid, heptadecenylsulfuric acid, octadecenylsulfuric acid , Nonadecyl sulfier, icosenyl sulfier group and isomers thereof.
[0113] 本明細書中、「C2〜20アルキ-ルスルフィエル基」とは、ェチ-ルスルフィエル、プ ロピニノレスノレフィニノレ、ブチニノレスノレフィニノレ、ペンチニノレスノレフィニノレ、へキシュノレ スノレフィ-ノレ、へプチ-ノレスノレフィ-ノレ、オタチ-ノレスノレフィ-ノレ、ノ-ニノレスノレフィ- ル、デシ-ルスルフィ -ル、ゥンデシ-ルスルフィ -ル、ドデシ-ルスルフィ -ル、トリ デシ-ルスルフィ -ル、テトラデシ-ルスルフィ -ル、ペンタデシュルスルフィ -ル、へ キサデシ-ルスルフィ -ル、ヘプタデシュルスルフィ -ル、ォクタデシ-ルスルフィ- ル、ノナデシ-ルスルフィ -ル、ィコシニルスルフィエル基およびそれらの異性体基を 意味する。  [0113] In the present specification, "C2-20 alkylsulfier group" refers to ethylsulfier, propyninoresnorefininore, butyninoresnorefininore, pentinoinoresnorefininore, hekisnoresnorefi-nore, Heptyl Noles Nore, Otachi Noles Nore Nore, Non-Ninoles Nore, Decyl Sulfyl, Undecyl Sulfyl, Dodecyl Sulfyl, Tridecyl Sulfyl, Tetradecyl Rusulfil, It means pentadesulfuryl, hexadecylsulfil, heptadesulfuryl, octadecylsulfil, nonadecylsulfuryl, icosinylsulfiel groups and their isomeric groups.
[0114] 本明細書中、 「C1〜20アルキルスルホ-ル基」とは、メチルスルホ -ル、ェチルス ノレホニノレ、プロピノレスノレホニノレ、ブチノレスノレホニノレ、ペンチノレスノレホニノレ、へキシノレ スノレホニノレ、ヘプチノレスノレホニノレ、ォクチノレスノレホニノレ、ノニノレスノレホニノレ、デシノレス ルホ -ル、ゥンデシルスルホ -ル、ドデシルスルホ -ル、トリデシルスルホ -ル、テトラ デシルスルホ -ル、ペンタデシルスルホ -ル、へキサデシルスルホ -ル、ヘプタデシ ノレスノレホニノレ、ォクタデシノレスノレホニノレ、ノナデシノレスノレホニノレ、ィコシノレスノレホニノレ 基およびそれらの異性体基を意味する。  [0114] In the present specification, the "C1-20 alkylsulfonyl group" means methylsulfol, ethyls norehoninole, propinolesnorehoninore, butinoresnorehoninore, pentinoresnorehoninore, Xinore, senorehoninore, heptinolesnorehoninore, octinoresnorehoninore, noninoresnorehoninore, decinolesol, undecylsulfol, dodecylsulfol, tridecylsulfol, tetradecylsulfol, It means pentadecylsulfol, hexadecylsulfol, heptadecinolesnorehoninore, octadecinoresnorehoninore, nonadecinoresnorehoninore, icosinoresnorehoninore group and isomers thereof.
[0115] 本明細書中、「C2〜20アルケ-ルスルホ -ル基」とは、エテュルスルホ -ル、プロ ぺ-ノレスノレホ-ノレ、ブテ レスノレホ-ノレ、ペンテ-ノレスノレホニノレ、へキセ-ノレスノレホ 二ノレ、へフテニノレスノレホニノレ、才クテニノレスノレホニノレ、ノ不ニノレスノレホニノレ、デで二ノレ スノレホニノレ、ゥンデセ-ノレスノレホ-ノレ、ドデセニノレスノレホ-ノレ、トリデセ-ノレスノレホ- ル、テトラデセ-ルスルホ -ル、ペンタデセニルスルホ -ル、へキサデセ-ルスルホ- ル、ヘプタデセニルスルホ -ル、ォクタデセ-ルスルホ -ル、ノナデセ-ルスルホ- ル、ィコセニルスルホ-ル基およびそれらの異性体基を意味する。  [0115] In the present specification, "C2-20 alkenylsulfol group" refers to etulsulfol, propenolesnorenore, buteresnorenore, pentenorenorenoinole, hexe- Noresnorejo Ninore, Hefteninoresnorehoninore, Taittenenoresnorehoninore, Nono Ninoresnorehoninore, Ninoreno, Undesenorejo-nore, Dodesenorenorenore, Toridese Nolesnoleol, tetradecylsulfol, pentadecenylsulfol, hexadecylsulfol, heptadecenylsulfol, octadecylsulfol, nonadecylsulfol, icocenylsulfur and These isomer groups are meant.
[0116] 本明細書中、「C2〜20アルキ-ルスルホ -ル基」とは、ェチ-ルスルホ -ル、プロ ピニノレスノレホニノレ、ブチニノレスノレホニノレ、ペンチニノレスノレホニノレ、へキシニノレスノレホ 二ノレ、ヘプチニノレスノレホニノレ、才クチニノレスノレホニノレ、ノニニノレスノレホニノレ、テン二ノレ スノレホニノレ、ゥンデシ-ノレスノレホ-ノレ、ドデシ-ノレスノレホ-ノレ、トリデシ-ノレスノレホニ ル、テトラデシ-ルスルホ -ル、ペンタデシュルスルホ -ル、へキサデシ-ルスルホ- ル、ヘプタデシュルスルホ -ル、ォクタデシ-ルスルホ -ル、ノナデシ-ルスルホ-ル 、ィコシニルスルホニル基およびそれらの異性体基を意味する。 [0116] In the present specification, "C2-20 alkylsulfol group" means ethylsulfol, propyninoresnorehoninore, butyninoresnorehoninore, pentyninoresnorehoninore, hexyl Ninoles Nore Ninore, Heptininoles Norehoninore, Kuchininores Norehoninore, Nonininores Norehoninore, Tenninore Sunorehoninore, Undeshi Noresnore Nore, Dodeci Nolesnorenore Nore , Tetradecyl sulfol, pentadecyl sulfol, hexadecyl sulfol, heptadecyl sulfol, octadecyl sulfol, nonadecyl sulfol, icosinylsulfonyl group and their isomerism It means body group.
[0117] 本明細書中、「C1〜20ァシル基」とは、メタノィル、エタノィル、プロパノィル、ブタノ ィル、ペンタノィル、へキサノィル、ヘプタノィル、オタタノィル、ノナノィル、デカノィル 、ゥンデカノィル、ドデカノィル、トリデカノィル、テトラデカノィル、ペンタデカノィル、 へキサデカノィル、ヘプタデカノィル、ォクタデカノィル、ノナデカノィル、ィコサノィル 基およびそれらの異性体基を意味する。  [0117] In the present specification, the "C1-20 acyl group" means methanol, ethanol, propanoyl, butanol, pentanoyl, hexanoyl, heptanoyl, otatanyl, nonanoyl, decanol, undecanol, tetradecanol, tridecanol, Hexadecanol, heptadecanol, octadecanol, nonadecanol, icosanol and their isomers.
[0118] 本明細書中、「C1〜20ァシルォキシ基」とは、メタノィルォキシ、エタノィルォキシ、 プロパノィルォキシ、ブタノィルォキシ、ペンタノィルォキシ、へキサノィルォキシ、へ プタノィルォキシ、オタタノィルォキシ、ノナノィルォキシ、デカノィルォキシ、ゥンデ力 ノィルォキシ、ドデカノィルォキシ、トリデカノィルォキシ、テトラデカノィルォキシ、ぺ ンタデカノィルォキシ、へキサデカノィルォキシ、ヘプタデカノィルォキシ、ォクタデカ ノィルォキシ、ノナデカノィルォキシ、ィコサノィルォキシ基およびそれらの異性体基 を意味する。  In the present specification, the “C1-20 acyloxy group” means methanoyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanooxy, hexanoyloxy, heptanoyloxy, otanoyloxy, nonanoyloxy, decanoxy, Undeoxy, dodecanoxy, tridecanoxy, tetradecanoxy, pentadecanoxy, hexadecanoyloxy, heptadecanoxy, octadecanoyloxy, nonadecanoxy, Means icosanoyloxy group and isomers thereof.
[0119] 本明細書中、一般式 (I)で示される化合物の幾何異性体とは、一般式 (Ig)  In the present specification, the geometric isomer of the compound represented by the general formula (I) is the general formula (Ig).
[0120] [0120]
Figure imgf000038_0001
Figure imgf000038_0001
[0121] [式中、 R1_lgおよび R2_lgは、それぞれ一般式 (I)における R1_1および R2_1と同じ意 味を表す。]を意味する。 [ Wherein R 1_lg and R 2_lg represent the same meaning as R 1_1 and R 2_1 in general formula (I), respectively. ] Means.
[0122] また、一般式 (I)で示される化合物、および一般式 (Ig)で示される化合物の互変異 性体とは、一般式 (It) [0122] The compound represented by the general formula (I) and the tautomer of the compound represented by the general formula (Ig) are those represented by the general formula (It).
[0123] [化 15] [0123] [Chemical 15]
Figure imgf000038_0002
[0124] [式中、 R1— "および IT "は、それぞれ一般式 (I)における R1一1および R2_1と同じ意 味を表す。 ]、および一般式 (Igt)
Figure imgf000038_0002
[Wherein R 1 — “and IT” represent the same meaning as R 1 1 1 and R 2_1 in general formula (I), respectively. ], And general formula (Igt)
[0125] [化 16] [0125] [Chemical 16]
Figure imgf000039_0001
Figure imgf000039_0001
[0126] [式中、 R1_lgtおよび R2_lgtは、それぞれ一般式 (I)における R1 _1および R2 [ Where R 1_lgt and R 2_lgt are R 1 _1 and R 2 in general formula (I), respectively.
意味を表す。]を意味する。  Represents meaning. ] Means.
[0127] 本明細書中、一般式 (I)における好ましいィ匕合物は、一般式 (IA) In the present specification, preferred compounds in the general formula (I) are represented by the general formula (IA)
[0128] [化 17] [0128] [Chemical 17]
Figure imgf000039_0002
Figure imgf000039_0002
[0129] [式中、 R1— 1Aおよび R2_ 1Aは、それぞれ国際公開第 2005/000281号パンフレットに記 載の R1および R2と同じ意味を表す。 ]で表すことができる。 [Wherein R 1 — 1A and R 2 — 1A represent the same meaning as R 1 and R 2 described in International Publication No. 2005/000281, respectively. ] Can be represented.
[0130] また、一般式 (IA)における、好ましい基や好ましいィ匕合物としては、例えば、国際 公開第 2005/000281号パンフレットに記載のそれと同様のもの、および実施例に記載 されたものを挙げることができる。 [0130] Further, examples of preferable groups and preferable compounds in general formula (IA) include those similar to those described in International Publication No. 2005/000281 and those described in Examples. Can be mentioned.
[0131] 本明細書中、一般式 (Π)における好ましい化合物は、一般式 (ΠΖ) [0131] In the present specification, preferred compounds in the general formula (Π) are represented by the general formula (ΠΖ).
[0132] [化 18]
Figure imgf000039_0003
[0132] [Chemical 18]
Figure imgf000039_0003
[0133] [式中、環 Azは前記環 Aと同じ意味を表し、環 ま置換基を有していてもよい 5〜6 員の飽和環を表し、 R1_2Zは前記 R1— 2と同じ意味を表し、 R2— 2Zは保護されていてもよ いメルカプト基を表す。 ]で表すことができる。 [Wherein ring A z represents the same meaning as ring A above, represents a 5- to 6-membered saturated ring optionally having a ring or a substituent, and R 1_2Z represents R 1 — 2 above. R 2 — 2Z represents an optionally protected mercapto group. ] Can be represented.
[0134] ここで、環 Bzが表す「置換基を有して!/、てもよ 、5〜6員の飽和環」における「5〜6 員の飽和環」としては、例えば、「5〜6員の飽和炭素環」および、「5〜6員の飽和複 素環」等が挙げられる。「5〜6員の飽和炭素環」としては、例えば、シクロペンタン、シ クロへキサン等が挙げられる。「5〜6員の飽和複素環」としては、例えば、ピロリジン、 イミダゾリジン、トリァゾリジン、テトラゾリジン、ビラゾリジン、ピぺリジン、ピぺラジン、パ ーヒドロピリミジン、パーヒドロピリダジン、テトラヒドロフラン、テトラヒドロピラン、テトラヒ ドロチォフェン、テトラヒドロチォピラン、テトラヒドロォキサゾール (ォキサゾリジン）、テ トラヒドロイソォキサゾール (イソォキサゾリジン）、テトラヒドロチアゾール（チアゾリジン )、テトラヒドロイソチアゾール (イソチアゾリジン）、テトラヒドロフラザン、テトラヒドロォキ サジァゾーノレ（ォキサジァゾリジン）、テトラヒドロォキサジン、テトラヒドロォキサジアジ ン、テトラヒドロチアジアゾール（チアジアゾリジン）、テトラヒドロチアジン、テトラヒドロ チアジアジン、モルホリン、チオモルホリン、ォキサチアン等が挙げられる。 [0134] here, represented by the ring B z "have a substituent! /, Even I, saturated ring of 5- to 6-membered,""5-6 in Examples of the “membered saturated ring” include “5- to 6-membered saturated carbocycle” and “5- to 6-membered saturated complex ring”. Examples of the “5- to 6-membered saturated carbocycle” include cyclopentane, cyclohexane and the like. Examples of the “5- to 6-membered saturated heterocyclic ring” include pyrrolidine, imidazolidine, triazolidine, tetrazolidine, virazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene. , Tetrahydrothipyran, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrosazazonole ( Oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydro Ajiajin, morpholine, thiomorpholine, Okisachian and the like.
[0135] 環 Bzが表す「置換基を有して 、てもよ 、5〜6員の飽和複素環」における「置換基」 は、置換基であれば特に限定されない。このような「置換基」としては、例えば、前記 一般式 (I)の「置換基を有して 、てもよ 、環状基」における「置換基」として例示したも のと同様のもの等が挙げられる。 [0135] represented Ring B z "substituent" in the "substituted, also O, 5-6 membered saturated heterocyclic ring" is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). Can be mentioned.
[0136] R2_2Zが表す「保護されていてもよいメルカプト基」としては、メルカプト基の他、例え ば、置換基を有していてもよい脂肪族炭化水素基で保護されたメルカプト基、置換基 を有していてもよい環状基で保護されたメルカプト基等が挙げられる。ここで、メルカ ブト基の保護に用いられる「置換基を有して 、てもよ 、脂肪族炭化水素基」や「置換 基を有して 、てもよ 、環状基」は、前記一般式 (I)の「置換基を有して 、てもよ 、脂肪 族炭化水素基」や「置換基を有して 、てもよ 、環状基」における「置換基」としてそれ ぞれ例示したものと同様のもの等が挙げられる。 [0136] The " optionally protected mercapto group" represented by R 2_2Z includes, in addition to mercapto groups, for example, mercapto groups protected with aliphatic hydrocarbon groups which may have substituents, substituted And a mercapto group protected with a cyclic group which may have a group. Here, “having a substituent, may be an aliphatic hydrocarbon group” or “having a substituent, may be a cyclic group” used for protecting a mercapto group is the above general formula. Examples of “substituent” in (I) “having a substituent, may be an aliphatic hydrocarbon group” or “having a substituent, but may be a cyclic group” And the like.
[0137] 本明細書中、一般式 (Π)におけるさらに好ましい化合物は、一般式 (ΠΒ)  [0137] In the present specification, a more preferable compound in the general formula (Π) is represented by the general formula (ΠΒ).
[0138] [化 19]  [0138] [Chemical 19]
Figure imgf000040_0001
[0139] [式中、 R1_2B、 R2_2B、 R3_2B、 R4_2B、および X2Bは、それぞれ国際公開第 99/05144 号パンフレットに記載の R1 R2、 R3、 R4、および Xと同じ意味を表す。 ]、一般式 (IIC)
Figure imgf000040_0001
[0139] [wherein R 1_2B , R 2_2B , R 3_2B , R 4_2B , and X 2B are R 1 R 2 , R 3 , R 4 , and X described in WO99 / 05144, respectively. Represents the same meaning. ], General formula (IIC)
[0140] [化 20] [0140] [Chemical 20]
Figure imgf000041_0001
Figure imgf000041_0001
[0141] [式中、 R1— 、 R2— 、 R3_2し、および R4_2Cは、それぞれ国際公開第 01/19826号パ ンフレットに記載の R1 R2、 R3、および R4と同じ意味を表す。 ]、一般式 (IID) [0141] [wherein R 1 —, R 2 —, R 3_2 and R 4_2C are the same as R 1 R 2 , R 3 and R 4 described in WO 01/19826 pamphlet, respectively. Represents meaning. ], General formula (IID)
[0142] [化 21]  [0142] [Chemical 21]
Figure imgf000041_0002
Figure imgf000041_0002
[0143] [式中、 R1_2D、 R2_2D、 R3_2D、および R4_2Dは、それぞれ国際公開第 01/36421号パ ンフレットに記載の R1 R2、 R3、および R4と同じ意味を表す。 ]、一般式 (ΠΕ) [0143] [wherein R 1_2D , R 2_2D , R 3_2D , and R 4_2D represent the same meaning as R 1 R 2 , R 3 , and R 4 described in WO 01/36421 pamphlet, respectively. . ], General formula (ΠΕ)
[0144] [化 22]  [0144] [Chemical 22]
Figure imgf000041_0003
Figure imgf000041_0003
[0145] [式中、 R1_2E、 R2_2E、および R3_2Eは、それぞれ国際公開第 01/36438号パンフレット
Figure imgf000041_0004
R2、および R3と同じ意味を表す。 ]、一般式 (IIF) [0145] [wherein R 1_2E , R 2_2E , and R 3_2E are WO 01/36438 pamphlets, respectively.
Figure imgf000041_0004
R 2 and R 3 have the same meaning. ], General formula (IIF)
[0146] [化 23]  [0146] [Chemical 23]
Figure imgf000041_0005
Figure imgf000041_0005
[0147] [式中、 R1_2F、 R2_2F、 R3_2F、 R4_2F、 R5_2F、および R6_2Fは、それぞれ国際公開第 9 9/41254号パンフレットに記載の
Figure imgf000042_0001
R5、および R6と同じ意味を表す。 ] 、および一般式 (IIG) [0147] [wherein R 1_2F , R 2_2F , R 3_2F , R 4_2F , R 5_2F , and R 6_2F are As described in the 9/41254 pamphlet
Figure imgf000042_0001
R 5 and R 6 have the same meaning. ], And general formula (IIG)
[0148] [化 24] [0148] [Chemical 24]
Figure imgf000042_0002
Figure imgf000042_0002
[0149] [式中、 R1_2G R2_2G R3 R4 および R2Gが表す基の意味は、それぞれ国際 公開第 00/34283号パンフレットに記載の R1 R2 R3 R4、および Rと同じ意味を表す 。 ]で表すことができる。 [0149] [wherein, R 1_2G R 2_2G R 3 R 4 and R 2G have the same meaning as R 1 R 2 R 3 R 4 and R described in WO 00/34283, respectively. Represents meaning. ] Can be represented.
[0150] また、一般式 (IIB) (IIC) (IID) （ΠΕ) (IIF) (IIG)、における、好まし 、基や 好ましい化合物としては、それぞれ、国際公開第 99/05144号パンフレット、国際公開 第 01/19826号パンフレット、国際公開第 01/36421号パンフレット、国際公開第 01/36 438号パンフレット、国際公開第 99/41254号パンフレット、および国際公開第 00/3428 3号パンフレットに記載のそれと同様のもの、および実施例に記載されたものを挙げる ことができる。  [0150] In addition, as preferred, groups and preferred compounds in the general formulas (IIB) (IIC) (IID) (ΠΕ) (IIF) (IIG), respectively, International Publication No. 99/05144 pamphlet, International Publication 01/19826, International Publication 01/36421, International Publication 01/36, 438, International Publication 99/41254, and International Publication 00/3428 3, The same thing and what was described in the Example can be mentioned.
[0151] 本明細書中、一般式 (ΠΙ)における好ましい化合物は、一般式 (ΠΙΗ)  [0151] In the present specification, preferred compounds in the general formula (ΠΙ) are represented by the general formula (ΠΙΗ).
[0152] [化 25] [0152] [Chemical 25]
Figure imgf000042_0003
Figure imgf000042_0003
[0153] 中、 R1— 3H R2— 3H R3— 3H R4— 3H X3H X2— 3H X3— 3H X4— 3H X5— 3H、および n3 Hが表す基の意味は、
Figure imgf000042_0004
In [0153], R 1 — 3H R 2 — 3H R 3 — 3H R 4 — 3H X 3H X 2 — 3H X 3 — 3H X 4 — 3H X 5 — 3H and the meaning of the group represented by n 3 H are ,
Figure imgf000042_0004
X X2 X3 X4 X5、および nと同じ意味を表す。 ]で表すことができる。 XX 2 X 3 X 4 X 5 represents the same meaning as n. ] Can be represented.
[0154] また、一般式 (ΙΠΗ)における、好ま 、基や好ま 、ィ匕合物としては、例えば、特 開 2005-179350号公報に記載のそれと同様のもの、および実施例に記載されたもの を挙げることができる。 [0155] 本明細書中、一般式 (IV)における好ましい化合物は、一般式 (IVJ) [0154] Further, in the general formula (ii), the preferred, group, preferred, and compound are, for example, the same as those described in JP 2005-179350 A, and those described in the examples. Can be mentioned. [0155] In the present specification, preferred compounds in the general formula (IV) are represented by the general formula (IVJ).
[0156] [化 26] [0156] [Chemical 26]
Figure imgf000043_0001
Figure imgf000043_0001
[0157] [式中、 R2_4J、 R3_4J、 R4_4J、 R5_4J、 R11_4J、 R12_4J、
Figure imgf000043_0002
および が表す基の意味 は、それぞれ特開 2005- 053903号公報に記載の R2、 R3、 R4、 R5、
Figure imgf000043_0003
R12、 X、およ ひ Ύと同じ意味を表す。 ]で表すことができる。 [0157] [where R 2_4J , R 3_4J , R 4_4J , R 5_4J , R 11_4J , R 12_4J ,
Figure imgf000043_0002
The meanings of the groups represented by and are respectively R 2 , R 3 , R 4 , R 5 , described in JP-A-2005-053903,
Figure imgf000043_0003
It has the same meaning as R 12 , X, and Ύ. ] Can be represented.
[0158] また、一般式 (IVJ)における、好ま 、基や好ま 、ィ匕合物としては、例えば、特開[0158] Further, examples of preferred, group, preferred, and compound in the general formula (IVJ) include, for example,
2005-053903号公報に記載のそれと同様のもの、および実施例に記載されたものを 挙げることができる。 Examples similar to those described in JP 2005-053903 A and those described in Examples can be mentioned.
[0159] また、本発明においてはさらに、「P2Y 受容体および  [0159] Further, in the present invention, "P2Y receptor and
12 Ζまたは Ρ2Υ 受容体プロ  12 Ζ or Ρ2Υ receptor pro
14  14
ッカーとしての低分子化合物」の好ましい具体例として、例えば、クロピドグレル、チタ ロピジン、カングレロール、プラスダレル、 AZD-6140、 INS-50589、 INS-49266, AR-C 66096、 ARL-67085、 GR-144043、ロキシフィバン、 MRS2395またはそれらの塩等を挙 げることができる。これらの化合物の詳細 (例えば、構造、薬理活性、製造方法等）に ついては、公知のデータベースやインターネット等で知ることができる力 何れも P2Y 受容体のアンタゴ-ストとして開発されている、もしくは開発されていたィ匕合物であ Preferable specific examples of `` low molecular weight compound as a cker '' include, for example, clopidogrel, titaropidine, cangrelor, prasdarrel, AZD-6140, INS-50589, INS-49266, AR-C 66096, ARL-67085, GR-144043, Roxifiban, MRS2395 or their salts can be mentioned. The details of these compounds (for example, structure, pharmacological activity, production method, etc.) have been developed or developed as antagonists of P2Y receptors. It was a compound
12 12
る。  The
[0160] 尚、本発明においては、特に断わらない限り、当業者にとって明らかなように記号 [0161] [化 27]  [0160] In the present invention, unless otherwise specified, the symbol [0161] [Chemical 27]
[0162] は紙面の向こう側（すなわち OC 配置）に結合していることを表し、 [0162] indicates binding to the other side of the page (ie OC placement)
[0163] [化 28]  [0163] [Chemical 28]
[0164] は紙面の手前側（すなわち β 配置）に結合していることを表し、 [0164] represents binding to the front side of the page (ie, β configuration)
[0165] [化 29] Z [0165] [Chemical 29] Z
[0166] は、 a 配置と j8—配置の任意の比率の混合物であることを表す。  [0166] represents a mixture of the a configuration and the j8-configuration in an arbitrary ratio.
[0167] 本発明にお ヽて、一般式 (I)で示される化合物、一般式 (II)で示される化合物、一 般式 (III)で示される化合物、一般式 (IV)で示される化合物（以下、これらをまとめて 、一般式 (I)〜 (IV)で示される化合物と略記する場合がある。）、または、クロピドダレ ル、チクロピジン、カングレロール、プラスダレル、 AZD-6140、 INS-50589、 INS-49266 、 AR- C66096、 ARL- 67085、 GR- 144043、ロキシフィバン、 MRS2395といった P2Y ァ [0167] In the present invention, a compound represented by the general formula (I), a compound represented by the general formula (II), a compound represented by the general formula (III), a compound represented by the general formula (IV) (Hereinafter, these may be collectively abbreviated as the compounds represented by the general formulas (I) to (IV).), Or clopidodarrel, ticlopidine, cangrelor, plusdarrel, AZD-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, Roxyfiban, MRS2395, P2Y
12 ンタゴ-スト等の塩には、薬理学的に許容されるものすべてが含まれる。薬理学的に 許容される塩は低毒性で、かつ水溶性のものが好ましい。適当な塩として、例えば、 アルカリ金属（例えば、カリウム、ナトリウム、リチウム等）の塩、アルカリ土類金属（例え ば、カルシウム、マグネシウム等）の塩、アンモ-ゥム塩（例えば、テトラメチルアンモ -ゥム塩、テトラプチルアンモ-ゥム塩等）、有機アミン (例えば、トリェチルァミン、メ チルァミン、ェチルァミン、ジメチルァミン、シクロペンチルァミン、ベンジルァミン、フ エネチルァミン、ピぺリジン、モノエタノールァミン、ジエタノールァミン、トリス（ヒドロキ シメチル）メチルァミン、リジン、アルギニン、オル-チン、 N—メチル D グルカミン 等)の塩、酸付加物塩 (例えば、無機酸塩 (例えば、塩酸塩、臭化水素酸塩、ヨウィ匕 水素酸塩、硫酸塩、硫酸水素塩、リン酸塩、硝酸塩等）、有機酸塩 (例えば、ギ酸塩、 酢酸塩、プロピオン酸塩、トリフルォロ酢酸塩、乳酸塩、酒石酸塩、シユウ酸塩、マロ ン酸塩、コハク酸塩、フマル酸塩、リンゴ酸塩、マレイン酸塩、安息香酸塩、クェン酸 塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホ ン酸塩、イセチオン酸塩、グルクロン酸塩、ダルコン酸塩、ァスパラギン酸塩、ダルタミ ン酸塩等)等)等が挙げられる。  12 Salts such as antagonists include all pharmacologically acceptable salts. The pharmacologically acceptable salt is preferably low-toxic and water-soluble. Suitable salts include, for example, alkali metal (eg, potassium, sodium, lithium, etc.) salts, alkaline earth metal (eg, calcium, magnesium, etc.) salts, ammonium salts (eg, tetramethylammonium − Salts, tetraptylammonium salts, etc.), organic amines (eg, triethylamine, methylamine, ethylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Salts of tris (hydroxymethyl) methylamine, lysine, arginine, orthine, N-methyl D-glucamine, etc., acid adduct salts (eg, inorganic acid salts (eg, hydrochloride, hydrobromide, yowi hydrogen) Acid salt, sulfate, hydrogen sulfate, phosphate, nitrate, etc.), organic acid salt (eg formate) Acetate, propionate, trifluoroacetate, lactate, tartrate, oxalate, malonate, succinate, fumarate, malate, maleate, benzoate, citrate, Methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, darconate, aspartate, dartrate, etc.)).
[0168] 本発明において、一般式 (I)〜 (IV)で示される化合物の溶媒和物としては、例えば 、水やアルコール系溶媒 (例えば、エタノール等)等の溶媒和物が挙げられる。溶媒 和物は低毒性で、かつ水溶性のものが好ましい。尚、一般式 (I)〜(IV)で示される 化合物の溶媒和物には、前記の塩の溶媒和物も含まれる。  [0168] In the present invention, examples of the solvate of the compounds represented by the general formulas (I) to (IV) include solvates such as water and alcohol solvents (for example, ethanol and the like). Solvates preferably have low toxicity and water solubility. The solvates of the compounds represented by the general formulas (I) to (IV) include solvates of the above salts.
[0169] 一般式 (I)〜（IV)で示される化合物、または、クロピドグレル、チクロビジン、カング レロール、プラスダレル、 AZD-6140、 INS-50589、 INS-49266, AR-C66096、 ARL-670 85、 GR-144043,ロキシフィバン、 MRS2395といった P2Y アンタゴ-スト等の化合物 [0169] Compounds represented by general formulas (I) to (IV), or clopidogrel, ticlovidin, cangrelor, prasdarrel, AZD-6140, INS-50589, INS-49266, AR-C66096, ARL-670 85, GR-144043, loxifiban, MRS2395 and other compounds such as P2Y antagost
12  12
は、公知の方法を用いて、容易に前記の塩や溶媒和物に変換することができる。  Can be easily converted to the above-mentioned salts and solvates using known methods.
[0170] 本発明において、一般式 (Π)で示される化合物の N ォキシド体とは、一般式 (II) で示される化合物の窒素原子が、酸化されたものを表す。また、一般式 (II)で示され る化合物の N—ォキシド体は、さらに上記のアルカリ（土類)金属塩、アンモ-ゥム塩 、有機アミン塩、酸付加物塩となっていてもよい。  [0170] In the present invention, the N-oxide form of the compound represented by the general formula (Π) represents an oxidized nitrogen atom of the compound represented by the general formula (II). Further, the N-oxide form of the compound represented by the general formula (II) may further be an alkali (earth) metal salt, an ammonium salt, an organic amine salt, or an acid adduct salt. .
[0171] 一般式 (I)で示される化合物、一般式 (Π)で示される化合物、または一般式 (III)で 示される化合物（以下、これらをまとめて、一般式 (I)〜 (III)で示される化合物と略記 する場合がある。）のプロドラッグは、生体内において酵素や胃酸等による反応により 一般式 (I)〜 (ΠΙ)で示される化合物に変換する化合物を!、う。一般式 (I)〜 (ΠΙ)で 示される化合物のプロドラッグとしては、例えば、一般式 (Ι)〜 (ΠΙ)で示される化合物 がアミノ基を有する場合、該ァミノ基がァシル化、アルキル化、リン酸化された化合物 [0171] A compound represented by the general formula (I), a compound represented by the general formula (Π), or a compound represented by the general formula (III) (hereinafter collectively referred to as general formulas (I) to (III) The prodrug is a compound that can be converted into a compound represented by the general formulas (I) to (ΠΙ) by a reaction with an enzyme, gastric acid, or the like in a living body. As prodrugs of the compounds represented by the general formulas (I) to (ΠΙ), for example, when the compounds represented by the general formulas (Ι) to (ΠΙ) have an amino group, the amino group is acylated or alkylated. , Phosphorylated compounds
(例えば、一般式 (Ι)〜(ΠΙ)で示される化合物のァミノ基が、エイコサノィル化、ァラニ ル化、ペンチルァミノカルボ-ル化、（5—メチル 2 ォキソ 1, 3 ジォキソレン —4—ィル)メトキシカルボ-ル化、テトラヒドロフラ-ル化、ピロリジルメチル化、ピバロ ィルォキシメチル化、ァセトキシメチル化、 tert プチルイ匕されたィ匕合物等）；一般式 (I)〜 (III)で示される化合物が水酸基を有する場合、該水酸基がァシル化、アルキ ル化、リン酸化、ホウ酸ィ匕されたィ匕合物（例えば、一般式 (Ι)〜(ΠΙ)で示される化合 物の水酸基が、ァセチル化、パルミトイル化、プロパノィル化、ビバロイル化、サクシ- ル化、フマリル化、ァラニル化、ジメチルァミノメチルカルボ二ルイ匕された化合物等）； 一般式 (I)〜 (ΠΙ)で示される化合物がカルボキシ基を有する場合、該カルボキシ基 がエステル化、アミド化されたィ匕合物 (例えば、一般式 (I)〜 (III)で示される化合物 のカルボキシ基が、ェチルエステル化、フエ-ルエステル化、カルボキシメチルエス テル化、ジメチルァミノメチルエステル化、ビバロイルォキシメチルエステル化、ェトキ シカルボ-ルォキシェチルエステル化、フタリジルエステル化、（5—メチルー 2 ォ キソ 1, 3 ジォキソレンー4 ィル）メチルエステル化、シクロへキシルォキシカル ボニルェチルエステル化、メチルアミドィ匕されたィ匕合物等）等が挙げられる。これらの 化合物は公知の方法によって製造することができる。また、一般式 (i)〜(m)で示さ れる化合物のプロドラッグは、廣川書店 1990年刊「医薬品の開発」第 7卷「分子設計 」163〜198頁に記載されているような、生理的条件で一般式 (Ι)〜(ΠΙ)で示される 化合物に変化するものであってもよい。さらに、一般式 (Ι)〜(ΠΙ)で示される化合物、 または一般式 (Π)で示される化合物のプロドラッグは、前記した塩、或いは溶媒和物 (例えば、水、アルコール系溶媒 (例えば、エタノール等)等の溶媒和物等)等であつ てもよく、同位元素 (例えば、 3H、 14C、 35S、 1251等)等で標識されていてもよい。 (For example, the amino groups of the compounds represented by the general formulas (Ι) to (ΠΙ) are converted to eicosanolation, aranylation, pentylaminocarbolation, (5-methyl-2-oxo-1,3-dioxolene-4- ) Methoxy carbolation, tetrahydro fullylation, pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compounds, etc.); compounds represented by the general formulas (I) to (III) Is a hydroxylated, alkylated, phosphorylated, boric acid compound (for example, a compound represented by the general formulas (Ι) to (ΠΙ)) Acetylated, palmitoylated, propanoylated, bivalylated, succiylated, fumarylated, valanylated, dimethylaminomethyl carbonylated compounds, etc.); compounds represented by general formulas (I) to (ΠΙ) Is a carboxy group A compound in which the carboxy group is esterified or amidated (for example, the carboxy group of the compounds represented by the general formulas (I) to (III) is converted to ethyl ester, phenyl ester, carboxymethyl Esterification, Dimethylaminomethyl esterification, Bivaloyloxymethyl esterification, Ethoxycarboxetyl esterification, Phthalidyl esterification, (5-Methyl-2-oxo-1,3 Dioxolene-4-yl) methyl Esterification, cyclohexyloxy esterification, methylamidated compounds, etc.). These compounds can be produced by known methods. Also represented by general formulas (i) to (m) Prodrugs of these compounds are represented by general formulas (Ι) to (ΠΙ) under physiological conditions as described in Yodogawa Shoten 1990, “Development of Pharmaceuticals”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to a compound. Furthermore, the prodrugs of the compounds represented by the general formulas (Ι) to (ΠΙ), or the compound represented by the general formula (Π) are the salts or solvates described above (for example, water, alcohol solvents (for example, A solvate such as ethanol) or the like, or may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 1251, etc.).
[0172] 一般式 (I)で示される化合物、その幾何異性体、その互変異性体、その塩、その溶 媒和物、またはそれらのプロドラッグ、一般式 (Π)で示される化合物、その塩、その N 一才キシド体、その溶媒和物、またはそれらのプロドラッグ、一般式 (ΠΙ)で示される 化合物、その塩、またはそれらのプロドラッグ、ならびに一般式 (IV)で示される化合 物、またはその塩は、それ自体公知の方法、例えば、国際公開第 2005/000281号パ ンフレット、国際公開第 99/05144号パンフレット、国際公開第 01/19826号パンフレット 、国際公開第 01/36421号パンフレット、国際公開第 01/36438号パンフレット、国際公 開第 99/41254号パンフレット、国際公開第 00/34283号パンフレット、特開 2005-1793 50号公報、特開 2005-053903号公報等に記載された方法、これらに準ずる方法、ま たはコンプリへンシヴ 'オーガニック ·トランスフォーメーションズ：ァ ·ガイド 'トウ一'ファ ンクショナル 'グループ'プレパレーシヨンズ、セカンド 'エディション（リチャード C.ラロ ック、ンヨンワイリ ~~ ンドサンズ Inc, 1999) [Comprehensive Organic Transformation s： A Guide to Functional Group Preparations, 2nd edition (Richardし. Larock, John Wiley & Sons Inc, 1999)]に記載された方法等に従って、またはそれらの方法を適宜 組み合わせることにより製造することができる。反応の生成物は通常の精製手段、例 えば、常圧下または減圧下における蒸留、シリカゲルまたはケィ酸マグネシウムを用 いた高速液体クロマトグラフィー、薄層クロマトグラフィー、或いはカラムクロマトグラフ ィーまたは洗浄、再結晶等の方法により精製することができる。また所望によって、凍 結乾燥等の処理に付してもょ 、。  [0172] Compound represented by general formula (I), geometric isomer, tautomer, salt, solvent, or prodrug thereof, compound represented by general formula (化合物), A salt, its N-year-old xoxide, its solvate, or a prodrug thereof, a compound represented by the general formula (ΠΙ), a salt thereof, or a prodrug thereof, and a compound represented by the general formula (IV) Or a salt thereof in a manner known per se, for example, WO 2005/000281 pamphlet, WO 99/05144 pamphlet, WO 01/19826 pamphlet, WO 01/36421 pamphlet. , WO 01/36438 pamphlet, WO 99/41254 pamphlet, WO 00/34283 pamphlet, JP 2005-179350 pamphlet, JP 2005-053903 pamphlet, etc. Methods, methods similar to these, Is Comprehensive 'Organic Transformations: A Guide' Toichi 'Functional' Group 'Preparations, Second' Edition (Richard C. Laroque, Nyonwiri ~~ Sands Inc, 1999) [Comprehensive Organic Transformation s: A Guide to Functional Group Preparations, 2nd edition (Richard and Larock, John Wiley & Sons Inc, 1999)], etc., or by appropriately combining these methods. The product of the reaction can be purified by conventional purification means such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization. It can refine | purify by methods, such as. If desired, it can be subjected to freezing and drying.
[0173] 本発明で用いられる一般式 (I)で示される化合物、その幾何異性体、その互変異 性体、その塩、その溶媒和物、またはそれらのプロドラッグ、一般式 (Π)で示される化 合物、その塩、その N—ォキシド体、その溶媒和物、またはそれらのプロドラッグ、一 般式 (m)で示される化合物、その塩、またはそれらのプロドラッグ、ならびに一般式（ IV)で示される化合物、またはその塩、ならびに、チクロビジン、カンダレロール、プラ スダレル、 AZD- 6140、 INS- 50589、 INS- 49266、 AR- C66096、 ARL- 67085、 GR-14404 3、ロキシフィバン、 MRS2395等の化合物は、実質的に純粋で単一な物質であるもの に限定されず、不純物 (例えば、製造工程に由来する副生成物、溶媒、原料等、また は分解物等)を、医薬品原薬として許容される範囲であれば含有していてもよい。医 薬品原薬として許容される不純物の含有量は、何れの化合物を用いるかでも異なる し、また医薬品としての投与形態 (例えば、静脈内投与、経口投与、経皮投与等）に よっても異なるので、適宜有効性と毒性を評価しつつその量を定めることが好まし ヽ [0173] The compound represented by the general formula (I) used in the present invention, its geometric isomer, its tautomer, its salt, its solvate, or their prodrug, represented by the general formula (Π) Compound, its salt, its N-oxide, its solvate, or prodrug thereof, A compound represented by the general formula (m), a salt thereof, or a prodrug thereof, and a compound represented by the general formula (IV), or a salt thereof, and ticlovidin, mandarelol, plasdarrel, AZD-6140, INS-50589 Compounds such as INS-49266, AR-C66096, ARL-67085, GR-144043, roxifiban, MRS2395, etc. are not limited to those that are substantially pure and single substances, but impurities (e.g. Derived by-products, solvents, raw materials, etc., or decomposed products) may be contained as long as they are acceptable as an active pharmaceutical ingredient. The content of impurities acceptable as an active pharmaceutical ingredient varies depending on which compound is used, and also differs depending on the dosage form as a pharmaceutical (eg, intravenous administration, oral administration, transdermal administration, etc.). It is preferable to determine the amount while assessing efficacy and toxicity as appropriate.
[0174] 本発明によって、疼痛の予防、治療および Zまたは症状進展抑制を目的に、前記「 P2Y 受容体および Zまたは P2Y 受容体ブロッカー」の有効量 (すなわち、疼痛の[0174] According to the present invention, an effective amount of the above-mentioned "P2Y receptor and Z or P2Y receptor blocker" (for example, pain prevention, treatment and suppression of Z or symptom progression)
12 14 12 14
予防、治療および Zまたは症状進展抑制効果を発揮するに充分な量)を哺乳動物（ 例えば、ヒトゃ非ヒト動物等、好ましくはヒト、特に好ましくは患者）に投与する方法が 開示される。  Disclosed is a method of administering prevention, treatment, and Z or an amount sufficient to exert a symptom progression inhibitory effect) to a mammal (eg, a human non-human animal, preferably a human, particularly preferably a patient).
[0175] 本発明において、「予防」とは疼痛がおこらないようにすること、またはおこっても軽 度の疼痛にとどめることを、「治療」とは疼痛をやわらげることを、「症状進展抑制」とは 疼痛の亢進 (例えば、疼痛範囲の拡大、疼痛程度の亢進、疼痛頻度の亢進等)をと どめることを意味する。また、「予防」には、周期的に訪れる痛みにおいて、次の痛み の発生を抑えるという意味や、痛覚閾値の低下を妨げるという意味も含まれ、「治療」 には、低下した痛覚閾値を正常に戻すという意味も含まれる。  [0175] In the present invention, "prevention" means that pain does not occur or only mild pain occurs, and "treatment" means that pain is relieved, "symptom progression suppression" The term “enhancement of pain” (for example, expansion of pain range, increase of pain level, increase of pain frequency, etc.) In addition, “prevention” includes the meaning of suppressing the occurrence of the next pain in periodic pains, and the meaning of preventing the pain threshold from being lowered. The meaning of returning to is also included.
[0176] 本発明において、疼痛としては、一般的に疼痛 [pain]と認知される感覚であればど のようなものであってもよい。例えば、三叉神経痛等のように、疼痛自体が疾患の主 体をなす疾患そのものであってもよぐ例えば、関節リウマチ等のように、疼痛を症状 の一つとして示す疾患、いわゆる有痛性疾患の一症状であってもよい。本発明は、こ れら何れの疼痛に対しても、予防、治療および Zまたは症状進展抑制方法として用 いられるちのである。  [0176] In the present invention, the pain may be any sensation that is generally recognized as pain. For example, the disease itself may be the disease itself, such as trigeminal neuralgia, for example, a disease that shows pain as one of the symptoms, such as rheumatoid arthritis, so-called painful disease It may be one symptom. The present invention is to be used as a prevention, treatment and Z or symptom progression suppression method for any of these pains.
[0177] 一般的に疼痛は、その特徴に応じて種々のカテゴリーに分類される。例えば、痛み の原因によって、例えば、侵害受容性疼痛 [nociceptive pain]、神経因性疼痛 [neuro genie pain] ,心因性疼痛 [psychogenic pain]等に分類されたり、痛みの発生部位によ つて、例えば、内臓痛 [visceral pain] ,体性痛 [somatic pain] (例えば、表面痛（表在 痛） [superficial pain]、深部痛 [deep pain] ,口腔顔面痛 [orofacial pain]等）、関連痛 [refferred pain]等に分類されたりする場合がある。また、痛みの種類によって、例え ば、速い痛み [fast pain]と遅い痛み [slow pain]、急性痛 [acute pain]と慢性痛 [chron ic pain]、自発痛 [spontaneous painjと ¾|発痛 [evoked painj、持 fee痛 [continuous pai n]と突出痛 [breakthrough pain]等に分類されたり、交感神経の関与の有無によって 、例えば、交感神経非依存性疼痛 [sympathetic independent pain]や交感神経依存 性疼痛 [sympathetic dependent pain]等に分類されたりする場合もある。さらに、痛み の原因疾患によって、例えば、癌性疼痛、帯状疱疹後神経痛、糖尿病性疼痛等に分 類されたりする場合もある。本発明における疼痛は、これらの分類において、いずれ の範疇に属するものであってもよい。また、本発明における疼痛には、「しびれ」と認 知される感覚も含まれる。すなわち、本発明における疼痛は、（2R)— 2—プロピルォ クタン酸、その塩、またはそのプロドラッグの投与対象となりうる哺乳動物（例えば、ヒト や非ヒト動物等、好ましくはヒト、特に好ましくは患者）が、「痛み」または「しびれ」と感 じて 、るものであればどのようなものであってもよ！/、。 [0177] Generally, pain is classified into various categories according to its characteristics. For example, pain Depending on the cause of, for example, nociceptive pain, neuro genie pain, psychogenic pain, etc. Pain [visceral pain], somatic pain [eg superficial pain], deep pain [deep pain], orofacial pain [orofacial pain], related pain [refferred pain ] May be classified. Also, depending on the type of pain, for example, fast pain [slow pain], acute pain [acute pain] and chronic pain [chron ic pain], spontaneous pain [spontaneous painj and ¾ | evoked painj, long-term pain [continuous pain] and breakthrough pain [breakthrough pain] etc., or depending on the presence or absence of sympathetic nerves, for example, sympathetic independent pain [sympathetic independent pain] and sympathetic nerve dependency It may be classified as pain [sympathetic dependent pain]. Furthermore, depending on the disease causing the pain, for example, it may be classified into cancer pain, postherpetic neuralgia, diabetic pain, and the like. The pain in the present invention may belong to any category in these classifications. The pain in the present invention includes a sensation recognized as “numbness”. That is, the pain in the present invention refers to a mammal that can be administered with (2R) -2-propyloctanoic acid, a salt thereof, or a prodrug thereof (eg, a human or a non-human animal, preferably a human, particularly preferably a patient). ) Is anything that feels “pain” or “numbness”! /.
[0178] 侵害受容性疼痛 [nociceptive pain]は、組織が傷つくこと、或いは組織が傷つく危 険性を持った刺激が加わることによっておこる痛みであればょ 、。侵害受容性疼痛 は、侵害受容器を介した疼痛であり、その原因によって、外来刺激による痛み (例え ば、侵害的機械刺激、熱刺激、化学刺激等)と内因性の刺激 (例えば、器質的疾患 による痛み、炎症性疼痛)等による痛みに分類することもできる。具体的には、例えば[0178] Nociceptive pain is pain caused by tissue injury or the addition of a stimulus with the risk of tissue injury. Nociceptive pain is pain through nociceptors, depending on the cause of pain from external stimuli (e.g., nociceptive mechanical, thermal, chemical, etc.) and endogenous stimuli (e.g., organic It can also be classified into pain due to disease, inflammatory pain) and the like. Specifically, for example
、切り傷、打撲、骨折、挫滅創、やけど、手術、癌等の、生体組織の傷害に起因する 痛み等が本発明における侵害受容性疼痛に含まれる。 Nociceptive pain in the present invention includes pain resulting from injuries to living tissues such as cuts, bruises, fractures, fractures, burns, surgery, and cancer.
[0179] 心因性疼痛 [psychogenic pain]は、心理的障害に関連して起こる痛みを意味する [0179] Psychogenic pain means pain associated with psychological disorders
1S 本発明においては、明確に心理的障害が存在しない場合であっても、解剖学的 に説明のつかない疼痛や、痛みに見合うだけの病変が見出されない痛みを感じる場 合も含むものとする。また、心因性疼痛は、慢性疼痛症候群と称されることもある。心 因性疼痛としては、例えば、疼痛性障害、身体表現性障害、精神生理的障害、心因 性疼痛障害等が含まれる。 1S In the present invention, even when there is no clear psychological disorder, it includes the case of feeling pain that cannot be explained anatomically, or pain that does not find a lesion suitable for pain. Psychogenic pain is also sometimes referred to as chronic pain syndrome. heart Examples of intrinsic pain include pain disorders, body expression disorders, psychophysiological disorders, psychogenic pain disorders, and the like.
[0180] 神経因性疼痛 [neurogenic pain]は、末梢神経或いは中枢神経系そのもの（脳、脊 髄等)の機能異常による病的な痛み、および Zまたは侵害受容器を介さず痛みの伝 導路の中で異常興奮が発生することによって生じる疼痛を 、、 1994年の国際疼痛 学会 [International Association for the Study of Pain]で提唱されているように、「神経 系の一過性の機能異常による痛み」と、いわゆる神経障害性疼痛 [neuropathic pain] と呼ばれるような、「末梢神経および Zまたは中枢神経の損傷や機能異常による病的 な痛み（中枢痛 [central pain] )」を包含するものとする。尚、神経障害の種類は単一 性神経障害であっても多発性神経障害であってもよい。具体的には、外傷、圧迫、 感染、癌、虚血、或いは糖尿病等の代謝性障害等の原因によって神経、神経叢、或 いは神経周囲軟組織が損傷または変性する神経障害をきたし、力かる神経障害によ つて惹き起こされる何らかの機能異常による疼痛閾値の低下等の持続する疼痛知覚 の異常な状態を意味する。  [0180] Neurogenic pain is pathological pain caused by dysfunction of the peripheral nerve or the central nervous system itself (brain, spinal cord, etc.), and pain pathways not via Z or nociceptors. Pain caused by the occurrence of abnormal excitement in the 1994, as proposed in the International Association for the Study of Pain [1994] Pain due to transient dysfunction of the nervous system ”And“ pathological pain (central pain) due to damage or dysfunction of the peripheral and Z or central nerves ”, so-called neuropathic pain. . The type of neuropathy may be single neuropathy or multiple neuropathy. Specifically, nerve damage that causes damage or degeneration of nerves, nerve plexus, or surrounding nerve soft tissue due to trauma, compression, infection, cancer, ischemia, or metabolic disorders such as diabetes, etc. It means an abnormal state of persistent pain perception, such as a decrease in pain threshold due to some abnormal function caused by neuropathy.
[0181] 以下、本発明における疼痛を、具体的に疾患名を挙げて例示する。前記したように 、これらの疾患名は、疼痛そのものを表す名称である場合と、有痛性疾患の名称であ る場合がある。また前記したように、痛みの分類にはいくつもの分類方法があるため、 以下の記載では、同一の疾患名が幾つかのカテゴリーで複数回例示されていてもよ いものとする。  [0181] Hereinafter, the pain in the present invention will be exemplified with specific disease names. As described above, these disease names may be names representing pain itself or names of painful diseases. As described above, since there are various classification methods for pain classification, in the following description, the same disease name may be exemplified multiple times in several categories.
[0182] 本発明において、疼痛としては、例えば、頭痛 (例えば、偏頭痛、筋緊張性頭痛、 群発頭痛、その他の症候性頭痛等)、口腔顔面痛 (例えば、歯痛、舌痛症、顎関節 症、三叉神経痛等)、頸肩腕痛 (例えば、頸部椎間板ヘルニア、変形性頸椎症、頸 肩腕症候群、肩関節周囲炎 (五十肩)、頸部脊柱管狭窄症、胸部出口症候群、腕神 経叢引き抜き損傷、肩手症候群、外傷性頸部症候群 (むち打ち症)等)、胸痛、腹痛 (例えば、急性腹症、胆石症、急性脾炎、尿路結石症等)、腰背部痛 (例えば、腰部 椎間板ヘルニア、変形性腰椎症、腰部脊柱管狭窄症、腰椎分離症、腰椎すベり症、 椎間関節症等)、膝の痛み、筋骨格系の痛み (例えば、筋肉痛 (例えば、筋'筋膜痛 症候群 (MPS)、線維性筋痛症候群 (FMS)等)、関節痛 (例えば、関節炎、関節リウマ チ (RA)、痛風等）、脊椎関連の痛み、骨の痛み等）、血流障害による痛み (例えば、 閉塞性動脈硬化症 (ASO)、バージャ一病 (TAO)等）、外傷による痛み、神経因性疼 痛 (例えば、神経痛 (例えば、三叉神経痛、肋間神経痛、感覚異常性大腿神経痛、 鼠径神経痛、伏在神経痛、正中神経痛、尺骨神経痛、坐骨神経痛、神経根痛等）、 帯状疱疹疼痛 (例えば、急性期帯状疱疹疼痛、帯状疱疹後疼痛 (慢性期)等)、糖尿 病性疼痛 (例えば、糖尿病性-ユーロパシー、大径線維-ユーロパシー、小径線維 ニューロパシー、近位筋優位運動-ユーロパシー、急性単神経障害、圧迫による麻 痺等)、絞扼性神経障害 (例えば、胸郭出口症候群、肩甲上神経絞扼障害、肩甲背 神経絞扼障害、四辺形間隙症候群、円回内筋症候群、前骨間神経症候群、肘部管 症候群、遅発性尺骨神経麻痺、後骨間神経症候群、手根管症候群、尺骨神経管症 候群、 Wartenberg病、 Blowler's thumb,知覚異常性大腿痛、梨状筋症候群、 Hunter 管症候群、総腓骨神経絞扼障害、足根管症候群、前足根管症候群、 Morton病、頸 部脊柱管狭窄症、腰部脊柱管狭窄症、広範脊柱管狭窄症等)、腰痛関連ニューロパ シー、腕神経叢引き抜き損傷、反射性交感神経性ジストロフィー (複雑性局所疼痛症 候群タイプ 1)、反射性交感神経性萎縮症、カウザルギー (灼熱痛、複雑性局所疼痛 症候群タイプ 2)、有痛性神経障害、脊髄損傷後疼痛、幻影痛 (例えば、幻肢痛、幻 歯痛等）、中枢性疼痛 (例えば、視床症候群、 Dejerine-Roussy症候群、視床痛 (例え ば、脳卒中後視床痛等)、脳卒中後痛等)、求心路遮断痛、医原性ニューロパシー、 交感神経依存性疼痛、逆行性 C線維興奮症候群 (ABC症候群 [Angry Backffiring C -nociceptor syndrome])、癌性疼痛、 HIV関連神経因性疼痛、結石誘発疼痛（例え ば、尿路結石 (例えば、腎結石、尿管結石、膀胱結石、尿道結石等）による疼痛、胆 嚢結石による疼痛、精管結石による疼痛等)、術後痛、慢性頭痛、口腔顔面痛 (例え ば、歯痛、舌痛症、顎関節症、三叉神経痛等)、非定型性顔面痛 (例えば、抜歯後等 の非定型性顔面痛等)、肩関節周囲炎、変形性関節症、関節炎、リウマチに伴う疼 痛、バックペイン、多発性硬化症、薬物治療によって誘発される疼痛、放射線治療に よって誘発される疼痛、麻薬性鎮痛薬の効果が十分に得られな!/、疼痛等)等が挙げ られる。 [0182] In the present invention, pain includes, for example, headache (for example, migraine, myotonic headache, cluster headache, other symptomatic headaches), orofacial pain (for example, toothache, glossodynia, temporomandibular joint) , Cervical disc herniation, degenerative cervical spondylosis, cervical shoulder arm syndrome, shoulder periarthritis (fifty shoulders), cervical spinal canal stenosis, thoracic outlet syndrome, brachial nerve Plexus withdrawal injury, shoulder-hand syndrome, traumatic neck syndrome (whiplash), chest pain, abdominal pain (e.g. acute abdomen, cholelithiasis, acute splenitis, urinary calculus etc.), back pain (e.g. Lumbar disc herniation, degenerative lumbar spondylosis, lumbar spinal canal stenosis, lumbar sequestration, lumbar spondylolisthesis, facet joints, etc., knee pain, musculoskeletal pain (e.g. muscle pain (e.g. muscle 'Fascial pain syndrome (MPS), fibromyalgia syndrome (FMS), etc.), joint pain (eg, arthritis, rheumatoid arthritis) (RA), gout, etc.), spinal pain, bone pain, etc., pain caused by blood flow disorders (eg, obstructive arteriosclerosis (ASO), Birja's disease (TAO), etc.), pain caused by trauma, Neuropathic pain (e.g. neuralgia (e.g. trigeminal neuralgia, intercostal neuralgia, sensory dysfunctional femoral neuralgia, inguinal neuralgia, saphenous neuralgia, median neuralgia, ulnar neuralgia, sciatica, nerve root pain, etc.), herpes zoster pain ( (E.g., acute herpes zoster pain, postherpetic pain (chronic), etc.), diabetic pain (e.g., diabetic-europathy, large-diameter fiber-europathy, small-diameter fiber neuropathy, proximal muscle dominant exercise-europathy, acute Mononeuropathy, paralysis due to compression, etc.), strangulation neuropathy (e.g., thoracic outlet syndrome, suprascapular nerve strangulation disorder, scapulodorsal nerve strangulation disorder, quadrilateral gap syndrome, circumflex muscle syndrome, anterior Interosseous nerve syndrome, elbow canal syndrome, slow Onset ulnar nerve palsy, posterior interosseous nerve syndrome, carpal tunnel syndrome, ulnar nerve canal syndrome, Wartenberg disease, Blowler's thumb, sensory abnormal femoral pain, piriformis syndrome, Hunter's canal syndrome, common peroneal nerve strangulation Disorders, tarsal tunnel syndrome, anterior tarsal tunnel syndrome, Morton disease, cervical spinal canal stenosis, lumbar spinal canal stenosis, extensive spinal canal stenosis, etc.), low back pain related neuropathy, brachial plexus withdrawal injury, reflex sympathy Nervous dystrophy (complex local pain syndrome group type 1), reflex sympathetic atrophy, causalgia (burning pain, complex local pain syndrome type 2), painful neuropathy, post-injury pain, phantom pain (E.g., phantom limb pain, phantom tooth pain, etc.), central pain (e.g., thalamic syndrome, Dejerine-Roussy syndrome, thalamic pain (e.g., post-stroke thalamic pain, etc.), post-stroke pain, etc.), afferent block pain, Iatrogenic neuropathy, sympathetic nerve-dependent pain, reverse C-fiber excitability syndrome (ABC syndrome [Angry Backffiring C-nociceptor syndrome]), cancer pain, HIV-related neuropathic pain, stone-induced pain (eg, urolithiasis (eg, kidney stone, ureteral stone, bladder) Pain due to stones, urethral stones, pain due to gallbladder stones, pain due to vagina stones), postoperative pain, chronic headache, orofacial pain (eg toothache, glossodynia, temporomandibular disorders, trigeminal neuralgia) ), Atypical facial pain (e.g., atypical facial pain after tooth extraction, etc.), shoulder periarthritis, osteoarthritis, arthritis, pain associated with rheumatism, back pain, multiple sclerosis, drug treatment Pain induced by radiation therapy, pain induced by radiation therapy, and the effects of narcotic analgesics cannot be fully obtained! /, Pain, etc.).
本発明において、好ましい疼痛は神経因性疼痛（とりわけ、癌性疼痛、帯状疱疹後 疼痛、糖尿病性疼痛、 HIV関連神経因性疼痛、結石誘発疼痛、神経痛、または口 腔顔面痛等)である。尚、本発明における神経因性疼痛としては、前記の疾患の他に 、知覚過敏 (特に痛覚過敏等)、自発痛等も好ましい。 In the present invention, the preferred pain is neuropathic pain (especially cancer pain, after herpes zoster) Pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, or orofacial pain. As the neuropathic pain in the present invention, in addition to the above-mentioned diseases, hypersensitivity (particularly hyperalgesia etc.), spontaneous pain and the like are also preferable.
[0184] 本発明の、「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカーを含有してなる [0184] According to the present invention, "P2Y receptor and お よ び or Ρ2Υ receptor blocker"
12 14  12 14
疼痛の予防、治療および Ζまたは症状進展抑制剤」（以下、本発明の剤と略記する 場合がある。）は、前記の疼痛のうち、神経因性疼痛を対象とすることが好ましい。特 に、癌性疼痛、帯状疱疹後疼痛、糖尿病性疼痛、 HIV関連神経因性疼痛、結石誘 発疼痛、神経痛、口腔顔面痛、または痛覚過敏等に対して用いることが好ましぐこ れらの痛みを、特にァロディ-ァによる痛みをも予防、治療および Ζまたは症状進展 抑帘 Uすることができる。  The “prevention and treatment of pain, and an epilepsy or symptom progression inhibitor” (hereinafter sometimes abbreviated as the agent of the present invention) is preferably targeted to neuropathic pain among the above pains. In particular, it is preferably used for cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia. Pain can be prevented, treated, and / or symptom-progressed, even with alodyya pain.
[0185] 本発明ではまた、 P2Y 受容体および または P2Y 受容体陽性細胞抑制を目的  [0185] The present invention also aims at inhibiting P2Y receptor and / or P2Y receptor positive cells.
12 Z 14  12 Z 14
に、さらには P2Y 受容体および Zまたは P2Y 受容体抑制を目的に、前記「P2Y  Further, for the purpose of inhibiting P2Y receptor and Z or P2Y receptor, the above-mentioned “P2Y
12 14 12 受容体および Ζまたは Ρ2Υ 受容体ブロッカー」の有効量 (すなわち、疼痛の予防、  12 14 12 Receptor and Ζ or Ρ2Υ receptor blocker '' effective amount (i.e. pain prevention,
14  14
治療および Ζまたは症状進展抑制効果を発揮するに充分な量)を哺乳動物 (例えば 、ヒトゃ非ヒト動物等、好ましくはヒト、特に好ましくは患者）に投与する方法が開示さ れる。  Disclosed is a method of administering a treatment and an amount sufficient to exert a sputum or symptom progression-suppressing effect) to a mammal (eg, a non-human animal, preferably a human, particularly preferably a patient).
[0186] ΓΡ2Υ 受容体および Ζまたは Ρ2Υ 受容体陽性細胞」とは、 Ρ2Υ 受容体および  [0186] ΓΡ2Υ receptor and Ζ or Ρ2Υ receptor positive cell ”means Ρ2Υ receptor and
12 14 12 12 14 12
Ζまたは Ρ2Υ 受容体を発現している細胞を意味するものであり、たとえ 1分子でも Ζ or Ρ2Υ means a cell expressing the receptor, even a single molecule
14  14
力かる受容体を発現していればその細胞は陽性細胞に含まれる。「Ρ2Υ  If a strong receptor is expressed, the cell is included in the positive cell. 「Ρ2Ρ
12受容体お よび Ζまたは Ρ2Υ 受容体陽性細胞抑制」とは、該 Ρ2Υ 受容体および  12 receptor and Ζ or Ρ2Υ receptor positive cell inhibition ”means the Ρ2 お よ び receptor and
14 12 Ζまたは Ρ2 14 12 Ζ or Ρ2
Υ 受容体陽性細胞を、「質的に」或いは「量的に」抑制することを意味し、具体的にを It means to suppress receptor positive cells “qualitatively” or “quantitatively”.
14 14
は、（1)該細胞を減少させたり、（2)該細胞の増加を抑制したり、或いは（3)該細胞 の細胞機能を抑制したりすること等が含まれる。ここで、（1)や（2)に記載の作用は、 細胞の分化、増殖、或いは寿命等の何れの調節に起因するものであってもよい。 (3) に記載の細胞機能は、普遍的に細胞が有する機能であってもよいが、なかでも、 Ρ2 Υ 受容体および Ζまたは Ρ2Υ 受容体が関連する細胞機能、とりわけ何らかの疾 This includes (1) reducing the number of cells, (2) suppressing the increase in the number of cells, or (3) suppressing the cell function of the cells. Here, the action described in (1) or (2) may be caused by any regulation of cell differentiation, proliferation, life span, or the like. The cell function described in (3) may be a function universally possessed by the cell. Among them, the cell function related to Ρ2 Υ receptor and Ζ or Ρ2Υ receptor, particularly any
12 14 12 14
患や病状を、特に後述の疼痛を導くような細胞機能が好ましく挙げられる。  A cell function that leads to a pain or a medical condition, particularly pain described later, is preferably mentioned.
[0187] 「Ρ2Υ 受容体および[0187] "Ρ2Υ receptor and
2 Ζまたは Ρ2Υ 受容体抑制」とは、該 Ρ2Υ 受容体および “2 Ζ or Ρ2Υ receptor inhibition” means the Ρ2Υ receptor and
1 14 12 Ζ または P2Y 受容体を、「質的に」或いは「量的に」抑制することを意味し、具体的に1 14 12 Ζ Or means to qualitatively or “quantitatively” inhibit P2Y receptors, specifically
14 14
は、（1)該受容体を減少させたり、（2)該受容体の増加を抑制したり、或いは（3)該 受容体の受容体機能を抑制したりすること等が含まれる。ここで、（1)や (2)に記載の 作用は、蛋白合成、蛋白分解、インターナリゼーシヨン（internalization)、或いはシェ デイング (shedding)等の何れの調節に起因するものであってもよい。 (3)に記載の受 容体機能としては、例えば、該受容体への生体内リガンドの結合、該受容体に生体 内リガンドが結合した際のシグナル伝達 (例えば、受容体のクラスタリング、蛋白質の リン酸化や脱リン酸化、セカンドメッセンジャーの生成、遺伝子発現等)等が好ましく 挙げられる。  This includes (1) decreasing the receptor, (2) suppressing the increase in the receptor, (3) suppressing the receptor function of the receptor, and the like. Here, the action described in (1) or (2) may be caused by any regulation such as protein synthesis, proteolysis, internalization, or shedding. . Examples of the receptor function described in (3) include binding of an in vivo ligand to the receptor, signal transduction when the in vivo ligand binds to the receptor (for example, receptor clustering, protein phosphorylation). (Oxidation, dephosphorylation, generation of second messenger, gene expression, etc.) are preferred.
[0188] 「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカー」の有効量を投与して、「Ρ  [0188] Administer an effective amount of "P2Y receptor and Ζ or Ρ2Ρ receptor blocker"
12 14  12 14
2Υ 受容体および Ζまたは Ρ2Υ 受容体陽性細胞」或いは「Ρ2Υ 受容体および 2Υ receptor and Ζ or Ρ2Υ receptor positive cells '' or Ρ2Υ receptor and
12 14 12 Ζ または Ρ2Υ 12 14 12 Ζ or Ρ2Υ
14受容体」を抑制することにより、前記の疼痛以外にも、これらの細胞或い は受容体が関与する疾患、例えば、感染症及び寄生虫症、新生物、血液および造 血器の疾患ならびに免疫機構の障害、内分泌'栄養および代謝疾患、精神および行 動の障害、神経系の疾患、眼および付属器の疾患、耳および乳様突起の疾患、循 環器系の疾患、呼吸器系の疾患、消ィヒ器系の疾患、皮膚および皮下組織の疾患、 筋骨格系および結合組織の疾患、尿路性器系の疾患等の予防、治療および Ζまた は症状進展抑制が可能である。これらの疾患の詳細については、国際疾病分類第 1 In addition to the pain described above, by inhibiting "14 receptors", diseases involving these cells or receptors, such as infections and parasitic diseases, neoplasms, blood and hematopoietic diseases, and Impaired immune system, endocrine 'nutrition and metabolic diseases, mental and behavioral disorders, nervous system diseases, eye and appendage diseases, ear and mastoid diseases, cardiovascular diseases, respiratory diseases It is possible to prevent, treat and suppress epilepsy or symptom progression of diseases, diseases of the congestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, diseases of the urogenital system. For more information on these diseases, see International Disease Classification 1
0版 (ICD10)に詳しく記載されている。 It is described in detail in the 0th edition (ICD10).
[0189] 前記したように、「Ρ2Υ 受容体および [0189] As mentioned above, “Ρ2Υ receptor and
12 Ζまたは Ρ2Υ 受容体ブロッカー」には、例  “12 Ζ or Ρ2Υ receptor blocker”
14  14
えば、（a)低分子化合物、（b)抗体、（c)アンチセンス、（d)短鎖干渉 RNA、（e)デコイ、（£) リボザィム、（g)アブタマ一等の形態を有するものが存在する。これらの物質を、疼痛 の予防、治療および Zまたは症状進展抑制を目的に、或いは P2Y  For example, (a) a low molecular weight compound, (b) an antibody, (c) an antisense, (d) a short interfering RNA, (e) a decoy, (£) a ribozyme, (g) an abutama Exists. These substances may be used for the purpose of preventing or treating pain and suppressing Z or symptom progression, or P2Y
12受容体および 12 receptors and
Zまたは P2Y 受容体陽性細胞抑制を目的に、さらには P2Y 受容体および For the purpose of Z- or P2Y receptor-positive cell suppression, P2Y receptor and
14 12 Zまた は P2Y 受容体抑制を目的に生体に投与する場合には、有効成分であるこれらの When administered to a living body for the purpose of 14 12 Z or P2Y receptor inhibition, these active ingredients
14 14
物質の形態にそれぞれ応じた医薬組成物として投与する必要がある。  It is necessary to administer as a pharmaceutical composition corresponding to the form of the substance.
[0190] 例えば、低分子化合物を哺乳動物に投与する場合、医薬組成物の形態としては、 例えば、経口投与用製剤 (例えば、内服用固形剤、内服用液剤等)や非経口投与用 製剤 (例えば、注射剤、外用液剤、軟膏剤、塗布剤、吸入剤、スプレー剤、坐剤、膣 坐剤等)等が挙げられる。 [0190] For example, when a low molecular weight compound is administered to a mammal, the form of the pharmaceutical composition includes, for example, a preparation for oral administration (for example, a solid preparation for internal use, a liquid preparation for internal use, etc.) or for parenteral administration. Formulations (for example, injections, liquids for external use, ointments, coating agents, inhalants, sprays, suppositories, vaginal suppositories, etc.) and the like.
[0191] 内服用固形剤としては、例えば、錠剤、丸剤、カプセル剤 (ノヽードカプセル剤、ソフ トカプセル剤）、散剤、顆粒剤等が挙げられる。これらの内服用固形剤は、有効成分 と種々の添加剤（例えば、賦形剤（例：ラタトース、マンニトール、グルコース、微結晶 セルロース、デンプン等）、結合剤（例：ヒドロキシプロピルセルロース、ポリビュルピロ リドン、メタケイ酸アルミン酸マグネシウム等）、崩壊剤（例:繊維素グリコール酸カルシ ゥム等）、滑沢剤 (例:ステアリン酸マグネシウム等）、安定剤、溶解補助剤 (例:グルタ ミン酸、ァスパラギン酸等)等）とを混合し、公知の方法を用いて製造することができる 。またこれらの内服用固形剤には所望によって、コーティング剤 (例：白糖、ゼラチン、 ヒドロキシプロピノレセルロース、ヒドロキシプロピノレメチノレセルロースフタレート等）を用 [0191] Examples of solid preparations for internal use include tablets, pills, capsules (node capsules, soft capsules), powders, granules and the like. These solid preparations for internal use consist of an active ingredient and various additives (for example, excipients (eg, ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (eg, hydroxypropylcellulose, polypyrrolopyrrolidone, Magnesium aluminate metasilicate, etc.), disintegrating agents (eg, calcium cellulose glycolate), lubricants (eg: magnesium stearate), stabilizers, solubilizers (eg: glutamic acid, aspartic acid) Etc.)) and the like, and can be produced using a known method. In addition, for these solid preparations for internal use, coating agents (eg, sucrose, gelatin, hydroxypropinolecellulose, hydroxypropenolemethinolecellulose phthalate, etc.) may be used as desired.
V、て、一層または二層以上のコーティングを施してもょ 、。 V. Apply one or more coatings.
[0192] 内服用液剤としては、例えば、薬剤的に許容される水剤、懸濁剤、乳剤、シロップ 剤、エリキシル剤等が挙げられる。これらの内服用液剤は、有効成分を一般的に用い られる希釈剤 (例えば、精製水、エタノールまたはそれらの混液等）に溶解、懸濁また は乳化して製造することができる。またこれらの内服用液剤には所望によって、種々 の添加剤（例えば、湿潤剤（例：グリセリン、プロピレングリコール等）、懸濁化剤（例： カルメロース、寒天、ゼラチン、メチルセルロース等）、乳化剤（例：アラビアゴム、ポピ ドン、モノステアリン酸グリセリン等）、甘味剤 (例:果糖、ブドウ糖等）、風味剤 (例:コ 一ヒー、茶、ココア等)、芳香剤 (例:オレンジ油、チモール等)、保存剤 (例:安息香酸 、安息香酸ナトリウム、パラォキシ安息香酸ェチル、パラォキシ安息香酸プロピル等） 、緩衝剤（例：クェン酸、リン酸水素ニナトリウム、クェン酸ナトリウム、炭酸水素ナトリウ ム、酢酸、乳酸等)等）を加えてもよい。  [0192] Examples of liquids for internal use include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. These liquid preparations for internal use can be produced by dissolving, suspending or emulsifying the active ingredient in a diluent generally used (for example, purified water, ethanol or a mixture thereof). These liquids for internal use may contain various additives (eg, wetting agents (eg, glycerin, propylene glycol, etc.), suspending agents (eg, carmellose, agar, gelatin, methylcellulose, etc.), emulsifiers (eg, : Arabic gum, popidone, glyceryl monostearate, etc.), sweeteners (eg, fructose, glucose, etc.), flavoring agents (eg, coffee, tea, cocoa, etc.), fragrances (eg, orange oil, thymol, etc.) ), Preservatives (eg, benzoic acid, sodium benzoate, ethyl parabenzoate, propyl parabenzoate), buffers (eg, citrate, disodium hydrogen phosphate, sodium citrate, sodium hydrogen carbonate, acetic acid) , Lactic acid, etc.) may be added.
[0193] 注射剤は、溶液である一般的な注射剤に加え、例えば、懸濁注射剤や乳濁注射剤 等であってもよぐさらには、用時に溶解または懸濁して用いる固形の注射剤（例えば 、凍結乾燥品）等であってもよい。これらの注射剤は、例えば、筋肉内、皮下、皮内、 動脈内、静脈内、腹腔内、脊髄腔内等に投与される。注射剤はまた、点滴で投与し てもよい。これらの注射剤は、有効成分を溶剤（例えば、注射用蒸留水、生理食塩水 、植物油、プロピレングリコール、ポリエチレングリコール、エタノールのようなアルコー ル類等およびそれらの組み合わせ等）に溶解、懸濁または乳化して製造することが できる。またこれらの注射剤には所望によって、種々の添加剤（例えば、安定剤、溶 解補助剤 (例:グルタミン酸、ァスパラギン酸、ポリソルベート 80 (登録商標)等）、懸濁 化剤（例：メチルセルロース、カルボキシメチルセルロース等）、乳化剤（例：ポリソルべ ート 80 (登録商標)等）、無痛化剤 (例:プロ力イン、塩酸リドカイン等）、緩衝剤 (例:塩 化ナトリウム、塩ィ匕カリウム、リン酸水素ニナトリウム、クェン酸、クェン酸ナトリウム等） 、保存剤（例：ベンジルアルコール等)等）をカ卩えてもよい。これらの注射剤は通常、最 終工程において滅菌する力 または無菌操作法によって製造される。また凍結乾燥 品等の固形の注射剤の場合は、用時 (使用前）に無菌化または無菌の注射用蒸留 水または他の溶剤に溶解して使用される。 [0193] In addition to general injections that are solutions, injections may be, for example, suspension injections or emulsion injections, and solid injections that are dissolved or suspended at the time of use. An agent (for example, freeze-dried product) or the like may be used. These injections are administered, for example, intramuscularly, subcutaneously, intradermally, intraarterially, intravenously, intraperitoneally, intrathecally. Injectables may also be administered by infusion. These injections contain active ingredients as solvents (for example, distilled water for injection, physiological saline). , Vegetable oils, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof). If desired, these injections may contain various additives (eg, stabilizers, solubilizers (eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), suspending agents (eg, methylcellulose, Carboxymethylcellulose, etc.), emulsifier (eg, polysorbate 80 (registered trademark), etc.), soothing agent (eg, pro-powered in, lidocaine hydrochloride, etc.), buffer (eg: sodium chloride, salted potassium, Disodium hydrogen phosphate, citrate, sodium citrate, etc.) and preservatives (eg, benzyl alcohol, etc.) may be added. These injections are usually produced by the force of sterilization in the final step or by aseptic manipulation. In the case of solid injections such as freeze-dried products, they are used after being used (before use) or dissolved in sterile distilled water for injection or other solvents.
[0194] その他の非経口投与用製剤、例えば、外用液剤、軟膏剤、塗布剤、吸入剤、スプ レー剤、坐剤、膣坐剤等の製剤についても、公知の処方に準じて製造することができ る。 [0194] Other preparations for parenteral administration, for example, preparations for external use, ointments, coatings, inhalants, sprays, suppositories, vaginal suppositories, etc. should be manufactured according to known formulations. You can.
[0195] また例えば、抗体を哺乳動物に投与する場合、医薬組成物の形態としては、例え ば、注射剤（点滴を含む）、坐剤、経鼻剤、舌下剤、経皮吸収剤等が挙げられる。モノ クローナル抗体やポリクローナル抗体は高分子蛋白質であることから、バイアル瓶等 のガラス容器や注射筒等への吸着が著しい上に不安定であり、種々の物理ィ匕学的 因子、例えば、熱、 pH及び湿度等により容易に失活することが予想される。従って、 安定な形で製剤化するために、安定化剤、 pH調整剤、緩衝剤、可溶化剤、界面活 性剤等を添加することが好ましい。安定化剤としては、例えば、グリシン、ァラニン等 のアミノ酸類、デキストラン 40及びマンノース等の糖類、ソルビトール、マン-トール、 キシリトール等の糖アルコール等が挙げられ、またこれらの二種以上を組み合わせて 使用してもよい。これらの安定化剤の添加量は、抗体の重量に対して概ね 0.01倍乃 至 100倍、特に 0.1倍乃至 10倍程度添加することが好ましい。これら安定化剤を加え ることにより、液状製剤或いは凍結乾燥製剤の保存安定性を向上することができる。 緩衝剤としては、例えば、リン酸バッファー、クェン酸バッファ一等が挙げられる。緩 衝剤は、液状製剤或いは凍結乾燥製剤の再溶解後の水溶液の pHを調製し、抗体 の安定性、溶解性を向上することができる。緩衝剤の添加量は、例えば、液状製剤 或いは凍結乾燥製剤を再溶解した後の液量に対して概ね ImM乃至 10mM程度と することが好ましい。界面活性剤としては、例えば、ポリソルベート 20、プル口ニック F — 68、ポリエチレングリコール等を用いることが好ましぐ特にポリソルベート 80等を 用いることが好ましい。またこれらの二種以上を組み合わせて使用してもよい。前記し たように、抗体のような高分子蛋白質は容器の材質であるガラスゃ榭脂等に吸着しや すい。従って、界面活性剤を添加することによって、液状製剤或いは凍結乾燥製剤 の再溶解後の抗体の、容器への吸着を防止することができる。界面活性剤の添加量 は、例えば、液状製剤或いは凍結乾燥製剤を再溶解した後の液の重量に対して概 ね 0.001%乃至 1.0%程度添加することが好ましい。以上のような安定化剤、緩衝剤、 或いは吸着防止剤を加えることで、前記抗体の製剤を調製することができるが、特に 医療用または動物用注射剤として用いる場合は、浸透圧として許容される浸透圧比 は 1乃至 2が好ましい。浸透圧比は、製剤化に際して塩ィ匕ナトリウムの増減により調製 することができる。製剤中の抗体含量は、適用疾患、適用投与経路などに応じて適 宜調整することができる。例えば、前記抗体をヒトに対して投与する際には、約 O.lmg Zkg乃至 lOOmgZkgを 1日乃至 30日間に 1回投与すればよい。 [0195] Also, for example, when an antibody is administered to a mammal, the form of the pharmaceutical composition includes, for example, an injection (including infusion), a suppository, a nasal agent, a sublingual agent, a transdermal absorption agent, and the like. Can be mentioned. Monoclonal antibodies and polyclonal antibodies are high molecular weight proteins, so they are extremely unstable and unstable in adsorption to glass containers such as vials and syringes, and various physical and physical factors such as heat, It is expected to be easily deactivated due to pH and humidity. Therefore, it is preferable to add a stabilizer, a pH adjuster, a buffering agent, a solubilizer, a surfactant, etc., in order to formulate in a stable form. Examples of the stabilizer include amino acids such as glycine and alanine, saccharides such as dextran 40 and mannose, sugar alcohols such as sorbitol, mannitol and xylitol, and combinations of two or more of these are used. May be. The added amount of these stabilizers is preferably about 0.01 to 100 times, particularly about 0.1 to 10 times the weight of the antibody. By adding these stabilizers, the storage stability of the liquid preparation or lyophilized preparation can be improved. Examples of the buffer include a phosphate buffer and a citrate buffer. The buffer is prepared by adjusting the pH of the aqueous solution after re-dissolution of the liquid preparation or lyophilized preparation. Stability and solubility can be improved. The addition amount of the buffering agent is preferably about ImM to 10 mM, for example, with respect to the liquid amount after redissolving the liquid preparation or lyophilized preparation. As the surfactant, for example, polysorbate 20, pull nick F-68, polyethylene glycol or the like is preferred, and polysorbate 80 or the like is particularly preferred. Moreover, you may use combining these 2 or more types. As described above, a high molecular protein such as an antibody is easily adsorbed to glass resin or the like which is a material of a container. Therefore, by adding a surfactant, it is possible to prevent adsorption of the antibody after re-dissolution of the liquid preparation or lyophilized preparation into the container. The amount of the surfactant added is preferably about 0.001% to 1.0% with respect to the weight of the liquid after redissolving the liquid preparation or lyophilized preparation, for example. The antibody preparation can be prepared by adding a stabilizer, a buffer, or an adsorption inhibitor as described above, but it is acceptable as an osmotic pressure, particularly when used as a medical or animal injection. The osmotic pressure ratio is preferably 1 to 2. The osmotic pressure ratio can be adjusted by increasing / decreasing sodium chloride at the time of formulation. The antibody content in the preparation can be appropriately adjusted according to the disease to be applied, the route of administration and the like. For example, when the antibody is administered to a human, about O.lmg Zkg to lOOmgZkg may be administered once every 1 to 30 days.
[0196] また例えば、アンチセンス、短鎖干渉 RNA、デコイ、リボザィム、ァプタマ一等の、 いわゆる核酸分子を哺乳動物に投与する場合、望ましい薬効を得るために、種々の 公知文献に記載されて 、るような医薬組成物を用いることが好まし 、。  [0196] In addition, for example, when a so-called nucleic acid molecule such as antisense, short interfering RNA, decoy, ribozyme, aptamer, etc. is administered to a mammal, it is described in various known literatures in order to obtain a desired medicinal effect. It is preferable to use such a pharmaceutical composition.
[0197] 例えば、核酸分子を投与する方法は、 Trends Cell Biol, 2, 139, 1992および Deliv ery Strategies for Antisense Oligonucleotide Therapeutics (ed. khtar, 1995)等に羊 しく記載されている。特に、 RNA分子を用いる方法については、国際公開第 94/025 95号パンフレットにも詳しく記載されている。これらの文献は、リボソームへの封入、ィ オントフォレーシス、或いは、他の媒体（例えば、ヒドロゲル、シクロデキストリン、生分 解性ナノカプセル、生体接着性小球体等)への組込み等につ!、て記載するものであ るが、本発明で用いる核酸分子を投与する方法は、これらに限定されるものではない 。例えば、核酸分子とこれら媒体の組み合わせを、或いは核酸分子そのものを、細胞 または組織に ex vivoで投与することもできるし、静脈内等に直接注入したり、カテー テルや注入ポンプ、ステント等を用いて投与することもできる。例えば、 Neuroscience Letters, 257, 135—138, 1998； Mol. Brain Research, 55, 151—164, 1998； J. Endocri nol., 157, 169-175, 1998； Neuroscience Letters, 247, 21-24, 1998には浸透圧ポン プを用いて、例えば、 Neurosurg. Focus, 3, article 4, 1997には直接注入によって、 中枢神経系にオリゴヌクレオチドを投与する方法が記載されて 、る。中枢神経系への 投与につ ヽて【ま、これ 外に ¾、 Drug Delivery systems： Technologies and Commer cial Opportunities, Decision Resources, 1998等に詳しく記載されている。 [0197] For example, a method for administering a nucleic acid molecule is extensively described in Trends Cell Biol, 2, 139, 1992 and Delivery Strategies for Antisense Oligonucleotide Therapeutics (ed. Khtar, 1995). In particular, the method using RNA molecules is described in detail in WO94 / 02595 pamphlet. These documents are related to ribosome encapsulation, iontophoresis, or incorporation into other media (eg hydrogels, cyclodextrins, biodegradable nanocapsules, bioadhesive spherules, etc.)! However, the method for administering the nucleic acid molecule used in the present invention is not limited to these. For example, a combination of a nucleic acid molecule and these media, or the nucleic acid molecule itself can be administered ex vivo to a cell or tissue, or can be directly injected into a vein or catheter. It can also be administered using a tellurium, an infusion pump, a stent or the like. For example, Neuroscience Letters, 257, 135-138, 1998; Mol. Brain Research, 55, 151-164, 1998; J. Endocri nol., 157, 169-175, 1998; Neuroscience Letters, 247, 21-24, 1998 Describes a method of administering oligonucleotides to the central nervous system using osmotic pumps, for example, Neurosurg. Focus, 3, article 4, 1997 by direct injection. The administration to the central nervous system is described in detail in Drug Delivery systems: Technologies and Commercial Opportunities, Decision Resources, 1998, etc.
[0198] その他の投与方法や投与経路、それに用いる医薬組成物の形態等については、 例えば、国際公開第 93/23569号パンフレット、国際公開第 99/05094号パンフレット、 国際公開第 99/04819号パンフレット、国際公開第 94/02595号パンフレット等に詳しく 記載されているので、これらを準用することができる。  [0198] Other administration methods, administration routes, and forms of pharmaceutical compositions used therefor are, for example, WO 93/23569 pamphlet, WO 99/05094 pamphlet, WO 99/04819 pamphlet. Since these are described in detail in the pamphlet of International Publication No. 94/02595, etc., these can be applied mutatis mutandis.
[0199] これらの医薬組成物を、疼痛、とりわけ神経因性疼痛等に対する予防、治療および Zまたは症状進展抑制に適用する場合、その医薬組成物の投薬期間は、例えば予 防効果を期待するものであれば実質的に疼痛の発生が抑制されるまで、例えば治療 効果を期待するものであれば実質的に治療が完了するまで、例えば症状進展抑制 効果を期待するものであれば症状進展が実質的に抑制されるまでの何れの期間で あってもよい。また所望によって適当な休薬期間をおいて、間歇的に投薬しても構わ ない。間歇的投与では、休薬期間は 1日以上 30日以下であることが好ましぐ例えば 、 1日おきの間歇的投与、 2日投与 1日休薬の間歇的投与、 5日連投後 2日休薬する 間歇的投与等や、一般的にカレンダー方式 (例えば、錠剤であればカレンダ一錠と 称される。）を用いた間歇的投与であってもよい。  [0199] When these pharmaceutical compositions are applied to the prevention, treatment and Z or symptom progression suppression of pain, particularly neuropathic pain, etc., the dosing period of the pharmaceutical composition is expected to have a prophylactic effect, for example. If it is expected to have a therapeutic effect, for example, if the therapeutic effect is expected to be substantially completed, for example if it is expected to have a symptom progression suppressing effect, the symptom progression is substantially It may be any period until it is suppressed. If desired, it may be administered intermittently with an appropriate drug holiday. In intermittent administration, it is preferable that the drug withdrawal period is 1 day or more and 30 days or less, for example, intermittent administration every other day, administration for 2 days, administration of intermittent treatment for 1 day, 2 days after continuous administration for 5 days It may be intermittent administration such as intermittent administration, etc., or a calendar system (for example, a tablet is called a calendar tablet).
[0200] 本発明の剤における具体的な投薬期間としては、例えば、経口的な投与であれば 、 1日乃至 5年間等、好ましくは 1日乃至 1年間等、より好ましくは 1日乃至 6ヶ月間等 、特に好ましくは 1日乃至 2ヶ月間等が挙げられる。また例えば、静脈内投与であれ ば、 1日乃至 100日間等、好ましくは 1日乃至 10日間等、より好ましくは 1日乃至 7日 間等、最も好ましくは、 7日間等が挙げられる。  [0200] The specific dosing period in the agent of the present invention is, for example, for oral administration, 1 day to 5 years, preferably 1 day to 1 year, more preferably 1 day to 6 months. Especially preferred is a period of 1 day to 2 months. Further, for example, in the case of intravenous administration, 1 day to 100 days, etc., preferably 1 day to 10 days, etc., more preferably 1 day to 7 days, etc., most preferably 7 days, etc. are mentioned.
[0201] これらの投薬期間中における 1日あたりの投薬回数としては、経口的な投与や静脈 内投与の投与形態では、例えば、 1回乃至 5回等、好ましくは 1回乃至 3回等、より好 ましくは 1回乃至 2回等、最も好ましくは 1回等が挙げられる。また経皮投与では、局 所的な作用が期待できるため、痛みを感じた時にその部位に投与することで、より優 れた効果を得ることができる。 [0201] The number of doses per day during these dosing periods is, for example, 1 to 5 times, preferably 1 to 3 times, etc. in the oral administration and intravenous administration forms. Good Preferably, it is once or twice, most preferably once. In addition, since transdermal administration can be expected to have a local action, it is possible to obtain superior effects by administering to the site when pain is felt.
[0202] 本発明に用いられる、 ΓΡ2Υ 受容体および [0202] ΓΡ2Υ receptor used in the present invention and
12 Zまたは P2Y 受容体ブロッカー」を  12 Z or P2Y receptor blocker "
14  14
含有してなる医薬組成物は、単剤で使用してもよいし、疼痛治療に用いられる他の薬 剤や治療方法等と併用することもできる。  The contained pharmaceutical composition may be used alone or in combination with other drugs or treatment methods used for pain treatment.
[0203] 他の薬剤と併用する場合は、 1つの製剤中に両成分を配合した配合剤の形態で投 与してもよぐまた別々の製剤として投与する形態をとつてもよい。別々の製剤として の投与には、同時投与および時間差による投与が含まれる。併用される他の薬剤と しては、例えば、ォピオイド鎮痛薬 (例えば、モルヒネ、コディン、フェンタニル、メペリ ジン、メサドン、プロポキシフェン、レボルファノール、ヒドロモルホン、ォキシコドン、ォ キシモルホン、ペンタゾシン等）、神経因性疼痛鎮痛薬 (例えば、 N型カルシウムチヤ ネル阻害薬（例えば、ジコノタイド、 ONO- 2921等）、 ABS-17、 AC-262271, ACP-102 、 ADX- 1、 AV- 333、 AZD- 6538、 CGP- 35024、 CPI- 1714、 DP- 236、 EN- 3215、ガラン タミン [galantamine]、 JO- 1614、 M- 58996、ネゥブラスチン [Neublastin]、 RWJ- 38116 、 VX- 409、 YT-1006、フェンタ-ルパッチ [fentanyl patch]、レべチラセタム [levetirac etam]ゝメマンチン [memantine]、チアガビン [tiagabine]、ゾニサミド [zonisamide]、 AB T- 894、 AZD- 4282、ラミクタル XR[Lamictal XR]、 M- 40403、 T- 62、ベカンパネル [be campanel]、 CNP- 3381、 CNS- 5161、 KDS- 2000、ケタミン 'ァミトリプチリンクリーム [ket amine + amitriptyline combination cream]、フダファ3 rンン [radafaxine]、フノレフイナミ ド [ralfinamide]、 REN- 1654、 ReN- 1869、トラキソプロジル [traxoprodil]、ヮルロセミド [ valrocemide]、ボツリヌス毒素製剤（例えば、 Dysport等）、ラコサミド [lacosamide]、 NG X- 4010、テクチン [Tectin]、 AVP- 923、ルフイナミド [rufinamide]、 GW- 1000、 P2Xァ ンタゴ-スト（例えば、 NF-023、 A-317491, A-317344等）等）、制吐薬（例えば、メトク 口ブラミド、ヒドロキシジン、プロクロルペラジン等）、非ォピオイド系鎮痛薬 (例えば、 非ステロイド系抗炎症薬 (NSAIDs) (例えば、アスピリン、イブプロフェン、ケトプロフエ ン、ナプロキセン、ァセトァミノフェン、セレコキシブ、口フエコキシブ、バルデコキシブ 等)等)、補助鎮痛薬 (例えば、鎮静薬 (例えば、ベンゾジァゼピン系抗不安薬 (例え ば、ジァゼパム、フルラゼパム等)等）、抗うつ薬 (例えば、アミトリプチリン、デシプラミ ン等）、抗てんかん薬 (例えば、ガバペンチノイド (例えば、ガバペンチン、プレガバリ ン等）、カルバマゼピン、フエニトイン、クロナゼパム、ジバルプロエックス、ラモトリジン 、トピラメート、オクスカルバゼピン等）、中枢性筋弛緩薬 (例えば、バクロフェン等）、 局所麻酔薬 (例えば、メキシレチン、リドカイン等)等)等が挙げられる。 [0203] When used in combination with other drugs, it may be administered in the form of a combination of both components in one preparation, or it may be administered as a separate preparation. Administration as separate formulations includes simultaneous administration and administration by time lag. Other drugs used in combination include, for example, opioid analgesics (eg morphine, codin, fentanyl, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxycodone, oxymorphone, pentazocine) Painkillers (eg, N-type calcium channel inhibitors (eg, Ziconotide, ONO-2921, etc.), ABS-17, AC-262271, ACP-102, ADX-1, AV-333, AZD-6538, CGP -35024, CPI-1714, DP-236, EN-3215, Galantamine, JO-1614, M-58996, Neublastin, RWJ-38116, VX-409, YT-1006, Fental patch [ fentanyl patch], levetiracetam [levetirac etam] ゝ memantine [memantine], tiagabine [tiagabine], zonisamide, AB T-894, AZD-4282, lamictal XR [Lamictal XR], M-40403, T-62 , Becan panel [be c ampanel], CNP-3381, CNS-5161, KDS-2000, Ketamine 'amitriptyline combination cream], Hudafa 3 runn [radafaxine], Funorefinamide [ralfinamide], REN-1654, ReN -1869, traxoprodil, valrocemide, botulinum toxin preparation (eg Dysport, etc.), lacosamide, NG X-4010, tectin, Tectin, AVP-923, rufinamide, GW-1000 , P2X antagonists (eg, NF-023, A-317491, A-317344, etc.), antiemetics (eg, methocral blamide, hydroxyzine, prochlorperazine, etc.), nonopioid analgesics (eg, For example, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, ibuprofen, ketoprofen, naproxen, acetaminophen, celecoxib, oral fuecoxib, valdecoxib ), Etc.), auxiliary analgesics (e.g., sedatives (e.g., Benzojiazepin anxiolytics (eg E.g., diazepam, flurazepam, etc.), antidepressants (e.g., amitriptyline, desipramine, etc.), antiepileptics (e.g., gabapentinoids (e.g., gabapentin, pregabalin, etc.), carbamazepine, phenytoin, clonazepam, divalpro X, lamotrigine, topiramate, oxcarbazepine etc.), central muscle relaxants (eg baclofen etc.), local anesthetics (eg mexiletine, lidocaine etc.) etc.
[0204] また、他の治療方法と組み合わせる場合においても、「P2Y 受容体および  [0204] Also, in combination with other treatment methods, "P2Y receptor and
12 Ζまた は Ρ2Υ 受容体ブロッカー」を含有してなる医薬組成物の投与と、他の治療方法は The administration of a pharmaceutical composition containing `` 12 Ζ or Ρ2 ロ ッ カ ー receptor blocker '' and other treatment methods include
14 14
同時に行ってもよいし、別々に行ってもよい。他の治療方法としては、例えば、神経 ブロック（例えば、トリガーポイントブロック、星状神経節ブロック、腕神経叢ブロック、 肩甲上神経ブロック、硬膜外ブロック、神経根ブロック、椎間関節ブロック、分離部ブ ロック、坐骨神経ブロック、肋間神経ブロック等）、脊髄刺激療法、無痙攣性通電、ィ オントフォレシス、鉞灸 (例えば、電気鉞、置鉞、灸等）、指圧、マッサージ、電気治療 It may be performed simultaneously or separately. Other treatment methods include, for example, nerve blocks (eg, trigger point block, stellate ganglion block, brachial plexus block, suprascapular nerve block, epidural block, nerve root block, facet joint block, isolation Block, sciatic nerve block, intercostal nerve block, etc.) spinal cord stimulation therapy, nonconvulsive energization, iontophoresis, acupuncture (eg, electric acupuncture, placement, acupuncture, etc.), acupressure, massage, electrotherapy
(例えば、経皮的電気神経刺激法 (TENS)、低周波等）、温熱療法 (例えば、ホット パック、冷却療法、ジァテルミ一、極超短波等）、光線治療 (例えば、低出力レーザー 、偏光近赤外線等)、温泉 (水)治療 (例えば、湯治、飲泉、鉱泥浴、水中機能訓練等 )、高圧酸素療法、ァロマセラピー、バイオフィードバックやその他の認知的技法 (例 えば、リラクゼーション訓練、催眠療法、注意そらし技法等）、心理カウンセリング等が 挙げられる。 (For example, transcutaneous electrical nerve stimulation (TENS), low frequency, etc.), hyperthermia (for example, hot pack, cooling therapy, diathermy, ultra high frequency, etc.), phototherapy (for example, low power laser, polarized near infrared) ), Hot spring (water) treatment (e.g., hot springs, drinking springs, mud baths, underwater function training, etc.), hyperbaric oxygen therapy, aromatherapy, biofeedback and other cognitive techniques (e.g. relaxation training, hypnosis, Distraction techniques), psychological counseling, etc.
[0205] ΓΡ2Υ 受容体および Zまたは P2Y 受容体ブロッカー」を含有してなる医薬組成  [0205] Pharmaceutical composition comprising a ΓΡ2Υ receptor and a Z or P2Y receptor blocker "
12 14  12 14
物と併用しうる前記の薬剤は例示であって、これらに限定されるものではない。併用 するこれらの薬剤の投与方法は特に限定されず、経口投与であっても非経口投与で あってもよい。また、これらの薬剤は、任意の 2種以上を組み合わせて投与してもよい 。これらの薬剤には、上記したメカニズムに基づいて、現在までに見出されているもの だけでなく今後見出されるものも含まれる。  The aforementioned drugs that can be used in combination with products are merely examples, and are not limited thereto. The administration method of these drugs used in combination is not particularly limited, and may be oral administration or parenteral administration. In addition, these drugs may be administered in combination of any two or more. These drugs include not only those that have been found so far, but also those that will be found in the future, based on the mechanism described above.
[毒性]  [Toxicity]
「P2Y 受容体および Ζまたは Ρ2Υ 受容体ブロッカー」の毒性は非常に低いもの Very low toxicity of “P2Y receptor and Ζ or Ρ2Υ receptor blocker”
12 14 12 14
であり、医薬として使用するために十分安全であると判断できる。例えば、クロピドグ レル硫酸水素塩やチクロビジンはすで販売されており、安全であることが確認されて いる。 It can be judged that it is safe enough to use as a medicine. For example, clopidogrel hydrogensulfate and ticlovidin are already sold and confirmed to be safe. Yes.
[医薬品への適用]  [Application to pharmaceutical products]
本発明は、疼痛の予防、治療および Zまたは症状進展抑制を目的として、或いは P 2Y 受容体および Zまたは P2Y 受容体陽性細胞抑制を目的として、さらには P2Y The present invention aims to prevent and treat pain and to suppress Z or symptom progression, or to suppress P 2Y receptor and Z or P2Y receptor positive cells, and further to P2Y.
12 14 12 14
受容体および Zまたは P2Y 受容体抑制を目的として、 ΓΡ2Υ 受容体および Zま For the purpose of receptor and Z or P2Y receptor inhibition, ΓΡ2Υ receptor and Z
12 14 12 12 14 12
たは P2Y 受容体ブロッカー」の有効量を投与することを特徴とするものである。本発  Or an effective amount of a “P2Y receptor blocker”. Main departure
14  14
明に用いられる「P2Y 受容体および たは Ρ2Υ 受容体ブロッカー」を含有して  Containing the “P2Y receptor or Ρ2Υ receptor blocker”
12 Ζま  12
14  14
なる医薬組成物は、哺乳動物（例えば、ヒト、非ヒト動物、例えば、サル、ヒッジ、ゥシ、 ゥマ、ィヌ、ネコ、ゥサギ、ラット、マウス等）において前記の目的のために使用すること ができる。  The pharmaceutical composition is used for the above purpose in mammals (eg, humans, non-human animals, eg, monkeys, hidges, mice, horses, dogs, cats, rabbits, rats, mice, etc.) be able to.
発明の効果  The invention's effect
[0206] 本発明によって、「Ρ2Υ 受容体および Ζまたは Ρ2Υ 受容体ブロッカー」を疼痛  [0206] According to the present invention, "Ρ2Υ receptor and Ζ or Ρ2Υ receptor blocker" is treated as pain.
12 14  12 14
に用いるための具体的な方法が開示される。「Ρ2Υ 受容体および  A specific method for use in is disclosed. “Ρ2Υ receptors and
12 Ζまたは Ρ2Υ  12 or 2
14 受容体ブロッカー」を投与することにより、疼痛の予防、治療および Ζまたは症状進 展抑制効果を示すことができる。特に、本発明は、既存の治療方法で改善できない 疼痛、例えば、ァロディニァ等の症状を示す患者にも有効な治療方法となる。  By administering “14 receptor blocker”, it is possible to prevent or treat pain and to have an effect of suppressing epilepsy or symptom progression. In particular, the present invention is an effective treatment method for patients who exhibit symptoms such as pain, such as alodynia, which cannot be improved by existing treatment methods.
図面の簡単な説明  Brief Description of Drawings
[0207] [図 1]坐骨神経切断後 3日目のラットにおける脊髄での Ρ2Υ 受容体 mRNA発現を  [0207] [Figure 1] The expression of Ρ2Υ receptor mRNA in the spinal cord in rats 3 days after sciatic nerve transection
12  12
示す in situ hybridization法写真（Ipsi:切断側、 Contra :反対側）白く光っている銀 粒子の集積が、 P2Y mRNA  In situ hybridization photo (Ipsi: cut side, Contra: opposite side) Aggregation of silver particles shining white, P2Y mRNA
12 発現を示す。  12 shows expression.
[図 2]坐骨神経切断後 3日目のラットにおける脊髄での P2Y 受容体 mRNA発現を  [Figure 2] P2Y receptor mRNA expression in the spinal cord of rats 3 days after sciatic nerve transection
14  14
示す in situ hybridization法写真（Ipsi:切断側、 Contra :反対側）白く光っている銀 粒子の集積が、 P2Y mRNA  In situ hybridization photo (Ipsi: cut side, Contra: opposite side) Aggregation of silver particles shining white, P2Y mRNA
14 発現を示す。  14 shows expression.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0208] 以下、実施例によって本発明を詳述するが本発明はこれらに限定されるものではな い。 [0208] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.
[0209] P2Y 受容体および Zまたは P2Y 受容体力 慢性疼痛モデルの作成時にグリア  [0209] P2Y receptor and Z or P2Y receptor strength
12 14  12 14
細胞上に発現すること、ならびに該受容体を拮抗或いは発現抑制することで疼痛が 抑制できることは、例えば、以下の実験によって証明された。また、以下の測定方法 は、測定精度および Zまたは測定感度の向上をは力るために、以下のように改良を 加えたものである。以下に詳細な実験方法を示す。 Pain on the cell by expressing it on the cell and antagonizing or suppressing the expression of the receptor The ability to suppress was proved, for example, by the following experiment. The following measurement methods have been improved as follows in order to improve measurement accuracy and Z or measurement sensitivity. The detailed experimental method is shown below.
実施例 1  Example 1
1 1)ラット坐骨神経切断モデルの作成  1 1) Creation of rat sciatic nerve cutting model
雄性 SDラット（200〜250g)を使用し、ペントバルビタールナトリウム麻酔下で坐骨神 経の切断を行った。術後 3、 7、 14、 30、および 60日後に脊髄を取り出し、急速凍 結させた後、 12 m厚の切片をクライオスタツトにより作成した。  Male SD rats (200-250 g) were used and the sciatic nerve was cut under pentobarbital sodium anesthesia. After 3, 7, 14, 30 and 60 days after surgery, the spinal cord was removed and snap frozen, and then a 12-m thick section was prepared with a cryostat.
1 2)RT— PCR法（P2Y 受容体、 P2Y 受容体の cRNAプローブ作成） 1 2) RT-PCR (P2Y receptor, P2Y receptor cRNA probe preparation)
12 14  12 14
P2Y 受容体（GenBank accession:#AF313450) Se 587-606, As 1013-994  P2Y receptor (GenBank accession: # AF313450) Se 587-606, As 1013-994
12  12
P2Y 受容体（GenBank accession:#U76206) Se 282-301, As 781-762  P2Y receptor (GenBank accession: # U76206) Se 282-301, As 781-762
14  14
以上のプライマー (primer)を設計し、ラット脊髄カゝら抽出したトータル RNAをテンプ レートにして RT— PCR法を行い、 cDNAを作成した。得られた cDNAは p— GEM T-easy vectorに形質転換を行ってシークェンスを確認し、これを cRNAプローブ 用のテンプレートに使用した。  The above primers were designed, and RT-PCR was performed using the total RNA extracted from rat spinal cord as a template to prepare cDNA. The obtained cDNA was transformed into p-GEM T-easy vector to confirm the sequence, and this was used as a template for cRNA probe.
1— 3) in situ hybridization法（P2Y 受容体、 P2Y 受容体の mRNA検出）  1— 3) in situ hybridization method (P2Y receptor, P2Y receptor mRNA detection)
12 14  12 14
前記 1— 2)で作成したテンプレートを使用して、ラジオアイソトープ標識 cRNAプロ ーブを作成し、 in situ hybridization法を行った。さらに、発現細胞同定のため、マイク ログリアのマーカーである Ibal、ァストロサイトのマーカーである GFAP、ニューロン のマーカーである Neu Nを、それぞれ抗 Ibal抗体（anti Ibal IgG)、抗 GFAP抗体（ anti GFAP IgG)、抗 Neu N抗体（anti Neu N IgG)を用いて染色することで、免疫組 織化学と in situ hybridization法の二重染色を行った。  Using the template prepared in 1-2) above, a radioisotope labeled cRNA probe was prepared, and in situ hybridization was performed. Furthermore, for identification of expressed cells, micrologria marker Ibal, astrocyte marker GFAP, and neuronal marker Neu N were combined with anti-Ibal antibody (anti-Ibal IgG) and anti-GFAP antibody (anti-GFAP antibody, respectively). Double staining of immunohistochemistry and in situ hybridization was performed by staining with IgG) and anti-NeuN antibody.
く結果〉 Result>
P2Y 受容体 mRNAは、ナイーブ（naive)の脊髄では Neu N陽性細胞や GFAP P2Y receptor mRNA is expressed in Neu N positive cells and GFAP in the naive spinal cord.
12 12
陽性細胞とは共存しておらず、 Ibal陽性細胞と共存していたため、マイクログリアに 発現していることが分力ゝつた。坐骨神経切断後 1日から脊髄の術側においてマイクロ グリアの増加が見られる力 それに合わせて増加する P2Y 受容体 mRNAの陽性細 Since it was not coexisting with positive cells but coexisting with Ibal positive cells, it was found that it was expressed in microglia. From 1 day after amputation of the sciatic nerve, the strength of the increase in microglia on the surgical side of the spinal cord is increased.
12  12
胞が確認でき、坐骨神経切断 3日（図 1に示す)をピークに少なくとも 30日まで増加し ていた。 Vesicles can be seen and increase up to at least 30 days peaking at 3 days after sciatic nerve cutting (shown in Figure 1) It was.
[0211] P2Y 受容体 mRNAは、ナイーブ (naive)ではほとんど発現していないが、坐骨神  [0211] P2Y receptor mRNA is hardly expressed in naive but is sciatic
14  14
経切断後 1日から増加し始め、少なくとも 14日までは術側において発現が認められ た。坐骨神経切断後 3日の脊髄の暗視野写真を図 2に示す。  It started to increase from 1 day after transection, and was observed on the operation side until at least 14 days. A dark field photograph of the spinal cord 3 days after sciatic nerve cutting is shown in FIG.
[0212] 実施例 2  [0212] Example 2
2— 1)ラット坐骨神経部分結紮モデル (Seltzerモデル)の作成  2-1) Creation of rat sciatic nerve partial ligation model (Seltzer model)
ラット坐骨神経部分結紮モデルは、 Seltzerらの報告（Pain, 43, 205-218, 1990)に準 じて作製した。具体的には、以下の手順で作製した。  The rat sciatic nerve partial ligation model was prepared according to the report of Seltzer et al. (Pain, 43, 205-218, 1990). Specifically, it was produced by the following procedure.
[0213] ペントバルビタールナトリウム麻酔下、雄性 SDラット（250〜350g)の片側の大腿を 切開し、坐骨神経を露出させた。この神経を周囲の結合組織力 注意深く分離し、 7- 0の絹糸を用いて神経の太さの 1Z3〜1Z2が結紮内に保持されるように結紮した。 筋肉と皮膚とをクリップで閉じ、傷口に抗生物質の粉末を振りかけた。尚、シャム処置 動物は、坐骨神経を露出したあと、結紮することなしに傷口を前記と同様の方法で縫 口し 7こ o  [0213] Under anesthesia with pentobarbital sodium, an incision was made in one thigh of male SD rats (250-350 g) to expose the sciatic nerve. The nerve was carefully separated by surrounding connective tissue force and ligated with 7-0 silk thread so that the nerve thickness 1Z3-1Z2 was retained in the ligature. The muscles and skin were closed with a clip and the wound was sprinkled with antibiotic powder. For sham-treated animals, after exposing the sciatic nerve, sew the wound in the same manner as above without ligating.
2— 2)薬物投与  2-2) Drug administration
2— 2— 1)薬物の入手元  2— 2— 1) Source of drug
P2Y 受容体アンチセンス、 P2Y 受容体アンチセンス、およびそれらのミスセンス P2Y receptor antisense, P2Y receptor antisense, and their missenses
12 14 12 14
は、 BIOGNOSTIK社 (ドイツ)で設計および製造したものをそれぞれ使用した。  Used and designed and manufactured by BIOGNOSTIK (Germany).
また、 MRS2395は、 Sigma社より購入（# M5942)したものを使用した。  Also, MRS2395 purchased from Sigma (# M5942) was used.
2— 2— 2)薬物の投与方法、投与期間  2— 2— 2) Drug administration method and administration period
P2Y 受容体アンチセンスおよびそのミスセンスは、浸透圧ポンプ（osmotic pump, P2Y receptor antisense and its missense are known as osmotic pump,
12 12
model 2001)を用いて投与した。具体的には、浸透圧ポンプに接続したカテーテルの 先端を腰椎 L4Z5レベルに留置し、坐骨神経部分結紮の 2日前から髄腔内に 1週間 持続投与（50pmolZhr)した。  model 2001). Specifically, the tip of the catheter connected to the osmotic pump was placed at the L4Z5 level of the lumbar vertebra, and it was continuously administered (50 pmolZhr) into the medullary canal for 2 days before partial sciatic nerve ligation.
[0214] P2Y 受容体アンチセンスおよびそのミスセンスは、上記と同様の方法により、坐骨 [0214] P2Y receptor antisense and its missense were detected by the same method as described above.
14  14
神経部分結紮時より髄腔内に 1週間持続投与 (50pmolZhr)した。  From the time of partial ligation of the nerve, administration was continued into the medullary canal for 1 week (50 pmolZhr).
[0215] P2Y 受容体アンタゴ-ストである MRS2395は、ジメチルスルホキシド（DMSO) 20 [0215] The P2Y receptor antagonist MRS2395 is a dimethyl sulfoxide (DMSO) 20
12  12
%含有生理食塩水（20% DMSO/Saline)に溶解し、上記と同様の方法により、坐骨神 経部分結紮の 2日前力も髄腔内に 1週間持続投与 (0. lnmol/hr, InMZhr)した Is dissolved in physiological saline containing 20% DMSO / Saline and is 2 days before trans-partial ligation was also administered intraperitoneally for 1 week (0.lnmol / hr, InMZhr)
2- 3)機械的刺激に対する過敏反応の評価 2-3) Evaluation of hypersensitive response to mechanical stimulation
ラット足底への機械的刺激に対する逃避閾値 (Withdrawal threshold) (g)をダイナミ ックプフンタ ~~ ·エスアン才メ ~~タ' ~~ (Dynamic Plantar Aesthesiometer) (manufacture d by Ugo Basile)によって計測することで、機械的刺激に対する過敏反応の評価を行 つた。計測は各個体毎に 4回行い、その平均値 (Mean)と標準誤差 (S.E.)を算出した く結果〉  By measuring the withdrawal threshold (g) for mechanical stimulation to the rat plantar by using Dynamic Plantar Aesthesiometer (manufacture d by Ugo Basile) We evaluated hypersensitivity reactions to mechanical stimuli. Measurement is performed 4 times for each individual, and the mean value (Mean) and standard error (S.E.) are calculated.
(1) P2Y 受容体アンチセンス投与試験  (1) P2Y receptor antisense administration study
12  12
坐骨神経部分結紮モデルラットに Ρ2Υ 受容体アンチセンスおよびそのミスセンス  ラ ッ ト 2Υ receptor antisense and its missense in sciatic nerve partial ligation model rats
12  12
を、坐骨神経結紮の 2日前力も髄腔内に 1週間持続投与した場合における、機械的 刺激に対する逃避閾値 (過敏反応）の経時的変化を以下の表 1に示した。  Table 1 shows the changes over time in the escape threshold (hypersensitivity response) to mechanical stimulation when 2 days of sciatic nerve ligation was continuously administered intrathecally for 1 week.
[0216] 尚、表中、「& 136^6」は132丫 受容体アンチセンス投与群を、「missense」は！^丫 [0216] In the table, “& 136 ^ 6” is the 1 3 2 丫 receptor antisense administration group, and “missense” is! ^ 丫
12 12 受容体ミスセンス投与群を、「n」は例数を、「pre」は薬物投与や坐突神経部分結紮を 行っていない段階での逃避閾値を意味する。経時変化は、坐骨神経部分結紮の処 置を行った日を day 0として、その前日は Day -1、その翌日は Day 1というように記載し た。  12 12 Receptor missense administration group, “n” means the number of cases, “pre” means the escape threshold when no drug administration or partial ligation of the sciatic nerve is performed. The change over time was described as Day 0 on the day when the partial sciatic nerve ligation was performed, Day -1 on the previous day, and Day 1 on the next day.
[0217] [表 1]  [0217] [Table 1]
Figure imgf000062_0001
Figure imgf000062_0001
[0218] Ρ2Υ 受容体アンチセンス投与群では、 Ρ2Υ 受容体ミスセンス投与群で見られた [0218] The Ρ2Υ receptor antisense group was seen in the Ρ2Υ receptor missense group
12 12  12 12
過敏反応が抑制された。特に坐骨神経部分結紮の処置日から 3〜5日（Day 3〜Day 5)でその傾向が強く観察された。 (2) P2Y 受容体アンチセンス投与試験 Hypersensitivity reaction was suppressed. In particular, the tendency was strongly observed 3 to 5 days (Day 3 to Day 5) from the treatment day of partial sciatic nerve ligation. (2) P2Y receptor antisense administration study
14  14
坐骨神経部分結紮モデルラットに Ρ2Υ 受容体アンチセンスおよびそのミスセンス  ラ ッ ト 2Υ receptor antisense and its missense in sciatic nerve partial ligation model rats
14  14
を、坐骨神経部分結紮時力も髄腔内に 1週間持続投与した場合における、機械的刺 激に対する逃避閾値 (過敏反応）の経時的変化を以下の表 2に示した。  Table 2 shows the changes over time of the escape threshold (hypersensitivity reaction) to mechanical stimulation when the sciatic nerve partial ligation force was also administered intrathecally for 1 week.
[0219] 尚、表中、「& 136^6」は132丫 受容体アンチセンス投与群を、「missense」は！^丫 [0219] In the table, “& 136 ^ 6” is the 1 3 2 丫 receptor antisense administration group, and “missense” is! ^ 丫
14 14 受容体ミスセンス投与群を意味し、その他は前記に倣って記載した。  14 14 Means the receptor missense administration group, and others are described above.
[0220] [表 2]  [0220] [Table 2]
Figure imgf000063_0001
Figure imgf000063_0001
[0221] P2Y 受容体アンチセンス投与群では、ミスセンス投与群で見られた過敏反応が抑 [0221] In the P2Y receptor antisense group, the hypersensitivity reaction observed in the missense group was suppressed.
14  14
制された。特に坐骨神経部分結紮の処置日から 3〜5日（Day 3〜Day 5)でその傾向 が強く観察された。  It was controlled. In particular, this tendency was strongly observed 3 to 5 days (Day 3 to Day 5) from the treatment day of partial sciatic nerve ligation.
(3) MRS2395投与試験  (3) MRS2395 administration study
坐骨神経部分結紮モデルラットに P2Y 受容体アンタゴニストである MRS2395を、  MRS2395, a P2Y receptor antagonist, was applied to a rat model of partial sciatic nerve ligation.
12  12
坐骨神経部分結紮の 2日前力も髄腔内に 1週間持続投与した場合における、機械的 刺激に対する逃避閾値 (過敏反応）の経時的変化を以下の表 3に示した。  Table 3 below shows the changes over time in the escape threshold (hypersensitivity response) to mechanical stimulation when 2 days of force before partial ligation of the sciatic nerve was continuously administered intrathecally for 1 week.
[0222] 尚、表中、「saline」は生理食塩水投与群を、「MRS2395」は P2Y 受容体アンタゴ-[0222] In the table, "saline" is the physiological saline administration group, and "MRS2395" is the P2Y receptor antagonist.
12 12
ストである MRS2395投与群をを意味し、その他は前記に倣って記載した。  Means the MRS2395 administration group, and the others were described in the same manner as described above.
[0223] [表 3] 3 [0223] [Table 3] Three
Figure imgf000064_0001
Figure imgf000064_0001
(Ms^tS.E.)  (Ms ^ tS.E.)
[0224] Ρ2Υ 受容体アンタゴニストである MRS2395を 1時間あたり 0. lnmolまたは lnmol [0224] RS2Υ receptor antagonist MRS2395
12  12
の割合で髄腔内に持続投与した群では、媒体である生理食塩水投与群で見られた 過敏反応が抑制された。  In the group that was continuously administered intrathecally at the rate of 1%, the hypersensitivity reaction observed in the group administered with physiological saline was suppressed.
[0225] [製剤例] [0225] [Formulation example]
製剤例 1  Formulation Example 1
プラスダレル（5.0kg)、カルボキシメチルセルロースカルシウム（0.2kg)、ステアリン 酸マグネシウム (0.1kg)、微結晶セルロース (4.7kg)の各成分を常法により混合した 後打錠して、一錠中に 50mgの活性成分を含有する錠剤 10万錠を得た。  Ingredients of Plasdalel (5.0 kg), carboxymethylcellulose calcium (0.2 kg), magnesium stearate (0.1 kg) and microcrystalline cellulose (4.7 kg) were mixed by conventional methods and then compressed into tablets. There were obtained 100,000 tablets containing the active ingredient.
製剤例 2  Formulation Example 2
プラスダレル (2.0kg)、マン-トール（20kg)、蒸留水（500L)の各成分を常法により 混合した後、除塵フィルターでろ過し、 5mLずつアンプルに充填し、オートクレーブ で加熱滅菌して、 1アンプル中 20mgの活性成分を含有するアンプル 10万本を得た 産業上の利用可能性  Each component of Plasdalel (2.0kg), Manntoll (20kg) and Distilled water (500L) is mixed by a conventional method, then filtered through a dust filter, filled in 5mL aliquots, sterilized by heating in an autoclave, Obtained 100,000 ampules containing 20 mg of active ingredient in one ampule Industrial applicability
[0226] 本発明の P2Y 受容体および Zまたは P2Y 受容体ブロッカーを含有してなる疼 [0226] A pain comprising the P2Y receptor of the present invention and a Z or P2Y receptor blocker
12 14  12 14
痛の予防、治療および Zまたは症状進展抑制剤は安全で、疼痛、特に神経因性疼 痛、例えば、癌性疼痛、帯状疱疹後疼痛、糖尿病性疼痛、 HIV関連神経因性疼痛、 結石誘発疼痛、神経痛、口腔顔面痛、または痛覚過敏等の疾患における疼痛を顕 著に改善することができるため、患者の生活の自由度を向上させ、 QOLを改善する ことができ、医薬として有用である。 Pain prevention, treatment and Z or symptom progression inhibitors are safe and pain, especially neuropathic pain, eg cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain In addition, pain in diseases such as neuralgia, orofacial pain, or hyperalgesia can be markedly improved, so that the degree of freedom of life of patients can be improved and QOL can be improved, which is useful as a medicine.
T809lC/900Zdf/X3d S9 SC60Z0/.00Z OAV T809lC / 900Zdf / X3d S9 SC60Z0 / .00Z OAV

Claims

請求の範囲 The scope of the claims
[1] P2Y 受容体および Zまたは P2Y 受容体ブロッカーを含有してなる P2Y 受容  [1] P2Y receptor comprising P2Y receptor and Z or P2Y receptor blocker
12 14 12 体および Zまたは P2Y 受容体陽性細胞抑制剤。  12 14 12 and Z or P2Y receptor positive cell inhibitors.
14  14
[2] P2Y 受容体および Zまたは P2Y 受容体抑制剤である請求の範囲 1記載の剤。  [2] The agent according to claim 1, which is a P2Y receptor and a Z or P2Y receptor inhibitor.
12 14  12 14
[3] 疼痛の予防、治療および Zまたは症状進展抑制剤である請求の範囲 1記載の剤。  [3] The agent according to claim 1, which is a prophylactic, therapeutic and Z or symptom progression inhibitor for pain.
[4] 疼痛が神経因性疼痛である請求の範囲 3記載の剤。 [4] The agent according to claim 3, wherein the pain is neuropathic pain.
[5] 神経因性疼痛が癌性疼痛、帯状疱疹後疼痛、糖尿病性疼痛、 HIV関連神経因性 疼痛、結石誘発疼痛、神経痛、口腔顔面痛、または痛覚過敏である請求の範囲 4記 載の剤。  [5] As described in claim 4, wherein the neuropathic pain is cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia Agent.
[6] P2Y 受容体および Zまたは P2Y 受容体ブロッカー力 （a)低分子化合物、（b)抗  [6] P2Y receptor and Z or P2Y receptor blocker power (a) low molecular weight compound, (b) anti-molecular
12 14  12 14
体、（c)アンチセンス、（d)短鎖干渉 RNA、（e)デコイ、（Dリボザィム、または (g)ァプタマ 一である請求の範囲 1記載の剤。  The agent according to claim 1, wherein the agent is (c) antisense, (d) short interfering RNA, (e) decoy, (D ribozyme, or (g) aptamer.
[7] 低分子化合物が、（1)P2Y 受容体アンタゴニスト、（2)Ρ2Υ 受容体アンタゴニスト、 [7] A low molecular weight compound is (1) a P2Y receptor antagonist, (2) a Ρ2Υ receptor antagonist,
12 14  12 14
または (3)Ρ2Υ 受容体と Ρ2Υ 受容体のデュアルアンタゴニストである請求の範囲 6  Or (3) Claim 6 which is a dual antagonist of Ρ2Υ receptor and 請求 2Υ receptor
12 14  12 14
記載の剤。  The agent described.
[8] 低分子化合物が、一般式 (I) [8] The low molecular weight compound is represented by the general formula (I)
[化 1]  [Chemical 1]
Figure imgf000066_0001
Figure imgf000066_0001
[式中、 R1_1は、水素原子、置換基を有していてもよい脂肪族炭化水素基、または置 換基を有していてもよい環状基を表し、 R2_1は、置換基を有していてもよい環状基を 表す。 ]で示される化合物、その幾何異性体、その互変異性体、その塩、その溶媒和 物、またはそれらのプロドラッグ、一般式 (II) [Wherein R 1_1 represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or a cyclic group which may have a substituent, and R 2_1 has a substituent. Represents an optionally cyclic group. , Geometric isomers, tautomers, salts, solvates thereof, or prodrugs thereof, represented by the general formula (II)
[化 2]
Figure imgf000066_0002
[式中、環 Aは置換基を有していてもよい 5〜7員の複素環を表し、 Qは置換基を有し て!ヽてもよ!/ヽ脂肪族炭化水素基または置換基を有して!/ヽてもよ!ヽ環状基を表し、 R1" 2は置換されていてもよいアミノ基を表し、 R2—2は置換基を表す。 ]で示される化合物 、その塩、その N—才キシド体、その溶媒和物、またはそれらのプロドラッグ、一般式 ( III) [Chemical 2]
Figure imgf000066_0002
[In the formula, ring A represents an optionally substituted 5- to 7-membered heterocyclic ring, Q may have a substituent! / ヽ an aliphatic hydrocarbon group or a substituent. !! a has /ヽbe I representヽcyclic group, R 1 "2 represents an amino group which may be substituted, R 2 -. 2 is a compound represented by representing] a substituent, the Salt, its N-xide, its solvate, or their prodrugs, general formula (III)
[化 3] [Chemical 3]
Figure imgf000067_0001
Figure imgf000067_0001
[式中、 R1—3は、水素原子、置換基を有していてもよいアルコキシ基、置換基を有し ていてもよい脂肪族炭化水素基、または置換基を有していてもよい環状基を表し、 R2 _3は、水素原子または置換基を表し、 R3—3は、置換基を有していてもよい環状基を 表し、 X1—3は、水素原子または置換基を表し、 n3は 0または 1〜2の整数を表し、環 D はさらに置換基を有していてもよいフエ-ル基を表す。 ]で示される化合物、その塩、 またはそれらのプロドラッグ、もしくは一般式 (IV) Wherein, R 1 - 3 is a hydrogen atom, an optionally substituted alkoxy group may have may have a substituent aliphatic hydrocarbon group or a substituted group, R 2 _ 3 represents a hydrogen atom or a substituent, R 3 — 3 represents a cyclic group which may have a substituent, and X 1 — 3 represents a hydrogen atom or a substituent. N 3 represents 0 or an integer of 1 to 2, and ring D represents a phenyl group which may further have a substituent. Or a salt thereof, or a prodrug thereof, or a compound represented by the general formula (IV)
[化 4] [Chemical 4]
Figure imgf000067_0002
Figure imgf000067_0002
[式中、 X4および Y4は、それぞれ独立して CH、 C—ハロゲン原子、 C—置換基を有 していてもよいアルキル基、または窒素原子を表し、 Eは、置換基を有していてもよい 環状基または置換されていてもよいアミノ基を表し、 R2—4は、置換基を有していてもよ い脂肪族炭化水素基または置換基を有していてもよい環状基を表し、 R3—4は、ハロ ゲン原子、置換基を有していてもよい脂肪族炭化水素基、または置換基を有してい てもよいアルコキシ基を表し、 R4—4は、置換基を有していてもよい脂肪族炭化水素基 または置換基を有していてもよい環状基を表し、 R5—4は、置換基を表す。 ]で示され る化合物、またはその塩である請求の範囲 7記載の剤。 [Wherein, X 4 and Y 4 each independently represent CH, C-halogen atom, C-alkyl group optionally having substituent (s), or nitrogen atom, and E has a substituent group. be also cyclic group or substituted represents the amino group, R 2 - 4 can may have an aliphatic hydrocarbon group or a substituent but it may also be substituted cyclic represents a group, R 3 - 4 represents halo gen atom, which may have a substituent aliphatic hydrocarbon group or an alkoxy group which may have a substituent,, R 4 - 4 is, It substituted represent also cyclic group also have an aliphatic hydrocarbon group or a substituent, R 5 - 4 represents a substituent. 8. The agent according to claim 7, which is a compound represented by the formula:
[9] 低分子化合物が、クロピドグレル、チクロビジン、カングレロール、プラスダレル、 AZ[9] Low molecular weight compounds include clopidogrel, ticlovidin, cangrelor, prasdarrel, AZ
D-6140、 INS-50589、 INS-49266、 AR-C66096、 ARL-67085、 GR-144043,ロキシフィ バン、 MRS2395またはそれらの塩である請求の範囲 7記載の剤。 The agent according to claim 7, which is D-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, roxifiban, MRS2395 or a salt thereof.
[10] さらに、ォピオイド鎮痛薬、非才ピオイド鎮痛薬、神経因性疼痛鎮痛薬、非ステロイ ド系抗炎症薬、鎮静薬、抗うつ薬、抗てんかん薬、中枢性筋弛緩薬、制吐薬、および 局所麻酔薬から選択される一種以上を組み合わせてなる請求の範囲 3記載の剤。  [10] In addition, opioid analgesics, non-aged pioid analgesics, neuropathic pain analgesics, non-steroidal anti-inflammatory drugs, sedatives, antidepressants, antiepileptics, central muscle relaxants, antiemetics, 4. The agent according to claim 3, comprising a combination of one or more selected from local anesthetics.
[11] 哺乳動物に対し、 P2Y 受容体および 2Y 受容体ブロッカーの有効量  [11] Effective doses of P2Y and 2Y receptor blockers for mammals
12 Zまたは P  12 Z or P
14  14
を投与することを特徴とする、 P2Y 受容体および P2Y 受容体陽性細胞  P2Y receptor and P2Y receptor positive cells, characterized by administration of
12 Zまたは  12 Z or
14  14
抑制方法。  Suppression method.
[12] P2Y 受容体および Zまたは P2Y 受容体抑制方法である請求の範囲 11記載の  [12] The method according to claim 11, which is a method for inhibiting P2Y receptor and Z or P2Y receptor
12 14  12 14
方法。  Method.
[13] 疼痛の予防、治療および Zまたは症状進展抑制方法である請求の範囲 11記載の 方法。  [13] The method according to claim 11, which is a method for preventing and treating pain and inhibiting Z or symptom progression.
[14] P2Y 受容体および Zまたは P2Y 受容体陽性細胞抑制剤を製造するための P2  [14] P2Y to produce P2Y receptors and Z or P2Y receptor positive cell inhibitors
12 14  12 14
Y 受容体および Zまたは P2Y 受容体ブロッカーの使用。  Use of Y receptors and Z or P2Y receptor blockers.
12 14  12 14
[15] P2Y 受容体および Zまたは P2Y 受容体陽性細胞抑制剤が P2Y 受容体およ  [15] P2Y receptor and Z or P2Y receptor positive cell inhibitor are P2Y receptor and
12 14 12  12 14 12
び Zまたは P2Y 受容体抑制剤である請求の範囲 14記載の使用。  15. Use according to claim 14, which is a Z or P2Y receptor inhibitor.
14  14
[16] P2Y 受容体および Zまたは P2Y 受容体陽性細胞抑制剤が疼痛の予防、治療  [16] P2Y receptor and Z or P2Y receptor positive cell inhibitor prevent or treat pain
12 14  12 14
および Zまたは症状進展抑制剤である請求の範囲 14記載の使用。  And the use according to claim 14, which is Z or a symptom progression inhibitor.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008072532A1 (en) * 2006-12-07 2008-06-19 Daiichi Sankyo Company, Limited Pharmaceutical composition having improved storage stability
JP2012520098A (en) * 2009-03-30 2012-09-06 エフ．ホフマン−ラ ロシュ アーゲー How to prevent fogging of glass
US9034860B2 (en) 2006-12-07 2015-05-19 Daiichi Sankyo Company, Limited Pharmaceutical composition containing low-substituted hydroxypropyl cellulose
JP2017505897A (en) * 2013-11-07 2017-02-23 ザ ジェネラル ホスピタル コーポレイション Compositions and methods for detecting and / or treating inflammation
CN106692121A (en) * 2016-11-03 2017-05-24 南昌大学 Application of A317491 in preparation of human immunodeficiency virus glycoprotein 120 induced neuropathy pain medicines
CN107648607A (en) * 2017-09-11 2018-02-02 南昌大学 Application of the purine 2Y12 receptor antagonists in diabetes nerve pathology damage disease medicine is prepared
CN114432315A (en) * 2020-11-05 2022-05-06 华东师范大学 Compound for preventing and treating pain and application thereof
US11708346B2 (en) * 2019-07-23 2023-07-25 Saint Louis University Treatment and prevention of neuropathic pain with P2Y14 antagonists

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2012634A1 (en) * 1990-03-20 1991-09-20 Hassan Salari Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases
WO1999005144A1 (en) * 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO1999041254A1 (en) * 1998-02-17 1999-08-19 Astrazeneca Uk Limited NOVEL TRIAZOLO(4,5-d)PYRIMIDINE COMPOUNDS
WO2000034283A1 (en) * 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
WO2001036421A1 (en) * 1999-11-15 2001-05-25 Astrazeneca Ab Novel [1,2,3]-triazolo[4,5-d]pyrimidine compounds
WO2001036438A1 (en) * 1999-11-15 2001-05-25 Astrazeneca Ab Novel ribose compounds
JP2003509426A (en) * 1999-09-15 2003-03-11 アストラゼネカ アクチボラグ New compound
WO2003057898A2 (en) * 2001-12-31 2003-07-17 Algos Therapeutics, Inc. Methods and materials for modulating p2x2
WO2004022075A1 (en) * 2002-09-04 2004-03-18 Novartis Ag Treatment of neurological disorders by dsrna adminitration
JP2004521074A (en) * 2000-08-21 2004-07-15 インスパイアー ファーマシューティカルズ，インコーポレイティド Compositions and methods for inhibiting platelet aggregation
WO2005000281A2 (en) * 2003-06-24 2005-01-06 Actelion Pharmaceuticals Ltd. Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors
JP2005053903A (en) * 2003-07-24 2005-03-03 Yamanouchi Pharmaceut Co Ltd Quinolone derivative or its salt

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2012634A1 (en) * 1990-03-20 1991-09-20 Hassan Salari Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases
WO1999005144A1 (en) * 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Novel compounds
WO1999041254A1 (en) * 1998-02-17 1999-08-19 Astrazeneca Uk Limited NOVEL TRIAZOLO(4,5-d)PYRIMIDINE COMPOUNDS
WO2000034283A1 (en) * 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
JP2003509426A (en) * 1999-09-15 2003-03-11 アストラゼネカ アクチボラグ New compound
WO2001036421A1 (en) * 1999-11-15 2001-05-25 Astrazeneca Ab Novel [1,2,3]-triazolo[4,5-d]pyrimidine compounds
WO2001036438A1 (en) * 1999-11-15 2001-05-25 Astrazeneca Ab Novel ribose compounds
JP2004521074A (en) * 2000-08-21 2004-07-15 インスパイアー ファーマシューティカルズ，インコーポレイティド Compositions and methods for inhibiting platelet aggregation
WO2003057898A2 (en) * 2001-12-31 2003-07-17 Algos Therapeutics, Inc. Methods and materials for modulating p2x2
WO2004022075A1 (en) * 2002-09-04 2004-03-18 Novartis Ag Treatment of neurological disorders by dsrna adminitration
WO2005000281A2 (en) * 2003-06-24 2005-01-06 Actelion Pharmaceuticals Ltd. Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors
JP2005053903A (en) * 2003-07-24 2005-03-03 Yamanouchi Pharmaceut Co Ltd Quinolone derivative or its salt

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GEREVICH Z. ET AL.: "P2Y1 RECEPTORS EXHIBIT ANTINOCICEPTIVE EFFECTS THROUGH INHIBITION OF N TYPE CALCIUM CHANNELS OF RAT DORSAL ROOT GANGLION NEURONS", SOCIETY FOR NEUROSCIENCE, 2003, XP003008750, Retrieved from the Internet <URL:https://www.sfn.scholarone.com> *
INOUE K. ET AL: "Shinkei Insei Totsu to ATP", PHARMACIA, vol. 41, no. 3, March 2005 (2005-03-01), pages 221 - 225, XP003008751 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008072532A1 (en) * 2006-12-07 2008-06-19 Daiichi Sankyo Company, Limited Pharmaceutical composition having improved storage stability
JPWO2008072532A1 (en) * 2006-12-07 2010-03-25 第一三共株式会社 Pharmaceutical composition with improved storage stability
US9034860B2 (en) 2006-12-07 2015-05-19 Daiichi Sankyo Company, Limited Pharmaceutical composition containing low-substituted hydroxypropyl cellulose
JP2012520098A (en) * 2009-03-30 2012-09-06 エフ．ホフマン−ラ ロシュ アーゲー How to prevent fogging of glass
US10935556B2 (en) 2013-11-07 2021-03-02 The General Hospital Corporation Compositions and methods for detecting and/or treating inflammation
US20180136237A1 (en) * 2013-11-07 2018-05-17 The General Hospital Corporation Compositions and methods for detecting and/or treating inflammation
JP2020042033A (en) * 2013-11-07 2020-03-19 ザ ジェネラル ホスピタル コーポレイション Compositions and methods for detecting and/or treating inflammation
JP2017505897A (en) * 2013-11-07 2017-02-23 ザ ジェネラル ホスピタル コーポレイション Compositions and methods for detecting and / or treating inflammation
US11719711B2 (en) 2013-11-07 2023-08-08 The General Hospital Corporation Compositions and methods for detecting and/or treating inflammation
CN106692121A (en) * 2016-11-03 2017-05-24 南昌大学 Application of A317491 in preparation of human immunodeficiency virus glycoprotein 120 induced neuropathy pain medicines
CN107648607A (en) * 2017-09-11 2018-02-02 南昌大学 Application of the purine 2Y12 receptor antagonists in diabetes nerve pathology damage disease medicine is prepared
US11708346B2 (en) * 2019-07-23 2023-07-25 Saint Louis University Treatment and prevention of neuropathic pain with P2Y14 antagonists
CN114432315A (en) * 2020-11-05 2022-05-06 华东师范大学 Compound for preventing and treating pain and application thereof

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