WO2007020935A1 - Agent thérapeutique pour soulager la douleur, comprenant un récepteur p2y12 et/ou un bloqueur de récepteur p2y14 - Google Patents

Agent thérapeutique pour soulager la douleur, comprenant un récepteur p2y12 et/ou un bloqueur de récepteur p2y14 Download PDF

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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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Japanese (ja)
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Koichi Noguchi
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Ono Pharmaceutical Co., Ltd.
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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

La présente invention concerne un agent thérapeutique pour soulager la douleur. Il s’agit d’un agent préventif, thérapeutique et/ou d’un agent destiné à inhiber le développement d’un symptôme de douleur, comprenant un récepteur P2Y12 et/ou un bloqueur de récepteur P2Y14. En administrant le récepteur P2Y12 et/ou le bloqueur de récepteur P2Y14, divers types de douleurs, particulièrement la douleur neuropathique, par exemple la douleur liée au cancer, la douleur post-zostérienne, la douleur diabétique, la douleur neuropathique découlant du VIH, la douleur causée par des calculs rénaux, la névralgie, la douleur orofaciale ou la douleur liée à une maladie telle que l’hyperalgésie, peuvent être soulagées de manière significative.
PCT/JP2006/316081 2005-08-17 2006-08-16 Agent thérapeutique pour soulager la douleur, comprenant un récepteur p2y12 et/ou un bloqueur de récepteur p2y14 WO2007020935A1 (fr)

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WO2008072532A1 (fr) * 2006-12-07 2008-06-19 Daiichi Sankyo Company, Limited Composition pharmaceutique présentant une stabilité au stockage améliorée
JP2012520098A (ja) * 2009-03-30 2012-09-06 エフ．ホフマン−ラ ロシュ アーゲー ガラスの曇りを防ぐための方法
US9034860B2 (en) 2006-12-07 2015-05-19 Daiichi Sankyo Company, Limited Pharmaceutical composition containing low-substituted hydroxypropyl cellulose
JP2017505897A (ja) * 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 炎症を検出および／または処置するための組成物および方法
CN106692121A (zh) * 2016-11-03 2017-05-24 南昌大学 A317491在制备人类免疫缺陷病毒糖蛋白120诱导神经病理痛药物中的应用
CN107648607A (zh) * 2017-09-11 2018-02-02 南昌大学 嘌呤2y12受体拮抗剂在制备糖尿病神经病理损伤疾病药物中的应用
US11708346B2 (en) * 2019-07-23 2023-07-25 Saint Louis University Treatment and prevention of neuropathic pain with P2Y14 antagonists

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008072532A1 (fr) * 2006-12-07 2008-06-19 Daiichi Sankyo Company, Limited Composition pharmaceutique présentant une stabilité au stockage améliorée
JPWO2008072532A1 (ja) * 2006-12-07 2010-03-25 第一三共株式会社 貯蔵安定性が改善された医薬組成物
US9034860B2 (en) 2006-12-07 2015-05-19 Daiichi Sankyo Company, Limited Pharmaceutical composition containing low-substituted hydroxypropyl cellulose
JP2012520098A (ja) * 2009-03-30 2012-09-06 エフ．ホフマン−ラ ロシュ アーゲー ガラスの曇りを防ぐための方法
JP2017505897A (ja) * 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 炎症を検出および／または処置するための組成物および方法
US20180136237A1 (en) * 2013-11-07 2018-05-17 The General Hospital Corporation Compositions and methods for detecting and/or treating inflammation
JP2020042033A (ja) * 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 炎症を検出および／または処置するための組成物および方法
US10935556B2 (en) 2013-11-07 2021-03-02 The General Hospital Corporation 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 (zh) * 2016-11-03 2017-05-24 南昌大学 A317491在制备人类免疫缺陷病毒糖蛋白120诱导神经病理痛药物中的应用
CN107648607A (zh) * 2017-09-11 2018-02-02 南昌大学 嘌呤2y12受体拮抗剂在制备糖尿病神经病理损伤疾病药物中的应用
US11708346B2 (en) * 2019-07-23 2023-07-25 Saint Louis University Treatment and prevention of neuropathic pain with P2Y14 antagonists

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