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

Abstract

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

Description

 Pain comprising P2Y receptor and Z or P2Y receptor blocker

12 14

Pain treatment

 Technical field

 [0001] The present invention comprises a P2Y receptor and a P2Y receptor blocker,

 12 Z

 14

 (1) pain prevention, treatment and Z or symptom progression inhibitor, (2) Ρ2Υ

 12 receptors and Ζ or Ρ2Υ receptor positive cell inhibitors, and (3) Ρ2Υ receptors and

 14 12 or 2

14 Receptor inhibitor and the like.

 Background art

 According to the “Classification of Chronic Pain” published at the International Association for the Study of Pain (IASP) in 1994, “Pain” Is an unpleasant sensation or an experience with unpleasant emotions that occurs when there is or is likely to cause tissue damage, or an unpleasant sensation expressed as such damage or An unpleasant sensory and e motional experience associated with actual or potential tissue damage, or described in terms such damage.

 [0003] Pain mainly consists of (1) "nociceptive pain", which is thought to be caused by persistent stimulation of nociceptors, and (2) abnormalities in the function of nerve fibers involved in pain transmission and inhibition mechanisms. “Neuropathic pain”, which is the result of the results, and (3) “Psychogenic pain” where emphasis is placed on emotions and emotions.

 [0004] Of these, neuropathic pain is refractory pain resulting from dysfunction of the peripheral or central nervous system, such as pressure on the peripheral nerve, plexus or perineural soft tissue, trauma or injury, Caused by injury to central somatosensory pathways (eg, ascending somatosensory pathways at the spinal cord, brainstem, thalamus or cortical level). Specific examples include neurodegenerative diseases, bone degenerative diseases, metabolic disorders (for example, diabetes), cancer, infection, inflammation, ischemia, surgery, trauma, radiation therapy, administration of anticancer drugs, etc. sell.

[0005] Although the mechanism of neuropathic pain is largely unknown, certain ion channels It is thought to include spontaneous firing of sensory nerves due to novel expression of mitochondrion, firing of sensory nerve fibers in various layers of the spinal cord, and changes in the expression of various neurotransmitters and receptors in the sensory nerve and spinal cord . Typical symptoms of neuropathic pain include Allodynia, Hypergesia, or Hyperesthesia. These symptoms present characteristic pains such as “burning”, “stinging with a needle” or “like electric shock”. For neuropathic pain, it is known that not only analgesics that are effective for normal nociceptive pain but also narcotic analgesics are not effective (The Lancet, 353, 1959-1966, 1999). . For example, morphine is known to have a powerful analgesic effect on nociceptive pain, but does not have a sufficient effect on neuropathic pain. Insufficient analgesic action by morphine is also a major feature of neuropathic pain, and it has been used for its diagnosis (Ayumi Medicine, 189 (10), 751-755, 1999). The reason why morphine is ineffective in neuropathic pain is thought to be due to neurological damage that caused functional and morphological changes in the nerve, resulting in degeneration of inhibitory neurons and a decrease in opioid receptors (latest Brain and Neuroscience Series, VI, “Pain Neuroscience”, Medical View, 97, 1997) o

 [0006] As described above, alodya is one of the typical symptoms of neuropathic pain. Alodya refers to a condition in which normal humans do not feel pain, but to feel a degree of stimulation as pain, and in alodynia, pain is caused by non-noxious stimuli such as light contact and pressure, moderate heat and cooling, etc. It is. In other words, there is a point that there is a qualitative change in sensory response, and that the threshold itself is lowered, which is considered to be a basic characteristic of alodiure. In post-herpetic pain, which is a typical example of neuropathic pain, 87% of patients have had alodidia, and the intensity of post-herpetic pain is proportional to the degree of alodiure. Has been. Alodia is attracting attention as a very important therapeutic target because it is a symptom that significantly lowers the patient's QOL in neuropathic pain including postherpetic pain.

[0007] Currently, neuropathic pain is treated by neurosurgical treatment such as nerve block and spinal epidural electrical stimulation (Ayumi of Medicine, 189 (10), 757-762, 1999), gabapentinya Gabapentinoids such as pregabalin, N-type calcium channel inhibitors such as ziconotide, Cyclic antidepressants (clinical and pharmacotherapy, 18 (7), 643-646, 1999), antiepileptics, local anesthetics, noclofen, etc. are used. However, a safe and effective treatment has not yet been established, and the development of an effective treatment for neuropathic pain is eagerly desired.

On the other hand, purine receptors include a P1 receptor having adenosine as a ligand, adenosine 5,

 There are known P2 receptors with triphosphate (ATP) and adenosine 5'-diphosphate (ADP) as ligands. P2 receptors are further classified into ion channel type (P2X receptor) in which the receptor protein itself constitutes an ion channel and metabolic control type (P2Y receptor) that functions by activating the G protein. Each is further classified into several subtypes.

 [0009] Among the P2 receptors, receptors such as P2X, P2X, P2X, P2Y, and P2Y

 2 3 4 1 2

 Has been suggested to be associated with pain. For example, in a neuropathic pain model in which the fifth lumbar spinal nerve of a rat is cut after ligation, P2X receptors are present in the microglia in the dorsal horn of the spinal cord.

 4 Expresses but inhibits P2X 2, —3, — O— (2,4,6 trinitrophenyl) adenosine

 Four

 N-5-triphosphate (TNP—ATP) to block the stimulation to its receptor can almost completely suppress alodysia, and instead of TNP—ATP, P2X

 It has been reported that administration of pyridoxal phosphate 1-6, azophenol 1, 2, 4, 1-disulfonic acid (PPADS), which does not inhibit 4 is not effective in inhibiting alodiurea (Nature, 242, 778-). 783, 2003).

[0010] Also, P2Y receptor subtype force conjugated to G, such as P2Y and P2Y, vanilloy

 1 2 q / 11

 To enhance pain caused by the receptor TRPV1 (Proc. Natl. Acad. Sci. USA, 98, 6951-6 956, 2001; J. Neurosci., 23, 6058-6062, 2003), and further to C-fiber Expressed P2Y

 2 It has been reported that alodiure develops upon receptor stimulation (Folia Pharmacol. Jpn., 124, 228-233, 2004).

[0011] On the other hand, some compounds have been reported to have P2Y receptor antagonism.

 12

 The For example, the general formula (A)

[0012] [Chemical 1]

[Wherein the formula R ^1A represents a hydrogen atom, optionally substituted alkyl, cycloalkyl, aryl, aryl, alkyl, heteroaryl, heteroaryl, or alkanol; ^2A represents aryl or heteroaryl. Compound, its several isomers, its tautomers, its salts, its esters, or their prodrugs, is a P 2Y receptor antagonistic action, for example, peripheral vascular disease, cardiovascular disease, brain Vascular disease

12

 It is also described that it is useful for prevention and Z or treatment of conditions involving platelet aggregation (see, for example, International Publication No. 2005Z000281 pamphlet (Patent Document 1)).

 [0014] Further, the general formula (B)

[0015] [Chemical 2]

[Wherein R represents an optionally substituted Cl to 6 alkyl, C3 to 8 cycloalkyl, or a phenyl, and R ^2B represents an optionally substituted Cl to 8 Represents an alkyl or the like, one of R ^3B and R ^4B represents a hydrogen atom, the other represents hydroxy, and X ^B represents ΟΗ or NHR ^5B or the like. However, only the necessary parts were extracted from the symbols in the formula. ] The compound, its salt, or its solvate shown by this is a P receptor (old name of P2Y receptor) antagonistic action.

 2T 12

 For example, it is described that it is useful for the treatment of platelet aggregation diseases (see, for example, International Publication No. 99Z05144 pamphlet (Patent Document 2)).

 [0017] Further, the general formula (C)

 [0018] [Chemical 3]

[In the formula, represents H, CH R ^5, COR ^b or the like, and may be substituted. Cl-6 alkyl or CI-6 alkyl etc., R ^3C represents an optionally substituted C3-8 cycloalkyl, R ^4G is optionally substituted with H or a halogen atom C1- 6 represents alkyl or the like. However, only the necessary parts were extracted from the symbols in the formula. Or a salt thereof, or a solvate thereof, exhibits P receptor antagonism, for example,

 2T

 , Myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, etc. are described as being useful for prevention and Z or treatment (for example, WO 01Z1982 6 pamphlet (patent Reference 3)).

 [0020] Further, the general formula (D)

 [0021] [Chemical 4]

 [In the formula, R represents OR or CH R and the like, and R 1 represents Cl to 6 alkyl or Cl to 6

 2

Represents haloalkyl, R ^3D represents an optionally substituted C 3-6 cycloalkyl or the like, and R ^4D represents Cl-6 alkyl. However, only the necessary parts were extracted from the symbols in the formula. ], A salt thereof, or a solvate thereof, exhibits P receptor antagonism.

 2T

 It is described that it is useful for prevention and Z or treatment of, for example, myocardial infarction, thrombotic stroke, transient ischemic attack, or peripheral vascular disease (for example, International Publication No. oiZ

36421 pamphlet (see Patent Document 4)).

[0023] Further, the general formula (E)

[0024] [Chemical 5]

[Wherein, it represents Cl to 6 alkyl or the like substituted with OH or COR, R ^2t represents C1 to 6 alkyl or Cl to 6 haloalkyl, and R ^3E represents an optionally substituted C3 to 6 Represents cycloalkyl and the like. However, only the necessary parts were extracted from the symbols in the formula. ] Compounds, salts thereof, or solvates thereof, exhibit P receptor antagonism, for example

 2T

 For example, it is described that it is useful for prevention and Z or treatment of myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, etc. (for example, WO 01Z364 38 pamphlet (patent Reference 5)).

 [0026] Further, the general formula (F)

 [0027] [Chemical 6]

[Wherein R is optionally substituted, Cl to 6 alkyl, 2 to 6 alkyl, C2 to 6 alkyl, C3 to 8 cycloalkyl, aryl, or chale, etc. R ^2F represents an optionally substituted Cl-8 alkyl, C2-87 ketone, C2-8 alkyl, C3-8 cycloalkyl, etc., R ^3F and R ^4F Both represent hydroxy, R ^5F represents a hydrogen atom or Cl- ⁶ alkyl, R ^6F represents an optionally substituted Cl-6 alkyl, and the like. However, only the necessary parts were extracted from the symbols in the formula. Or a salt thereof, or a solvate thereof, exhibits P receptor antagonist activity, such as angina pectoris,

 2T

 It is described that it is useful for prevention and Z or treatment of myocardial infarction or the like (for example, see International Publication No. 99Z41254 (Patent Document 6)).

[0029] Further, the general formula (G)

[0030] [Chemical 7]

[In the formula, R ¹ l represents an optionally substituted C3-5 alkyl, etc., IT ^G represents a phenyl optionally substituted with a fluorine atom, R ^3G and R ^4G are Both represent hydroxy, R ^G represents X ^G OH, X ^G represents CH, OCH CH, or a bond. However, in the formula

 2 2 2

Only the necessary parts were extracted from the symbol. Or a salt thereof, or a solution thereof. The solvate is P

 It shows 2T receptor antagonistic action and is described as being useful for prevention and Z or treatment of, for example, myocardial infarction, thrombotic stroke, transient ischemic attack, or peripheral vascular disease! , International Publication No. 00Z34283 pamphlet (Patent Document 7)).

[0032] Further, the general formula (H)

[0033] [Chemical 8]

[Wherein R ^lh represents a hydrogen atom, an optionally substituted Cl-6 alkyl group, a C3-6 cycloalkyl group, a Cl-6 alkoxy group, a C6-10 aryl group, or the like, R ^2H is a hydrogen atom, Cl to 7 alkanoyl group, C7 to: L 1 aryl hydrocarbon group, C 6 to 10 aryl sulfo group, C 7 to 16 alkyl aryl sulfo group, Cl to 6 alkyl sulfur R ^3H represents an optionally substituted C6-10 aryl group, heteroaryl group, etc., x ^1H , x ^2H , x ^3H , x ^4H , and x ^5H are independently hydrogen atoms Represents a halogen atom or the like, and n ^H represents an integer of 0 to 2. However, only the necessary parts were extracted from the symbols in the formula. ], A pharmacologically acceptable salt thereof, and a prodrug thereof. It has an ADP receptor antagonism and is useful for the prevention or treatment of thromboembolic diseases and the like! (See, for example, JP-A-2005-179350 (Patent Document 8)).

 [0035] Further, the general formula (J)

 [0036] [Chemical 9]

[Wherein, represents C—R ”or N, represents C—R ^W or N, and R ^1U represents a hydrogen atom, an optionally substituted lower alkyl, or an optionally substituted. R ¹ represents an amino optionally substituted with lower alkyl, R ¹ represents a hydrogen atom, or lower alkyl or aryl each optionally substituted, R ^1U and R ¹ represent an adjacent nitrogen atom and Together, R may form an optionally substituted cyclic amino, each independently represents an optionally substituted lower alkyl, cycloalkyl, aryl or heterocycle, wherein R is halogen, Represents lower alkyl, or —O-lower alkyl, represents a lower alkyl substituted with cycloalkyl or non-aromatic heterocyclic ring, or cycloalkyl, each optionally substituted; Substituted with hydrogen atom, halogen, cyano, nitro, lower alkyl, halogeno lower alkyl, cycloalkyl, aryl, heterocycle, O lower alkyl, OH, mono NHCO lower alkyl, N (lower alkyl) CO —lower alkyl, lower alkyl Represents an optionally substituted or substituted cyclic amino, and R ^W represents a hydrogen atom, halogen, lower alkyl Or halogeno lower alkyl, and R ″ represents a hydrogen atom, halogen, lower alkyl or halogeno lower alkyl. However, the symbols in the formula are extracted only as necessary.] The quinolone derivative represented by Acceptable salt has P2Y inhibitory action, and platelets

 12

 It is described that it is useful as an aggregation inhibitor (see, for example, JP-A-2005-053903 (Patent Document 9)).

[0038] However, so far, among P2Y receptors, especially G such as P2Y and P2Y.

 Receptor subtypes conjugated with 12 14 i are associated with the development of pain, particularly neuropathic pain, and there is no mention that these receptor blockers are useful for the treatment of pain.

 [0039] 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

 Disclosure of the invention

Problems to be solved by the invention [0040] An object of the present invention is to provide a preventive, therapeutic and Z or symptom progression inhibitor for pain, particularly neuropathic pain.

 Means for solving the problem

[0041] As a result of study using the rat sciatic nerve cutting model, the present inventors have found that P2Y receptor and P2Y receptor development in spinal microglia peaked at 3 days after nerve cutting.

 12 14

 I found the surprising phenomenon that the present increases selectively. The present inventors made further studies based on this finding and completed the present invention.

[0042] That is, the present invention provides

 [1] P2Y receptor and Ζ or Ρ2Υ receptor blocker containing Ρ2Υ receptor

12 14 12 volume and Ζ or Ρ2Υ receptor positive cell inhibitor;

 14

 [2] The agent according to [1], which is a Ρ2Υ receptor and a Ζ or Ρ2Υ receptor inhibitor;

12 14

 [3] The prevention and treatment of pain and the agent according to the above [1], which is an agent for suppressing epilepsy or symptom progression; [4] the agent according to the above [3], wherein the pain is neuropathic pain;

 [5] The agent according to [4], wherein the neuropathic pain is cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia. ;

 [6] Ρ2Υ receptor and Ζ or Ρ2Υ receptor blocker force (

 12 14 a) a low molecular compound, (b) an antibody, (c) an antisense, (d) a short interfering RNA, (e) a decoy, (D ribozyme, or (g) an aptamer Agent;

 [7] Low molecular weight compounds are (1) P2Y receptor antagonists, (2) Ρ2Υ receptor antagonists

 12 14

 Or (3) the dual antagonist of the 記 2 デ ュ ア ル receptor and the Ρ2 受 容 receptor [6] above

 12 14

 Listed agents;

 [8] The low molecular weight compound is represented by the general formula (I)

[0043] [Chemical 10]

[Wherein R ^1_1 represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or a cyclic group which may have a substituent, and R ^2_1 represents a substituent. It represents a cyclic group which may have a group. , Geometric isomers, tautomers, salts, solvates thereof, or prodrugs thereof, represented by the general formula (II)

[0045] [Chemical 11]

[In the formula, ring A represents an optionally substituted 5- to 7-membered heterocyclic ring, Q represents a substituent, and may be! / An aliphatic hydrocarbon group. !! or an substituted /ヽI beヽcyclic group, R ¹ "2 represents an amino group which may be substituted, R ² - ² are shown and represented] a substituent. Compound, salt, N-xide, solvate, or prodrug thereof, general formula (III)

 [0047] [Chemical 12]

[In the formula, R ^{1 —} ° has a hydrogen atom, an alkoxy group which may have a substituent, an aliphatic hydrocarbon group which may have a substituent, or a substituent. represent also cyclic group, R ² _ ³ represents a hydrogen atom or a substituent, R ³ - ³ represents a cyclic group which may have a substituent, X ¹ - ³ is a hydrogen atom or Represents a substituent, n ³ represents 0 or an integer of 1 to 2, and ring D represents a phenyl group which may further have a substituent. Or a salt thereof, or a prodrug thereof, or a compound represented by the general formula (IV)

 [0049] [Chemical 13]

[Wherein, X ⁴ and Y ⁴ each independently represent CH, C-halogen atom, C-alkyl group optionally having substituent (s), or nitrogen atom, and E represents a substituent group. the represents an amino group which is also cyclic group, or a substituted have, R ² - ⁴ are have an aliphatic hydrocarbon group, or a substituent not good may have a substituent R ³ — ⁴ represents a halogen atom, an aliphatic hydrocarbon group which may have a substituent, or an alkoxy group which may have a substituent, R ⁴ — ^4, have a which may have an aliphatic hydrocarbon group or an optionally substituted a substituent represent also cyclic group, R ⁵ - ⁴ represents a substituent. The agent of the above-mentioned [7], which is a compound represented by the formula:

 [9] The low molecular weight compound is clopidogrel, ticlovidin, cangrelor, prasdarrel, A ZD-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, oral xyfiban, MRS2395 or those The agent according to the above [7], which is a salt;

 [10] In addition, opioid analgesics, non-aged pioid analgesics, neuropathic pain analgesics, non-steroidal anti-inflammatory drugs, sedatives, antidepressants, antiepileptics, central muscle relaxants, antiemetics, [11] The agent according to the above [3], comprising a combination of at least one selected from local anesthetic powers; and [11] having a P2Y receptor or a P2Y receptor blocker for a mammal.

 12 Z

 14

 A P2Y receptor characterized by administering an effective dose and

 12 Z or P2Y receptor positive

 14

 Cell suppression method;

 [12] The method according to [11] above, wherein the method is a method for inhibiting P2Y receptor and Ζ or Ρ2Υ receptor

 12 14

 Method;

 [13] The method according to [11] above, which is a method for preventing, treating and suppressing epilepsy or symptom progression;

 [14] For producing Ρ2Υ receptor and Ζ or Ρ2Υ receptor positive cell inhibitor

 12 14

 Ρ2Υ receptors and

 12 Ζ or Ρ2Υ use of receptor blockers;

 14

 [15] Ρ2Υ receptor and Ζ2 or Ρ2Υ receptor positive cell inhibitor is Ρ2 受 容 receptor

 12 14 12 and use according to [14] above, which is a Ζ or Ρ2Υ receptor inhibitor; and

 14

 [16] Ρ2Υ receptor and Ζ or Ρ2Υ receptor-positive cell inhibitor prevent or treat pain

 12 14

 And the use according to [14] above, which is an acupuncture or symptom progression inhibitor.

[0051] In the present invention, "体 2Υ receptor and Ζ or Ρ2Υ receptor blocker" means Ρ In at least one of 2Y receptor and P2Y receptor,

12 14

 Any substance may be used as long as a receptor suppresses a signal that is also transmitted to cells when a host (eg, cocoon, ADP, etc.) is bound. That is, it may be a substance that decreases the binding between a receptor and an in vivo ligand, such as a so-called receptor antagonist (antagonist), and it is coupled to these receptors to produce a G protein ( G) or later

 i / o

 It may be a substance that suppresses signal. It may also be one that reduces the expression level of the receptor itself. Such substances, i.e. P2Y receptor and Z or P2Y receptor

 12 14 Container blockers include, for example, (a) low molecular weight compounds, (b) antibodies, (c) antisense, (d) short interfering RNAs, (e) decoys, (D ribozymes, (g) Abutamas, etc. The thing which has the form of is mentioned.

 [0052] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"

 12 14

 “Antibodies” include, for example, anti-2 receptor antibodies and anti-2 receptor antibodies. This

 12 14

 These antibodies should be Ρ2Υ receptors or antibodies that can recognize Ρ2Υ receptors, respectively.

 12 14

 Either a polyclonal antibody or a monoclonal antibody may be used. In addition, the site that recognizes the Ρ2Υ receptor and the site that recognizes the Ρ2Υ receptor in one antibody molecule

 12 14

 It is possible to obtain a bispecific antibody by providing. Particularly preferred are antibodies that can be safely administered to humans, such as human antibodies (eg, human monoclonal antibodies) or humanized antibodies. These antibodies are (1) Ρ2Υ 2Υ

 12 receptors or Ρ

 14 receptors

, (2) Ρ2Υ receptor or Ρ2Υ complex of receptor and carrier protein, or (3)

 12 14

 Induction with amino group or carboxyl group in Ρ2Υ receptor or 鎖 2Υ receptor side chain

 12 14

 It can be produced according to a known antibody or antiserum production method using a complex of the antibody and carrier protein as an antigen. An example of the specific method is shown below.

 [Preparation of monoclonal antibody]

 (a) Preparation of monoclonal antibody-producing cells

 Antigens for producing anti-P2Y receptor antibodies or anti-P2Y receptor antibodies are:

 12 14

It is administered to a mammal alone or together with a carrier or diluent. In order to enhance antibody production during administration, complete Freund's adjuvant or incomplete Freund's adjuvant is used. It may be administered. Dosing is usually performed once every 2 to 6 weeks, 2 to 10 times in total. As the mammal to be used, for example, a power mouse and a rat including a monkey, a rabbit, a dog, a guinea pig, a mouse, a rat, a hedge, a goat and the like are preferably used. In addition, the administration site is not particularly limited, as long as the antibody can be produced. Monoclonal antibody-producing cells are prepared by selecting a warm-blooded animal that has been immunized with an antigen, for example, an individual with an antibody titer, such as a mouse, and collecting the spleen or lymph nodes 2 to 5 days after the final immunization. Monoclonal antibody-producing hyperpridoma can be prepared by fusing the antibody-producing cells contained therein with myeloma cells. The antibody titer in the antiserum can be measured, for example, by reacting the labeled P2Y receptor or the P2Y receptor with the antiserum.

 12 14

Can be performed by measuring the activity of the labeling substance bound to the antibody.

. The fusion operation with myeloma cells can be performed according to a known method, for example, the method of Kohler and Milstein (Nature, 256, 495, 1975). In order to promote fusion, for example, polyethylene glycol (PEG), Sendai virus or the like (preferably PEG or the like) is used. Here, examples of myeloma cells include NS-1, P3U1, SP2Z0, etc., and P3U1 is preferred. The preferred ratio between the number of antibody-producing cells (spleen cells) and the number of myeloma cells used is about 1: 1 to 20: 1, and PEG (preferably PEG1000 to PE)

G6000) 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.

 Various methods can be used to screen for monoclonal antibody-producing hybridomas. For example, antigens such as P2Y receptor and P2Y receptor can be used directly or with a carrier.

 12 14

Anti-immunoglobulin antibody labeled with radioactive substance or enzyme etc. is added to the solid phase (for example, microplate) adsorbed together, and then labeled with radioactive substances or enzymes (if the cells used for cell fusion are mice, (Anti-mouse immunoglobulin antibody is used) or protein A is added to detect monoclonal antibody bound to the solid phase. Hypridoma culture supernatant is added to the solid phase adsorbed with anti-immunoglobulin antibody or protein A. And a method of detecting a monoclonal antibody bound to a solid phase by adding a receptor protein labeled with a radioactive substance or an enzyme. Monoclonal antibody selection is well known or Is a force that can be performed according to a similar method. Usually, it can be performed in a medium for animal cells to which HAT (hypoxanthine, aminopterin, thymidine) is added. Any medium can be used as a selection and breeding medium as long as it is capable of growing Hypridoma. For example, RPMI-1640 medium containing 1% to 20%, preferably 10% to 20% fetal bovine serum, GIT medium (made by Wako Pure Chemical Industries) containing 1% to 10% fetal bovine serum, or hybridoma culture Serum-free medium (SFM-101, manufactured by Nissui Pharmaceutical) etc. can be used. The culture temperature is usually 20 ° C to 40 ° C, preferably about 37 ° C. The culture time is usually 5 days to 3 weeks, preferably 1 week to 2 weeks. Cultivation can usually be performed under 5% carbon dioxide gas. The antibody titer of the cell culture supernatant can be determined in the same manner as the measurement of the antibody titer in the antiserum.

(b) Purification of monoclonal antibody

The separation and purification of the monoclonal antibody can be carried out according to the method of separating and purifying immunoglobulin in the same manner as the separation and purification of ordinary polyclonal antibodies. Examples of such purification methods include salting out, alcohol precipitation, isoelectric precipitation, electrophoresis, adsorption / desorption using ion exchangers (eg DEAE), ultracentrifugation, gel filtration And a specific purification method in which the antibody is obtained by collecting only the antibody using an antigen-binding solid phase or an active adsorbent such as protein A or protein G, and dissociating the binding.

 [Preparation of polyclonal antibody]

The polyclonal antibody can be produced according to a known method or a method analogous thereto. For example, P2Y receptor or P2Y receptor that is an immunizing antigen and carrier protein

 12 14

And then immunize mammals in the same manner as the monoclonal antibody production method described above. From such immunized animals, antibodies against P2Y receptor or P2Y receptor are obtained.

 12 14

It can be produced by collecting the contained material and performing separation and purification of the antibody. In the complex of immunizing antigen and carrier protein used to immunize mammals, the type of carrier protein and the mixing ratio of carrier and hapten are the same as those of immunized knotten cross-linked with carrier. Can be cross-linked at any ratio. For example, urine serum albumin, cythyroglobulin, keyhole limpet hemocyanin, etc. Ratio to hapten 1 On the other hand, a method of coupling at a ratio of about 0.1 to about 20, preferably about 1 to about 5, is used. In addition, various condensing agents can be used for coupling the hapten and the carrier, but an active ester reagent containing glutaraldehyde, carbodiimide, maleimide active ester, thiol group, or dithiopyridyl group is preferably used. The condensation product is administered to a mammal alone or together with a carrier or diluent. In addition, the administration site is not particularly limited as long as the antibody can be produced. In order to enhance antibody production ability upon administration, complete Freund's adjuvant or incomplete Freund's adjuvant may be administered. The administration is usually performed once every 2 to 6 weeks, for a total of 2 to 10 times. The polyclonal antibody can also collect blood, ascites, etc., preferably blood power of the immunized mammal. The polyclonal antibody titer in the antiserum can be measured in the same manner as the above-described measurement of the antibody titer in the serum. Separation and purification of the polyclonal antibody can be performed according to the same immunoglobulin separation and purification method as the above-described monoclonal antibody separation and purification.

[Production of human monoclonal antibody]

 Human monoclonal antibodies can be produced according to a known method or a method analogous thereto. For example, using a transformed or transchromosomal mouse (eg, HuMAb mouse (registered trademark), KM mouse (registered trademark), etc.) containing the human immune system, or phage display for screening a human immunoglobulin gene library It can be produced by using a method or using an SCID mouse in which human immune cells are reconstituted so that a human antibody response is generated by immunization.

[0057] HuMAb mice (registered trademark) (Medarex) have non-rearranged human heavy chains (μ and κ) and κ light chain immunoglobulins with target mutations that inactivate endogenous μ and κ chain loci. Since it contains a human immunoglobulin gene minilocus that encodes a sequence, it is a mouse that can produce a high-affinity human IgG κ monoclonal antibody by an immune response (Handbook of Experimental Pharmacology, 1 丄 << 3, 49— 101, 1994; Intern. Rev. Immunol., 13, 6 5-93, 1995; Ann. NY Acad. Sci., 764, 536-546, 1995). By eliciting an immune response in the mouse using the antigen described above, the “P2Y receptor and

 12 Ζ or Ρ2

“Antibodies as receptor blockers” can be obtained. Also, HuMAb mouse (Register (Trademark) instead of KM mouse (registered trademark) (WO02 / 043478) Xenomouse (Abgenix) (US Patents 5939598, 6075181, 6114598, 6150584, and 6162963), Tc mouse (Proc. Natl. Acad. Sci USA, 97, 722-727, 2000), and Ushi (Nature Biotechnology, 20, 889-894, 2002) having human heavy and light chain transchromosomes can also be used.

 [0058] A method for obtaining a human monoclonal antibody using a phage display method for screening a human immunoglobulin gene library has been established by a known technique. For example, it can be carried out according to the methods described in US Pat.

 [0059] In addition, a method for obtaining a human monoclonal antibody using SCID mice in which human immune cells have been reconstructed so that a human antibody response occurs by immunization has been established in the publicly known art. For example, it can be performed according to the methods described in US Pat. Nos. 5,476,996 and 5,698,767.

 [0060] In the present invention, "P2Y receptor and

 12 Ζ or Ρ2Υ as a receptor blocker

 14

 Antisense refers to, for example, the 塩 基 2Υ receptor or the DNA sequence of the Υ2Υ receptor.

 12 14

 Any nucleotide sequence may be used as long as it contains a complementary or substantially complementary nucleotide sequence or a part thereof, and has an action capable of suppressing the expression of the DNA. A, DNA, or a modified nucleic acid (RNA, DNA) may be used. Specific examples of the modified nucleic acid include, for example, nucleic acid sulfur derivatives, thiophosphate derivatives, and those that are resistant to degradation of oligonucleotides or oligonucleoside amides. P2Y

 The nucleotide sequence substantially complementary to the DNA of 12 receptor or P2Y receptor is, for example, P2

 14

 Base sequence complementary to DNA of Y receptor or P2Y receptor (ie P2Y acceptor)

The total base sequence or partial base sequence of 12 14 12 container or complementary strand of P2Y receptor DNA) and about

 14

 Examples thereof include base sequences having homology of 70% or more, preferably about 80% or more, more preferably about 90% or more, and particularly preferably about 95% or more. In particular, the P2Y receptor or P2

 12

 Of the entire nucleotide sequence of the complementary strand of the Y receptor DNA, (A) an antisense directed to translation inhibition

14

The N-terminal site of the P2Y receptor or P2Y receptor protein. About 70% or more, preferably about 80% or more, more preferably about 90% or more, particularly preferably about 95% or more. Antisense with homology (B) In the case of antisense directed to RNA degradation by RNaseH, the entire P2Y receptor or P2Y receptor DNA containing introns

 12 14

 Antisense having about 70% or more, preferably about 80% or more, more preferably about 90% or more, particularly preferably about 95% or more of homology with the complementary strand of the base sequence is suitable.

 [0061] Antisense is usually composed of about 10 to 40, preferably about 15 to 30 basic forces. The antisense used in the present invention is, for example, a phosphate residue (phosphate) of each nucleotide constituting the antisense in order to prevent degradation by a hydrolytic enzyme such as nuclease. It may be substituted with a chemically modified phosphate residue such as phosphonate or phosphorodithionate. In addition, the sugar (deoxyribose) of each nucleotide may be substituted with a chemically modified sugar structure such as 2′-O-methyli 匕, and the base part (pyrimidine, purine) is also chemically modified. Also good. Of course, in addition to these, antisense in the cell is made more stable, the cell permeability of the antisense is increased, the affinity for the target sense strand is increased, and if it is toxic In some cases, various modifications may be made for the purpose of reducing the toxicity of the antisense. Many such modifications have been reported, for example, in Pharm Tech Japan, 8 卷, 247 or 395, 1992, Antisense Research and Applications, CRC Pres, 1993, and the like. These antisenses can be produced using a known DNA synthesizer or the like.

 [0062] In the present invention, "P2Y receptor and

 12 Ζ or Ρ2Υ as a receptor blocker

 14

 “Short interfering RNA” includes, for example, RNA encoding Ρ2Υ receptor or P2Y receptor

 12 14

 A double-stranded RNA containing a part of RNA and RNA complementary thereto. Such a short interfering RNA can be obtained according to a known method (Nature, 411, 494, 2001) etc.

 12

 Can be designed and produced based on the RNA sequence encoding the P2Y receptor.

 14

 [0063] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"

 12 14

`` Decoy '' includes, for example, Ρ2Ρ receptor or a gene that regulates gene expression of Ρ2Υ receptor A short, double-stranded nucleic acid that mimics a site on a nucleic acid to which a factor such as a protein (eg, transcription factor) binds (single-stranded nucleic acid designed to “fall back” on itself) Such a decoy competitively inhibits the protein (for example, a transcription factor, etc.), so that the gene expression of P2Y receptor or P2Y receptor can be suppressed.

 12 14

 it can. A method for identifying and constructing decoys is described, for example, in US Pat. No. 5,716,780.

 [0064] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"

 12 14

 Ribozyme includes, for example, 高度 2Υ receptor or Ρ2Υ receptor mRNA

 12 14

 Synthetic RNA molecules that catalyze endoribonuclease activity specific to and derivatives thereof. Such a ribozyme can be obtained by using a known method (TRENDS in Molecular Medicine, 7, 22 21, 2001) or the like, and a sequence of RNA encoding P2Y receptor or P2Y receptor.

 12 14

 It can be designed and manufactured based on this. For example, by replacing a part of the known ribozyme sequence with a part of RNA encoding P2Y receptor or P2Y receptor.

12 14

 Can be built. As part of the RNA encoding the P2Y receptor or P2Y receptor

 12 14

 Examples include sequences in the vicinity of a consensus sequence NUX (wherein N represents all bases and X represents a base other than G) that can be cleaved by a known ribozyme.

[0065] In the present invention, as "P2Y receptor and Ζ or Ρ2Υ receptor blocker"

 12 14

 For example, プ タ 2Υ receptor or Ρ2Υ receptor, or its signal

 12 14

 Examples include single-stranded oligonucleotides that specifically bind to protein molecules involved in transmission.

 [0066] In the present invention, "Ρ2Υ receptor and

 12 Ζ or Ρ2Υ as a receptor blocker

 14

 Low molecular weight compounds include, for example, Ρ2Ρ and Ρ2Υ receptors.

 12 Ζ or

 14

 In combination, it regulates low molecular weight compounds that exhibit antagonism and signal transduction of strong receptor power (for example, receptor clustering, protein phosphorylation and dephosphorylation, second messenger generation, target gene expression, etc.) Low molecular weight compounds are included. Among them, 低 2 体 receptor and Ζ or Ρ2Υ receptor directly bind to and antagonize

12 14

 (A) P2Y receptor antagonist, (b) P2Y receptor antagonist

 12 14

Or (c) a dual antagonist of P2Y receptor and P2Y receptor, etc. are preferred. here, The low molecular weight compound means an organic compound having a molecular weight of 1000 or less (preferably a molecular weight of 100 to 700, etc., more preferably a molecular weight of 150 to 500). Dual antagonist refers to a compound that exhibits antagonistic action on both P2Y receptor and P2Y receptor. these

 12 14

 Low molecular weight compounds can be obtained by known methods, such as, for example, the Comprehensive 'Organic' Transformation: A Guide · To ^ · · Functional · Group · Preparations, Second Edition (Richard C. Larock, John Wiley and Sons Inc, 1999) [Comprehensive urganic iransformations: A Guiae to junctional roup Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)]. The product of the reaction can be obtained by usual purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization, etc. It can refine | purify by the method of. If desired, it may be subjected to a treatment such as freeze-drying. These low molecular weight compounds are the P2Y receptor and

 12 Z or P2

Y

 14For example, whether or not the signal through the receptor is suppressed depends on whether the receptor binds to the receptor or the low molecular weight compound is a receptor force signal due to ligand stimulation (for example, ATP stimulation or ADP stimulation). This can be done by using an assembly that evaluates whether or not to suppress transmission.

 [0067] In the present invention, "P2Y receptor and Ζ or Ρ2Υ receptor blocker"

 12 14

 It is preferable that it takes the form of a child compound. For example, a compound represented by the general formula (I), a geometric isomer, a tautomer, a salt, a solvate thereof, or a prodrug thereof, a compound represented by the general formula (Π), Its salt, its 才 -xoxide, its solvate, or their prodrugs are preferred. Further, a compound represented by the general formula (III), a salt thereof, or a prodrug thereof, a compound represented by the general formula (IV), or a salt thereof is also preferable.

 In the present specification, in the general formula (I), the “cyclic group” in the “cyclic group optionally having substituent (s)” is arbitrarily selected from, for example, “carbocycle” or “heterocycle” And a monovalent group formed by removing one hydrogen atom.

[0069] Examples of the "carbocycle" include "C3-15 carbocycle". "C3-15 charcoal "Prime ring" includes "C3-15 monocyclic, bicyclic or tricyclic carbocycle" and "C3-15 spiro-linked bicyclic carbocycle and bridged bicyclic carbocycle". . Examples of the `` C3-15 monocyclic, bicyclic or tricyclic carbocycle '' include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclo Dodecane, Cyclotridecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclopentene, Cyclopentagen, Cyclohexagen, Cyclohexadiene, Cyclooctagen, Benzene, Pentalene, Perhydropentalene , Azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, 6, 7-dihydro-5H-benzo [7] anulene, 5H-benzo [7] anu Len, heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene, acenenaphthylene, acenenaphthene, fluorene, phenalene, phenanthrene, anthracene ring and the like. “C3-15 spiro-bonded bicyclic carbocycles and bridged bicyclic carbocycles” include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] Ndecane, bicyclo [2. 2. 1] heptane, bicyclo [2. 2. 1] hepter 2-ene, bicyclo [3. 1. 1] heptane, bicyclo [3. 1. 1] hepter 2-en Bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, bicyclo [2.2.2] octane 2-adamantane, noradamantane ring and the like.

Examples of the “heterocycle” include “a 3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom”. “3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom” includes “1 to 5 nitrogen atoms, 1 to 2 3-15 membered monocyclic, bicyclic or tricyclic heterocycle containing 1 oxygen atom and Z or 1 sulfur atom "and" 1-5 nitrogen atom, 1-2 oxygen atom and Z Or a 3 to 15-membered spiro-linked bicyclic heterocycle and a bridged bicyclic heterocycle containing one sulfur atom. “3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom” includes, for example, pyrrole Imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, fura , Pyran, oxepin, thiophene, thiopyran, chepine, oxazonole, isoxazole, thiazole, isothiazole, furazane, oxazine, oxazine, oxazazine, oxazepine, oxadiazepine, thiadiazonole, thiazine, thiadiazine, thiazepine, indhiazole Indole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole , Benzothiazole, benzimidazole, chromene, benzoxepin, benzoxazepine, benzox Diazepine, benzochepine, benzothiazepine, benzothiadiazepine, benzodiazepine, benzodiazepine, benzofurazan, benzothiadiazonole, benzotriazole, carbazole, 13 carboline, atalidine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothiazine, Phenoxazine, phenoxathiin, thianthrene, phenanthridine, phenanthorin, perimidine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, virazolidine, dihydropyridine, dihydropyridine, dihydropyridine , Dihydrovirazine, tetrahydrovirazine, piperazine, dihydropyrimidine, Toluhydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, nohydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxsilane, oxetane, dihydrofuran, Tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydroxepin, perhydrooxepin, thiirane, chetan, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrochepin, tetrahydrochepin, par Hydrochepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, te Lahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadi Azol (oxaziazolidin), Dihydrooxazine, Tetrahydrooxazine, Dihydrooxadiazine, Tetrahydro Oxaziazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (Thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiazine Asian Zepin, Monorephorin, Thiomorpholine, Oxathian, Indoline, Isoindoline, Dihydrobenzofuran, Perhydrobenzofuran, Dihydroisobenzofuran, Perhydroisobenzofuran, Dihydrobenzo Thiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthal Razine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline , Perhydrocinnoline, benzoxanthian, dihydrobenzox Gin, dihydrobenzothiazine, pyrazino monoreforin, dihydrobenzoxazonole, perhydrobenzoxazonole, dihydrobenzothiazonore, nohydrobenzozozonole, dihydrobenzimidazole, nohydrobenzimidazole, dihydrobenzase Pin, tetrahydrobenzozepine, dihydrobenzazodiapine, tetrahydrobenzodiazepine, benzodi-aged xepane, dihydrobenzo-aged xazezepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, nohydroataridin, Dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothi And phosphene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane, dioxaidane, benzodioxane, chromene, chromane, benzodithiolane, and benzodithian ring. As "3- to 15-membered spiro-bonded bicyclic heterocycles and bridged bicyclic heterocycles containing 1-5 nitrogen atoms, 1-2 oxygen atoms and Z or 1 sulfur atom" Is For example, azaspiro [4. 4] nonane, oxazaspiro [4. 4] nonane, oxazaspiro [2.5] octane, azaspiro [4.5] decane, 1, 3, 8—triazaspiro [4.5] decane, 2, 7—Jazaspiro [4. 5] decane, 1, 4, 9—Triazaspiro [5.5] Undecane, Oxazas Piro [4.5] Decane, Azaspiro [5.5] Undecane, Azabicyclo [2. 2. 1] heptane , Azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane (8-azabicyclo [3.2.1] octane ring, etc.), azabicyclo [2.2.2] octane (2-azabicyclo) [2. 2. 2] Otane ring, etc.) and azabicyclo [2.1.1] hexane (5-azabicyclo [2. 1. 1] hexane ring, etc.) ring.

 In the present specification, in the general formula (I), the “substituent” in the “cyclic group optionally having substituent (s)” is not particularly limited as long as it is a substituent. The “substituent” includes, for example, (1) substituted or C1-20 alkyl group, (2) substituted !, C2-20 alkyl group, (3 ) An optionally substituted C2-20 alkyl group, (4) an optionally substituted Cl-20 alkylidene group, (5) an optionally substituted cyclic group, (6) an oxo group, ( 7) Hydroxyl group, (8) Cl-20 alkyloxy group optionally substituted, (9) Optionally substituted

V, C2-20 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)

, (23) optionally substituted Cl-20 alkyl sulfonyl group, (24) optionally substituted! / ヽ C2-20 alkenyl sulfonyl group, (25) substituted!ヽ C2-20 alkynylsulfol group, (26) substituted !, may! /, Sulfonyl groups substituted with cyclic groups (eg phenylsulfonyl groups, etc.), (27) substituted Optionally substituted sulfino group, (28) substituted, may be sulfo group, (29) substituted !, may be sulfamoyl group (eg For example, an unsubstituted sulfamoyl group, N-mono or di (optionally substituted Cl-20 alkyl) sulfamoyl group (eg, N-mono-C 1-6 alkylsulfamoyl group (eg, N-methylsulfayl group) Moyl group, N-ethylsulfamoyl group, N-propylsulfamoyl group, N-isopropylsulfamoyl group, N-butylsulfamoyl group, N-isobutylsulfamoyl group, N- (tert-butyl) sulfamoyl group, N-penty Rusulfamoyl group, N-hexylsulfamoyl group, etc.), N, N DiCl-6 alkyl sulfamoyl group (eg, N, N dimethylsulfamoyl group, N, N Jetylsulfamoyl group, N, N Dipropylsulfamoyl group) N, N-dibutylsulfamoyl group, N, N dipentylsulfamoyl group, N, N dihexylsulfamoyl group, N Methyl) -Nethylsulfamoyl group, etc.)))), (30) substituted !, or carbo group (eg methoxy carbo ol group, ethoxy carbo ol group, t-butoxy carbo- C16 alkoxy carbonyl group such as thiol group, etc., for example, C3-8 cycloalkanoyl group such as cyclopentyl carbo yl group, cyclohexyl carbo yl group, etc., for example, C6-10 aryl carbonate such as benzoyl group, etc. (E.g., a heterocyclic carbonyl group which may have a substituent such as morpholine-4-ylcarbol group, piperidine 1-ylcarbol group, 1-methylpiperazine 4-ylcarbol group, etc.), (31 ) May be substituted Cl to 20 acyl groups (eg formyl, acetyl, propanol, bivaloyl, etc.), (32) may be substituted! Carbamoyl (eg, unsubstituted) Force ruby N-mono or di (optionally substituted Cl-20 alkyl) force rubamoyl group (for example, N-mono-Cl-6 alkyl force rubamoyl group (for example, N-methylcarbamoyl group, N ethylcarbamoyl group) N-propyl rubamoyl group, N isopropyl rubamoyl group, N butyl carbamoyl group, N isobutyl carbamoyl group, N— (tert butyl) force rubamoyl group, N pentyl carbamoyl group, N hexyl carbamoyl group, etc. N-Mono Cl-6 alkyl group rubamoyl group (eg, N hydroxymethylcarbamoyl group, N— (2-hydroxyethyl) group rubamoyl group, N— (3-hydroxypropyl) group rubamoyl group, N— (4-hydroxy Butyl) carbamoyl group), amino group or dimethylamino group substituted N mono Cl-6 alkyl strength Luba Moyl group (eg N aminomethylcarbamoyl group, N— (2-aminoethyl) force Rubamoyl group, N— (3-Aminopropyl) force rubamoyl group, N— (4-Aminobutyl) force Rubamoyl group, N- (dimethylamino) methylcarbamoyl group, N— (2-dimethylaminoethyl) force rubamoyl group, N— ( 3) -dimethylaminopropyl) strong rubamoyl group, N— (4-dimethylaminobutyl) strong rubamoyl group, etc.), N, N—diCl-6 alkyl rubamoyl group (for example, N, N-dimethylcarbamoyl group, N, N-Jetylcarbamoyl group, N, N-Dipropyl-carbamoyl group, N, N-dibutylcarbamoyl group, N, N-dipentylcarbamoyl group, N, N-dihexylcarbamoyl group, N-methyl-N -Ethylcarbamoyl group, etc.), N-mono or di (optionally substituted carbocycle or heterocycle) force rubamoyl group (eg N-mono (substituted, optionally carbocycle)) Rubamoyl group (eg, N-cyclopropyl-powered rubamoyl group, N-cyclopentylcarbamoyl group, N-cyclohexylcarbamoyl group, N-phenylcarbamoyl group, etc.))), (33) cyano group, (34) optionally substituted amidino group, (35) nitro group, (36) nitroso group, (37) optionally substituted imino group (for example, unsubstituted imino group, Cl-6 alkyl group) A substituted imino group (for example, methylimino group, ethylimino group, etc.), an optionally substituted C6-10 aryl group substituted with an imino group (for example, a feu-rimino group, a p-fluorofluoroimino group, p-chlorophenimino group, etc.), an imino group substituted with a hydroxyl group such as a hydroxyimino group), (38) an optionally substituted amino group (eg mono- or di-C1-6 alkylamino) Group (for example, Methylamino group, ethylamino group, propylamino group, dimethylamino group, jetylamino group, etc.), mono- or di-C6-10 allylamamino group (eg, phenolamino group, diphenylamino group, etc.), mono-Cl-6 Alkyl mono mono C6-l 0 arylamino group (eg, N-ferro-N-methylamino group, N-ferro-N-ethylamino group, etc.), (39) halogen atom, (40) carboxy group, ( 41) Phosphono group (one PO (OH)), (42) Dihydroxyboryl group (—B (OH)), (43) C1-20 alkyl carb

 twenty two

Borhydrazino group (for example, methylcarbohydrazino group, ethylcarbohydrazino group, etc.), (44) For example, it may have a substituent such as benzaldehyde hydrazone group, p-methoxybenzaldehyde hydrazone group, etc. C6˜: L0 arylhydrazone group and the like can be mentioned, and these optional substituents may be substituted by any number that can be substituted at any substitutable position. (29), (32), (34), (38) “Sulphamoyl group”, “substituted, or rubamoyl group”, “substituted and optionally amidino group” and “optionally substituted amino group” have two substituents. Sometimes together with the nitrogen atom to which they are attached, form a 5-7 membered monocyclic heterocycle containing 1-5 nitrogen atoms, 1 oxygen atom and Z or 1 sulfur atom. This hetero ring formed may be substituted with a Cl-8 alkyl group, a hydroxyl group or an amino group.

 In the present specification, in the general formula (I), among the substituents exemplified in (1) to (44) as the “substituent” in the “cyclic group optionally having substituent (s)”, “cyclic The “group” means a monovalent group formed by removing any one hydrogen atom from the “carbocycle” or “heterocycle”.

[0073] In the present specification, in the general formula (I), among the substituents exemplified in (1) to (44) as "substituents" in the "optionally substituted cyclic group", The description may be, for example, (1) C1-20 alkyl group, (2) C2-20 alkenyl group, (3) C2-20 alkynyl group, (4) C1 ~ 20 alkylidene groups, (5) cyclic groups, (6) Cl-20 alkyl groups substituted with cyclic groups, (7) oxo groups, (8) hydroxyl groups, (9) C1-20 alkyloxy groups, (10) C2- 20 alkyloxy groups, (11) C2-20 alkyloxy groups, (12) hydroxyl groups protected with cyclic groups, (13) C1-20 acyloxy groups, (14) thixo groups, (15) mercapto groups, 16) C1-20 alkylthio group, (17) C2-20 alkylthio group, (18) C2-20 alkylthio group, (19) mercapto group substituted with cyclic group, (20) C1-20 alkyls group Rufyl group, (21) C2-20a Kellsulfiel group, (22) C2-20 alkylsulfur group, (23) Sulfiel group substituted with cyclic group, (24) C1-20 alkylsulfur group, (25) C2-20 alkene -Sulfol group, (26) C2-20 alkylsulfonyl group, (27) sulfonyl group substituted with cyclic group, (28) Cl-20 alkylsulfol group substituted with cyclic group, (29 ) Sulfino group, (30) sulfo group, (31) sulfamoyl group, (32) C1-20 acyl group, (33) Cl-20 substituted with cyclic group, (34) substituted with cyclic group Carbonyl group, (35) force rumoyl group, (36) cyano group, (37) amidino group, (38) -tro group, (39) -troso group, (40) imino group, (41) amino group, ( 42) It means that it may be substituted with a substituent such as a halogen atom and (43) a carboxy group. These optional substituents are substituted by any number that can be substituted at any substitutable position. May be. Of these substituents, “cyclic group” means a monovalent group formed by removing any one hydrogen atom from the “carbocycle” or “heterocycle”.

 In the present specification, in the general formula (I), examples of the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” include “C1-20 alkyl group”. ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.

 In the present specification, in the general formula (I), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified above as the “substituent” in the “cyclic group optionally having substituent (s)”.

In the present specification, in the general formula (Π), the “5- to 7-membered heterocycle” in the “optionally substituted 5- to 7-membered heterocycle” includes, for example, “oxygen” Atoms, nitrogen atoms and sulfur atomic forces, including 5 to 7-membered monocyclic heterocycles containing 1 to 3 selected heteroatoms. Examples of the “5- to 7-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom” include pyrrole, imidazole, pyrazole, pyridine, pyrazine and pyrimidine. , Pyridazine, azepine, diazepine, furan, pyran, age xepin, thiophene, thiopiran, chepin, oxazonole, isoxazolene, thiazole, isothiazole, furazane, oxazine, oxazepine, oxadiazepine, thiazine, thiazepine, thiazepine, pyrroline , Pyrrolidine, imidazoline, imidazolidine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydrobiazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, no Hydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydroviran, tetrahydropyran , Dihydrooxepin, tetrahydroxepin, perhydroxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrochepin, tetrahydrochepin, perhydrochepin, dihydrox Xazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tet Hydro thiazole ( Thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxazine, tetrahydrooxazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine , Dihydroxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazine, tetrahydrothiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiazepine, perhydrothiazepine And hydrothiadiazepine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane and the like.

 In the present specification, in the general formula (基), the “substituent” in the “optionally substituted 5- to 7-membered heterocycle” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). It is done.

 In the present specification, in the general formula (Π), the “aliphatic hydrocarbon group” in the “optionally substituted aliphatic hydrocarbon group” includes, for example, “C1-20 alkyl group” ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.

 In the present specification, in the general formula (ii), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). .

 In the present specification, in the general formula (Π), examples of the “cyclic group optionally having a substituent” include, for example, “having a substituent” in the general formula (I). Examples include those similar to those exemplified as “cyclic group”.

In the present specification, in the general formula (Π), the “optionally substituted amino group” is an unsubstituted one, so-called an amino group, or one or two groups depending on an arbitrary substituent. Examples thereof include a substituted amino group. Such amino groups include, for example, (Cl-8 alkyl) sulfo-lumamino groups (eg, methylsulfo-amino-substituted ethyl sulfo-amino-containing propylsulfonyl-containing butylsulfonylamino, pentylsulfonylamino-containing hexylsulfonylamino, heptyl sulfone). -Luamine-octylsulfo-luamino group and its isomers Etc.), 5- to 7-membered heterocyclic (Cl-6 alkanoyl) amino group (for example, pyridylmethylcarbolamino group), 5- to 7-membered heterocyclic carboamino group (for example, furoyl, tenol, nicotinol group, etc.) ), C5-7 carbocyclic (Cl-6 alkanoyl) amino groups (eg, benzylcarboamino groups, etc.), C5-7 carbocyclic carboamino groups (eg, benzoylamino groups, etc.), N, N-di-Cl ~ 4 alkyl strength ruberamoylamino groups (for example, N, N-dimethylcarbamoylami group N, N-jetylcarbamoylami group N, N-dipropyl power ruberamoylamino, N, N-dibutylcarbamoylamino group, etc.), N- C1 ~ 4 alkyl carbamoylamino groups (for example, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propyl, rubamoylami, N-isopropyl, rubamoylami) N-butyl-powered ruberamoylamino group, etc.), N-acyl-N- (1-6 alkyl) amino groups (1-6 alkyl in the group include, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl) Etc.), N-aryl-N— (Cl-6 alkyl) amino group (for example, N-phenyl-N-methylamino N-phenyl N-ethylamino N-phenyl N-propylamino N — Phenyl-N-butylamino N-Fellow N-Pentylami-containing N-Fellow-N-Hexylamino group, etc., N-Carbocyclic amino group (eg, Cyclohexylami-modified phenyl-containing diphenylamine) Butoxyphen-lamino group, etc.), N-heterocyclic amino group (eg, N-pyridylamino-containing N-quinolylamino group, etc.), islamamino group (eg, Cl-8 alkyl group, such as acetylamino-containing propanolamine group) Butylylamino valeryl amide hexanol amide heptanoyl amide otatanyl amide bivalylamino groups and isomers thereof, etc.), amino groups, aryl sulfonylamino groups (eg, phenylsulfolamino, p-toluenesulfo-lumino groups, etc.) ), Alkylsulfo-ramino groups (for example, methylsulfo-l-amino-substituted ethylsulfo-l-amino-containing benzylsulfo-lamino groups, etc.), rubamoyl (Cl-10 alkyl) amino groups (for example, 1-force rubamoyl- (2-cyclo) (Hexyl) ethylamino group, etc.), strong ruberamoylamino group, mono- or di- (ci-10 alkyl) amino group (eg methylamino, ethylamino, n-propylamino-containing isopropylamino, n-butylamido-isobutylamido tert-butylamido-containing) n-pentylamino, isopen Ruami input Neopenchiruami input n- to Kishiruami input Hepuchiruami input OTA Chiruamino, dimethylaminopyridine input Jechiruami input Jipuropiruami input diisopropyl amino Nyuji Dibutylamino, diheptylamino, dioctylamino, dioctylami, methylpropylami, methylpropylami, and ethylpropylamino, N-butyl-N—cyclohexylmethylamino, etc.), mono- or di- (C6-10 aryl) An amino group (eg, phenylamino, diphenyl-lumino group, etc.), a sulfolamino group substituted with a hydrocarbon group (eg, methylsulfonylamino group, etc.), an oxygen atom in addition to a carbon atom and one nitrogen atom, Sulfur atom, nitrogen atom, etc. 3 to 6 membered cyclic amino group which may contain 1 to 3 selected heteroatoms (eg, acetylidyl, azetidyl, pyrrolidyl, pyrrolinyl, pyrrolyl, imidazolyl, Virazolyl, imidazolidinyl, piperidinated morpholino, dihydropyridyl, pyridyl, N-methylbiperazi- And N-ethylbiperazyl group).

During [0082] this specification, in the general formula (Π), R ² - ² "substituent" represented by is not particularly limited as long as it is a substituent. Examples of such “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I).

 In the present specification, in the general formula (ΠΙ), the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group optionally having a substituent” includes, for example, “C1-20 alkyl group” ”,“ C2-20 alkyl group ”,“ C2-20 alkyl group ”and the like.

 In the present specification, in the general formula (ii), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). Can be mentioned.

 In the present specification, in the general formula (基), examples of the “alkoxy group” in the “optionally substituted alkoxy group” include “C1-20 alkoxy group” and the like. .

 In the present specification, in the general formula (基), the “substituent” in the “alkoxy group which may have a substituent” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). It is done.

In this specification, in the general formula (III), R ¹ — ³ and R ³ — ³ represent “having a substituent. Examples of the “optional cyclic group” include those similar to those exemplified as the “cyclic group optionally having substituent (s)” in the general formula (I).

 [0088] In the present specification, in the general formula (「), the" substituent "in the" optionally substituted phenyl group "represented by ring D is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). .

During [0089] this specification, in the general formula (III), R ² - ³ and X ¹ - ³ represent "substituent" is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those represented by the general formula (I).

Examples thereof include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent.

 In the present specification, in the general formula (IV), examples of the “alkyl group” in the “optionally substituted alkyl group” include “C1-20 alkyl group” and the like. It is done.

 In the present specification, in the general formula (IV), the “substituent” in the “alkyl group optionally having substituent (s)” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). Can be mentioned.

In the present specification, in the general formula (IV), the “cyclic group optionally having substituent (s)” represented by E, R ² — ⁴ and R ⁴ — ⁴ includes, for example, the above general formula ( Examples thereof include those similar to those exemplified as the “optionally substituted cyclic group” in I).

[0093] In the present specification, in the general formula (IV),

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 ".

 In the present specification, in the general formula (IV), the “substituent” in the “optionally substituted aliphatic hydrocarbon group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). Can be mentioned.

[0095] In the present specification, in the general formula (IV), "optionally substituted alkoxy group" Examples of the “alkoxy group” include “C1-20 alkoxy group” and the like.

In the present specification, in the general formula (IV), the “substituent” in the “optionally substituted alkoxy group” is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those exemplified as the “substituent” in the “cyclic group optionally having substituent (s)” in the general formula (I). It is done.

 In the present specification, in the general formula (IV), the “optionally substituted amino group” is an unsubstituted one, that is, a so-called amino group, or one or two substituents by an arbitrary substituent. Amino groups and the like. Examples of such an amino group include those similar to those exemplified as the “optionally substituted amino group” in the general formula (IV).

During [0098] this specification, in the general formula (IV), R ⁵ - ⁴ represent "substituent" is not limited especially if it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). I can get lost.

 In this specification, “halogen atom” means a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom.

 In the present specification, “C1-20 alkyl group” means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Noel, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl Hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl groups and their isomer groups.

 [0101] In the present specification, the "C1-8 alkyl group" means a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.

 [0102] In the present specification, "C2-20 alkyl group" refers to ethyl, probe, butenyl, pentyl, hexyl, heptul, otatur, nonel, decel, It means undecyl, dodecyl, tridecenyl, tetradecyl, pentadecyl, hexadecyl, heptadecenyl, octadecenyl, nonadecenyl, icosyl groups and their isomeric groups.

[0103] In the present specification, the "C2-20 alkyl group" means ethynyl, probule, butur, pentininore, hexnore, hept-nore, octinore, no-nore, decinore, Undeshi Nore, It means dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecynyl, icosinyl groups and their isomeric groups.

 In the present specification, the “C1-20 alkylidene group” means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, otatilidene, no-lidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentade It means a silidene, hexadecylidene, heptadecylidene, octadecidylidene, nonadecylidene, icosilidene group and isomer groups thereof.

 [0105] In the present specification, the "C1-20 alkyloxy group" means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, It means pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy groups and their isomer groups.

 [0106] In the present specification, the "C2-20 alkoxy group" refers to ethuroxy, propyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, none-loxy, dec-loxy, undec It means -loxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecenyloxy, heptadecyloxy, octadecyloxy, nonadeceroxy, icocenyloxy and their isomeric groups.

 [0107] In the present specification, the "C2-20 alkyloxy group" means ethuroxy, propoxy, butynyloxy, pentynyloxy, hexyloxy, heptynyloxy, octyloxy, nitro-oxy, decoxyloxy. , Undecyloxy, dodecyloxy, tridecyloxy, tetradecynyloxy, pentadecyloxy, hexadecinyloxy, heptadesuloxy, octadecyloxy, nonadecyloxy, icosyloxy and their isomerism It means body group.

In the present specification, the “C1-20 alkylthio group” means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, no It means diruthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadecylthio, octadecylthio, nonadecylthio, icosylthio groups and isomeric groups thereof.

 [0109] In the present specification, the "C2-20 alkthio group" refers to etyrthio, probethio, butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio, nonethylthio, decthiolthio. , Undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecenylthio, hexadecenylthio, heptadecylthio, octadecenylthio, nonadecenylthio, icosenylthio and their isomeric groups means.

 [0110] In the present specification, "C2-20 alkylthio group" refers to ethylthio, propylthio, butynylthio, pentynylthio, hexylthio, heptynylthio, octynylthio, no-- Ruthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadesurio, octadedecylthio, nonadecylthio, icosylthio groups and their It means an alien group.

 [0111] In the present specification, "C1-20 alkyl sulfier group" means methyl sulfier, ethyl snorefi-nore, propinoles norefi-nore, butinoles norefi-nore, pentinores norefi -Nore, Hexinoles Norefi-Nore, Heptinoles Norefi-Nore, Otacinores Norefi-Nore, Noninoles Norefirl, Decyl Sulfiel, Undecyl Sulfiel, Dodecyl Sulfiel, Tridecyl Means sulfiel, tetradecylsulfur, pentadecylsulfyl, hexadecylsulfinyl, heptadecylsulfuryl, octadecylsulfuryl, nonadecylsulfinyl, icosylsulfyl groups and their isomeric groups To do.

[0112] In the present specification, "C2-20 alkenylsulfier group" refers to etulsulfier, propenonolesnorefininore, buteninoresnorefininore, penteninoresnorefininore, hexenoresnorefininore, Hepteninolesnorefininole, otateninoresnorefininore, noneninoresnorefinil, decenylsulfier, undecenylsulfier, dodecenylsulfier, tridecenylsulfuryl, tetradecenyls Luffyol, pentadecenylsulfuric acid, hexadecenylsulfuric acid, heptadecenylsulfuric acid, octadecenylsulfuric acid , Nonadecyl sulfier, icosenyl sulfier group and isomers thereof.

 [0113] In the present specification, "C2-20 alkylsulfier group" refers to ethylsulfier, propyninoresnorefininore, butyninoresnorefininore, pentinoinoresnorefininore, hekisnoresnorefi-nore, Heptyl Noles Nore, Otachi Noles Nore Nore, Non-Ninoles Nore, Decyl Sulfyl, Undecyl Sulfyl, Dodecyl Sulfyl, Tridecyl Sulfyl, Tetradecyl Rusulfil, It means pentadesulfuryl, hexadecylsulfil, heptadesulfuryl, octadecylsulfil, nonadecylsulfuryl, icosinylsulfiel groups and their isomeric groups.

 [0114] In the present specification, the "C1-20 alkylsulfonyl group" means methylsulfol, ethyls norehoninole, propinolesnorehoninore, butinoresnorehoninore, pentinoresnorehoninore, Xinore, senorehoninore, heptinolesnorehoninore, octinoresnorehoninore, noninoresnorehoninore, decinolesol, undecylsulfol, dodecylsulfol, tridecylsulfol, tetradecylsulfol, It means pentadecylsulfol, hexadecylsulfol, heptadecinolesnorehoninore, octadecinoresnorehoninore, nonadecinoresnorehoninore, icosinoresnorehoninore group and isomers thereof.

 [0115] In the present specification, "C2-20 alkenylsulfol group" refers to etulsulfol, propenolesnorenore, buteresnorenore, pentenorenorenoinole, hexe- Noresnorejo Ninore, Hefteninoresnorehoninore, Taittenenoresnorehoninore, Nono Ninoresnorehoninore, Ninoreno, Undesenorejo-nore, Dodesenorenorenore, Toridese Nolesnoleol, tetradecylsulfol, pentadecenylsulfol, hexadecylsulfol, heptadecenylsulfol, octadecylsulfol, nonadecylsulfol, icocenylsulfur and These isomer groups are meant.

[0116] In the present specification, "C2-20 alkylsulfol group" means ethylsulfol, propyninoresnorehoninore, butyninoresnorehoninore, pentyninoresnorehoninore, hexyl Ninoles Nore Ninore, Heptininoles Norehoninore, Kuchininores Norehoninore, Nonininores Norehoninore, Tenninore Sunorehoninore, Undeshi Noresnore Nore, Dodeci Nolesnorenore Nore , Tetradecyl sulfol, pentadecyl sulfol, hexadecyl sulfol, heptadecyl sulfol, octadecyl sulfol, nonadecyl sulfol, icosinylsulfonyl group and their isomerism It means body group.

 [0117] In the present specification, the "C1-20 acyl group" means methanol, ethanol, propanoyl, butanol, pentanoyl, hexanoyl, heptanoyl, otatanyl, nonanoyl, decanol, undecanol, tetradecanol, tridecanol, Hexadecanol, heptadecanol, octadecanol, nonadecanol, icosanol and their isomers.

 In the present specification, the “C1-20 acyloxy group” means methanoyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanooxy, hexanoyloxy, heptanoyloxy, otanoyloxy, nonanoyloxy, decanoxy, Undeoxy, dodecanoxy, tridecanoxy, tetradecanoxy, pentadecanoxy, hexadecanoyloxy, heptadecanoxy, octadecanoyloxy, nonadecanoxy, Means icosanoyloxy group and isomers thereof.

 In the present specification, the geometric isomer of the compound represented by the general formula (I) is the general formula (Ig).

[0120]

[ ^Wherein R ^1_lg and R ^2_lg represent the same meaning as R ^1_1 and R ^2_1 in general formula (I), respectively. ] Means.

[0122] The compound represented by the general formula (I) and the tautomer of the compound represented by the general formula (Ig) are those represented by the general formula (It).

[0123] [Chemical 15]

[Wherein R ¹ — “and IT” represent the same meaning as R ¹ 1 ¹ and R ^2_1 in general formula (I), respectively. ], And general formula (Igt)

[0125] [Chemical 16]

[ ^Where R ^1_lgt and R ^2_lgt are R ^{1 _1} and R ² in general formula (I), respectively.

 Represents meaning. ] Means.

In the present specification, preferred compounds in the general formula (I) are represented by the general formula (IA)

[0128] [Chemical 17]

[Wherein R ¹ — ^1A and R ² — ^1A represent the same meaning as R ¹ and R ² described in International Publication No. 2005/000281, respectively. ] Can be represented.

[0130] Further, examples of preferable groups and preferable compounds in general formula (IA) include those similar to those described in International Publication No. 2005/000281 and those described in Examples. Can be mentioned.

[0131] In the present specification, preferred compounds in the general formula (Π) are represented by the general formula (ΠΖ).

[0132] [Chemical 18]

[Wherein ring A ^z represents the same meaning as ring A above, represents a 5- to 6-membered saturated ring ^optionally having a ring or a substituent, and R ^1_2Z represents R ¹ — ² above. R ² — ^2Z represents an ^optionally protected mercapto group. ] Can be represented.

[0134] here, represented by the ring B ^z "have a substituent! /, Even I, saturated ring of 5- to 6-membered,""5-6 in Examples of the “membered saturated ring” include “5- to 6-membered saturated carbocycle” and “5- to 6-membered saturated complex ring”. Examples of the “5- to 6-membered saturated carbocycle” include cyclopentane, cyclohexane and the like. Examples of the “5- to 6-membered saturated heterocyclic ring” include pyrrolidine, imidazolidine, triazolidine, tetrazolidine, virazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene. , Tetrahydrothipyran, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrosazazonole ( Oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydro Ajiajin, morpholine, thiomorpholine, Okisachian and the like.

[0135] represented Ring B ^z "substituent" in the "substituted, also O, 5-6 membered saturated heterocyclic ring" is not particularly limited as long as it is a substituent. Examples of such a “substituent” include those similar to those exemplified as the “substituent” in the “cyclic group” which may have a substituent in the general formula (I). Can be mentioned.

[0136] The " ^optionally protected mercapto group" represented by R ^2_2Z includes, in addition to mercapto groups, for example, mercapto groups protected with aliphatic hydrocarbon groups which may have substituents, substituted And a mercapto group protected with a cyclic group which may have a group. Here, “having a substituent, may be an aliphatic hydrocarbon group” or “having a substituent, may be a cyclic group” used for protecting a mercapto group is the above general formula. Examples of “substituent” in (I) “having a substituent, may be an aliphatic hydrocarbon group” or “having a substituent, but may be a cyclic group” And the like.

 [0137] In the present specification, a more preferable compound in the general formula (Π) is represented by the general formula (ΠΒ).

 [0138] [Chemical 19]

[0139] [wherein R ^1_2B , R ^2_2B , R ^3_2B , R ^4_2B , and X ^2B are R ¹ R ² , R ³ , R ⁴ , and X described in WO99 / 05144, respectively. Represents the same meaning. ], General formula (IIC)

[0140] [Chemical 20]

[0141] [wherein R ¹ —, R ² —, R ^3_2 and R ^4_2C are the same as R ¹ R ² , R ³ and R ⁴ described in WO 01/19826 pamphlet, respectively. Represents meaning. ], General formula (IID)

 [0142] [Chemical 21]

[0143] [wherein R ^1_2D , R ^2_2D , R ^3_2D , and R ^4_2D represent the same meaning as R ¹ R ² , R ³ , and R ⁴ described in WO 01/36421 pamphlet, respectively. . ], General formula (ΠΕ)

 [0144] [Chemical 22]

[0145] [wherein R ^1_2E , R ^2_2E , and R ^3_2E are WO 01/36438 pamphlets, respectively.

R ² and R ³ have the same meaning. ], General formula (IIF)

 [0146] [Chemical 23]

[0147] [wherein R ^1_2F , R ^2_2F , R ^3_2F , R ^4_2F , R ^5_2F , and R ^6_2F are As described in the 9/41254 pamphlet

R ⁵ and R ⁶ have the same meaning. ], And general formula (IIG)

[0148] [Chemical 24]

[0149] [wherein, R ^1_2G R ^2_2G R ³ R ⁴ and R ^2G have the same meaning as R ¹ R ² R ³ R ⁴ and R described in WO 00/34283, respectively. Represents meaning. ] Can be represented.

 [0150] In addition, as preferred, groups and preferred compounds in the general formulas (IIB) (IIC) (IID) (ΠΕ) (IIF) (IIG), respectively, International Publication No. 99/05144 pamphlet, International Publication 01/19826, International Publication 01/36421, International Publication 01/36, 438, International Publication 99/41254, and International Publication 00/3428 3, The same thing and what was described in the Example can be mentioned.

 [0151] In the present specification, preferred compounds in the general formula (ΠΙ) are represented by the general formula (ΠΙΗ).

[0152] [Chemical 25]

In [0153], R ¹ — ^3H R ² — ^3H R ³ — ^3H R ⁴ — ^3H X ^3H X ² — ^3H X ³ — ^3H X ⁴ — ^3H X ⁵ — ^3H and the meaning of the group represented by n ³ H are ,

XX ² X ³ X ⁴ X ⁵ represents the same meaning as n. ] Can be represented.

[0154] Further, in the general formula (ii), the preferred, group, preferred, and compound are, for example, the same as those described in JP 2005-179350 A, and those described in the examples. Can be mentioned. [0155] In the present specification, preferred compounds in the general formula (IV) are represented by the general formula (IVJ).

[0156] [Chemical 26]

[0157] [where 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 Ύ. ] Can be represented.

[0158] Further, examples of preferred, group, preferred, and compound in the general formula (IVJ) include, for example,

Examples similar to those described in JP 2005-053903 A and those described in Examples can be mentioned.

 [0159] Further, in the present invention, "P2Y receptor and

 12 Ζ or Ρ2Υ receptor pro

 14

 Preferable specific examples of `` low molecular weight compound as a cker '' include, for example, clopidogrel, titaropidine, cangrelor, prasdarrel, AZD-6140, INS-50589, INS-49266, AR-C 66096, ARL-67085, GR-144043, Roxifiban, MRS2395 or their salts can be mentioned. The details of these compounds (for example, structure, pharmacological activity, production method, etc.) have been developed or developed as antagonists of P2Y receptors. It was a compound

12

 The

 [0160] In the present invention, unless otherwise specified, the symbol [0161] [Chemical 27]

[0162] indicates binding to the other side of the page (ie OC placement)

 [0163] [Chemical 28]

[0164] represents binding to the front side of the page (ie, β configuration)

[0165] [Chemical 29] Z

 [0166] represents a mixture of the a configuration and the j8-configuration in an arbitrary ratio.

[0167] In the present invention, a compound represented by the general formula (I), a compound represented by the general formula (II), a compound represented by the general formula (III), a compound represented by the general formula (IV) (Hereinafter, these may be collectively abbreviated as the compounds represented by the general formulas (I) to (IV).), Or clopidodarrel, ticlopidine, cangrelor, plusdarrel, AZD-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, Roxyfiban, MRS2395, P2Y

 12 Salts such as antagonists include all pharmacologically acceptable salts. The pharmacologically acceptable salt is preferably low-toxic and water-soluble. Suitable salts include, for example, alkali metal (eg, potassium, sodium, lithium, etc.) salts, alkaline earth metal (eg, calcium, magnesium, etc.) salts, ammonium salts (eg, tetramethylammonium − Salts, tetraptylammonium salts, etc.), organic amines (eg, triethylamine, methylamine, ethylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Salts of tris (hydroxymethyl) methylamine, lysine, arginine, orthine, N-methyl D-glucamine, etc., acid adduct salts (eg, inorganic acid salts (eg, hydrochloride, hydrobromide, yowi hydrogen) Acid salt, sulfate, hydrogen sulfate, phosphate, nitrate, etc.), organic acid salt (eg formate) Acetate, propionate, trifluoroacetate, lactate, tartrate, oxalate, malonate, succinate, fumarate, malate, maleate, benzoate, citrate, Methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, darconate, aspartate, dartrate, etc.)).

 [0168] In the present invention, examples of the solvate of the compounds represented by the general formulas (I) to (IV) include solvates such as water and alcohol solvents (for example, ethanol and the like). Solvates preferably have low toxicity and water solubility. The solvates of the compounds represented by the general formulas (I) to (IV) include solvates of the above salts.

[0169] Compounds represented by general formulas (I) to (IV), or clopidogrel, ticlovidin, cangrelor, prasdarrel, AZD-6140, INS-50589, INS-49266, AR-C66096, ARL-670 85, GR-144043, loxifiban, MRS2395 and other compounds such as P2Y antagost

 12

 Can be easily converted to the above-mentioned salts and solvates using known methods.

 [0170] In the present invention, the N-oxide form of the compound represented by the general formula (Π) represents an oxidized nitrogen atom of the compound represented by the general formula (II). Further, the N-oxide form of the compound represented by the general formula (II) may further be an alkali (earth) metal salt, an ammonium salt, an organic amine salt, or an acid adduct salt. .

 [0171] A compound represented by the general formula (I), a compound represented by the general formula (Π), or a compound represented by the general formula (III) (hereinafter collectively referred to as general formulas (I) to (III) The prodrug is a compound that can be converted into a compound represented by the general formulas (I) to (ΠΙ) by a reaction with an enzyme, gastric acid, or the like in a living body. As prodrugs of the compounds represented by the general formulas (I) to (ΠΙ), for example, when the compounds represented by the general formulas (Ι) to (ΠΙ) have an amino group, the amino group is acylated or alkylated. , Phosphorylated compounds

(For example, the amino groups of the compounds represented by the general formulas (Ι) to (ΠΙ) are converted to eicosanolation, aranylation, pentylaminocarbolation, (5-methyl-2-oxo-1,3-dioxolene-4- ) Methoxy carbolation, tetrahydro fullylation, pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compounds, etc.); compounds represented by the general formulas (I) to (III) Is a hydroxylated, alkylated, phosphorylated, boric acid compound (for example, a compound represented by the general formulas (Ι) to (ΠΙ)) Acetylated, palmitoylated, propanoylated, bivalylated, succiylated, fumarylated, valanylated, dimethylaminomethyl carbonylated compounds, etc.); compounds represented by general formulas (I) to (ΠΙ) Is a carboxy group A compound in which the carboxy group is esterified or amidated (for example, the carboxy group of the compounds represented by the general formulas (I) to (III) is converted to ethyl ester, phenyl ester, carboxymethyl Esterification, Dimethylaminomethyl esterification, Bivaloyloxymethyl esterification, Ethoxycarboxetyl esterification, Phthalidyl esterification, (5-Methyl-2-oxo-1,3 Dioxolene-4-yl) methyl Esterification, cyclohexyloxy esterification, methylamidated compounds, etc.). These compounds can be produced by known methods. Also represented by general formulas (i) to (m) Prodrugs of these compounds are represented by general formulas (Ι) to (ΠΙ) under physiological conditions as described in Yodogawa Shoten 1990, “Development of Pharmaceuticals”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to a compound. Furthermore, the prodrugs of the compounds represented by the general formulas (Ι) to (ΠΙ), or the compound represented by the general formula (Π) are the salts or solvates described above (for example, water, alcohol solvents (for example, A solvate such as ethanol) or the like, or may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ^1251, etc.).

 [0172] Compound represented by general formula (I), geometric isomer, tautomer, salt, solvent, or prodrug thereof, compound represented by general formula (化合物), A salt, its N-year-old xoxide, its solvate, or a prodrug thereof, a compound represented by the general formula (ΠΙ), a salt thereof, or a prodrug thereof, and a compound represented by the general formula (IV) Or a salt thereof in a manner known per se, for example, WO 2005/000281 pamphlet, WO 99/05144 pamphlet, WO 01/19826 pamphlet, WO 01/36421 pamphlet. , WO 01/36438 pamphlet, WO 99/41254 pamphlet, WO 00/34283 pamphlet, JP 2005-179350 pamphlet, JP 2005-053903 pamphlet, etc. Methods, methods similar to these, Is Comprehensive 'Organic Transformations: A Guide' Toichi 'Functional' Group 'Preparations, Second' Edition (Richard C. Laroque, Nyonwiri ~~ Sands Inc, 1999) [Comprehensive Organic Transformation s: A Guide to Functional Group Preparations, 2nd edition (Richard and Larock, John Wiley & Sons Inc, 1999)], etc., or by appropriately combining these methods. The product of the reaction can be purified by conventional purification means such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization. It can refine | purify by methods, such as. If desired, it can be subjected to freezing and drying.

[0173] The compound represented by the general formula (I) used in the present invention, its geometric isomer, its tautomer, its salt, its solvate, or their prodrug, represented by the general formula (Π) Compound, its salt, its N-oxide, its solvate, or prodrug thereof, A compound represented by the general formula (m), a salt thereof, or a prodrug thereof, and a compound represented by the general formula (IV), or a salt thereof, and ticlovidin, mandarelol, plasdarrel, AZD-6140, INS-50589 Compounds such as INS-49266, AR-C66096, ARL-67085, GR-144043, roxifiban, MRS2395, etc. are not limited to those that are substantially pure and single substances, but impurities (e.g. Derived by-products, solvents, raw materials, etc., or decomposed products) may be contained as long as they are acceptable as an active pharmaceutical ingredient. The content of impurities acceptable as an active pharmaceutical ingredient varies depending on which compound is used, and also differs depending on the dosage form as a pharmaceutical (eg, intravenous administration, oral administration, transdermal administration, etc.). It is preferable to determine the amount while assessing efficacy and toxicity as appropriate.

[0174] According to the present invention, an effective amount of the above-mentioned "P2Y receptor and Z or P2Y receptor blocker" (for example, pain prevention, treatment and suppression of Z or symptom progression)

12 14

 Disclosed is a method of administering prevention, treatment, and Z or an amount sufficient to exert a symptom progression inhibitory effect) to a mammal (eg, a human non-human animal, preferably a human, particularly preferably a patient).

 [0175] In the present invention, "prevention" means that pain does not occur or only mild pain occurs, and "treatment" means that pain is relieved, "symptom progression suppression" The term “enhancement of pain” (for example, expansion of pain range, increase of pain level, increase of pain frequency, etc.) In addition, “prevention” includes the meaning of suppressing the occurrence of the next pain in periodic pains, and the meaning of preventing the pain threshold from being lowered. The meaning of returning to is also included.

 [0176] In the present invention, the pain may be any sensation that is generally recognized as pain. For example, the disease itself may be the disease itself, such as trigeminal neuralgia, for example, a disease that shows pain as one of the symptoms, such as rheumatoid arthritis, so-called painful disease It may be one symptom. The present invention is to be used as a prevention, treatment and Z or symptom progression suppression method for any of these pains.

[0177] Generally, pain is classified into various categories according to its characteristics. For example, pain Depending on the cause of, for example, nociceptive pain, neuro genie pain, psychogenic pain, etc. Pain [visceral pain], somatic pain [eg superficial pain], deep pain [deep pain], orofacial pain [orofacial pain], related pain [refferred pain ] May be classified. Also, depending on the type of pain, for example, fast pain [slow pain], acute pain [acute pain] and chronic pain [chron ic pain], spontaneous pain [spontaneous painj and ¾ | evoked painj, long-term pain [continuous pain] and breakthrough pain [breakthrough pain] etc., or depending on the presence or absence of sympathetic nerves, for example, sympathetic independent pain [sympathetic independent pain] and sympathetic nerve dependency It may be classified as pain [sympathetic dependent pain]. Furthermore, depending on the disease causing the pain, for example, it may be classified into cancer pain, postherpetic neuralgia, diabetic pain, and the like. The pain in the present invention may belong to any category in these classifications. The pain in the present invention includes a sensation recognized as “numbness”. That is, the pain in the present invention refers to a mammal that can be administered with (2R) -2-propyloctanoic acid, a salt thereof, or a prodrug thereof (eg, a human or a non-human animal, preferably a human, particularly preferably a patient). ) Is anything that feels “pain” or “numbness”! /.

[0178] Nociceptive pain is pain caused by tissue injury or the addition of a stimulus with the risk of tissue injury. Nociceptive pain is pain through nociceptors, depending on the cause of pain from external stimuli (e.g., nociceptive mechanical, thermal, chemical, etc.) and endogenous stimuli (e.g., organic It can also be classified into pain due to disease, inflammatory pain) and the like. Specifically, for example

Nociceptive pain in the present invention includes pain resulting from injuries to living tissues such as cuts, bruises, fractures, fractures, burns, surgery, and cancer.

 [0179] Psychogenic pain means pain associated with psychological disorders

1S In the present invention, even when there is no clear psychological disorder, it includes the case of feeling pain that cannot be explained anatomically, or pain that does not find a lesion suitable for pain. Psychogenic pain is also sometimes referred to as chronic pain syndrome. heart Examples of intrinsic pain include pain disorders, body expression disorders, psychophysiological disorders, psychogenic pain disorders, and the like.

 [0180] Neurogenic pain is pathological pain caused by dysfunction of the peripheral nerve or the central nervous system itself (brain, spinal cord, etc.), and pain pathways not via Z or nociceptors. Pain caused by the occurrence of abnormal excitement in the 1994, as proposed in the International Association for the Study of Pain [1994] Pain due to transient dysfunction of the nervous system ”And“ pathological pain (central pain) due to damage or dysfunction of the peripheral and Z or central nerves ”, so-called neuropathic pain. . The type of neuropathy may be single neuropathy or multiple neuropathy. Specifically, nerve damage that causes damage or degeneration of nerves, nerve plexus, or surrounding nerve soft tissue due to trauma, compression, infection, cancer, ischemia, or metabolic disorders such as diabetes, etc. It means an abnormal state of persistent pain perception, such as a decrease in pain threshold due to some abnormal function caused by neuropathy.

 [0181] Hereinafter, the pain in the present invention will be exemplified with specific disease names. As described above, these disease names may be names representing pain itself or names of painful diseases. As described above, since there are various classification methods for pain classification, in the following description, the same disease name may be exemplified multiple times in several categories.

[0182] In the present invention, pain includes, for example, headache (for example, migraine, myotonic headache, cluster headache, other symptomatic headaches), orofacial pain (for example, toothache, glossodynia, temporomandibular joint) , Cervical disc herniation, degenerative cervical spondylosis, cervical shoulder arm syndrome, shoulder periarthritis (fifty shoulders), cervical spinal canal stenosis, thoracic outlet syndrome, brachial nerve Plexus withdrawal injury, shoulder-hand syndrome, traumatic neck syndrome (whiplash), chest pain, abdominal pain (e.g. acute abdomen, cholelithiasis, acute splenitis, urinary calculus etc.), back pain (e.g. Lumbar disc herniation, degenerative lumbar spondylosis, lumbar spinal canal stenosis, lumbar sequestration, lumbar spondylolisthesis, facet joints, etc., knee pain, musculoskeletal pain (e.g. muscle pain (e.g. muscle 'Fascial pain syndrome (MPS), fibromyalgia syndrome (FMS), etc.), joint pain (eg, arthritis, rheumatoid arthritis) (RA), gout, etc.), spinal pain, bone pain, etc., pain caused by blood flow disorders (eg, obstructive arteriosclerosis (ASO), Birja's disease (TAO), etc.), pain caused by trauma, Neuropathic pain (e.g. neuralgia (e.g. trigeminal neuralgia, intercostal neuralgia, sensory dysfunctional femoral neuralgia, inguinal neuralgia, saphenous neuralgia, median neuralgia, ulnar neuralgia, sciatica, nerve root pain, etc.), herpes zoster pain ( (E.g., acute herpes zoster pain, postherpetic pain (chronic), etc.), diabetic pain (e.g., diabetic-europathy, large-diameter fiber-europathy, small-diameter fiber neuropathy, proximal muscle dominant exercise-europathy, acute Mononeuropathy, paralysis due to compression, etc.), strangulation neuropathy (e.g., thoracic outlet syndrome, suprascapular nerve strangulation disorder, scapulodorsal nerve strangulation disorder, quadrilateral gap syndrome, circumflex muscle syndrome, anterior Interosseous nerve syndrome, elbow canal syndrome, slow Onset ulnar nerve palsy, posterior interosseous nerve syndrome, carpal tunnel syndrome, ulnar nerve canal syndrome, Wartenberg disease, Blowler's thumb, sensory abnormal femoral pain, piriformis syndrome, Hunter's canal syndrome, common peroneal nerve strangulation Disorders, tarsal tunnel syndrome, anterior tarsal tunnel syndrome, Morton disease, cervical spinal canal stenosis, lumbar spinal canal stenosis, extensive spinal canal stenosis, etc.), low back pain related neuropathy, brachial plexus withdrawal injury, reflex sympathy Nervous dystrophy (complex local pain syndrome group type 1), reflex sympathetic atrophy, causalgia (burning pain, complex local pain syndrome type 2), painful neuropathy, post-injury pain, phantom pain (E.g., phantom limb pain, phantom tooth pain, etc.), central pain (e.g., thalamic syndrome, Dejerine-Roussy syndrome, thalamic pain (e.g., post-stroke thalamic pain, etc.), post-stroke pain, etc.), afferent block pain, Iatrogenic neuropathy, sympathetic nerve-dependent pain, reverse C-fiber excitability syndrome (ABC syndrome [Angry Backffiring C-nociceptor syndrome]), cancer pain, HIV-related neuropathic pain, stone-induced pain (eg, urolithiasis (eg, kidney stone, ureteral stone, bladder) Pain due to stones, urethral stones, pain due to gallbladder stones, pain due to vagina stones), postoperative pain, chronic headache, orofacial pain (eg toothache, glossodynia, temporomandibular disorders, trigeminal neuralgia) ), Atypical facial pain (e.g., atypical facial pain after tooth extraction, etc.), shoulder periarthritis, osteoarthritis, arthritis, pain associated with rheumatism, back pain, multiple sclerosis, drug treatment Pain induced by radiation therapy, pain induced by radiation therapy, and the effects of narcotic analgesics cannot be fully obtained! /, Pain, etc.).

In the present invention, the preferred pain is neuropathic pain (especially cancer pain, after herpes zoster) Pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, or orofacial pain. As the neuropathic pain in the present invention, in addition to the above-mentioned diseases, hypersensitivity (particularly hyperalgesia etc.), spontaneous pain and the like are also preferable.

[0184] According to the present invention, "P2Y receptor and お よ び or Ρ2Υ receptor blocker"

 12 14

 The “prevention and treatment of pain, and an epilepsy or symptom progression inhibitor” (hereinafter sometimes abbreviated as the agent of the present invention) is preferably targeted to neuropathic pain among the above pains. In particular, it is preferably used for cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia. Pain can be prevented, treated, and / or symptom-progressed, even with alodyya pain.

 [0185] The present invention also aims at inhibiting P2Y receptor and / or P2Y receptor positive cells.

 12 Z 14

 Further, for the purpose of inhibiting P2Y receptor and Z or P2Y receptor, the above-mentioned “P2Y

 12 14 12 Receptor and Ζ or Ρ2Υ receptor blocker '' effective amount (i.e. pain prevention,

 14

 Disclosed is a method of administering a treatment and an amount sufficient to exert a sputum or symptom progression-suppressing effect) to a mammal (eg, a non-human animal, preferably a human, particularly preferably a patient).

 [0186] ΓΡ2Υ receptor and Ζ or Ρ2Υ receptor positive cell ”means Ρ2Υ receptor and

 12 14 12

Ζ or Ρ2Υ means a cell expressing the receptor, even a single molecule

 14

 If a strong receptor is expressed, the cell is included in the positive cell. 「Ρ2Ρ

 12 receptor and Ζ or Ρ2Υ receptor positive cell inhibition ”means the Ρ2 お よ び receptor and

 14 12 Ζ or Ρ2

を It means to suppress receptor positive cells “qualitatively” or “quantitatively”.

14

 This includes (1) reducing the number of cells, (2) suppressing the increase in the number of cells, or (3) suppressing the cell function of the cells. Here, the action described in (1) or (2) may be caused by any regulation of cell differentiation, proliferation, life span, or the like. The cell function described in (3) may be a function universally possessed by the cell. Among them, the cell function related to Ρ2 Υ receptor and Ζ or Ρ2Υ receptor, particularly any

12 14

 A cell function that leads to a pain or a medical condition, particularly pain described later, is preferably mentioned.

[0187] "Ρ2Υ receptor and

 “2 Ζ or Ρ2Υ receptor inhibition” means the Ρ2Υ receptor and

1 14 12 Ζ Or means to qualitatively or “quantitatively” inhibit P2Y receptors, specifically

14

 This includes (1) decreasing the receptor, (2) suppressing the increase in the receptor, (3) suppressing the receptor function of the receptor, and the like. Here, the action described in (1) or (2) may be caused by any regulation such as protein synthesis, proteolysis, internalization, or shedding. . Examples of the receptor function described in (3) include binding of an in vivo ligand to the receptor, signal transduction when the in vivo ligand binds to the receptor (for example, receptor clustering, protein phosphorylation). (Oxidation, dephosphorylation, generation of second messenger, gene expression, etc.) are preferred.

 [0188] Administer an effective amount of "P2Y receptor and Ζ or Ρ2Ρ receptor blocker"

 12 14

 2Υ receptor and Ζ or Ρ2Υ receptor positive cells '' or Ρ2Υ receptor and

12 14 12 Ζ or Ρ2Υ

 In addition to the pain described above, by inhibiting "14 receptors", diseases involving these cells or receptors, such as infections and parasitic diseases, neoplasms, blood and hematopoietic diseases, and Impaired immune system, endocrine 'nutrition and metabolic diseases, mental and behavioral disorders, nervous system diseases, eye and appendage diseases, ear and mastoid diseases, cardiovascular diseases, respiratory diseases It is possible to prevent, treat and suppress epilepsy or symptom progression of diseases, diseases of the congestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, diseases of the urogenital system. For more information on these diseases, see International Disease Classification 1

It is described in detail in the 0th edition (ICD10).

[0189] As mentioned above, “Ρ2Υ receptor and

 “12 Ζ or Ρ2Υ receptor blocker”

 14

 For example, (a) a low molecular weight compound, (b) an antibody, (c) an antisense, (d) a short interfering RNA, (e) a decoy, (£) a ribozyme, (g) an abutama Exists. These substances may be used for the purpose of preventing or treating pain and suppressing Z or symptom progression, or P2Y

 12 receptors and

For the purpose of Z- or P2Y receptor-positive cell suppression, P2Y receptor and

 When administered to a living body for the purpose of 14 12 Z or P2Y receptor inhibition, these active ingredients

14

 It is necessary to administer as a pharmaceutical composition corresponding to the form of the substance.

[0190] For example, when a low molecular weight compound is administered to a mammal, the form of the pharmaceutical composition includes, for example, a preparation for oral administration (for example, a solid preparation for internal use, a liquid preparation for internal use, etc.) or for parenteral administration. Formulations (for example, injections, liquids for external use, ointments, coating agents, inhalants, sprays, suppositories, vaginal suppositories, etc.) and the like.

 [0191] Examples of solid preparations for internal use include tablets, pills, capsules (node capsules, soft capsules), powders, granules and the like. These solid preparations for internal use consist of an active ingredient and various additives (for example, excipients (eg, ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (eg, hydroxypropylcellulose, polypyrrolopyrrolidone, Magnesium aluminate metasilicate, etc.), disintegrating agents (eg, calcium cellulose glycolate), lubricants (eg: magnesium stearate), stabilizers, solubilizers (eg: glutamic acid, aspartic acid) Etc.)) and the like, and can be produced using a known method. In addition, for these solid preparations for internal use, coating agents (eg, sucrose, gelatin, hydroxypropinolecellulose, hydroxypropenolemethinolecellulose phthalate, etc.) may be used as desired.

V. Apply one or more coatings.

 [0192] Examples of liquids for internal use include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. These liquid preparations for internal use can be produced by dissolving, suspending or emulsifying the active ingredient in a diluent generally used (for example, purified water, ethanol or a mixture thereof). These liquids for internal use may contain various additives (eg, wetting agents (eg, glycerin, propylene glycol, etc.), suspending agents (eg, carmellose, agar, gelatin, methylcellulose, etc.), emulsifiers (eg, : Arabic gum, popidone, glyceryl monostearate, etc.), sweeteners (eg, fructose, glucose, etc.), flavoring agents (eg, coffee, tea, cocoa, etc.), fragrances (eg, orange oil, thymol, etc.) ), Preservatives (eg, benzoic acid, sodium benzoate, ethyl parabenzoate, propyl parabenzoate), buffers (eg, citrate, disodium hydrogen phosphate, sodium citrate, sodium hydrogen carbonate, acetic acid) , Lactic acid, etc.) may be added.

[0193] In addition to general injections that are solutions, injections may be, for example, suspension injections or emulsion injections, and solid injections that are dissolved or suspended at the time of use. An agent (for example, freeze-dried product) or the like may be used. These injections are administered, for example, intramuscularly, subcutaneously, intradermally, intraarterially, intravenously, intraperitoneally, intrathecally. Injectables may also be administered by infusion. These injections contain active ingredients as solvents (for example, distilled water for injection, physiological saline). , Vegetable oils, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof). If desired, these injections may contain various additives (eg, stabilizers, solubilizers (eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), suspending agents (eg, methylcellulose, Carboxymethylcellulose, etc.), emulsifier (eg, polysorbate 80 (registered trademark), etc.), soothing agent (eg, pro-powered in, lidocaine hydrochloride, etc.), buffer (eg: sodium chloride, salted potassium, Disodium hydrogen phosphate, citrate, sodium citrate, etc.) and preservatives (eg, benzyl alcohol, etc.) may be added. These injections are usually produced by the force of sterilization in the final step or by aseptic manipulation. In the case of solid injections such as freeze-dried products, they are used after being used (before use) or dissolved in sterile distilled water for injection or other solvents.

[0194] Other preparations for parenteral administration, for example, preparations for external use, ointments, coatings, inhalants, sprays, suppositories, vaginal suppositories, etc. should be manufactured according to known formulations. You can.

[0195] Also, for example, when an antibody is administered to a mammal, the form of the pharmaceutical composition includes, for example, an injection (including infusion), a suppository, a nasal agent, a sublingual agent, a transdermal absorption agent, and the like. Can be mentioned. Monoclonal antibodies and polyclonal antibodies are high molecular weight proteins, so they are extremely unstable and unstable in adsorption to glass containers such as vials and syringes, and various physical and physical factors such as heat, It is expected to be easily deactivated due to pH and humidity. Therefore, it is preferable to add a stabilizer, a pH adjuster, a buffering agent, a solubilizer, a surfactant, etc., in order to formulate in a stable form. Examples of the stabilizer include amino acids such as glycine and alanine, saccharides such as dextran 40 and mannose, sugar alcohols such as sorbitol, mannitol and xylitol, and combinations of two or more of these are used. May be. The added amount of these stabilizers is preferably about 0.01 to 100 times, particularly about 0.1 to 10 times the weight of the antibody. By adding these stabilizers, the storage stability of the liquid preparation or lyophilized preparation can be improved. Examples of the buffer include a phosphate buffer and a citrate buffer. The buffer is prepared by adjusting the pH of the aqueous solution after re-dissolution of the liquid preparation or lyophilized preparation. Stability and solubility can be improved. The addition amount of the buffering agent is preferably about ImM to 10 mM, for example, with respect to the liquid amount after redissolving the liquid preparation or lyophilized preparation. As the surfactant, for example, polysorbate 20, pull nick F-68, polyethylene glycol or the like is preferred, and polysorbate 80 or the like is particularly preferred. Moreover, you may use combining these 2 or more types. As described above, a high molecular protein such as an antibody is easily adsorbed to glass resin or the like which is a material of a container. Therefore, by adding a surfactant, it is possible to prevent adsorption of the antibody after re-dissolution of the liquid preparation or lyophilized preparation into the container. The amount of the surfactant added is preferably about 0.001% to 1.0% with respect to the weight of the liquid after redissolving the liquid preparation or lyophilized preparation, for example. The antibody preparation can be prepared by adding a stabilizer, a buffer, or an adsorption inhibitor as described above, but it is acceptable as an osmotic pressure, particularly when used as a medical or animal injection. The osmotic pressure ratio is preferably 1 to 2. The osmotic pressure ratio can be adjusted by increasing / decreasing sodium chloride at the time of formulation. The antibody content in the preparation can be appropriately adjusted according to the disease to be applied, the route of administration and the like. For example, when the antibody is administered to a human, about O.lmg Zkg to lOOmgZkg may be administered once every 1 to 30 days.

 [0196] In addition, for example, when a so-called nucleic acid molecule such as antisense, short interfering RNA, decoy, ribozyme, aptamer, etc. is administered to a mammal, it is described in various known literatures in order to obtain a desired medicinal effect. It is preferable to use such a pharmaceutical composition.

[0197] For example, a method for administering a nucleic acid molecule is extensively described in Trends Cell Biol, 2, 139, 1992 and Delivery Strategies for Antisense Oligonucleotide Therapeutics (ed. Khtar, 1995). In particular, the method using RNA molecules is described in detail in WO94 / 02595 pamphlet. These documents are related to ribosome encapsulation, iontophoresis, or incorporation into other media (eg hydrogels, cyclodextrins, biodegradable nanocapsules, bioadhesive spherules, etc.)! However, the method for administering the nucleic acid molecule used in the present invention is not limited to these. For example, a combination of a nucleic acid molecule and these media, or the nucleic acid molecule itself can be administered ex vivo to a cell or tissue, or can be directly injected into a vein or catheter. It can also be administered using a tellurium, an infusion pump, a stent or the like. For example, Neuroscience Letters, 257, 135-138, 1998; Mol. Brain Research, 55, 151-164, 1998; J. Endocri nol., 157, 169-175, 1998; Neuroscience Letters, 247, 21-24, 1998 Describes a method of administering oligonucleotides to the central nervous system using osmotic pumps, for example, Neurosurg. Focus, 3, article 4, 1997 by direct injection. The administration to the central nervous system is described in detail in Drug Delivery systems: Technologies and Commercial Opportunities, Decision Resources, 1998, etc.

 [0198] Other administration methods, administration routes, and forms of pharmaceutical compositions used therefor are, for example, WO 93/23569 pamphlet, WO 99/05094 pamphlet, WO 99/04819 pamphlet. Since these are described in detail in the pamphlet of International Publication No. 94/02595, etc., these can be applied mutatis mutandis.

 [0199] When these pharmaceutical compositions are applied to the prevention, treatment and Z or symptom progression suppression of pain, particularly neuropathic pain, etc., the dosing period of the pharmaceutical composition is expected to have a prophylactic effect, for example. If it is expected to have a therapeutic effect, for example, if the therapeutic effect is expected to be substantially completed, for example if it is expected to have a symptom progression suppressing effect, the symptom progression is substantially It may be any period until it is suppressed. If desired, it may be administered intermittently with an appropriate drug holiday. In intermittent administration, it is preferable that the drug withdrawal period is 1 day or more and 30 days or less, for example, intermittent administration every other day, administration for 2 days, administration of intermittent treatment for 1 day, 2 days after continuous administration for 5 days It may be intermittent administration such as intermittent administration, etc., or a calendar system (for example, a tablet is called a calendar tablet).

 [0200] The specific dosing period in the agent of the present invention is, for example, for oral administration, 1 day to 5 years, preferably 1 day to 1 year, more preferably 1 day to 6 months. Especially preferred is a period of 1 day to 2 months. Further, for example, in the case of intravenous administration, 1 day to 100 days, etc., preferably 1 day to 10 days, etc., more preferably 1 day to 7 days, etc., most preferably 7 days, etc. are mentioned.

[0201] The number of doses per day during these dosing periods is, for example, 1 to 5 times, preferably 1 to 3 times, etc. in the oral administration and intravenous administration forms. Good Preferably, it is once or twice, most preferably once. In addition, since transdermal administration can be expected to have a local action, it is possible to obtain superior effects by administering to the site when pain is felt.

[0202] ΓΡ2Υ receptor used in the present invention and

 12 Z or P2Y receptor blocker "

 14

 The contained pharmaceutical composition may be used alone or in combination with other drugs or treatment methods used for pain treatment.

[0203] When used in combination with other drugs, it may be administered in the form of a combination of both components in one preparation, or it may be administered as a separate preparation. Administration as separate formulations includes simultaneous administration and administration by time lag. Other drugs used in combination include, for example, opioid analgesics (eg morphine, codin, fentanyl, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxycodone, oxymorphone, pentazocine) Painkillers (eg, N-type calcium channel inhibitors (eg, Ziconotide, ONO-2921, etc.), ABS-17, AC-262271, ACP-102, ADX-1, AV-333, AZD-6538, CGP -35024, CPI-1714, DP-236, EN-3215, Galantamine, JO-1614, M-58996, Neublastin, RWJ-38116, VX-409, YT-1006, Fental patch [ fentanyl patch], levetiracetam [levetirac etam] ゝ memantine [memantine], tiagabine [tiagabine], zonisamide, AB T-894, AZD-4282, lamictal XR [Lamictal XR], M-40403, T-62 , Becan panel [be c ampanel], CNP-3381, CNS-5161, KDS-2000, Ketamine 'amitriptyline combination cream], Hudafa ³ runn [radafaxine], Funorefinamide [ralfinamide], REN-1654, ReN -1869, traxoprodil, valrocemide, botulinum toxin preparation (eg Dysport, etc.), lacosamide, NG X-4010, tectin, Tectin, AVP-923, rufinamide, GW-1000 , P2X antagonists (eg, NF-023, A-317491, A-317344, etc.), antiemetics (eg, methocral blamide, hydroxyzine, prochlorperazine, etc.), nonopioid analgesics (eg, For example, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, ibuprofen, ketoprofen, naproxen, acetaminophen, celecoxib, oral fuecoxib, valdecoxib ), Etc.), auxiliary analgesics (e.g., sedatives (e.g., Benzojiazepin anxiolytics (eg E.g., diazepam, flurazepam, etc.), antidepressants (e.g., amitriptyline, desipramine, etc.), antiepileptics (e.g., gabapentinoids (e.g., gabapentin, pregabalin, etc.), carbamazepine, phenytoin, clonazepam, divalpro X, lamotrigine, topiramate, oxcarbazepine etc.), central muscle relaxants (eg baclofen etc.), local anesthetics (eg mexiletine, lidocaine etc.) etc.

 [0204] Also, in combination with other treatment methods, "P2Y receptor and

 The administration of a pharmaceutical composition containing `` 12 Ζ or Ρ2 ロ ッ カ ー receptor blocker '' and other treatment methods include

14

 It may be performed simultaneously or separately. Other treatment methods include, for example, nerve blocks (eg, trigger point block, stellate ganglion block, brachial plexus block, suprascapular nerve block, epidural block, nerve root block, facet joint block, isolation Block, sciatic nerve block, intercostal nerve block, etc.) spinal cord stimulation therapy, nonconvulsive energization, iontophoresis, acupuncture (eg, electric acupuncture, placement, acupuncture, etc.), acupressure, massage, electrotherapy

(For example, transcutaneous electrical nerve stimulation (TENS), low frequency, etc.), hyperthermia (for example, hot pack, cooling therapy, diathermy, ultra high frequency, etc.), phototherapy (for example, low power laser, polarized near infrared) ), Hot spring (water) treatment (e.g., hot springs, drinking springs, mud baths, underwater function training, etc.), hyperbaric oxygen therapy, aromatherapy, biofeedback and other cognitive techniques (e.g. relaxation training, hypnosis, Distraction techniques), psychological counseling, etc.

 [0205] Pharmaceutical composition comprising a ΓΡ2Υ receptor and a Z or P2Y receptor blocker "

 12 14

 The aforementioned drugs that can be used in combination with products are merely examples, and are not limited thereto. The administration method of these drugs used in combination is not particularly limited, and may be oral administration or parenteral administration. In addition, these drugs may be administered in combination of any two or more. These drugs include not only those that have been found so far, but also those that will be found in the future, based on the mechanism described above.

 [Toxicity]

 Very low toxicity of “P2Y receptor and Ζ or Ρ2Υ receptor blocker”

12 14

It can be judged that it is safe enough to use as a medicine. For example, clopidogrel hydrogensulfate and ticlovidin are already sold and confirmed to be safe. Yes.

 [Application to pharmaceutical products]

 The present invention aims to prevent and treat pain and to suppress Z or symptom progression, or to suppress P 2Y receptor and Z or P2Y receptor positive cells, and further to P2Y.

12 14

 For the purpose of receptor and Z or P2Y receptor inhibition, ΓΡ2Υ receptor and Z

12 14 12

 Or an effective amount of a “P2Y receptor blocker”. Main departure

 14

 Containing the “P2Y receptor or Ρ2Υ receptor blocker”

 12

 14

 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.

 The invention's effect

 [0206] According to the present invention, "Ρ2Υ receptor and Ζ or Ρ2Υ receptor blocker" is treated as pain.

 12 14

 A specific method for use in is disclosed. “Ρ2Υ receptors and

 12 or 2

 By administering “14 receptor blocker”, it is possible to prevent or treat pain and to have an effect of suppressing epilepsy or symptom progression. In particular, the present invention is an effective treatment method for patients who exhibit symptoms such as pain, such as alodynia, which cannot be improved by existing treatment methods.

 Brief Description of Drawings

 [0207] [Figure 1] The expression of Ρ2Υ receptor mRNA in the spinal cord in rats 3 days after sciatic nerve transection

 12

 In situ hybridization photo (Ipsi: cut side, Contra: opposite side) Aggregation of silver particles shining white, P2Y mRNA

 12 shows expression.

 [Figure 2] P2Y receptor mRNA expression in the spinal cord of rats 3 days after sciatic nerve transection

 14

 In situ hybridization photo (Ipsi: cut side, Contra: opposite side) Aggregation of silver particles shining white, P2Y mRNA

 14 shows expression.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0208] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

 [0209] P2Y receptor and Z or P2Y receptor strength

 12 14

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.

 Example 1

 1 1) Creation of rat sciatic nerve cutting model

 Male SD rats (200-250 g) were used and the sciatic nerve was cut under pentobarbital sodium anesthesia. After 3, 7, 14, 30 and 60 days after surgery, the spinal cord was removed and snap frozen, and then a 12-m thick section was prepared with a cryostat.

1 2) RT-PCR (P2Y receptor, P2Y receptor cRNA probe preparation)

 12 14

 P2Y receptor (GenBank accession: # AF313450) Se 587-606, As 1013-994

 12

 P2Y receptor (GenBank accession: # U76206) Se 282-301, As 781-762

 14

 The above primers were designed, and RT-PCR was performed using the total RNA extracted from rat spinal cord as a template to prepare cDNA. The obtained cDNA was transformed into p-GEM T-easy vector to confirm the sequence, and this was used as a template for cRNA probe.

 1— 3) in situ hybridization method (P2Y receptor, P2Y receptor mRNA detection)

 12 14

 Using the template prepared in 1-2) above, a radioisotope labeled cRNA probe was prepared, and in situ hybridization was performed. Furthermore, for identification of expressed cells, micrologria marker Ibal, astrocyte marker GFAP, and neuronal marker Neu N were combined with anti-Ibal antibody (anti-Ibal IgG) and anti-GFAP antibody (anti-GFAP antibody, respectively). Double staining of immunohistochemistry and in situ hybridization was performed by staining with IgG) and anti-NeuN antibody.

Result>

 P2Y receptor mRNA is expressed in Neu N positive cells and GFAP in the naive spinal cord.

12

Since it was not coexisting with positive cells but coexisting with Ibal positive cells, it was found that it was expressed in microglia. From 1 day after amputation of the sciatic nerve, the strength of the increase in microglia on the surgical side of the spinal cord is increased.

 12

Vesicles can be seen and increase up to at least 30 days peaking at 3 days after sciatic nerve cutting (shown in Figure 1) It was.

 [0211] P2Y receptor mRNA is hardly expressed in naive but is sciatic

 14

 It started to increase from 1 day after transection, and was observed on the operation side until at least 14 days. A dark field photograph of the spinal cord 3 days after sciatic nerve cutting is shown in FIG.

 [0212] Example 2

 2-1) Creation of rat sciatic nerve partial ligation model (Seltzer model)

 The rat sciatic nerve partial ligation model was prepared according to the report of Seltzer et al. (Pain, 43, 205-218, 1990). Specifically, it was produced by the following procedure.

 [0213] Under anesthesia with pentobarbital sodium, an incision was made in one thigh of male SD rats (250-350 g) to expose the sciatic nerve. The nerve was carefully separated by surrounding connective tissue force and ligated with 7-0 silk thread so that the nerve thickness 1Z3-1Z2 was retained in the ligature. The muscles and skin were closed with a clip and the wound was sprinkled with antibiotic powder. For sham-treated animals, after exposing the sciatic nerve, sew the wound in the same manner as above without ligating.

 2-2) Drug administration

 2— 2— 1) Source of drug

 P2Y receptor antisense, P2Y receptor antisense, and their missenses

12 14

 Used and designed and manufactured by BIOGNOSTIK (Germany).

 Also, MRS2395 purchased from Sigma (# M5942) was used.

 2— 2— 2) Drug administration method and administration period

 P2Y receptor antisense and its missense are known as osmotic pump,

12

 model 2001). Specifically, the tip of the catheter connected to the osmotic pump was placed at the L4Z5 level of the lumbar vertebra, and it was continuously administered (50 pmolZhr) into the medullary canal for 2 days before partial sciatic nerve ligation.

[0214] P2Y receptor antisense and its missense were detected by the same method as described above.

 14

 From the time of partial ligation of the nerve, administration was continued into the medullary canal for 1 week (50 pmolZhr).

[0215] The P2Y receptor antagonist MRS2395 is a dimethyl sulfoxide (DMSO) 20

 12

Is dissolved in physiological saline containing 20% DMSO / Saline and is 2 days before trans-partial ligation was also administered intraperitoneally for 1 week (0.lnmol / hr, InMZhr)

2-3) Evaluation of hypersensitive response to mechanical stimulation

 By measuring the withdrawal threshold (g) for mechanical stimulation to the rat plantar by using Dynamic Plantar Aesthesiometer (manufacture d by Ugo Basile) We evaluated hypersensitivity reactions to mechanical stimuli. Measurement is performed 4 times for each individual, and the mean value (Mean) and standard error (S.E.) are calculated.

 (1) P2Y receptor antisense administration study

 12

 ラ ッ ト 2Υ receptor antisense and its missense in sciatic nerve partial ligation model rats

 12

 Table 1 shows the changes over time in the escape threshold (hypersensitivity response) to mechanical stimulation when 2 days of sciatic nerve ligation was continuously administered intrathecally for 1 week.

[0216] In the table, “& 136 ^ 6” is the 1 ³ 2 丫 receptor antisense administration group, and “missense” is! ^ 丫

 12 12 Receptor missense administration group, “n” means the number of cases, “pre” means the escape threshold when no drug administration or partial ligation of the sciatic nerve is performed. The change over time was described as Day 0 on the day when the partial sciatic nerve ligation was performed, Day -1 on the previous day, and Day 1 on the next day.

 [0217] [Table 1]

[0218] The Ρ2Υ receptor antisense group was seen in the Ρ2Υ receptor missense group

 12 12

Hypersensitivity reaction was suppressed. In particular, the tendency was strongly observed 3 to 5 days (Day 3 to Day 5) from the treatment day of partial sciatic nerve ligation. (2) P2Y receptor antisense administration study

 14

 ラ ッ ト 2Υ receptor antisense and its missense in sciatic nerve partial ligation model rats

 14

 Table 2 shows the changes over time of the escape threshold (hypersensitivity reaction) to mechanical stimulation when the sciatic nerve partial ligation force was also administered intrathecally for 1 week.

[0219] In the table, “& 136 ^ 6” is the 1 ³ 2 丫 receptor antisense administration group, and “missense” is! ^ 丫

 14 14 Means the receptor missense administration group, and others are described above.

 [0220] [Table 2]

[0221] In the P2Y receptor antisense group, the hypersensitivity reaction observed in the missense group was suppressed.

 14

 It was controlled. In particular, this tendency was strongly observed 3 to 5 days (Day 3 to Day 5) from the treatment day of partial sciatic nerve ligation.

 (3) MRS2395 administration study

 MRS2395, a P2Y receptor antagonist, was applied to a rat model of partial sciatic nerve ligation.

 12

 Table 3 below shows the changes over time in the escape threshold (hypersensitivity response) to mechanical stimulation when 2 days of force before partial ligation of the sciatic nerve was continuously administered intrathecally for 1 week.

[0222] In the table, "saline" is the physiological saline administration group, and "MRS2395" is the P2Y receptor antagonist.

12

 Means the MRS2395 administration group, and the others were described in the same manner as described above.

[0223] [Table 3] Three

 (Ms ^ tS.E.)

[0224] RS2Υ receptor antagonist MRS2395

 12

 In the group that was continuously administered intrathecally at the rate of 1%, the hypersensitivity reaction observed in the group administered with physiological saline was suppressed.

[0225] [Formulation example]

 Formulation Example 1

 Ingredients of Plasdalel (5.0 kg), carboxymethylcellulose calcium (0.2 kg), magnesium stearate (0.1 kg) and microcrystalline cellulose (4.7 kg) were mixed by conventional methods and then compressed into tablets. There were obtained 100,000 tablets containing the active ingredient.

 Formulation Example 2

 Each component of Plasdalel (2.0kg), Manntoll (20kg) and Distilled water (500L) is mixed by a conventional method, then filtered through a dust filter, filled in 5mL aliquots, sterilized by heating in an autoclave, Obtained 100,000 ampules containing 20 mg of active ingredient in one ampule Industrial applicability

[0226] A pain comprising the P2Y receptor of the present invention and a Z or P2Y receptor blocker

 12 14

Pain prevention, treatment and Z or symptom progression inhibitors are safe and pain, especially neuropathic pain, eg cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain In addition, pain in diseases such as neuralgia, orofacial pain, or hyperalgesia can be markedly improved, so that the degree of freedom of life of patients can be improved and QOL can be improved, which is useful as a medicine.

T809lC / 900Zdf / X3d S9 SC60Z0 / .00Z OAV

Claims

The scope of the claims

 [1] P2Y receptor comprising P2Y receptor and Z or P2Y receptor blocker

 12 14 12 and Z or P2Y receptor positive cell inhibitors.

 14

 [2] The agent according to claim 1, which is a P2Y receptor and a Z or P2Y receptor inhibitor.

 12 14

 [3] The agent according to claim 1, which is a prophylactic, therapeutic and Z or symptom progression inhibitor for pain.

[4] The agent according to claim 3, wherein the pain is neuropathic pain.

 [5] As described in claim 4, wherein the neuropathic pain is cancer pain, postherpetic pain, diabetic pain, HIV-related neuropathic pain, stone-induced pain, neuralgia, orofacial pain, or hyperalgesia Agent.

 [6] P2Y receptor and Z or P2Y receptor blocker power (a) low molecular weight compound, (b) anti-molecular

 12 14

 The agent according to claim 1, wherein the agent is (c) antisense, (d) short interfering RNA, (e) decoy, (D ribozyme, or (g) aptamer.

[7] A low molecular weight compound is (1) a P2Y receptor antagonist, (2) a Ρ2Υ receptor antagonist,

 12 14

 Or (3) Claim 6 which is a dual antagonist of Ρ2Υ receptor and 請求 2Υ receptor

 12 14

 The agent described.

[8] The low molecular weight compound is represented by the general formula (I)

 [Chemical 1]

[Wherein R ^1_1 represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or a cyclic group which may have a substituent, and R ^2_1 has a substituent. Represents an optionally cyclic group. , Geometric isomers, tautomers, salts, solvates thereof, or prodrugs thereof, represented by the general formula (II)

[Chemical 2]

[In the formula, ring A represents an optionally substituted 5- to 7-membered heterocyclic ring, Q may have a substituent! / ヽ an aliphatic hydrocarbon group or a substituent. !! a has /ヽbe I representヽcyclic group, R ^{1 "2} represents an amino group which may be substituted, R ² -. ² is a compound represented by representing] a substituent, the Salt, its N-xide, its solvate, or their prodrugs, general formula (III)

[Chemical 3]

Wherein, R ¹ - ³ is a hydrogen atom, an optionally substituted alkoxy group may have may have a substituent aliphatic hydrocarbon group or a substituted group, R ² _ ³ represents a hydrogen atom or a substituent, R ³ — ³ represents a cyclic group which may have a substituent, and X ¹ — ³ represents a hydrogen atom or a substituent. N ³ represents 0 or an integer of 1 to 2, and ring D represents a phenyl group which may further have a substituent. Or a salt thereof, or a prodrug thereof, or a compound represented by the general formula (IV)

[Chemical 4]

[Wherein, X ⁴ and Y ⁴ each independently represent CH, C-halogen atom, C-alkyl group optionally having substituent (s), or nitrogen atom, and E has a substituent group. be also cyclic group or substituted represents the amino group, R ² - ⁴ can may have an aliphatic hydrocarbon group or a substituent but it may also be substituted cyclic represents a group, R ³ - ⁴ represents halo gen atom, which may have a substituent aliphatic hydrocarbon group or an alkoxy group which may have a substituent,, R ⁴ - ⁴ is, It substituted represent also cyclic group also have an aliphatic hydrocarbon group or a substituent, R ⁵ - ⁴ represents a substituent. 8. The agent according to claim 7, which is a compound represented by the formula:

[9] Low molecular weight compounds include clopidogrel, ticlovidin, cangrelor, prasdarrel, AZ

The agent according to claim 7, which is D-6140, INS-50589, INS-49266, AR-C66096, ARL-67085, GR-144043, roxifiban, MRS2395 or a salt thereof.

 [10] In addition, opioid analgesics, non-aged pioid analgesics, neuropathic pain analgesics, non-steroidal anti-inflammatory drugs, sedatives, antidepressants, antiepileptics, central muscle relaxants, antiemetics, 4. The agent according to claim 3, comprising a combination of one or more selected from local anesthetics.

 [11] Effective doses of P2Y and 2Y receptor blockers for mammals

 12 Z or P

 14

 P2Y receptor and P2Y receptor positive cells, characterized by administration of

 12 Z or

 14

 Suppression method.

 [12] The method according to claim 11, which is a method for inhibiting P2Y receptor and Z or P2Y receptor

 12 14

 Method.

 [13] The method according to claim 11, which is a method for preventing and treating pain and inhibiting Z or symptom progression.

 [14] P2Y to produce P2Y receptors and Z or P2Y receptor positive cell inhibitors

 12 14

 Use of Y receptors and Z or P2Y receptor blockers.

 12 14

 [15] P2Y receptor and Z or P2Y receptor positive cell inhibitor are P2Y receptor and

 12 14 12

 15. Use according to claim 14, which is a Z or P2Y receptor inhibitor.

 14

 [16] P2Y receptor and Z or P2Y receptor positive cell inhibitor prevent or treat pain

 12 14

 And the use according to claim 14, which is Z or a symptom progression inhibitor.