WO2005072746A1 - P2x受容体阻害剤 - Google Patents
P2x受容体阻害剤 Download PDFInfo
- Publication number
- WO2005072746A1 WO2005072746A1 PCT/JP2005/001067 JP2005001067W WO2005072746A1 WO 2005072746 A1 WO2005072746 A1 WO 2005072746A1 JP 2005001067 W JP2005001067 W JP 2005001067W WO 2005072746 A1 WO2005072746 A1 WO 2005072746A1
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- WIPO (PCT)
- Prior art keywords
- pain
- bone
- receptor
- receptors
- minodronic acid
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the present invention relates to a medicament, particularly a P2X receptor inhibitor and an analgesic containing minodronic acid as an active ingredient.
- Adenosine 5'-triphosphate (ATP) which is produced in mitochondria, not only plays a role as an energy currency in cells, but also is a channel-type P2X receptor and G-protein-coupled P2Y present on cell membranes. It plays an important role in signaling and cell death via receptors.
- the P2X receptor subtype P2X receptor and P2X receptor are specifically expressed in sensory nerves responsible for pain transmission, and various types of nociceptive pain, inflammatory pain and neuropathic pain are expressed. Known as a molecule involved in pain.
- ATP released from injured cells or cancer cells is a P2X receptor and / or P2X receptor (hereinafter, P2X receptor) located at the peripheral and central ends of sensory nerves.
- P2X receptor P2X receptor
- Receptors abbreviated as receptors
- produce pain [Bumstock G., Trends Pharmacol. ScL, 22, pl82 (2001)].
- Trinitrophenyl (TNP) -ATP and selective P2X receptor antagonist A-317491 were used in various pain models (eg, Honore P., Pain, 96, p99 (2002), and Javis MF, Proc Natl. Acad. Sci "USA, 99. pl7179-84 (2002)) shows that drugs that block P2X receptors are useful for the treatment or prevention of pain in nociceptive pain, inflammatory pain and neuropathic pain. Therefore, compounds with P2X receptor function inhibitory activity are expected to be a new type of pain treatment or pain prevention drug.
- Compounds having P2X receptor antagonistic activity include N-[(1S) -1,2,3,4-tetrahydro-1-naphthalenyl] benzamide derivatives such as A-317491 (eg, Patent Document 1), and dinutreoside 'There is a report of a polyphosphate derivative (for example, Patent Document 2).
- suramin an anticancer drug reported to show a decrease in pain scores in clinical trials, is a nonselective P2X and P2Y receptor antagonist (Pharmacol. Rev., 50, p413 (1998 )).
- minodronic acid (1-hydroxy-2- (imidazo [1,2-a] pyridine-3-yl) ethane-1,1,1-bisphosphonic acid
- the salt is a bisphosphonic acid compound having a condensed heterocyclic skeleton
- Patent Documents 3 and 4 disclose excellent bone resorption inhibiting action, anti-inflammatory action, and antipyretic analgesic action, and have Pageet's disease, hypercalcemia.
- minodronic acid has both an effect of inhibiting bone resorption associated with multiple myeloma and an effect of inhibiting the progression of multiple myeloma itself, at doses and administration frequencies that are clinically acceptable in human clinical practice.
- it has been reported that it has a therapeutic effect on multiple myeloma and its bone lesions (see Patent Document 5).
- Bone lesions in multiple myeloma include bone pain, osteolysis, fracture, skeletal destruction, and / or a decrease in bone density associated with bone resorption enhanced by multiple myeloma. It has been reported that in patients with multiple myeloma who received oral administration of acid hydrate 6 mg once daily, pain consumption was reduced and bone pain improved 24 weeks later.
- Non-patent document 1 Some of the bisphosphonate compounds have a direct analgesic effect.
- nomidronate and clodronate had a dose-dependent analgesic effect in the taiHlick test and the like (Non-patent document 1) .
- continuous administration of zoledronate for 19 days improved bone mass.
- Mechanical arodinia and suppression of mechanical hyperalgesia associated with cancer pain were observed (Non-Patent Document 2).
- its mechanism of action is unknown There is no report of pharmacological action common to bisphosphonates.
- Patent Document 1 International Publication WO02 / 094767 pamphlet
- Patent Document 2 JP-A-2003-238418
- Patent Document 3 Japanese Patent Publication No. 6-99457
- Patent Document 4 International Publication No. 94/00462 pamphlet
- Patent Document 5 International Publication No. 00/38694 pamphlet
- Non-patent literature l Bonabello A. Pain, 91, p269 (2001)
- Non-Patent Document 2 Walker K. Pain, 100, p219 (2002)
- the present inventors diligently searched for a new type of compound that inhibits the P2X receptor, and found that minodronic acid, a type of bisphosphonate having a bone resorption inhibitory action, has a favorable P2X receptor.
- the present inventors have found that the compound has a body inhibitory effect and has a good analgesic effect in various pain models involving P2X receptors, and completed the present invention. That is, the present invention relates to P2X, a receptor inhibitor, particularly an analgesic, comprising minodronic acid or a salt thereof as an active ingredient.
- a prophylactic or therapeutic agent for pain consisting of nociceptive pain, inflammatory pain and neuropathic pain (excluding bone pain associated with multiple myeloma), especially for the prevention or prevention of cancer pain and bone pain.
- the present invention relates to a therapeutic agent, particularly an agent for preventing or treating bone pain in a patient who has undergone bone metastasis of cancer.
- P2X and / or P2X receptor inhibitor of the present invention is a P2X receptor known as a molecule involved in various pains including nociceptive pain, inflammatory pain and neuropathic pain. P2X receptors are involved in the transmission of pain It is useful for the prevention or treatment of pain.
- minodronic acid has a high affinity for bone tissue and has a high transferability to bone tissue, and is therefore useful as a preventive or therapeutic agent for bone pain (bone pain) associated with cancer, inflammation, and neuropathy.
- bone pain bone pain associated with cancer, a form of cancer pain, is released from cancer cells and damaged peripheral cells when cancer cells activate osteoclasts, lowering bone density and infiltrating bone.
- the P2X and / or P2X receptor inhibitor of the present invention containing minodronic acid as an active ingredient is particularly useful as an agent for preventing or treating bone pain in patients who have developed bone metastasis from cancer.
- the P2X receptor inhibitor of the present invention is expected to be useful for rapid pain reduction, particularly in patients with nociceptive, inflammatory or neuropathic bone pain.
- FIG. 1 is a graph showing the inhibitory effect of minodronic acid on j3-meATP-induced pain behavior in Example 2 by intraperitoneal administration.
- the vertical axis indicates the total pain action time (second / 5 minutes), Con indicates the control group, Mino indicates minodronic acid, and * indicates the significant difference from the control group (**: p ⁇ 0.01).
- FIG. 2 is a graph showing the inhibitory effect of minodronic acid on cti3 _meATP-induced pain behavior by subcutaneous administration in Example 2.
- the vertical axis represents the total time of pain behavior (seconds / 5 minutes), Con represents the control group, Mino represents the minodronate administration group, * represents a significant difference from the control group (*: p * 0.05, **: p * 0.01 , ***: p * 0.001).
- FIG. 3 shows the inhibitory effect of minodronate on acetic acid-induced pain behavior in Test 3 of Example 3.
- the vertical axis indicates the number of writings (times)
- Con indicates the control group
- Mino indicates the minodronate administration group.
- Fig. 4 shows the inhibitory effect of minodronate on acetic acid-induced pain behavior in Test 3 of Example 3.
- the vertical axis represents the number of times of writhing (times)
- Con represents the control group
- Mino represents the minodronate-administered group
- * represents a significant difference from the control group (*: p ⁇ 0.05).
- FIG. 5 shows the inhibitory action of minodronate on formalin-induced pain behavior in Example 4.
- the vertical axis represents the total time (seconds) of lifting and licking that occurs in each phase
- Con represents the control group
- Mino represents the minodronate administration group
- * represents the significant difference from the control group (***: p ⁇ 0.001 ) Are shown.
- minodronic acid or a salt thereof is minodronic acid or a pharmaceutically acceptable salt thereof.
- the salt include sodium, potassium, magnesium, calcium, aluminum and the like.
- examples thereof include salts with an inorganic base containing a metal, and an organic base such as methylamine, ethylamine, ethanolamine, lysine, ordinine and the like.
- minodronic acid when used as a solid preparation for oral administration, it is preferable to use minodronic acid hydrate.
- Nociceptive pain, inflammatory pain, and neuropathic pain include cancer and other diseases involving P2X receptors, regardless of the location of pain, the degree of pain, and the underlying disease.
- pain associated with the disease caused by various stimuli, or caused by inflammation or neuropathy.
- pains caused by various cancers pains associated with neuropathy of diabetes, pains associated with viral diseases such as herpes, pains associated with osteoarthritis and chronic rheumatism, occipital neuralgia, migraine, etc.
- the present invention is not limited to this.
- the therapeutic agent of the present invention may be used in combination with other drugs as necessary.
- Can be used in combination with other analgesics for example, opioids (morphine, fantanyl), sodium channel blockers (novocaine, lidocaine), NSAIDs (aspirin, ibuprofen), Cox-2 inhibitors (celecoxib, oral fuecoxib) And the like. It is also used for cancer pain When used, it can be used in combination with an anticancer agent such as a chemotherapeutic agent.
- the therapeutic agent of the present invention comprises one or more bisphosphonates and a pharmaceutically acceptable carrier, specifically, a pharmaceutical carrier, an excipient, and other additives usually used in formulation.
- a pharmaceutically acceptable carrier specifically, a pharmaceutical carrier, an excipient, and other additives usually used in formulation.
- the compound can be prepared by a commonly used method using the agent. Administration can be either oral administration, such as tablets, pills, capsules, granules, powders, and liquids, or parenteral administration, such as injections such as intravenous and intramuscular injections, suppositories, and transdermals. Is also good.
- the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, corn starch, polybutylpyrrolidone, metasilicate. It is mixed with magnesium acid aluminate.
- the composition may contain additives other than inert diluents, for example, lubricating agents such as magnesium stearate, disintegrating agents such as calcium cellulose glycolate, stabilizers, gnoletamic acid or aspartic acid. Such a dissolution aid may be contained.
- Tablets or pills may be coated with sugar coating or a film of gastric or enteric substance consisting of sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, etc., if necessary. .
- Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents.
- inert diluents for example, purified water and ethanol.
- the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents and preservatives.
- compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
- water-insoluble solutions and suspensions include propylene dalicol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
- Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending of a bactericide or irradiation. Is done. They can also be used in the manufacture of sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.
- the dose is appropriately determined depending on the individual case in consideration of the patient's weight, symptoms, age, sex, and the like.
- a daily dosage of about 0.1 to 200 mg, preferably about 1 to 100 mg, most preferably about 1 to 50 mg is appropriate. It may be given once daily or in divided doses 2 to 4 times, once every 2 to 14 days or once every 113 months.
- a single dose of about 0.01 to 100 mg, preferably about 0.1 to 10 mg, more preferably about 0.5 to 5 mg is appropriate.
- test examples showing the effect of the therapeutic agent of the present invention will be shown as examples.
- the scope of the present invention is not limited by the following examples.
- CHO cells in which rat-type P2X receptor was forcibly expressed were cultured in 10% fetal bovine serum (FBS).
- a Ham's F-12 nutrient mixture containing 100 units / ml penicillin, 100 ⁇ g / ml streptomycin and 400 ⁇ g / ml G-418 was cultured under the conditions of 5% CO and 37 ° C. Test cells
- test substance 275 ⁇ ⁇ 1 4 C] - guanidine hydrochloride guanidium
- 4 mu Micromax Fei / 3 -methylene ATP (shed j3 _meATP) at room temperature for 15 minutes in a reaction buffer one containing Incubated. Wash 4 times with ice-cold wash buffer, add O. 1N NaOH, shake for 5 minutes, then
- the concentration (IC value) that inhibits 50% was determined.
- the minodronic acid of the present invention is a P2X and P2X receptor antagonist
- P2Y receptor antagonist suramin It had good receptor inhibitory activity.
- zoledronate, pamidronate and clodronate bisphosphonate which have been reported to have analgesic effects, have P2X receptor inhibitory activity.
- mice were intraperitoneally administered a test substance or a solvent in a volume of 10 ml / kg G.P.). 30 minutes later P2X and P2X receptor agonist
- i3-meATP (0.6 x mol / 2Cl) was subcutaneously administered to the sole of the left leg.
- the results are shown in Figure 1.
- FIG. 2 shows the results of a test performed in the same manner as described above except that the test substance or solvent was subcutaneously administered (sc) to the mouse at a volume of 10 ml / kg to the mouse.
- the vehicle-administered group was set as a control group, and a statistical significance test was performed using the Du dish et method with the test substance-administered group.
- Minodronic acid suppressed cti3-meATP-induced pain behavior at a dose of 30 mg / kg ip and 10_50 mg / kg s. With a significant difference from the control group. No adverse behavioral effects were observed during pain behavior observation.
- Example 3 Effect on acetic acid-induced pain behavior
- test was performed with reference to the method described in Pain, 96, p99 (2002).
- the test was performed twice, Test 1 and Test 2. The results are shown in FIGS. 3 and 4 .
- the group administered with the solvent was used as a control group, and a statistically significant difference test was performed between the group administered with the test substance and the group administered with the test substance using the Dimnet method.
- test was performed with reference to the method described in Br. J. Pharmacol., 128, pl497 (1999).
- the test substance or the solvent was subcutaneously administered to the mouse at a volume of 10 ml / kg.
- formalin was subcutaneously administered to the soles (2.0%, 20 / i1 / body).
- the total time of lifting (acting to remove the sole of the administration side from the floor) and licking (acting to lick and pan the sole of the administration side) was measured every 5 minutes for 30 minutes immediately after administration of formalin.
- Phases 0 to 5 minutes after formalin administration were defined as Phase I (Phase I) and 10 to 30 minutes were defined as Phase II (Phase I), and the total time of lifting and licking occurring in each phase was calculated.
- Fig. 5 shows the results. Minodronic acid hydrate, at a dose of 30 mg / kg, inhibited only phase I analgesic behavior without affecting phase I. No adverse side effects were observed at the time of pain behavior observation.
- the "P2X and / or P2X receptor inhibitor" of the present invention is a P2X receptor known as a molecule involved in various pains including nociceptive pain, inflammatory pain and neuropathic pain. It can be applied to the prevention or treatment of various types of pain in which the P2X receptor is involved in pain transmission.
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Abstract
本発明者等はP2X2/3, 3受容体を阻害する新しいタイプの化合物を鋭意探索していたところ、骨吸収抑制作用を有するビスホスホネートの１種であるミノドロン酸が良好なP2X2/3, 3受容体阻害作用を有し、各種疼痛の予防もしくは治療剤となりうることを見出し、本発明を完成した。即ち、本発明は、ミノドロン酸若しくはその塩を有効成分として含有するP2X2/3, 3受容体阻害剤、殊に鎮痛剤に関するものである。
本発明の、「P2X2/3及び/又はP2X3受容体阻害剤」は、侵害受容性疼痛、炎症性疼痛及び神経因性疼痛の様々な痛みに関わる分子として知られているP2X2/3, 3受容体の機能を阻害することから、P2X2/3, 3受容体が痛みの伝達に関与している各種疼痛の予防もしくは治療に有用である。
Description
明 細 書
P2X受容体阻害剤
技術分野
[0001] 本発明は、医薬、殊にミノドロン酸を有効成分として含有する P2X 受容体阻害剤 並びに鎮痛剤に関する。
背景技術
[0002] ミトコンドリアで産生される adenosine 5 ' -triphosphate (ATP)は、細胞内でのェネル ギー通貨としての役割以外に、細胞膜上に存在するチャネル型の P2X受容体や G蛋 白質共役型の P2Y受容体を介して情報伝達、細胞死などにおいて重要な役割を果 たしている。その中で P2X受容体のサブタイプの P2X 受容体及び P2X受容体は、 痛覚伝達を担う知覚神経に特異的に発現しており、侵害受容性疼痛、炎症性疼痛 及び神経因性疼痛の様々な痛みに関わる分子として知られている。例えば、癌性疼 痛にぉレ、て、傷害を受けた細胞や癌細胞から放出された ATPは知覚神経の末梢端 および中枢端に存在する P2X 受容体及び/又は P2X受容体（以下、 P2X 受容 体と略記する）を刺激して痛みを発生する [Bumstock G.， Trends Pharmacol. ScL, 22, pl82 (2001)]。
一方、 P2X受容体及び P2X 受容体受容体拮抗薬である
trinitrophenyl(TNP)- ATPや選択的 P2X 受容体拮抗薬 A- 317491を用レ、た各種疼 痛モデルにおける試験結果（例えば、 Honore P.， Pain, 96， p99 (2002)、および Javis M.F., Proc. Natl. Acad. Sci" USA, 99. pl7179- 84 (2002))より、 P2X 受容体を阻 害する薬剤は、侵害受容性疼痛、炎症性疼痛及び神経因性疼痛における痛みの治 療あるいは予防に有効であることが示されている。よって、 P2X 受容体機能阻害 作用をもつ化合物は新しいタイプの疼痛治療薬あるいは疼痛予防薬として期待され る。
P2X 受容体拮抗作用を有する化合物としては、 A-317491等の N-[(1S)-1，2，3,4- テトラヒドロ- 1-ナフタレニル]ベンザミド誘導体 (例えば、特許文献 1)、およびジヌタレ オシド 'ポリホスフェート誘導体 (例えば特許文献 2)の報告がある。また、癌患者に対
する臨床試験において疼痛スコアの低減が観察されることが報告された抗癌剤 suraminが、非選択的 P2X、 P2Y受容体拮抗薬である事が報告されている（Pharmacol. Rev., 50， p413 (1998))。
一方、骨吸収抑制作用を有するビスホスホネートの 1つであるミノドロン酸（1—ヒドロ キシ— 2— (イミダゾ [ 1， 2— a]ピリジン— 3—ィル）ェタン— 1 , 1—ビスホスホン酸）又はそ の塩は、縮合複素環骨格を有するビスホスホン酸化合物であり、特許文献 3および 4 には、優れた骨吸収抑制作用、抗炎症作用、解熱鎮痛作用を有し、ページエツト病、 高カルシウム血症、癌の骨転移、骨粗鬆症、慢性関節リウマチ等の炎症性関節疾患 に伴う骨吸収の亢進等の骨吸収を抑制し、骨量の減少を防止し或いは骨吸収亢進 に伴う血清カルシウム値の上昇等を防止または低下させる薬剤として使用できると記 載されている。明細書にはミノドロン酸の骨吸収抑制作用を裏付ける血清カルシウム 低下を示す薬理試験が開示されるが、解熱鎮痛作用については何等具体的開示が ハ、、レ νヽ
また、ミノドロン酸は、ヒトの臨床において臨床上許容される投与量 ·投与頻度にお いて、多発性骨髄腫に伴う骨吸収の抑制作用と多発性骨髄腫自体の進展抑制作用 の両作用を有し、多発性骨髄腫やその骨病変の治療作用を有することが報告されて いる (特許文献 5参照)。多発性骨髄腫の骨病変としては、多発性骨髄腫によって亢 進される骨吸収に伴う、骨痛、骨融解、骨折、骨格破壊、及び/または、骨密度の低 下等が挙げられ、ミノドロン酸水和物 6mgを 1日 1回経口投与した多発性骨髄腫患者 において、 24週後に鎮痛剤の使用量が低減し骨痛が改善されたことが報告されてい る。
しかしながら、ミノドロン酸の直接的な鎮痛作用を示す知見は、現在まで何等報告 が無い。
なお、ビスホスホネート化合物中には、直接的な鎮痛作用を有するものが報告され ている。例えば、ノ ミドロネートとクロドロネートは taiHlick試験等において用量依存的 な鎮痛作用を有していた (非特許文献 1)、ラット癌性疼痛モデルにおいてゾレドロネ ートを 19日間連続投与すると、骨量の改善と癌性疼痛に伴う機械ァロディニァと機械 痛覚過敏の抑制がみられた（非特許文献 2)。しかしながら、その作用機序は不明で
あり、ビスホスホネートに共通する薬理作用との報告は無い。
[0004] 特許文献 1：国際公開 WO02/094767号パンフレット
特許文献 2：特開 2003-238418号公報
特許文献 3：特公平 6-99457号公報
特許文献 4 :国際公開 94/00462号パンフレット
特許文献 5：国際公開 00/38694号パンフレット
非特許文献 l : Bonabello A. Pain, 91, p269 (2001)
非特許文献 2 : Walker K. Pain, 100， p219 (2002)
発明の開示
発明が解決しょうとする課題
[0005] P2X 受容体阻害に基づぐ侵害受容性疼痛、炎症性疼痛及び神経因性疼痛の 治療あるいは予防に有効な、新しいタイプの疼痛治療薬あるいは疼痛予防薬の開発 が望まれている。
課題を解決するための手段
[0006] 本発明者等は P2X 受容体を阻害する新しレ、タイプの化合物を鋭意探索してレ、 たところ、骨吸収抑制作用を有するビスホスホネートの 1種であるミノドロン酸が良好 な P2X 受容体阻害作用を有し、さらに P2X 受容体が関与する各種疼痛モデル において良好な鎮痛作用を有することを見出し、本発明を完成した。即ち、本発明は 、ミノドロン酸若しくはその塩を有効成分として含有する P2X ， 受容体阻害剤、殊に 鎮痛剤に関するものである。更に詳しくは、侵害受容性疼痛、炎症性疼痛及び神経 因性疼痛からなる疼痛 (但し、多発性骨髄腫に伴う骨痛を除く）の予防もしくは治療 剤、特に癌性疼痛や骨痛の予防もしくは治療剤、中でも癌の骨転移を生じた患者に おける骨痛の予防もしくは治療剤に関する。
発明の効果
[0007] 本発明の、「P2X 及び/又は P2X受容体阻害剤」は、侵害受容性疼痛、炎症性疼 痛及び神経因性疼痛からなる様々な痛みに関わる分子として知られている P2X 受容体の機能を阻害することから、 P2X 受容体が痛みの伝達に関与している各種
疼痛の予防もしくは治療に有用である。
殊に、ミノドロン酸は骨組織への親和性が高ぐ骨組織への移行性が高いことから、 癌や炎症 ·神経障害に伴う骨の痛み (骨痛）の予防もしくは治療剤として有用である。 癌性疼痛の 1つである癌に伴う骨痛は、癌細胞が破骨細胞を活性化し、骨密度を低 下させ骨への浸潤が進行すると、癌細胞や障害を受けた周辺細胞から放出された
ATPが骨膜等の近くの神経終末に存在する P2X 受容体を刺激して痛みを伝達す ることによって生じる。癌後期には、転移した腫瘍による神経の圧迫に起因する神経 因性疼痛も加わると考えられている。よって、ミノドロン酸を有効成分とする本発明の P2X 及び/又は P2X受容体阻害剤は、癌の骨転移を生じた患者における骨痛の予 防もしくは治療剤として特に有用である。
乳癌骨転移患者及び肺癌骨転移患者に、ミノドロン酸 1又は 2mgを 2週間に 1回、合 計 6回、 12週間投与した臨床試験において、早期の鎮痛作用発現、即ち投与後の最 初の評価時（1週目）から疼痛値の低下傾向が認められる結果が確認されており、殊 に、骨痛の程度の高い患者 (例えば、動作時痛みが常にある患者や、数日に 1回程 度であっても強い骨痛を有する患者）において鎮痛効果が顕著であった。これらの事 実より、当該ミノドロン酸の骨痛抑制作用には、本発明の P2X 受容体阻害作用に 基づく直接的な鎮痛作用が関与することが推定される。
よって、本発明の P2X 受容体阻害剤は、殊に侵害受容性、炎症性又は神経因 性の骨痛を有する患者の迅速な痛み低減に有用であることが期待される。
図面の簡単な説明
[図 1]図 1は、実施例 2 腹腔内投与におけるひ j3 -meATP誘発疼痛行動に対するミノ ドロン酸の抑制作用を示すグラフである。縦軸は疼痛行動合計時間（秒 /5分)を、 Conはコントロール群を、 Minoはミノドロン酸を、 *はコントロール群との有意差（** : pく 0.01)をそれぞれ示す。
[図 2]図 2は、実施例 2 皮下投与における ct i3 _meATP誘発疼痛行動に対するミノド ロン酸の抑制作用を示すグラフである。縦軸は疼痛行動合計時間（秒 /5分）を、 Con はコントロール群を、 Minoはミノドロン酸投与群を、 *はコントロール群との有意差（* : p く 0.05、 ** : pく 0.01、 *** : pく 0.001)をそれぞれ示す。
[図 3]図 3は、実施例 3 試験 1の酢酸誘発疼痛行動に対するミノドロン酸の抑制作用 を示す。縦軸はライジング回数（回）を、 Conはコントロール群を、 Minoはミノドロン酸 投与群をそれぞれ示す。
[図 4]図 4は、実施例 3 試験 2の酢酸誘発疼痛行動に対するミノドロン酸の抑制作用 を示す。縦軸はライジング回数（回）を、 Conはコントロール群を、 Minoはミノドロン酸 投与群を、 *はコントロール群との有意差（*： pく 0.05)をそれぞれ示す。
[図 5]図 5は、実施例 4における formalin誘発疼痛行動に対するミノドロン酸の抑制作 用を示す。縦軸はそれぞれの相に起こる liftingと lickingの合計時間 (秒)を、 Conはコン トロール群を、 Minoはミノドロン酸投与群を、 *はコントロール群との有意差（*** : pく 0.001)をそれぞれ示す。
発明を実施するための最良の形態
[0009] 本発明において、ミノドロン酸若しくはその塩としては、ミノドロン酸（minodronic acid )若しくはその製薬学的に許容される塩であり、塩としては、ナトリウム、カリウム、マグ ネシゥム、カルシウム、アルミニウム等の金属を含む無機塩基、メチルァミン、ェチル ァミン、エタノールァミン、リジン、オル二チン等の有機塩基との塩が挙げられる。また
、これらの水和物や溶媒和物、及び結晶多形の物質であってもよい。例えば、ミノドロ ン酸を経口投与用固形製剤として用いる場合はミノドロン酸水和物を用いるのが好ま しい。
侵害受容性疼痛、炎症性疼痛及び神経因性疼痛としては、痛みの生じる部位、痛 みの程度、原因疾患等にかかわらず、 P2X 受容体の関与する、癌やその他の疾
2/3, 3
患に伴う、各種刺激に起因する或いは炎症や神経障害によって引き起こされる各種 の疼痛である。例えば、各種癌による痛み、糖尿病の神経障害に伴う痛み、ヘルぺス などウィルス性疾患に伴う痛み、変形性関節症や慢性リウマチに伴う痛み、後頭神経 痛、偏頭痛等が挙げられるが、これらに限定されるものではない。
[0010] 本発明の治療剤は、必要に応じて他の薬剤と併用されても良い。他の鎮痛剤と併 用されてもよぐ例えば、ォピオイド（モルヒネ、ファンタニール）、ナトリウムチャンネル 遮断剤（ノボカイン、リドカイン）、 NSAID (アスピリン、イブプロフェン）、 Cox-2阻害剤（ セレコキシブ、口フエコキシブ）等との併用が挙げられる。また、癌性疼痛に使用され
るときは、化学療法剤等の抗癌剤と併用することができる。
[0011] 本発明の治療剤は，ビスホスホネートの 1種又は 2種以上と、製薬学的に許容され る担体、具体的には、通常製剤化に用いられる薬剤用担体、賦形剤，その他添加剤 を用いて、通常使用されている方法によって調製することができる。投与は錠剤，丸 剤，カプセル剤，顆粒剤，散剤，液剤等による経口投与，又は，静注，筋注等の注射 剤，坐剤，経皮等による非経口投与のいずれの形態であってもよい。
本発明の経口投与用の固体組成物としては，錠剤，散剤，顆粒剤等が用いられる 。このような固体組成物においては，ひとつ又はそれ以上の活性物質が，少なくとも ひとつの不活性な希釈剤，例えば乳糖，マンニトール，ブドウ糖，ヒドロキシプロピル セルロース，微結晶セルロース，トウモロコシデンプン，ポリビュルピロリドン，メタケイ 酸アルミン酸マグネシウムと混合される。組成物は，常法に従って，不活性な希釈剤 以外の添加剤，例えばステアリン酸マグネシウムのような滑沢剤や繊維素グリコール 酸カルシウムのような崩壊剤，安定化剤，グノレタミン酸又はァスパラギン酸のような溶 解補助剤を含有していてもよい。錠剤又は丸剤は必要によりショ糖，ゼラチン，ヒドロ キシプロピルセルロース，ヒドロキシプロピルメチルセルロース，ヒドロキシプロピルメチ ルセルロースフタレートなどからなる、糖衣又は胃溶性若しくは腸溶性物質のフィル ムで被膜してもよレ、。
[0012] 経口投与用の液体組成物は，薬剤的に許容される乳濁剤，溶液剤，懸濁剤，シロ ップ剤，エリキシル剤等を含み，一般的に用いられる不活性な希釈剤，例えば精製 水，エタノールを含む。この組成物は不活性な希釈剤以外に湿潤剤，懸濁剤のよう な補助剤，甘味剤，風味剤，芳香剤，防腐剤を含有していてもよい。
非経口投与用の注射用組成物としては，無菌の水性又は非水性の溶液剤，懸濁 剤，乳濁剤を含有する。水性の溶液剤，懸濁剤としては，例えば注射用蒸留水及び 生理食塩液が含まれる。非水溶性の溶液剤，懸濁剤としては，例えばプロピレンダリ コール，ポリエチレングリコール，ォリーブ油のような植物油，エタノールのようなアル コール類，ポリソルベート 80等がある。このような組成物は，さらに防腐剤，湿潤剤， 乳化剤，分散剤，安定化剤，溶解補助剤のような補助剤を含んでもよい。これらは例 えばバクテリア保留フィルターを通す濾過，殺菌剤の配合又は照射によって無菌化
される。これらはまた無菌の固体組成物を製造し，使用前に無菌水又は無菌の注射 用溶媒に溶解して使用することもできる。
[0013] 投与量は、患者の体重、症状，年令，性別等を考慮して個々の場合に応じて適宜 決定される。
経口投与の場合、 1日の投与量は，約 0. 1から 200mg、好ましくは約 1から lOOmg 、最も好ましくは約 1から 50mgが適当である。これを 1日 1回あるいは 2ないし 4回に 分けて投与するか、 2— 14日毎に 1回あるいは 1一 3ヶ月に 1回で投与してもよい。静 脈投与される場合は、 1回の投与量が約 0. 01から lOOmg、好ましくは約 0. 1から 10 mg、更に好ましくは約 0. 5から 5mgが適当であり、これを 2 6週に 1回、好ましくは 3 一 5週に 1回、より好ましくは、 4週に 1回、 10 60分、好ましくは 30分力けて、点滴 静脈内投与することができる。
実施例
[0014] 以下に、本発明の治療剤の効果を示す試験例を実施例として示す。なお、本発明 の範囲は以下の実施例により何等限定されることはない。
実施例 1 : P2X 受容体阻害活性
2/3
試験は、 Br. J. Pharmacol., 108， p436 (1993)を参考に以下の様にして行った。 ラット型 P2X 受容体を強制発現させた CHO細胞を， 10 % fetal bovine serum (FBS)
2/3
, 100 unit/ml penicillin, 100 μ g/ml streptomycinおよび 400 μ g/ml G— 418を含む Ham's F-12 nutrient mixtureを用レ、， 5 % CO , 37°C条件下で培養した。細胞を試験
2
前日に約 6xl04 cells/wellの密度で 96_weU培養プレート上に播種し， apyrase 2 unit/mlを含む培地で 24時間培養した。試験当日に培地を除去した後，被験物質， 275 μ Μ 1 4C]- guanidine hydrochloride guanidium)および 4 μ Μ ひ /3 -methylene ATP (ひ j3 _meATP)を含む反応バッファ一にて 15分間室温でインキュベートした。氷 冷した洗浄バッファーで 4回洗浄し， O. lN NaOHを加え 5分間振盪し，次いで
microscint-PSを加え 10分間振盪した後に放射活性を測定し、 P2X 受容体の機能を
2/3
50%阻害する濃度（IC 値）を求めた。
50
結果を下表に示す。本発明のミノドロン酸は P2X及び P2X 受容体拮抗薬である
1 2/3, 3
TNP-ATPには劣るものの、非選択的 P2X、 P2Y受容体拮抗薬 suraminと同等以上の
良好な受容体阻害活性を有していた。一方、鎮痛作用の報告があるゾレドロネート、 パミドロネートおよびクロドロネートのビスホスホネートは P2X 受容体阻害活性を有さ
2/3
ず、これらの鎮痛作用は P2X受容体を介するものではないと予想された。よって、ミノ ドロン酸は、鎮痛作用の報告がある他のビスホスホネート類とは異なる作用メカニズム を有するものと推定される。
[表 1]
Br. J. Pharmacol. , 122, p365 (1997)並びに J. Neurosci. , 20, pl6 (2000)に記載され た方法を参考にして試験を実施した。マウス (n=6)に被験物質または溶媒を 10 ml/kg の容量で腹腔内投与 G.P.)した。その 30分後に P2X及び P2X 受容体作動薬である
1 2/3, 3
i3 -meATP (0.6 x mol/2C l)を左肢足裏に皮下投与した。 ひ /3 -meATP投与直後 から 5分間に起こる lifting (投与側足裏を床面から離す行動）と licking (投与側足裏を 舐めたり嚙んだりする行動）の合計時間を測定した。結果を図 1に示す。
また、マウスに被験物質または溶媒を 10 ml/kgの容量で背側部に皮下投与 (s.c.)す る以外は上記と同様にして試験した結果を、図 2に示す。
溶媒投与群をコントロール群とし、被験物質投与群との間で Du皿 et法を用いた統 計学的有意差検定を行った。
ミノドロン酸は、 30mg/kg i.p.、並びに 10_50mg/kg s. 投与時、コントロール群に対 して有意差をもって ct i3 -meATP誘発疼痛行動を抑制した。なお、疼痛行動観察時 において行動上の副作用は確認されな力つた。
実施例 3：酢酸誘発疼痛行動に対する作用
Pain, 96, p99 (2002)に記載された方法を参考にして試験を実施した。マウス (n=8)に 被験物質または溶媒を 10 ml/kgの容量で皮下投与した。その 30分後に 0.6 %酢酸腹 腔内投与（10 ml/kg)した。酢酸投与後 2-17分の 15分間に起こる writhing (体躯よじり 行動）回数を計測した。試験は試験 1と試験 2の 2回行った。それぞれの結果を図 3及 び図 4に示す。溶媒投与群を対照群とし、被験物質投与群との間で Dimnet法を用い た統計学的有意差検定を行った。
ミノドロン酸は、 10及び 30mg/kgの範囲で用量依存的に writhing行動を抑制した。な お、疼痛行動観察時において行動上の副作用は確認されなかった。
[0016] 実施例 4： formalin誘発疼痛行動に対する作用
Br. J. Pharmacol., 128, pl497 (1999)に記載された方法を参考にして試験を実施し た。マウスに被験物質または溶媒を 10 ml/kgの容量で皮下投与した。その 30分後に formalinを足裏に皮下投与（2.0 %, 20 /i 1/body)した。 formalin投与直後から 30分間に わたり 5分毎の lifting (投与側足裏を床面から離す行動）と licking (投与側足裏を舐め たり嚙んだりする行動）の合計時間を計測した。 formalin投与後 0-5分を第 I相 (Phase I), 10-30分を第 II相 (Phase Π)と定義し，それぞれの相に起こる liftingと lickingの合計 時間を算出した。結果を図 5に示す。ミノドロン酸水和物は 30 mg/kgの投与量で第 I 相には影響を与えずに第 Π相の鎮痛行動のみを抑制した。なお、疼痛行動観察時に ぉレ、て行動上の副作用は確認されなかった。
産業上の利用可能性
[0017] 本発明の、「P2X 及び/又は P2X受容体阻害剤」は、侵害受容性疼痛、炎症性疼 痛及び神経因性疼痛からなる様々な痛みに関わる分子として知られている P2X 受容体の機能を阻害し、 P2X 受容体が痛みの伝達に関与している各種疼痛の予 防もしくは治療に適用できる。
Claims
[1] ミノドロン酸若しくはその塩を有効成分として含有する P2X 及び/又は P2X受容体
2/3 3 阻害剤。
[2] 侵害受容性疼痛、炎症性疼痛及び神経因性疼痛からなる疼痛 (但し、多発性骨髄 腫に伴う骨痛を除く）の予防もしくは治療剤である請求項 1記載の剤。
[3] 癌性疼痛の予防もしくは治療剤である請求項 2記載の剤。
[4] 骨痛の予防もしくは治療剤である請求項 2記載の剤。
[5] 癌の骨転移を生じた患者における骨痛の予防もしくは治療剤である請求項 3若しくは 4記載の剤。
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/587,866 US20070191311A1 (en) | 2004-01-30 | 2005-01-27 | P2x receptor inhibitor |
| JP2005517475A JPWO2005072746A1 (ja) | 2004-01-30 | 2005-01-27 | Ｐ２ｘ受容体阻害剤 |
| EP05704173A EP1709968A1 (en) | 2004-01-30 | 2005-01-27 | P2x receptor inhibitor |
| CA002554749A CA2554749A1 (en) | 2004-01-30 | 2005-01-27 | P2x receptor inhibitor |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004024118 | 2004-01-30 | ||
| JP2004-024118 | 2004-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005072746A1 true WO2005072746A1 (ja) | 2005-08-11 |
Family
ID=34823908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2005/001067 WO2005072746A1 (ja) | 2004-01-30 | 2005-01-27 | P2x受容体阻害剤 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20070191311A1 (ja) |
| EP (1) | EP1709968A1 (ja) |
| JP (1) | JPWO2005072746A1 (ja) |
| CA (1) | CA2554749A1 (ja) |
| WO (1) | WO2005072746A1 (ja) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019014684A (ja) * | 2017-07-07 | 2019-01-31 | 国立大学法人大阪大学 | 真菌感染における宿主応答抑制剤 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110166223A1 (en) * | 2008-08-19 | 2011-07-07 | Cedars-Sinai Medical Center | Methods of inhibiting fgfr3 signaling |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000038694A1 (fr) * | 1998-12-25 | 2000-07-06 | Yamanouchi Pharmaceutical Co., Ltd. | Compositions de medicaments servant a traiter les lesions osseuses dans le myelome multiple |
| WO2002043738A2 (en) * | 2000-11-29 | 2002-06-06 | Novartis Ag | Use of bisphosphonates for pain treatment |
| JP2002527398A (ja) * | 1998-10-09 | 2002-08-27 | エフ．ホフマン−ラ ロシュ アーゲー | ジホスホン酸を含有する組成物 |
| JP2003137814A (ja) * | 2001-08-10 | 2003-05-14 | Takeda Chem Ind Ltd | ＧｎＲＨアゴニストの併用剤 |
| JP2003535889A (ja) * | 2000-06-20 | 2003-12-02 | ノバルティス アクチエンゲゼルシャフト | ビホスホネートの投与法 |
| JP6099457B2 (ja) * | 2013-03-28 | 2017-03-22 | 株式会社Pfu | 画像処理装置、領域決定方法及びコンピュータプログラム |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4990503A (en) * | 1988-08-12 | 1991-02-05 | Yamanouchi Pharmaceutical Co., Ltd. | Heterocyclic bisphosphonic acid derivatives |
-
2005
- 2005-01-27 CA CA002554749A patent/CA2554749A1/en not_active Abandoned
- 2005-01-27 JP JP2005517475A patent/JPWO2005072746A1/ja not_active Withdrawn
- 2005-01-27 WO PCT/JP2005/001067 patent/WO2005072746A1/ja not_active Application Discontinuation
- 2005-01-27 US US10/587,866 patent/US20070191311A1/en not_active Abandoned
- 2005-01-27 EP EP05704173A patent/EP1709968A1/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002527398A (ja) * | 1998-10-09 | 2002-08-27 | エフ．ホフマン−ラ ロシュ アーゲー | ジホスホン酸を含有する組成物 |
| WO2000038694A1 (fr) * | 1998-12-25 | 2000-07-06 | Yamanouchi Pharmaceutical Co., Ltd. | Compositions de medicaments servant a traiter les lesions osseuses dans le myelome multiple |
| JP2003535889A (ja) * | 2000-06-20 | 2003-12-02 | ノバルティス アクチエンゲゼルシャフト | ビホスホネートの投与法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019014684A (ja) * | 2017-07-07 | 2019-01-31 | 国立大学法人大阪大学 | 真菌感染における宿主応答抑制剤 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2554749A1 (en) | 2005-08-11 |
| EP1709968A1 (en) | 2006-10-11 |
| JPWO2005072746A1 (ja) | 2007-10-11 |
| US20070191311A1 (en) | 2007-08-16 |
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