JPH07508530A - Medicines for treating visceral pain and migraines - Google Patents

Medicines for treating visceral pain and migraines

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JPH07508530A
JPH07508530A JP6503078A JP50307893A JPH07508530A JP H07508530 A JPH07508530 A JP H07508530A JP 6503078 A JP6503078 A JP 6503078A JP 50307893 A JP50307893 A JP 50307893A JP H07508530 A JPH07508530 A JP H07508530A
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サンガー，ガレス・ジョン
バナー，スティーブン・エドワード
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スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

【発明の詳細な説明】 内臓の痛みおよび偏頭痛の治療薬 本発明は、内臓鎮痛剤としての５−ＨＴ、受容体アンタゴニストである、ある種 の化合物に関する。[Detailed description of the invention] Medicines for treating visceral pain and migraines The present invention relates to certain types of 5-HT receptor antagonists as visceral analgesics. Concerning the compound.

ＥＰ−Ａ−第７９５１２号（ビーチャム・グループ・パブリック・リミテンド・ カンパニー（Ｂｅｅｃｈａｍ　Ｇｒｏｕｐ　ｐ、　１．　ｃ、　））には、内臓 の痛みの治療における、グラニセトロン（ｇｒａｎｉｓｅｔｒｏｎ）　（キトリ ル（ＫＹＴＲＩＬ））をはじめとするある種の５−ＨＴ３受容体の使用が記載さ れている。EP-A-No. 79512 (Beacham Group Public Limited Company (Beecham Group p, 1.c, )) has internal organs. granisetron (granisetron) in the treatment of pain in The use of certain 5-HT3 receptors, including KYTRIL), has been described. It is.

内臓の痛みは、過敏性腸症候群（ＩＢＳ）の症状であり、グラニセトロノは、１ ２０μｇ／ｋｇおよび５０μｇ／ｋｇの用量（１２０μｇ／ｋｇが最も有効であ る）での二重盲検偽薬対照試験（ｄｏｕｂｌｅ−ｂｌｉｎｄ−ｐｌａｃｅｂｏ− ｃｏｎｔｒｏｌｌｅｄ　５ｔｕｄｉｅｓ）により示されたように、ｒ　Ｂ　Ｓ　 、ｅ者の直腸の感覚を失わせることが見いだされている（グライア−（Ｐｒｉｏ ｒ）およびリード（Ｒｅａｄ）　、　１９９０年：ガソト（Ｃｕｔ）第３１巻（ １０）Ａ１１７４）。Visceral pain is a symptom of irritable bowel syndrome (IBS), and Granicetrono doses of 20 μg/kg and 50 μg/kg (120 μg/kg being the most effective). double-blind-placebo- r　B　S　as shown by 5 studies) has been found to cause loss of rectal sensation in persons (Prio r) and Read, 1990: Gasoto (Cut) Volume 31 ( 10) A1174).

グラニセトロンは、膨張に対する直腸の感受性に関する動物モデルにおいて活性 があることが示されている（後記方法参照）。Granisetron is active in animal models of rectal sensitivity to distension It has been shown that there is (see method below).

このモデルにおいてグラニセドロンと同じ効果を有する５　ＨＴ３受容受容体ア フタコニストては、ザトセトロン（ｚａｔａｓｅｔｒｏｎ＞　（リリー（Ｌｉｌ ｌｙ））およびメトクロプラミド（ｍｅｔｏｃｌｏｐｒａｍｉｄｅ）が挙げられ る。In this model, the 5HT3 receptor receptor receptor has the same effect as granisedrone. The fuconist is zatasetron (Lil). ly)) and metoclopramide. Ru.

それゆえ本発明は、ＩＢＳの痛みの症状のごとき内臓の痛み、そしてまた偏頭痛 の治療において、ベツォルトーヤリノユ（Ｂｅｚｏｌｄ−Ｊａｒｉｓｃｈ）モデ ルのごとき標準的試験において５−ＨＴ３受容体アンタゴニスト活性が観察され る用量として測定された用量で動物モデルにおいて活性を示すそれらの５−ＨＴ 、受容体アンタゴニストの使用に関する。Therefore, the present invention is useful for treating visceral pain, such as the pain symptoms of IBS, and also for migraines. In the treatment of 5-HT3 receptor antagonist activity has been observed in standard tests such as Those 5-HT exhibiting activity in animal models at doses measured as , regarding the use of receptor antagonists.

好ましい化合物は、５−ＨＴ３受容受容体アフタコニスト用量も少ない用量で活 性を示す。承認または臨床試験中の化合物は、抗嘔吐用達と同様の投与レヘルで 活性を示す。Preferred compounds are also active at 5-HT3 receptor aftaconist doses. Show your gender. Compounds approved or in clinical trials may be administered at the same level of administration as antiemetics. Shows activity.

投与、処方等についての適当なモデルはＥＰ−Ａ−第２７９５１２号に記載さ本 発明のために考慮されるべき５−ＨＴ、受容体アンタゴニストは、ＥＰ−Ａ−東 ４５０７５７号（グラクツ・グループ・リミテッド（Ｇｌａｘｏ　Ｇｒｏｕｐ　 Ｌｉｍ１ｔｅｄ））に特別におよび一般的に開示され、参照された５−ＨＴ、ア ンタゴニストを包含結腸−ｉ腸膨張ラット・モデル ハロタン（ｈａｌｏｔｈａｎ）麻酔下で、６〜７ｃｍのラテックスＮ／＜ルーノ をオスのウィスター（ｆｉｓｔａｒ）ラット（２５０〜６５０　ｇ）の肛門から 挿入した。バルーンのカテーテルをテープで尾に止めた。回復後、動物を運動制 限せず、担体（セイライン）または５−ヒドロキノトリプトファン（５ＨＴＰｌ ｏｍｇｋｇ−’を皮下注射）いずれかを投与した。投与５分後、内臓運動の生起 が観察されるまで約１０〜３０秒間結腸−直腸バルーンを膨張させた。ついで、 刺激を直ちに止め、圧力闇値を記録した。この膨張を５分間隔で繰り返した。３ 回の安定した応答が得られた後であって５−ＨＴＰまたはセイライン投与４５分 以内に５−ＨＴ！受容体アンタゴニストまたはセイラインを皮下注射した。つい で、内臓運動の閾値をさらに３０分間記録した。同様のモデルが、オス（Ｎｅｓ ｓ）およびゲブハート（Ｇｅｂｈａｒｔ）　（１９８８年、プレイン・リサーチ （Ｂｒａｉｎ　Ｒｅｓ、　）第４５０巻、１５３〜１６９頁）により記載されて いる。膨張圧のパーセント値の最大変化（後の投与３０分以内の期間）を、先の 投与の記録の平均値と比較した。ついて、セイライン対照値を１００として、薬 剤により誘導された変化を直接比較した。Suitable models for administration, formulation etc. are described in EP-A-279512. 5-HT, receptor antagonists to be considered for the invention are EP-A-East No. 450757 (Glaxo Group Limited) 5-HT, as specifically and generally disclosed and referenced in Antagonist-inclusive colon-i intestinal distension rat model Under halothane anesthesia, 6-7 cm of latex N/<runo from the anus of a male Wistar rat (250-650 g). Inserted. The balloon catheter was taped to the tail. After recovery, the animal is placed on exercise regime. without limitation, the carrier (Saline) or 5-hydroquinotryptophan (5HTPl) omgkg-' subcutaneous injection). 5 minutes after administration, occurrence of visceral movements The colorectal balloon was inflated for approximately 10-30 seconds until observed. Then, Stimulation was immediately stopped and pressure dark values were recorded. This expansion was repeated at 5 minute intervals. 3 45 minutes after 5-HTP or saline administration after a stable response was obtained. 5-HT within! Receptor antagonists or saline were injected subcutaneously. unintentionally Visceral motor thresholds were then recorded for an additional 30 minutes. A similar model is a male (Nes) s) and Gebhart (1988, Plain Research (Brain Res, ) Vol. 450, pp. 153-169) There is. Maximum change in percent inflation pressure (within 30 minutes of subsequent administration) Comparisons were made with the average values of the administration records. Then, with the saline control value as 100, the drug The changes induced by the agents were directly compared.

セイライン対照は、内臓運動閾値に全く影響を与えなかったが、５−ＨＴＰ投与 により、有害な刺激に対する応答を誘導するのに必要な膨張圧が減少した（減少 の平均３０７±４４％）。したがって、腸の分泌を劇的には増加させなむ＼用量 の５−ＨＴＰを用いることにより、ラット・結腸−直腸が結腸−直腸膨張に対し て敏感となり得た。Saline control had no effect on visceromotor thresholds, whereas 5-HTP administration reduced the inflation pressure required to induce a response to noxious stimuli (decreased average of 307±44%). Therefore, doses that do not dramatically increase intestinal secretion By using 5-HTP of It could be very sensitive.

５−ＨＴＰの先の投与をした後のセイラインの添加は、５−ＨＴＰによる圧力閾 値の減少に影響しなかった。比較すると、いくつかの（しかしすべてではない） ５−ＨＴ３受容体アンタゴニストは、５−ＨＴＰ投与後に投与された場合、従属 的に内臓運動閾値を先の投与値より大きなものにし、それにより、敏感になって いる結腸−１！腸の感度の低下を与え、内臓膨張の有害なレベルに対する無痛を もたらした。選択された５−ＨＴ３受容体アンタゴニスト間の相違を表に示す。Addition of saline after a previous dose of 5-HTP increases the pressure threshold due to 5-HTP. It did not affect the decrease in value. In comparison, some (but not all) 5-HT3 receptor antagonists, when administered after 5-HTP administration, visceromotor threshold to be greater than the previous dose, thereby making it more sensitive. Colon-1! Provides decreased intestinal sensitivity and relief from harmful levels of visceral distension Brought. Differences between selected 5-HT3 receptor antagonists are shown in the table.

内臓の鎮痛剤として活性のあるそれらのアンタゴニストすべてが釣り鏡型の用量 効果曲線を示したことに注意すべきである。All of those antagonists that are active as visceral analgesics are found in mirror-type doses. It should be noted that effect curves are shown.

化合物　用量　インデックス値　標準偏差μｇ／ｋｇ−’ セイライン　１．　ＯＯ０，２７ ５−ＨＴＰ　１００００　−１．６３　０．２３グラニセトロン　１　２．１７ 　０．４０１０　４．１８　０．５９ １００　２．８６　０．６６ １０００　２．１７　０．３７ １００００　２．００　０．６９ トロピセトロン　１０　１．３１　０．３３１００　１．７７　０．７３ メトクロプラミド　１　１，８８　０．３５１０　２、６９　０．４３ １００　２．１５　０．６５ 化合物　用量　インデックス値　標準偏差μｇ／ｋｇ−’ ＢＲＬ４６４７０　１　０．４６　０．３８１０　１．５０　０．３２ １００　０、０２　０．２８ １０００　０．５５　０．３９ Ｅ５”　１　２，５４　０．８７ １０　４、３１　０．６０ １００　１．７９　０．５６ オンダンセトロン　１０　１，０３　０．１５１００　０．９４　０．２０ １０００　０．４４　０．２４ １００００　１．６１　０．４９ ザトセトロン　１　２，７３　０．７７１０　３、５５　０．４４ １００　２．６６　０．５５ ”　ＥＰ−Ａ−ｉ３７７９６７号の実施例５したがって、グラニセトロン、Ｅ５ およびザトセトロンが本発明の範囲内の内臓鎮痛剤である（対照に対する闇値４ 倍以上）ことが理解されつる。Compound Dose Index Value Standard Deviation μg/kg-' Sailine 1. OO0,27 5-HTP 10000 -1.63 0.23 Granisetron 1 2.17 0.4010 4.18 0.59 100 2.86 0.66 1000 2.17 0.37 10000 2.00 0.69 Tropisetron 10 1.31 0.33100 1.77 0.73 Metoclopramide 1 1,88 0.3510 2,69 0.43 100 2.15 0.65 Compound Dose Index Value Standard Deviation μg/kg-' BRL46470 1 0.46 0.3810 1.50 0.32 100 0, 02 0.28 1000 0.55 0.39 E5” 1 2,54 0.87 10 4, 31 0.60 100 1.79 0.56 Ondansetron 10 1,03 0.15100 0.94 0.20 1000 0.44 0.24 10000 1.61 0.49 Zatosetron 1 2,73 0.7710 3,55 0.44 100 2.66 0.55 "Example 5 of EP-A-i377967 Therefore, granisetron, E5 and zatosetron are visceral analgesics within the scope of the invention (dark value 4 versus control). (more than twice) is understood.

グラニセトロン（１００ｍｇ）の鞘内投与もまた、良好な無痛活性を示し、内臓 鎮痛剤であるそれらの５−ＨＴ３受容体アンタゴニストの作用部位はを髄中であ るかもしれないことを示した。さらに、新生期にカブサイノン処理されたＣ−線 維求心路遮断ラットから最近得られた証拠は、初期求心性線維上にお１プるこれ らの５−ＨＴＳ受容体の存在、またはカブサイノン感受性求心性神経により伝達 される感覚プロセンノングにおけるこれらの受容体に関する役割が示唆されてい る。Intrathecal administration of granisetron (100 mg) also showed good painless activity and The site of action of these 5-HT3 receptor antagonists, which are analgesics, is in the spinal cord. showed that it may be possible. In addition, C-lines treated with cabcynon during the neonatal period Recent evidence from fiber deafferented rats shows that this presence of 5-HTS receptors in et al. or transmitted by cabcynon-sensitive afferents A role for these receptors in sensory processing has been suggested. Ru.

国際調査報告 −噌、、、１−ｍｍ１ｍ廟ＰＣＴ／Ｇ田１１０１１７７国際調査報告 国際調査報告 Ｓ＾　７６５２６ 国際調査報告 国際調査報告 国際調査報告 国際調査報告 ＧＯ９３０１３７７ フロントページの続き （８１）指定国　ＥＰ（ＡＴ、ＢＥ、ＣＨ，ＤＥ。international search report - 噌、、、1mm1m TemplePCT/G田1101177International Investigation Report international search report S^76526 international search report international search report international search report international search report GO9301377 Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

ＤＫ、ＥＳ、ＦＲ，ＧＢ、ＧＲ，ＩＥ、ＩＴ、ＬＵ、ＭＣ，ＮＬ、ＰＴ、ＳＥ） 、０Ａ（ＢＦ、ＢＪ、ＣＦ、ＣＧ、　ＣＩ、　ＣＭ、　ＧＡ、　ＧＮ、　ＭＬ、 　ＭＲ，ＮＥ、ＳＮ。DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.

ＴＤ、　ＴＧ）、　ＡＴ、　ＡＵ、　ＢＢ、ＢＧ、　ＢＲ，ＣＡ。TD, TG), AT, AU, BB, BG, BR, CA.

ＣＨ，ＣＺ、　ＤＥ、　ＤＫ、　ＥＳ、ＦＩ、　ＧＢ、　ＨＵ、ＪＰ、ＫＰ、Ｋ Ｒ，ＫＺ、ＬＫ、ＬＵ、ＭＧ、ＭＮ、ＭＷ、ＮＬ、Ｎｏ、ＮＺ、ＰＬ、ＰＴ、Ｒ ○、　ＲＵ、　ＳＤ。CH, CZ, DE, DK, ES, FI, GB, HU, JP, KP, K R, KZ, LK, LU, MG, MN, MW, NL, No, NZ, PL, PT, R ○, RU, SD.

ＳＥ、　ＳＫ、　ＵＡ、　ＵＳ （７２）発明者　バナー、ステイーブン・ニドワードイギリス国エセックス・シ ーエム１９・５エイデイー、バーロウ、ザ・ピナクルズ、コールドハーバ−・ロ ード（番地の表示なし）　スミスクライン・ビーチャム・ファ一マシューティカ ルズSE, SK, UA, US (72) Inventor Banner, Stephen Nidward Essex City, UK -M19.5Aday, Barlow, The Pinnacles, Coldharbour Lo (No address displayed) SmithKline Beecham Pharmaceutica Luz

Claims (9)

【特許請求の範囲】[Claims] １．ヒトを含む哺乳動物の内臓の痛みの治療および／または予防方法であって、 かかる治療および／または予防を必要とする哺乳動物に、ベツォルト−ヤリシュ （Ｂｅｚｏｌｄ−Ｊａｒｉｓｃｈ）モデルのごとき標準的試験において５−ＨＴ ３受容体アンタゴニスト活性が観察される用量として測定された用量で動物モデ ルにおいて活性を示す有効量および／または予防量の５−ＨＴ３受容体アンタゴ ニストを投与することからなる方法。1. A method for treating and/or preventing visceral pain in mammals including humans, comprising: For mammals in need of such treatment and/or prophylaxis, In standard tests such as the (Bezold-Jarisch) model, 5-HT 3 receptor antagonist activity was observed in animal models at the dose measured as the dose at which receptor antagonist activity was observed. an effective and/or prophylactic amount of a 5-HT3 receptor antagonist that exhibits activity in A method consisting of administering a drug. ２．内臟の痛みの治療において、ベツォルト−ヤリシュ（Ｂｅｚｏｌｄ−Ｊａｒ ｉｓｃｈ）モデルのごとき標準的試験において５−ＨＴ３受容体アンタゴニスト 活性が観察される用量として測定された用量で動物モデルにおいて活性を示すそ れらの５−ＨＴ３受容体アンタゴニストの使用。2. In the treatment of internal vaginal pain, Bezold-Jar 5-HT3 receptor antagonists in standard tests such as the isch) model. A drug that exhibits activity in animal models at the dose measured as the dose at which activity is observed. Use of these 5-HT3 receptor antagonists. ３．ベツォルト−ヤリシュ（Ｂｅｚｏｌｄ−Ｊａｒｉｓｃｈ）モデルのごとき標 準的試験において５−ＨＴ３受容体アンタゴニスト活性が観察される用量として 測定された用量で動物モデルにおいて活性を示す５−ＨＴ３受容体アンタゴニス ト、および医薬上許容される担体からなる、内臓の痛みの治療および／または予 防に用いる医薬組成物。3. Standards such as the Bezold-Jarisch model As the dose at which 5-HT3 receptor antagonist activity is observed in a quasi-standard test 5-HT3 receptor antagonists showing activity in animal models at measured doses and a pharmaceutically acceptable carrier for the treatment and/or prophylaxis of visceral pain. Pharmaceutical composition used for prevention. ４．化合物が５−ＨＴ３受容体アンタゴニスト用量よりも少ない用量で活性を示 す請求項１、２または３記載の方法、使用または組成物。4. The compound exhibits activity at a lower dose than the 5-HT3 receptor antagonist dose. 4. A method, use or composition according to claim 1, 2 or 3. ５．ＩＢＳの痛みの症状の治療のための請求項４記載の方法、使用または組成物 。5. 5. A method, use or composition according to claim 4 for the treatment of IBS pain symptoms. . ６．また偏頭痛の治療のための請求項５記載の方法、使用または組成物。6. 6. A method, use or composition according to claim 5, also for the treatment of migraine. ７．５−ＨＴ３受容体アンタゴニストがＥＰ−Ａ−第４５０７５７号（グラクソ ・グル−プ・リミテッド（Ｇｌａｘｏ　Ｇｒｏｕｐ　Ｌｉｍｉｔｅｄ））におい て特別におよび一般的に開示ならびに参照された５−ＨＴ受容体アンタゴニスト から選択される請求項１、２または３記載の方法、使用または組成物。7.5-HT3 receptor antagonists are disclosed in EP-A-450757 (Glaxo ・Glaxo Group Limited) Smell 5-HT receptor antagonists specifically and generally disclosed and referenced in 4. A method, use or composition according to claim 1, 2 or 3 selected from: ８．５−ＨＴ３受容体アンタゴニストがグラニセトロン（ｇｒａｎｉｓｅｔｏｎ ）である請求項１、２または３記載の方法、使用または組成物。8.5-HT3 receptor antagonist granisetron ) The method, use or composition according to claim 1, 2 or 3. ９．５−ＨＴ３受容体アンタゴニストがザトセトロン（ｚａｔｏｓｅｔｒｏｎ） （リリ−（Ｌｉｌｌｙ））またはメトクロプラミド（ｍｅｔｏｃｌｏｐｒａｍｉ ｄｅ）である請求項１、２または３記載の方法、使用または組成物。9.5-HT3 receptor antagonist is zatosetron (Lilly) or metoclopramide (metoclopramide) 4. A method, use or composition according to claim 1, 2 or 3 which is de).
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