JPH07508530A - Medicines for treating visceral pain and migraines - Google Patents
Medicines for treating visceral pain and migrainesInfo
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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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- 208000009935 visceral pain Diseases 0.000 title claims description 6
- 229940079593 drug Drugs 0.000 title claims description 5
- 239000003814 drug Substances 0.000 title claims description 5
- 208000019695 Migraine disease Diseases 0.000 title claims description 4
- 230000000694 effects Effects 0.000 claims description 15
- 229940044551 receptor antagonist Drugs 0.000 claims description 11
- 239000002464 receptor antagonist Substances 0.000 claims description 11
- 102000035037 5-HT3 receptors Human genes 0.000 claims description 10
- 108091005477 5-HT3 receptors Proteins 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 claims description 7
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 claims description 7
- 229960003727 granisetron Drugs 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000010171 animal model Methods 0.000 claims description 5
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
- 229960004503 metoclopramide Drugs 0.000 claims description 4
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000012360 testing method Methods 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 3
- SPKBYQZELVEOLL-QDMKHBRRSA-N chembl2111147 Chemical group N([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C1=CC(Cl)=CC2=C1OC(C)(C)C2 SPKBYQZELVEOLL-QDMKHBRRSA-N 0.000 claims description 3
- 230000036407 pain Effects 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 229950001074 zatosetron Drugs 0.000 claims description 3
- 229940127239 5 Hydroxytryptamine receptor antagonist Drugs 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 206010069055 Vulvovaginal pain Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 206010027599 migraine Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 230000009278 visceral effect Effects 0.000 description 6
- 229940035676 analgesics Drugs 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- MFWNKCLOYSRHCJ-AGUYFDCRSA-N 1-methyl-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]-3-indazolecarboxamide Chemical compound C1=CC=C2C(C(=O)NC3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-AGUYFDCRSA-N 0.000 description 1
- ILXWRFDRNAKTDD-GOOCMWNKSA-N 3,3-dimethyl-n-[(1r,5s)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-2h-indole-1-carboxamide Chemical compound C1C(C)(C)C2=CC=CC=C2N1C(=O)NC(C1)C[C@H]2CC[C@@H]1N2C ILXWRFDRNAKTDD-GOOCMWNKSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 210000002011 intestinal secretion Anatomy 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000031893 sensory processing Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- 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)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (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)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929214184A GB9214184D0 (en) | 1992-07-03 | 1992-07-03 | Pharmaceuticals |
| GB9214184.5 | 1992-07-03 | ||
| PCT/GB1993/001377 WO1994001095A2 (en) | 1992-07-03 | 1993-06-30 | Medicaments for the treatment of visceral pain and migraine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07508530A true JPH07508530A (en) | 1995-09-21 |
Family
ID=10718169
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| Application Number | Title | Priority Date | Filing Date |
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| JP6503078A Pending JPH07508530A (en) | 1992-07-03 | 1993-06-30 | Medicines for treating visceral pain and migraines |
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| Country | Link |
|---|---|
| EP (1) | EP0650355A1 (en) |
| JP (1) | JPH07508530A (en) |
| KR (1) | KR950702112A (en) |
| AU (1) | AU4507693A (en) |
| CA (1) | CA2139440A1 (en) |
| GB (1) | GB9214184D0 (en) |
| WO (1) | WO1994001095A2 (en) |
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| JP2002503689A (en) * | 1998-02-21 | 2002-02-05 | アスタ メディカ アクチエンゲゼルシャフト | Pharmaceutical combinations containing tramadol |
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| US5998409A (en) * | 1992-03-12 | 1999-12-07 | Smithkline Beecham Plc | Condensed indole derivatives as 5HT4 -receptor antagonists |
| US5852014A (en) * | 1992-03-12 | 1998-12-22 | Smithkline Beecham P.L.C. | Condensed indole derivatives as 5HT4 -receptor antagonists |
| US5726187A (en) * | 1992-10-16 | 1998-03-10 | Smithkline Beecham Plc | N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems as 5-HT4 receptor antagonists |
| GB9721139D0 (en) | 1997-10-07 | 1997-12-03 | Glaxo Group Ltd | Medicaments |
| ES2327600T3 (en) | 1999-02-18 | 2009-11-02 | Novasearch Ag | USE OF ANTAGONISTS OF THE 5-HT3 RECEPTOR FOR THE TREATMENT OF MUSCLE SKELETIC DISEASES. |
| TWI263496B (en) * | 1999-12-10 | 2006-10-11 | Novartis Ag | Pharmaceutical combinations and their use in treating gastrointestinal disorders |
| GB0216027D0 (en) | 2002-07-10 | 2002-08-21 | Arachnova Therapeutics Ltd | New therapeutic use |
| NZ541009A (en) | 2003-01-13 | 2007-09-28 | Dynogen Pharmaceuticals Inc | Method of treating nausea, vomiting, retching or any combination thereof |
| GB0302662D0 (en) * | 2003-02-05 | 2003-03-12 | Strakan Ltd | Transdermal granisetron |
| US20060263421A1 (en) | 2005-05-18 | 2006-11-23 | Abeille Pharmaceuticals Inc | Transdermal Method and Patch for Nausea |
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| EP0189002B1 (en) * | 1984-12-20 | 1993-03-03 | Sandoz Ag | Treatment of gastrointestinal disorders using 5-ht3 antagonists |
| GB8617994D0 (en) * | 1986-07-23 | 1986-08-28 | Glaxo Group Ltd | Heterocyclic compounds |
| EP0254584B1 (en) * | 1986-07-25 | 1992-10-07 | Beecham Group Plc | Azabicyclic compounds, process for their preparation, and their pharmaceutical use |
| GB8623819D0 (en) * | 1986-10-03 | 1986-11-05 | Glaxo Group Ltd | Heterocyclic compounds |
| GB8812002D0 (en) * | 1988-05-20 | 1988-06-22 | Glaxo Group Ltd | Chemical compounds |
| GB8630080D0 (en) * | 1986-12-17 | 1987-01-28 | Glaxo Group Ltd | Medicaments |
| GB8806990D0 (en) * | 1988-03-23 | 1988-04-27 | Beecham Group Plc | Novel compounds |
| GB8701022D0 (en) * | 1987-01-19 | 1987-02-18 | Beecham Group Plc | Treatment |
| DE3852145T2 (en) * | 1987-02-18 | 1995-04-06 | Beecham Group Plc | Indole derivatives, processes for their preparation and pharmaceutical preparations containing them. |
| DE3881950T2 (en) * | 1987-04-25 | 1993-09-30 | Beecham Group Plc | Azabicyclic compounds, processes for their preparation and pharmaceutical preparations containing them. |
| GB8723157D0 (en) * | 1987-10-02 | 1987-11-04 | Beecham Group Plc | Compounds |
| JPH01258673A (en) * | 1987-10-22 | 1989-10-16 | Glaxo Group Ltd | Ketone derivative |
| EP0315390B1 (en) * | 1987-11-04 | 1994-07-20 | Beecham Group Plc | Novel 4-oxobenzotriazines and 4-oxoquinazolines |
| EP0336759A1 (en) * | 1988-04-07 | 1989-10-11 | Glaxo Group Limited | Imidazole derivatives |
| GB8814277D0 (en) * | 1988-06-16 | 1988-07-20 | Glaxo Group Ltd | Chemical compounds |
| IT1226389B (en) * | 1988-07-12 | 1991-01-15 | Angeli Inst Spa | NEW AMIDID AND GUANIDINE DERIVATIVES |
| US5017573A (en) * | 1988-07-29 | 1991-05-21 | Dainippon Pharmaceutical Co., Ltd. | Indazole-3-carboxylic acid derivatives |
| JPH02167280A (en) * | 1988-08-15 | 1990-06-27 | Glaxo Group Ltd | Lactam derivative |
| GB8820650D0 (en) * | 1988-09-01 | 1988-10-05 | Glaxo Group Ltd | Medicaments |
| AU627221B2 (en) * | 1988-09-27 | 1992-08-20 | Fujisawa Pharmaceutical Co., Ltd. | Pyridoindole derivatives and processes for preparation thereof |
| US5173493A (en) * | 1988-09-27 | 1992-12-22 | Fujisawa Pharmaceutical Company, Ltd. | Pyridoindole derivatives and processes for preparation thereof |
| GB8823980D0 (en) * | 1988-10-13 | 1988-11-23 | Glaxo Group Ltd | Chemical compounds |
| GB8829079D0 (en) * | 1988-12-13 | 1989-01-25 | Beecham Group Plc | Novel compounds |
| CA2004911A1 (en) * | 1988-12-22 | 1990-06-22 | Mitsuaki Ohta | 4,5,6,7-tetrahydrobenzimidazole derivatives |
| DE69028934T2 (en) * | 1989-02-02 | 1997-03-20 | Yamanouchi Pharma Co Ltd | Tetrahydrobenzimidazole derivatives |
| GB8904551D0 (en) * | 1989-02-28 | 1989-04-12 | Glaxo Group Ltd | Chemical compounds |
| EP0387431A1 (en) * | 1989-03-14 | 1990-09-19 | Beecham Group Plc | Imidazole derivatives, process for their preparation and their pharmaceutical use |
| GB8916682D0 (en) * | 1989-07-21 | 1989-09-06 | Beecham Group Plc | Pharmaceutical compounds |
| DK443489D0 (en) * | 1989-09-08 | 1989-09-08 | Ferrosan As | SUBSTITUTED URINARY COMPOUNDS, THEIR PREPARATION AND USE |
| US4992461A (en) * | 1989-09-11 | 1991-02-12 | G. D. Searle & Co. | N-azabicyclo(3.3.0)octane amides of aromatic acids, compositions, and methods of use thereof |
| US5126343A (en) * | 1989-09-11 | 1992-06-30 | G. D. Searle & Co. | N-azabicyclo [3.3.0]octane amides of aromatic acids |
| WO1991007402A1 (en) * | 1989-11-17 | 1991-05-30 | Pfizer Inc. | Azabicyclo amides and esters as 5-ht3 receptor antagonists |
| DK40890D0 (en) * | 1990-02-16 | 1990-02-16 | Ferrosan As | SUBSTITUTED URINARY COMPOUNDS, THEIR PREPARATION AND USE |
| EP0450757A3 (en) * | 1990-02-22 | 1993-09-15 | Glaxo Group Limited | Use of 5-hydroxytryptamine-antagonists in the treatment of mental disorders originating in childhood |
| US5140023A (en) * | 1990-04-27 | 1992-08-18 | G. D. Searle & Co. | Azatetracycle compounds |
| GB9020927D0 (en) * | 1990-09-26 | 1990-11-07 | Beecham Group Plc | Pharmaceuticals |
| GB9027487D0 (en) * | 1990-12-19 | 1991-02-06 | Beecham Group Plc | Pharmaceuticals |
| AU1161292A (en) * | 1991-01-09 | 1992-08-17 | Smithkline Beecham Plc | Azabicydic and azatricydic derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them |
| GB9103839D0 (en) * | 1991-02-23 | 1991-04-10 | Smithkline Beecham Plc | Pharmaceuticals |
| US5260303A (en) * | 1991-03-07 | 1993-11-09 | G. D. Searle & Co. | Imidazopyridines as serotonergic 5-HT3 antagonists |
| US5137893A (en) * | 1991-03-07 | 1992-08-11 | G. D. Searle & Co. | Pharmaceutically useful meso-azacyclic amides of imidazopyridine carboxylic acids and analogs thereof |
| EP0517984A1 (en) * | 1991-06-11 | 1992-12-16 | Merrell Dow Pharmaceuticals Inc. | Derivatives of amide analogs of certain methano bridged quinolizines |
| DK0554794T3 (en) * | 1992-02-04 | 1999-04-26 | Eisai Co Ltd | aminobenzoic |
-
1992
- 1992-07-03 GB GB929214184A patent/GB9214184D0/en active Pending
-
1993
- 1993-06-30 JP JP6503078A patent/JPH07508530A/en active Pending
- 1993-06-30 AU AU45076/93A patent/AU4507693A/en not_active Abandoned
- 1993-06-30 WO PCT/GB1993/001377 patent/WO1994001095A2/en not_active Ceased
- 1993-06-30 CA CA002139440A patent/CA2139440A1/en not_active Abandoned
- 1993-06-30 EP EP93914854A patent/EP0650355A1/en not_active Withdrawn
-
1994
- 1994-12-31 KR KR1019940704887A patent/KR950702112A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002503689A (en) * | 1998-02-21 | 2002-02-05 | アスタ メディカ アクチエンゲゼルシャフト | Pharmaceutical combinations containing tramadol |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9214184D0 (en) | 1992-08-12 |
| CA2139440A1 (en) | 1994-01-20 |
| WO1994001095A3 (en) | 1994-04-14 |
| KR950702112A (en) | 1995-06-19 |
| AU4507693A (en) | 1994-01-31 |
| WO1994001095A2 (en) | 1994-01-20 |
| EP0650355A1 (en) | 1995-05-03 |
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