TW200406199A - Preventive and/or therapeutic agent for heart failure - Google Patents
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- TW200406199A TW200406199A TW092123985A TW92123985A TW200406199A TW 200406199 A TW200406199 A TW 200406199A TW 092123985 A TW092123985 A TW 092123985A TW 92123985 A TW92123985 A TW 92123985A TW 200406199 A TW200406199 A TW 200406199A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
Description
200406199 Π) 玖、發明說明 【S明所屬之技術領域】 本發明係關於預防及/或治療心臟衰竭用劑 【先前技術】 正常的心臟係於安靜時及日常活動時，擔任供給充份 血液予全身各臟器及組織之唧筒的角色，但是因各種原因 使心臟的啷筒機能降低，心臟不能送出充份的血液給身體 時所產的異常狀態，將例如呼吸困難或坐位呼吸、水腫、 胸腹積水、鬱血性肝及寡尿等之症候群，臨床上定義爲心 臟衰竭。 因此，心臟衰竭係複合地形成各種心臟異常，造成心 室機能衰竭，如先前所示之臨床症狀者。因此，認爲心臟 衰竭係同時存在各種原因，以單一的預防及/或治療劑對 此進行預防及/或治療係不夠的，而成爲期待具有新穎機 制之預防及/或治療劑之領域。 現在心臟衰竭的治療，除使用利尿劑、血管收縮素轉 化酵素（ACE)抑制劑或宿根草製劑之外，亦廣泛地使用α 阻斷藥等。 作爲降血壓劑，於南美、東南亞及歐洲廣泛地使用之 具有α阻斷作用之五羥色胺（5ΗΤ2)受體拮抗劑之 Ketanserin，報告指出對於鬱血性心臟衰竭之患者具有效 性（Demoulin JC. et al·: Lancet 11186-1188，1981)。然而 ，於大規模之臨床上檢討’亦指出多數使用本藥劑者中發 (2) 200406199 現有致死之心室性心律不整（Singh BN. et al.:Eur. Heart J. 8:667-668， 1987) 〇 另一方面，報告指出代表鹽酸沙格雷酯（Sarp ogre late H y d r o c h 1 o r i d e )之以下述式（2 ) occh2ch2cooh 0 、CHf H2N<= (2) 善 _200406199 Π) 发明 Description of the invention [Technical field to which Sming belongs] The present invention relates to an agent for the prevention and / or treatment of heart failure [Prior art] The normal heart is responsible for supplying sufficient blood to the body at rest and during daily activities The role of the organs of various organs and tissues in the body, but the heart's organs are reduced for various reasons, and the heart can not send sufficient blood to the body, which produces abnormal conditions such as dyspnea or sitting breathing, edema, chest Symptoms of ascites, congestive liver, and oligouria are clinically defined as heart failure. Therefore, heart failure is a composite of various cardiac abnormalities that cause ventricular failure, as shown in the clinical symptoms previously shown. Therefore, it is considered that there are various causes of heart failure at the same time, and it is not enough to prevent and / or treat it with a single preventive and / or therapeutic agent, and it is an area where a preventive and / or therapeutic agent with a novel mechanism is expected. In the treatment of heart failure, in addition to diuretics, angiotensin-converting enzyme (ACE) inhibitors, and rattan preparations, alpha blockers are also widely used. Ketanserin, an alpha-blocking serotonin (5ΗΤ2) receptor antagonist, widely used in South America, Southeast Asia, and Europe as a hypotensive agent, has been reported to be effective in patients with congestive heart failure (Demoulin JC. Et al ·: Lancet 11186-1188, 1981). However, a large-scale clinical review 'also pointed out that most of the patients who use this agent (2) 200406199 have existing lethal ventricular arrhythmias (Singh BN. Et al .: Eur. Heart J. 8: 667-668, 1987 ) 〇 On the other hand, the report pointed out that the following formula (2) occh2ch2cooh 0, CHf H2N < = (2) good _
所表示之特定構造之aminopropoxybibenzyl (胺基丙 氧基二苯基）類係對於5HT2受體顯示高的選擇性，對於血 壓幾乎不給予任何影響，另外，亦幾乎無嚴重的副作用， 顯示高安全性之藥劑。另外，已知對於至今之腦循環障礙 、缺血性心臟病及末梢循環障礙等之疾病中，基於血栓 春 成及血管收縮之各種微小循環障礙之改善有效（特開平2 —3 04 022號公報）。另外，報告亦指出使用結紮冠狀動脈 之大鼠作成心肌梗塞模式之實驗中，與無治療組比較，以 鹽酸沙格雷酯治療時，梗塞部位爲有意義地減少（J.The specific structure of the aminopropoxybibenzyl (aminopropoxydiphenyl) system shows high selectivity for the 5HT2 receptor, and it hardly affects blood pressure. In addition, it has almost no serious side effects and shows high safety. Of the potion. In addition, it has been known to be effective in improving various microcirculatory disorders based on thrombosis and vasoconstriction in diseases such as cerebral circulatory disorders, ischemic heart disease, and peripheral circulatory disorders (Japanese Patent Laid-Open No. 2-3 04 022). ). In addition, the report also pointed out that in the experiment of using myocardial ligation in rats to establish a myocardial infarction model, compared with the non-treated group, the infarct site was significantly reduced when treated with sagrelate hydrochloride (J.
Cardiovasc. Pharmacol. Therapeut. 7(1)，1 7 5 -9. 2 0 0 2 . ) 〇 然而，一般式（2 )所表示之化合物對於預防及/或治 療心臟衰竭有效一事，就本發明者所知，至今仍未有相關 報告。 (3) (3)200406199 【發明內容】 發明之揭示 本發明之課題係提供關於預防及/或治療心臟衰竭之 新穎藥劑。 本發明者等發現已知作爲5HT2受體拮抗劑之特定構造 之胺基丙氧基二苯基類，對於預防及/或治療心臟衰竭有 效，而完成本發明。 亦即，本發明之要旨如下所述。 (1)以下述一般式（1)所表示之胺基烷氧基二苯基 類、其藥學上所容許之鹽及此等之溶劑化物爲有效成份之 預防及/或治療心臟衰竭用劑。Cardiovasc. Pharmacol. Therapeut. 7 (1), 175-9. 2 0 0 2.) 〇 However, the compound represented by the general formula (2) is effective in preventing and / or treating heart failure, and the present inventors As far as we know, there are no related reports. (3) (3) 200406199 [Summary of the Invention] Disclosure of the Invention The subject of the present invention is to provide a novel agent for preventing and / or treating heart failure. The present inventors have found that aminopropoxydiphenyls having a specific structure known as a 5HT2 receptor antagonist are effective for preventing and / or treating heart failure, and completed the present invention. That is, the gist of this invention is as follows. (1) An agent for the prevention and / or treatment of heart failure, which uses the aminoalkoxydiphenyls represented by the following general formula (1), pharmaceutically acceptable salts thereof, and these solvates as active ingredients.
〔上述式中，R1係表不氨原子、_素原子、C1至C5 之院.氧基、或C2至C6之二烷胺基，R2係表示氫原子、鹵 素原子、或C1至C5之烷氧基、R3係表示氫原子、羥基、 —0〜（CH2) n— COOH(式中，η係表示1至5之整數。 )、或 0— CO— ( CH2 ) 1— COOH(式中，1 係表示 1 至 3 έ整數。），R4係表示—N(R5) ( R6 )(式中，R5及 R6係表示分別獨立之氫原子或C1S C8之烷基。）或 (4) 200406199[In the above formula, R1 represents an ammonia atom, a prime atom, a C1 to C5.oxy group, or a C2 to C6 dialkylamino group, and R2 represents a hydrogen atom, a halogen atom, or a C1 to C5 alkane Oxygen and R3 represent a hydrogen atom, a hydroxyl group, —0 to (CH2) n—COOH (where η represents an integer from 1 to 5.), or 0—CO— (CH2) 1—COOH (where, 1 is an integer from 1 to 3.), R4 is -N (R5) (R6) (where R5 and R6 are independent hydrogen atoms or C1S C8 alkyl groups.) Or (4) 200406199
(式中，A爲羧基所取代亦可之C 3至C 5之烯 ，m係表示0至5之整數。〕 (2 )上述之預防及/或治療心臟衰竭用劑中之 式（1 )所表示之化合物係以選自下述式（2 )所表 合物、其鹽及此等之溶劑化物爲特徵。 基c ) 以一般 示之化(In the formula, A is an olefin of C 3 to C 5 which may be substituted by a carboxyl group, and m is an integer of 0 to 5.] (2) Formula (1) in the above-mentioned agent for preventing and / or treating heart failure The compound represented is characterized by being selected from a compound represented by the following formula (2), a salt thereof, and a solvate thereof. The group c) is represented by a general formula
h3coh3co
CH2CH2\^>vCH2CH2 \ ^ > v
ch2chch2n ^ch3 \ch3 occh2ch2cooh (3 )上述之預防及/或治療心臟衰竭用劑中之 鹽酸鹽爲特徵。 .(4 )上述之預防及/或治療心臟衰竭用劑中之 式（1 )所表示之化合物係以選自下述式（3 )所表 合物、其鹽及此等之溶劑化物爲特徵。 Μ \ch2chch2n<^3 (cch2chch2n ^ ch3 \ ch3 occh2ch2cooh (3) The hydrochloride in the above-mentioned agent for preventing and / or treating heart failure is characterized. (4) The compound represented by formula (1) in the above-mentioned agent for the prevention and / or treatment of heart failure is characterized by being selected from the group consisting of the compound represented by the following formula (3), its salt, and solvates thereof. . Μ \ ch2chch2n < ^ 3 (c
OH 鹽係靡_ 以一般 示之化 (5) (5)200406199 (5 )上述之預防及/或治療心臟衰竭用劑中之心臟衰 竭係以鬱血性心臟衰竭爲特徵。 (6 )上述之預防及/或治療心臟衰竭用劑係以倂用投 予已經投予選自 ACE抑制劑、利尿劑或宿根草製劑之藥 劑之患者爲特徵。 用以實施發明之最佳型態 以下，詳細地說明本發明。 有關本發明之預防及/或治療心臟衰竭用劑係以上述 一般式（1)所示之胺基烷氧基二苯基類以及其藥學上所 容許之鹽及此等之溶劑化物爲有效成份（另外，本說明書 中之鹽廣義上亦包含酯。）。 上述一般式（1 )所表示的化合物係已知作爲五羥色 胺（serotonin )拮抗劑，對於腦循環障礙、缺血性心臟病 及末梢循環障礙等之疾病中，基於血栓生成及血管收縮之 各種微小循環障礙之改善有效（特開平2 - 3 04022號公幸P )。然而，此化合物作爲預防及/或治療心臟衰竭用劑有 效，完全是意想不到的。 關於上述一般式（1 )之化合物，更具體地說明時， 式中，R1係表示氫原子；氯原子及氟原子等之鹵素原子； 甲氧基、乙氧基及丁氧基等之C1至C5之烷氧基；二甲胺 基、二乙胺基及甲基乙胺基等之C2至C6之二烷胺基。R2 係表示氫原子；氯原子及氟原子等之鹵素原子；甲氧基、 乙氧基及丁氧基等之C1至C5之烷氧基。R3係表示氫原子 (6) (6)200406199 ；經基；一O— (CH2) 2— COOH、一〇一（CH2) 3 - C〇OH等之一O— (CH2) n— COOH(式中，n係表示〗至5 之整數。）；—0— CO— (CH2) 2— COOH 及—0— CO — (CH2 ) 3 - COOH 等之一 0— CO— (CH2) 1— C0 0H (式 中，1係表示1至3之整數。）。R4係表示胺基或甲胺基、 乙胺基、丁胺基、己胺基、庚胺基、二甲胺基、二乙胺基 及甲基乙胺基等之碳原子數爲1至8之烷基具有1至2個胺基 ，或於三亞甲基胺基、五亞甲基胺基及3 -羧基五亞甲基 胺基等之環上，羧基取代亦可之4至6環之多亞甲基胺基。 上述一般式（1 )之化合物中之幾個適合本發明使用 者，如表一 1所示。The OH salt is superficially characterized by the general indications (5) (5) 200406199 (5) The heart failure in the above-mentioned agent for the prevention and / or treatment of heart failure is characterized by congestive heart failure. (6) The above-mentioned agent for preventing and / or treating heart failure is characterized by administering to a patient who has been administered a drug selected from the group consisting of an ACE inhibitor, a diuretic or a rattan preparation. Best Mode for Carrying Out the Invention The present invention will be described in detail below. The agent for preventing and / or treating heart failure according to the present invention contains the aminoalkoxydiphenyls represented by the general formula (1) above, and pharmaceutically acceptable salts and solvates thereof as active ingredients. (In addition, the salts in this specification also include esters in a broad sense.) The compound represented by the general formula (1) is known as a serotonin antagonist, and is used for various microcirculations based on thrombogenesis and vasoconstriction in diseases such as cerebral circulatory disturbance, ischemic heart disease, and peripheral circulatory disturbance. The improvement of the obstacle is effective (Japanese Patent Laid-Open No. 2-3 04022, Gongxing P). However, it is completely unexpected that this compound is effective as an agent for preventing and / or treating heart failure. Regarding the compound of the above general formula (1), when it is more specifically described, in the formula, R1 represents a hydrogen atom; a halogen atom such as a chlorine atom and a fluorine atom; and C1 to methoxy, ethoxy, and butoxy. C5 alkoxy; C2 to C6 dialkylamino groups such as dimethylamino, diethylamino and methylethylamino. R2 represents a hydrogen atom; a halogen atom such as a chlorine atom and a fluorine atom; a C1 to C5 alkoxy group such as a methoxy group, an ethoxy group, and a butoxy group. R3 represents a hydrogen atom (6) (6) 200406199; a radical; one of O— (CH2) 2—COOH, one— (CH2) 3—COH, etc.—O— (CH2) n—COOH (formula Where n is an integer from 5 to 5.); -0— CO— (CH2) 2— COOH and —0— CO — (CH2) 3-COOH etc. 0— CO— (CH2) 1— C0 0H (In the formula, 1 is an integer of 1 to 3.) R4 is an amino group or a methylamino group, an ethylamino group, a butylamino group, a hexylamino group, a heptylamine group, a dimethylamino group, a diethylamino group, a methylethylamino group, etc. The alkyl group has 1 to 2 amine groups, or on the ring of trimethyleneamino group, pentamethyleneamino group and 3-carboxypentamethyleneamino group, etc., and the carboxyl group may also have 4 to 6 rings. Polymethyleneamine. Some of the compounds of the above general formula (1) are suitable for the users of the present invention, as shown in Table 1-1.
-9 - (7) 200406199 (7)-9-(7) 200406199 (7)
表一 1 化 合 物 號 碼 2 8 R2 5 s 〇CH2CH-(CH2)ni-R< R3 R1 R2 胺基烷氧 基的位置 R3 m R4 1 Η Η 2位 Η 0 n(ch3)2 2 Η Η 2位 Η 1 N(CH3)2 3 Η Η 2位 Η 2 N(CHs)2 4 Η Η 2位 Η 3 N(CH3)2 5 Η Η 2位 Η 4 N(CH3)2 6 Η Η 2位 Η 2 NHCH3 7 Η Η 2位 Η 2 nh2 8 Η Η 2位 Η 2 〇 9 Η Η 2位 Η 2 〇c 10 Η Η 3位 Η 2 N(CHs)2 11 Η Η 4位 Η 2 N(CH3)2 12 3-OCHg Η 2位 Η 2 N(CH3)2 13 4-N(CH3)2 Η 2位 Η 1 咖S)2 14 3-0CH3 Η 2位 ococch2)2cooh 1 _3)2 -10- (8) 200406199 秦1(續) 化合物7 號碼 R1 R2 胺基烷氧^ 基的位置 Rs m 15 3-OCH3 Η 2位 0H 1 _)2 16 ,3-0CH3 Η 2位 o(ch2)2cooh 1 N(CHs)2 17 3-F Η 2位 DC0(CH2)2C00H 1 N(CH8)2 18 Η Η 2&1 OH 1 N(CH3)2 19 3-C1 Η 2位 H 2 n(ch3)2 20 Η 5-C1 2位 H 2 N(CH3)2 21 Η 3OCH3 2位 H 2 N(CH3)2 此等中係以胺基烷氧基一 OCH2C ( R3 ) H— ( CH2 ) m — R 4鍵結於苯基之2位者爲宜。另外，R 1係以氫原子、 C1至 C5之烷氧基或 C2至 C6之二烷胺基爲宜，R2係以氫 原子爲宜，R4係至少具有1個C1至C8烷基之胺基，或具 有三亞甲基胺基、五亞甲基胺基之4至6環之多亞甲基胺g 爲宜。尤其適合的是R1爲甲氧基、R2爲氫原子，R3爲羥 基，R4爲二甲胺基之No· 15之化合物（以下，將此稱爲r Ml」）及其琥珀酸酯之No.14之化合物。 本發明中，亦可使用一般式（1)所表示之化合物之 藥劑上所容許的鹽。形成如此鹽之酸，例如鹽酸、氯漠酸 、硫酸、磷酸、硝酸、醋酸、琥珀酸、已二酸、丙酸、酒 石酸、馬來酸、草酸、檸檬酸、苯甲酸、甲苯磺酸及甲擴 酸等。另外’可使用一般式（1 )所表示之化合物或其鹽 之溶劑化物，例如水合物。此等中尤其適宜者係下述式（ &4S · 11 - 200406199 Ο) 4)所袠示之（±) — 1 — ：0— :2— （間甲氧基苯基）乙 基〕苯氧基〕一 3—(二甲胺基）2-丙基氫琥珀酸之鹽酸 鹽（以下，亦將其稱爲「鹽酸沙格雷酯」）。 \ch2chch2n<^|3 ·| \CH3Table 1 Compound number 2 8 R2 5 s 〇CH2CH- (CH2) ni-R < R3 R1 R2 Position of amino alkoxy group R3 m R4 1 Η Η 2 position Η 0 n (ch3) 2 2 Η Η 2 position Η 1 N (CH3) 2 3 Η Η 2 place Η 2 N (CHs) 2 4 Η Η 2 place Η 3 N (CH3) 2 5 Η Η 2 place Η 4 N (CH3) 2 6 Η Η 2 place Η 2 NHCH3 7 Η Η Η 2Η 2 nh2 8 Η Η 2Η Η 2 〇9 Η Η 2Η Η 2 〇c 10 Η Η 3Η N 2 N (CHs) 2 11 Η Η 4Η Η 2 N (CH3) 2 12 3-OCHg Η 2 place Η 2 N (CH3) 2 13 4-N (CH3) 2 Η 2 place Η 1 coffee S) 2 14 3-0CH3 Η 2 place ococch2) 2cooh 1 _3) 2 -10- (8 ) 200406199 Qin 1 (continued) Compound 7 Number R1 R2 Position of amino alkoxy group Rs m 15 3-OCH3 Η 2 position 0H 1 _) 2 16, 3-0CH3 Η 2 position o (ch2) 2cooh 1 N ( CHs) 2 17 3-F Η 2-digit DC0 (CH2) 2C00H 1 N (CH8) 2 18 Η & 2 & 1 OH 1 N (CH3) 2 19 3-C1 Η 2-digit H 2 n (ch3) 2 20 Η 5-C1 2-position H 2 N (CH3) 2 21 Η 3OCH3 2-position H 2 N (CH3) 2 These are bound by aminoalkoxy-OCH2C (R3) H— (CH2) m — R 4 It is suitable for the two phenyl groups. In addition, R 1 is preferably a hydrogen atom, an alkoxy group of C1 to C5 or a dialkylamino group of C2 to C6, R2 is preferably a hydrogen atom, and R4 is an amine group having at least one C1 to C8 alkyl group. Or a polymethyleneamine g having 4 to 6 rings of a trimethyleneamino group and a pentamethyleneamino group is preferable. Particularly suitable are compounds in which R1 is a methoxy group, R2 is a hydrogen atom, R3 is a hydroxyl group, and R4 is a dimethylamino group of No. 15 (hereinafter, this is referred to as "r Ml") and its succinate. 14 of the compound. In the present invention, a pharmaceutically acceptable salt of the compound represented by the general formula (1) may be used. Acids forming such salts, such as hydrochloric acid, chloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, and formic acid Acid expansion and so on. In addition, a solvate such as a hydrate of the compound represented by the general formula (1) or a salt thereof can be used. Particularly suitable among these are (±) shown in the following formula (& 4S · 11-200406199 Ο) 4) — 1 —: 0 —: 2 — (m-methoxyphenyl) ethyl] benzene Oxy] -3- (dimethylamino) 2-propylhydrosuccinic acid hydrochloride (hereinafter, this is also referred to as "sagrelate hydrochloride"). \ ch2chch2n < ^ | 3 · | \ CH3
HCI occh2ch2coohHCI occh2ch2cooh
ο 本發明中所使用之一般式（1)之胺基烷氧基二苯基 類係如上述之已知化合物，依據如特開昭5 8 — 3 2 8 4 7號公ο The amino alkoxydiphenyls of the general formula (1) used in the present invention are known compounds as described above, according to, for example, JP 5 8 — 3 2 8 4 7
報所記載之方法或以其爲基準之方法，可容易地合成。另 外’上述式（4)所表示之化合物之鹽酸沙格雷酯爲有效 成份之醫藥係由三菱Pharma株式會社所市售之Anplag( 註冊商標），本發明中亦可直接使用Anplag。 | 本發明中’將上述化合物供予預防及/或治療心臟衰 竭。尤其適合供予預防及/或治療鬱血性心臟衰竭。 另外’於本發明中，對於已經投予選自 ACE抑制劑 、利尿劑或宿根草製劑之藥劑之患者，亦可倂用投予本發 明之藥劑。 作爲上述之 ACE抑制劑，可舉例如 quinapril hydrochloride ( Conan) 、captoril ( Bristol) 、enalapril maleate ( Renivace ) 、a 1 a c e p r i 1 ( S e t ap r i 1 ) 、delapril hydrochloride ( Adecut ) > cilazapril ( Inhibace )、 -12- (10) (10)200406199 lisinopril ( Longes，Zestril ) 、benazepril hydrochloride (Cibacen ) 、imidapril ( Tanatril ’ Novae) 、temocapril hydrochloride ( Acecol ) 、trandolapril ( Odric，Preran ) 及 p e r i n d o p r i 1 e r b u m i n e ( C o v e r s y 1 )等，作爲利尿劑，可 舉例如 Bumetanide ( Lunetoron) 、Piretanide ( Arelax) 、 azosemide ( Diart ) 、 torasemide ( Luprac ) 、The method described in the report or the method based on it can be easily synthesized. In addition, the medicine of sagrelide hydrochloride of the compound represented by the above formula (4) is an anplag (registered trademark) commercially available from Mitsubishi Pharma Co., Ltd., and Anplag can also be used directly in the present invention. In the present invention, 'the aforementioned compound is used for the prevention and / or treatment of heart failure. Particularly suitable for the prevention and / or treatment of congestive heart failure. In addition, in the present invention, a patient who has already administered a drug selected from the group consisting of an ACE inhibitor, a diuretic agent, and a rattan preparation may also use the drug administered to the present invention. Examples of the above ACE inhibitors include quinapril hydrochloride (Conan), captoril (Bristol), enalapril maleate (Renivace), a 1 acepri 1 (S et ap ri 1), delapril hydrochloride (Adecut) > cilazapril (Inhibace) , -12- (10) (10) 200406199 lisinopril (Longes, Zestril), benazepril hydrochloride (Cibacen), imidapril (Tanatril 'Novae), temocapril hydrochloride (Acecol), trandolapril (Odric, Preran C) and perindopripri 1), etc., as the diuretic, for example, Bumetanide (Lunetoron), Piretanide (Arelax), azosemide (Diart), torasemide (Luprac),
Spironolactone ( Aldactone-A ) 、 hydrochlorothiazide (Spironolactone (Aldactone-A), hydrochlorothiazide (
Dichlotride ) 、 methyclothiazide ( Enduron ) 、 trichlormethiazide ( Fluitran ) 、 cyclopenthiazide (Dichlotride), methyclothiazide (Enduron), trichlormethiazide (Fluitran), cyclopenthiazide (
Navidrex ) 、 benzylhydrochlorothiazide ( Behyd ) 、 penflutizide(Butizide)等。另外，作爲宿根草製劑，可 舉例如 digitoxin ( Digitoxin ) 、digoxin (Digoxin，Navidrex), benzylhydrochlorothiazide (Behyd), penflutizide (Butizide), etc. In addition, examples of perennial grass preparations include digitoxin (Digitoxin), digoxin (Digoxin,
Digosin ) 、m e t h y 1 d i g o x i n ( Lanirapid ) 、deslanoside (Digosin), me t h y 1 d i g o x i n (Lanirapid), deslanoside (
Digilanogen C ) 、lanatoside C ( Digilanogen C ) 、Digilanogen C), lanatoside C (Digilanogen C),
proscillaridin ( Taliisin，Caradrin)等。另外，上述括號 內均爲註冊商。 I 有關本發明之預防及/或治療心臟衰竭用劑之投予方 法係任意的。 亦即，可以皮下注射、靜脈注射、肌肉注射及腹腔內 注射等之非經口投予，亦可經□投予。 投予量係依據患者年齡、健康狀態、體重、若有同時 處理時，其種類、處置頻率及所需效果之性質等而決定。 一般有效成份之每日投予量爲0.5至5 0mg/kg體重，通 常爲1至30 mg/kg體重，投予1次或以上。 •13- (11)200406199 經口投予本發明化合物時，錠劑、膠囊劑 劑及酏劑等之型態，另外，非經口投予時係以 化劑等之殺菌液狀之型態使用。以如上述之型 固體或液體之無毒性製劑之載體亦可包含於組 固體載體之例，可使用通常之明膠型之膠 有效成份與補助藥或沒有的情況下錠劑化，粉 此等膠囊、錠劑、粉所含有的有效成份， 95%，以5至90%重量尤佳。 亦即，於此等之投予型式，每次投予所含 份爲5至500mg，以25至250mg爲宜。 作爲液體載體，可使用水或石油、花生油 礦物油及芝麻油等之來自於動植物的油或合成: 另外，一般係以生理食鹽水、糊精或類似 、乙二醇、丙二醇及聚乙二醇等之甘醇類作爲 宜，尤其使用生理食鹽水之注射液時，通常含 爲0.5至20%，以1至10%重量爲宜。 【實施方式】 實施例 以下，基於實施例具體地說明本發明，只 本發明之要旨下’並不局限於下述之實施例。 所使用之Anplag係三菱Pharma株式會社市1 (註冊商標）。 、粉劑、液 液劑或懸濁 態使用時， 成中c 囊。另外， 末包裝。 一般爲5至 有的有效成 、大豆油、 油。 之蔗糖溶液 液狀載體爲 有有效成份proscillaridin (Taliisin, Caradrin), etc. In addition, the registrars are in parentheses. I The method of administering the agent for preventing and / or treating heart failure of the present invention is arbitrary. That is, it can be administered parenterally by subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc., or by □ administration. The amount to be administered is determined based on the patient's age, health status, weight, and the type, frequency of treatment, and the nature of the desired effect if there is simultaneous treatment. The daily effective amount of the active ingredient is 0.5 to 50 mg / kg body weight, usually 1 to 30 mg / kg body weight, and it is administered once or more. • 13- (11) 200406199 When the compound of the present invention is administered orally, tablets, capsules, and tinctures, etc., and in the case of parenteral administration, it is in the form of a germicidal liquid such as a chemical agent. use. Taking the above-mentioned solid or liquid non-toxic preparation as a carrier, which can also be included in the group of solid carriers, ordinary gelatin-type active ingredients and supplementary medicines can be used, or tablets can be made without powder, and these capsules can be powdered. , Tablets, powders contain 95% of active ingredients, especially 5 to 90% by weight. That is, in these types of administration, the content of each administration is 5 to 500 mg, preferably 25 to 250 mg. As a liquid carrier, water or petroleum, peanut oil, mineral oil, sesame oil, or other animal or plant-derived oils or synthetics can be used: In addition, physiological saline, dextrin or similar, ethylene glycol, propylene glycol, and polyethylene glycol are generally used. Glycols are suitable, especially when physiological saline injections are used, usually containing 0.5 to 20%, preferably 1 to 10% by weight. [Embodiments] Examples Hereinafter, the present invention will be specifically described based on examples, and only the gist of the present invention is not limited to the following examples. Anplag used is Mitsubishi Pharma Co., Ltd. 1 (registered trademark). When used in powder, powder, liquid or suspended state, it becomes a medium c capsule. Also, unpacked. Generally 5 to some effective ingredients, soybean oil, oil. Sucrose solution, liquid carrier is with active ingredients
要於不踰越 另外，以下 I 之 Anplag -14- (12) (12)200406199 實施例i 5 8歲、女性。具有基礎疾病之本態性高血壓症、糖尿 病、高脂血症及慢性動脈阻塞症。 病人訴說爬樓梯等之勞動時之呼吸困難以及腳部麻痺 感，測定血中腦利鈉性胜肽 （brain natriuretic peptide:BNP)濃度時，因爲顯示75.6pg/dl之高値（正常 爲2 Op g/dl未滿），而判定因高血壓及糖尿病之鬱血性心 臟衰竭之狀態，開始對於心臟衰竭進行治療。 開始治療時，服用 Tanatril (田邊製藥社）5mg /日、 Maintate (田邊製藥社）5mg/日、Basen (武田藥品工業 社）0.2mgx3 次 / 回及 Mevalotin (三共社）10mg /日。 開始治療5個月後，爲治療慢性動脈阻塞症，追加 Anplag 錠 100mgx3次 / 日。 追加倂用 A η p 1 a g 1個月後，改善了追加倂用前顯示咼 値之血中 BNP濃度爲42.1pg/dl，於15個月後，認爲胸部 不適及勞動時之呼吸困難有所改善。另外，認爲安靜時β 心電圖並無缺血性變化。 另外，於 ΝΥΗΑ ( New York Heart Association ’ 紐約 心臟協會）Π級之輕度心臟衰竭狀態，依據長期投予 Anplag，預測可改善至ΝΥΗΑ I級之無症候性心臟衰竭。 實施例2 7 8歲，男性。具有基礎疾病之本態性高血壓症、糖尿 病及狹心症。In order not to exceed In addition, the following I of Anplag -14- (12) (12) 200406199 Example i 5 8 years old, female. Essential hypertension, diabetes, hyperlipidemia and chronic arterial obstruction with underlying diseases. The patient reported dyspnea during work such as climbing stairs and a feeling of paralysis of the feet. When measuring the concentration of brain natriuretic peptide (BNP) in the blood, it showed a high level of 75.6 pg / dl (normally 2 Op g / dl is not full), determine the status of congestive heart failure due to hypertension and diabetes, and start treatment for heart failure. When starting treatment, take Tanatril (Tanabe Pharmaceutical Co.) 5mg / day, Maintate (Tanabe Pharmaceutical Co.) 5mg / day, Basen (Takeda Pharmaceutical Co., Ltd.) 0.2mgx3 times / day and Mevalotin (Sankyo) 10mg / day. Five months after the start of treatment, to treat chronic arterial obstruction, Anplag tablets were added 100 mg x 3 times per day. One month after the additional application of A η p 1 ag, the BNP concentration in the blood before the additional application was improved, showing that the BNP concentration in the blood was 42.1 pg / dl. After 15 months, chest discomfort and dyspnea at work were considered Improved. In addition, it is believed that there is no ischemic change in the beta electrocardiogram at rest. In addition, mild heart failure at the ΠΥΗΑ (New York Heart Association 'New York Heart Association) level Ⅱ, based on long-term administration of Anplag, is expected to improve to ΝΑΑ level I asymptomatic heart failure. Example 2 78 years old, male. Essential hypertension, diabetes, and autism with underlying diseases.
-15- (13) (13)200406199 以治療基礎疾病爲目的時’服用Blopress (武田藥品 工業社）8 1^/日、？61(1丨卩丨11(山之內製藥社）6〇1112/曰、 Seloken ( AstraZeneca 社）60mg /日、Sig mart (中外製藥 社）1 5 m g / 日及 N i t r 〇 d e r m T T S ( N 〇 v a r t i s P h a r m a 社）1 枚 / 曰，並同時進行飮食療法。 約於平成1 4年3月起，病人訴說有時勞動時會發生心 悸。於胸部X光片，雖未發現心臟陰影的擴大，但是血 中BNP値上升至81.8pg/dl，認爲係ΝΥΗΑΠ級程度之鬱 血性心臟衰竭。之後，訴說下肢有麻痺感。另外，因爲由 所見之容積脈波認爲亦合倂輕度的慢性動脈阻塞症，於平 成14年5月起追加Anplag錠100mgx3次/日。 追加倂用 Anplag2個月後，認爲勞動時之心悸變輕， 改善成爲N Y H A I級之狀態。另外，追加倂用前顯示高値 之血中BNP濃度顯示55· lpg/dl之降低傾向。-15- (13) (13) 200406199 For the purpose of treating basic diseases, ‘Take Blopress (Takeda Pharmaceutical Co., Ltd.) 8 1 ^ / day ,? 61 (1 丨 卩 丨 11 (Yamanoi Pharmaceutical Co.) 6〇1112 /, Seloken (AstraZeneca) 60mg / day, Sig mart (Chinowai Pharmaceutical Co.) 15 mg / day, and Nitro 〇derm TTS (N 〇 vartis P harma) 1 tablet per day, and at the same time, taking food therapy at the same time. About March 2014, patients reported that palpitations sometimes occurred during work. On chest X-rays, although the heart shadow was not enlarged However, BNP 値 in the blood increased to 81.8pg / dl, which is considered to be NDΥΗΑΠ grade congestive heart failure. Later, it was reported that the lower limbs had numbness. In addition, because of the volumetric pulse seen, it was also considered mild For chronic arterial obstruction, Anplag tablets 100mg x 3 times / day have been added since May, 2014. Two months after the additional application of Anplag, the heart palpitations during work are considered to be lighter, and the state becomes NYHAI grade. In addition, before the additional application It was shown that the BNP concentration in the blood of high salamander showed a tendency to decrease by 55. lpg / dl.
進而，追加倂用A η p 1 a g 4個月後，血中b N P濃度降低 爲4 5.0pg/dl，之後維持同樣的狀態。 I 依據此等結果，顯示對於預防及/或治療心臟衰竭， A η p 1 a g係有效的。 產業上利用性 本發明可提供對於心臟衰竭有效的預防及/或治療用 劑。 另外’本申請書係主張日本特許出願特願2 0 〇 2 — 254654號具有優先權而申請者。 -16-Furthermore, after 4 months of additional application of A η p 1 ag, the concentration of b N P in blood decreased to 4 5.0 pg / dl, and the same condition was maintained thereafter. Based on these results, it has been shown that A η p 1 a g is effective for preventing and / or treating heart failure. Industrial Applicability The present invention can provide a prophylactic and / or therapeutic agent effective for heart failure. In addition, this application claims that the Japanese Patent Application No. 2002-254654 has priority and is an applicant. -16-
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002254654 | 2002-08-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW200406199A true TW200406199A (en) | 2004-05-01 |
Family
ID=31972848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW092123985A TW200406199A (en) | 2002-08-30 | 2003-08-29 | Preventive and/or therapeutic agent for heart failure |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPWO2004019926A1 (en) |
| AU (1) | AU2003257591A1 (en) |
| TW (1) | TW200406199A (en) |
| WO (1) | WO2004019926A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8827988D0 (en) * | 1988-11-30 | 1989-01-05 | Smith Kline French Lab | Chemical compounds |
| JPH02304022A (en) * | 1989-05-18 | 1990-12-17 | Mitsubishi Kasei Corp | Serotonin antagonistic agent |
| JP2544239B2 (en) * | 1989-08-31 | 1996-10-16 | 花王株式会社 | Vasodilator |
| US5585361A (en) * | 1994-06-07 | 1996-12-17 | Genzyme Corporation | Methods for the inhibition of platelet adherence and aggregation |
| CN1299690C (en) * | 2000-07-28 | 2007-02-14 | 生物能量公司 | Compositions and methods for improving cardiovascular function |
| DE60138768D1 (en) * | 2000-12-28 | 2009-07-02 | Kissei Pharmaceutical | Glucopyranosylpyrrazole derivatives and their use in medicines |
-
2003
- 2003-08-29 AU AU2003257591A patent/AU2003257591A1/en not_active Abandoned
- 2003-08-29 JP JP2004532769A patent/JPWO2004019926A1/en active Pending
- 2003-08-29 WO PCT/JP2003/011011 patent/WO2004019926A1/en active Application Filing
- 2003-08-29 TW TW092123985A patent/TW200406199A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004019926A1 (en) | 2004-03-11 |
| AU2003257591A1 (en) | 2004-03-19 |
| JPWO2004019926A1 (en) | 2005-12-15 |
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