JPH04164033A - Preventive and remedy for cardiac disease - Google Patents
Preventive and remedy for cardiac diseaseInfo
- Publication number
- JPH04164033A JPH04164033A JP29100290A JP29100290A JPH04164033A JP H04164033 A JPH04164033 A JP H04164033A JP 29100290 A JP29100290 A JP 29100290A JP 29100290 A JP29100290 A JP 29100290A JP H04164033 A JPH04164033 A JP H04164033A
- Authority
- JP
- Japan
- Prior art keywords
- preventive
- remedy
- addition salt
- acid addition
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 208000019622 heart disease Diseases 0.000 title claims abstract description 18
- 230000003449 preventive effect Effects 0.000 title abstract description 11
- 208000020446 Cardiac disease Diseases 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 9
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- -1 methyl pyridin-5-yl Chemical group 0.000 claims description 7
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 17
- 208000031225 myocardial ischemia Diseases 0.000 abstract description 5
- 230000004087 circulation Effects 0.000 abstract description 3
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 230000000747 cardiac effect Effects 0.000 abstract description 2
- 208000010125 myocardial infarction Diseases 0.000 abstract description 2
- WJFYLCXWEXZNHU-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-b]pyridine Chemical class N1C=CC=C2SCCC21 WJFYLCXWEXZNHU-UHFFFAOYSA-N 0.000 abstract 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 210000004351 coronary vessel Anatomy 0.000 description 7
- 230000000004 hemodynamic effect Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010065929 Cardiovascular insufficiency Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は心臓疾患の予防または治療剤に関する。[Detailed description of the invention] [Industrial application field] The present invention relates to a preventive or therapeutic agent for heart disease.
〔従来の技術及び発明が解決しようとする課題〕近年、
心臓疾患は、我国における死因の順位において、脳血管
障害を抜き、ガンに次いで第２位を占めるに至っている
。また、最近、虚血性心疾患に代表される心臓疾患の羅
患年齢は低下し、働きざかり０４０代の患者が増加しつ
つある。[Problems to be solved by conventional techniques and inventions] In recent years,
Heart disease has surpassed cerebrovascular disorders and has become the second leading cause of death in Japan, after cancer. Furthermore, recently, the age of patients suffering from heart diseases such as ischemic heart disease has been decreasing, and the number of patients in their 40s who are in the prime of their careers is increasing.
これら心臓疾患に対する治療剤としては、従来β−ブロ
ッカ−、カルシウムアンタゴニスト、冠血管拡張剤、強
心剤等が用いられている。Conventional therapeutic agents for these heart diseases include β-blockers, calcium antagonists, coronary vasodilators, cardiotonic agents, and the like.
しかしながら、従来の心臓疾患治療剤は治療効果の強い
ものは副作用が多く、副作用が少ないものは治療効果が
充分でない等の問題があり、臨床的に充分満足できるも
のではなかった。However, conventional therapeutic agents for heart diseases have problems such as those with strong therapeutic effects having many side effects, and those with few side effects having insufficient therapeutic effects, and have not been clinically fully satisfactory.
かかる実状において、本発明者らは数多くの化合物につ
いての薬理作用を心臓疾患モデルを用いて検討してきた
ところ、下記式（Ｉ）で示されるテトラヒドロチェノピ
リジン誘導体またはその酸付加塩が優れた心臓疾患の予
防または治療作用を有し、かつ安全性も高いことを見出
し、本発明を完成した。Under these circumstances, the present inventors have investigated the pharmacological effects of a number of compounds using heart disease models, and have found that the tetrahydrochenopyridine derivative represented by the following formula (I) or its acid addition salt has excellent cardiac effects. The present invention was completed based on the discovery that it has a preventive or therapeutic effect on diseases and is highly safe.
すなわち、本発明は次式（Ｉ）
（Ｉ）
で表わされる（Ｓ） −２−（２−クロロフェニル＞
−２−（４，５，６，７−チトラヒドロチエノ（３，２
−ｃ）ピリジン−５−イル）酢酸メチルエステルまたは
その酸付加塩を有効成分とする心臓疾患の予防または治
療剤を提供するものである。That is, the present invention provides (S) -2-(2-chlorophenyl>
-2-(4,5,6,7-titrahydrothieno(3,2
-c) Pyridin-5-yl) methyl acetate or an acid addition salt thereof as an active ingredient, the present invention provides a preventive or therapeutic agent for heart disease.
本発明の心臓疾患の予防または治療剤の有効成分である
化合物（Ｉ）およびその酸付加塩は、例えば特開昭６３
−２０３６８４号公報記載の方法に従って製造できる既
知の化合物であるが、心臓疾患に対する予防および治療
作用については全く知られていない。化合物（Ｉ）の酸
付加塩としては、硫酸塩、塩酸塩、リン酸塩、硝酸塩等
の無機酸塩、マレイン酸塩、フマル酸塩、シュウ酸塩等
の有機酸塩が挙げられる。Compound (I), which is an active ingredient of the preventive or therapeutic agent for heart disease of the present invention, and its acid addition salt can be used, for example, in JP-A-63
Although it is a known compound that can be produced according to the method described in JP-203684, its preventive and therapeutic effects on heart diseases are not known at all. Examples of the acid addition salt of compound (I) include inorganic acid salts such as sulfate, hydrochloride, phosphate, and nitrate, and organic acid salts such as maleate, fumarate, and oxalate.
上記化合物（Ｉ）またはその酸付加塩は、後記実施例に
示す如く虚血心疾患モデルにおいて優れた冠循環動態の
低下を抑制する作用を有し、心臓疾患、特に狭心症、心
筋梗塞等の虚血性心疾患や心不全の予防または治療剤と
して有用である。また、例えば化合物（Ｉ）硫酸塩の経
口投与における急性毒性（ＬＤ、。、ｍｇ／ｋｇ）は下
記第１表の通りであり、化合物（Ｉ）は安全性が極めて
高いものである。The above-mentioned compound (I) or its acid addition salt has an excellent effect of suppressing the decline in coronary hemodynamics in ischemic heart disease models, as shown in the Examples below, and is effective in preventing heart diseases, particularly angina pectoris, myocardial infarction, etc. It is useful as a preventive or therapeutic agent for ischemic heart disease and heart failure. Further, for example, the acute toxicity (LD, ., mg/kg) of compound (I) sulfate upon oral administration is as shown in Table 1 below, and compound (I) is extremely safe.
第１表
本発明心臓疾患の予防または治療剤は、通常経口投与さ
れ、その投与量は患者の体重、年齢、性別、投与方法、
体調、症状等により異なるが、経口投与の場合、化合物
（Ｉ）またはその酸付加塩として通常１日１０〜１００
ｍｇ／成人とすればよい。Table 1 The preventive or therapeutic agent for heart disease of the present invention is usually administered orally, and the dosage is determined based on the patient's weight, age, sex, administration method, etc.
Although it varies depending on physical condition, symptoms, etc., in the case of oral administration, the dosage of Compound (I) or its acid addition salt is usually 10 to 100 per day.
mg/adult.
本発明心臓疾患の予防または治療剤は、化合物（Ｉ）ま
たはその酸付加塩を配合し、通常の方法で錠剤、顆粒剤
、カプセル剤、懸濁剤、注射剤等の種々の剤型とするこ
とができる。経口用の固形製剤を製造するには、化合物
（Ｉ）またはその酸付加塩に賦形剤、更に必要に応じて
結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤、増量剤
、被覆剤、糖衣剤などを加えた後、常法により錠剤、顆
粒剤、散剤、カプセル剤等とすればよい。注射剤を調製
する場合は、化合物（Ｉ）またはその酸付加塩を注射用
蒸留水等の水性担体にあらかじめ溶解、分散、乳化等す
るか、または注射用の粉末にして、用量に溶解等すれば
よい。The prophylactic or therapeutic agent for heart diseases of the present invention is formulated with Compound (I) or its acid addition salt and prepared into various dosage forms such as tablets, granules, capsules, suspensions, and injections by conventional methods. be able to. To produce a solid preparation for oral use, compound (I) or an acid addition salt thereof is added with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a filler, After adding coating agents, sugar coating agents, etc., tablets, granules, powders, capsules, etc. may be prepared by conventional methods. When preparing an injection, compound (I) or its acid addition salt should be dissolved, dispersed, or emulsified in advance in an aqueous carrier such as distilled water for injection, or it should be made into a powder for injection and dissolved in the appropriate dosage. Bye.
以下、本発明を実施例により説明するが、本発明はこれ
に限定されるものではない。EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited thereto.
実施例１
ピーグル犬（体重９．５−１３．５ｋｇ ）をベンドパ
ルビタールで麻酔し、人工呼吸下に開胸して左冠動脈前
下行技を剥離した。心臓を虚血に陥らせるためにコラー
ゲンの粉末を充填した細いカテーテルを左冠動脈前下行
技にその分枝から挿入した。循環動態は大腿動脈にポリ
エチレン製カニユーレを挿入して全身血圧と心拍数を測
定した。左冠動脈前下行技に血流量測定用プローブと左
冠動脈前下行枝末端にポリエチレン製カニユーレを挿入
してそれぞれ冠血流量と冠動脈血圧を測定した。コラー
ゲンを充填したカテーテルを挿入した部位で左冠動脈前
下行技をその血流量が約２０％低下するように狭窄して
冠循環不全モデルを作成した。Example 1 A peagle dog (weight 9.5-13.5 kg) was anesthetized with bendoparbital, and the chest was opened under artificial respiration to remove the left anterior descending coronary artery. To induce ischemia in the heart, a thin catheter filled with collagen powder was inserted into the left anterior descending coronary artery through its branch. For hemodynamics, a polyethylene cannula was inserted into the femoral artery and systemic blood pressure and heart rate were measured. Coronary blood flow and coronary blood pressure were measured by inserting a blood flow measurement probe into the left anterior descending coronary artery and a polyethylene cannula at the end of the left anterior descending coronary artery. A model of coronary circulatory insufficiency was created by narrowing the left anterior descending coronary artery at the site where a collagen-filled catheter was inserted so that the blood flow rate decreased by approximately 20%.
実験は本モデルに対して、左冠動脈前下行技を狭窄する
２０分前に化合物Ｈ）の硫酸塩を３ｍｇ／ｋｇの用量で
静注し、その後の変化を観察した。対照群には生理食塩
水を投与した。実験の例数は各群１０例とした。In this experiment, the sulfate of compound H) was intravenously injected at a dose of 3 mg/kg 20 minutes before stenosis of the left anterior descending coronary artery, and subsequent changes were observed. Physiological saline was administered to the control group. The number of experimental cases was 10 in each group.
得られた結果を第２表に示す。The results obtained are shown in Table 2.
以下余白
第２表より、化合物（Ｉ）は虚血後に生じた冠動脈血圧
低下、すなわち冠循環血行動態の悪化を有意に抑制した
。一方、化合物（Ｉ）は全身血圧と心拍数等の全身循環
動態には影響を与えなかった。以上のことから、化合物
（Ｉ）は虚血時の心臓において冠循環の悪化を抑制する
ことが確認され、化合物（Ｉ）は心臓疾患に有用である
ことが明らかになった。From Table 2 in the margin below, compound (I) significantly suppressed the decrease in coronary artery blood pressure that occurred after ischemia, that is, the deterioration of coronary circulation hemodynamics. On the other hand, compound (I) did not affect systemic hemodynamics such as systemic blood pressure and heart rate. From the above, it was confirmed that compound (I) suppresses deterioration of coronary circulation in the heart during ischemia, and it became clear that compound (I) is useful for heart diseases.
以上that's all
Claims (1)
−（４，５，６，７−テトラヒドロチエノ〔３，２−ｃ
〕ピリジン−５−イル）酢酸メチルエステルまたはその
酸付加塩を有効成分とする心臓疾患の予防または治療剤
。[Claims] 1. (S)-2-(2-chlorophenyl)-2 represented by the following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I)
-(4,5,6,7-tetrahydrothieno[3,2-c
] A prophylactic or therapeutic agent for heart disease containing methyl pyridin-5-yl acetate or its acid addition salt as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29100290A JP2949366B2 (en) | 1990-10-26 | 1990-10-26 | Agent for preventing or treating heart disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29100290A JP2949366B2 (en) | 1990-10-26 | 1990-10-26 | Agent for preventing or treating heart disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04164033A true JPH04164033A (en) | 1992-06-09 |
| JP2949366B2 JP2949366B2 (en) | 1999-09-13 |
Family
ID=17763188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29100290A Expired - Lifetime JP2949366B2 (en) | 1990-10-26 | 1990-10-26 | Agent for preventing or treating heart disease |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2949366B2 (en) |
-
1990
- 1990-10-26 JP JP29100290A patent/JP2949366B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2949366B2 (en) | 1999-09-13 |
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