WO2010092811A1 - Prophylactic or therapeutic agent for hypertension - Google Patents
Prophylactic or therapeutic agent for hypertension Download PDFInfo
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- WO2010092811A1 WO2010092811A1 PCT/JP2010/000830 JP2010000830W WO2010092811A1 WO 2010092811 A1 WO2010092811 A1 WO 2010092811A1 JP 2010000830 W JP2010000830 W JP 2010000830W WO 2010092811 A1 WO2010092811 A1 WO 2010092811A1
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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
- C07D295/12—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 or doubly bound nitrogen atoms
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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
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a drug for preventing and treating hypertension.
- Hypertension is one of lifestyle-related diseases called metabolic syndrome along with obesity, hyperlipidemia and diabetes. Although hypertension itself often has no subjective symptoms, etc., it is a risk factor such as ischemic heart disease, stroke, and renal failure, so it is extremely important to maintain the blood pressure within the normal range. Treatment of hypertension is mainly performed by pharmacotherapy and diet therapy with antihypertensive drugs. As antihypertensive drugs, diuretics, calcium antagonists, ACE inhibitors, angiotensin II receptor antagonists, ⁇ -blockers, and the like are properly used depending on symptoms and causes. However, there are some patients whose blood pressure cannot be sufficiently controlled by these drugs, and further development of new drugs for preventing and treating hypertension is desired.
- biphenylcarboxamide represented by 4′-acetyl-N- [4- [4- (2-methoxyphenyl) -1-piperazinyl] butyl]-[1,1′-biphenyl] -4-carboxamide (GR103691)
- the compound is commercially available as a dopamine D3 receptor antagonist (Non-patent Documents 1 and 2). Further, it has been reported that GR103691 also has an affinity for ⁇ receptors and 5-HT receptors (Non-patent Document 2), but it has been clarified whether the action is an inhibitory action or a stimulating action. Not.
- An object of the present invention is to provide a new drug for preventing and treating hypertension.
- the present inventors examined the blood pressure lowering action of various compounds using animals, and surprisingly, the biphenylcarboxamide compound known as an antagonist of dopamine D3 receptor has an excellent blood pressure lowering action. As a result, the present invention has been completed.
- the antihypertensive agent for hypertension which uses the biphenyl carboxamide compound represented by these as an active ingredient is provided.
- the present invention also provides a pharmaceutical composition for preventing and treating hypertension, comprising a biphenylcarboxamide compound represented by the above formula (1) and a pharmaceutically acceptable carrier.
- the present invention also provides use of the biphenylcarboxamide compound represented by the above formula (1) for the production of a prophylactic and therapeutic agent for hypertension.
- the present invention provides a method for preventing and treating hypertension, which comprises administering an effective amount of the biphenylcarboxamide compound represented by the above formula (1).
- the compound of the formula (1) exhibits an excellent blood pressure lowering action and is useful as a new antihypertensive drug.
- the active ingredient of the antihypertensive drug of the present invention is a biphenylcarboxamide compound represented by the formula (1).
- the lower alkoxy group represented by R 1 includes an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a butoxy group, and the like. Is particularly preferred.
- the lower alkanoyl group represented by R 2 includes an alkanoyl group having 2 to 6 carbon atoms, such as an acetyl group, a propionyl group, and a butyryl group, and an acetyl group is particularly preferable.
- n represents a number of 2 to 5, but 3 to 5, particularly 4 is preferable.
- a compound in which R 1 is a methoxy group, R 2 is an acetyl group, and n is 4 is more preferable, especially GR103691 (4′-acetyl-N- [4- [4- (2-methoxyphenyl) ) -1-piperazinyl] butyl]-[1,1′-biphenyl] -4-carboxamide) is preferred.
- the compound of formula (1) is known per se.
- GR103691 is commercially available as a dopamine D3 receptor antagonist.
- the compound of the formula (1) showed an excellent blood pressure lowering action as shown in Examples described later.
- the blood pressure lowering effect is considered to be mainly due to adrenergic ⁇ 1 receptor blockade. Therefore, the compound of the formula (1) is useful as a therapeutic agent for preventing hypertension.
- the medicament or pharmaceutical composition of the present invention comprises a compound of formula (1), an excipient, a binder, a lubricant, a disintegrant, a coating agent, an emulsifier, a suspending agent, a solvent, a stabilizer, an absorption aid. It is obtained by appropriately adding one or more pharmaceutically acceptable carriers such as an ointment base and formulating it into a dosage form for oral administration, for injection, for rectal administration, for external use, etc. by a conventional method. .
- Preparations for oral administration include granules, tablets, dragees, capsules, pills, liquids, emulsions, suspensions, etc .; preparations for injection administration include intravenous injection, intramuscular injection, subcutaneous injection, infusion Preparations for injection and the like; As preparations for rectal administration, suppository soft capsules and the like are preferable.
- the medicament of the present invention can be administered to mammals including humans as a preparation as described above.
- the medicament of the present invention is preferably administered about 1 to 500 mg / kg as the compound of formula (1) 1 to 4 times per day.
- Example 1 Animals used: Wistar / ST male rat invasive blood pressure measurement at 10 to 11 weeks of age: invasive blood pressure measurement method that continuously derives arterial pressure and heart rate directly from the cannula inserted into the anesthetized rat artery It was. After injecting intraperitoneally with 600 mg / kg of urethane and 60 mg / kg of chloralose and confirming that anesthesia was sufficiently applied, the iliac arteries and iliac veins of the rats were exposed, each half-incised and cannulated. The arterial cannula was connected to a blood pressure measurement device via a pressure sensor, and blood pressure (mmHg) and heart rate (times / minute) were recorded on a recorder.
- mmHg blood pressure
- heart rate times / minute
- Drug administration All drugs were prepared so that the dose was 1 mL per kg body weight.
- GR103691 was dissolved in 5% acetic acid, pH was adjusted to about 5 with 1 mol / L NaOH, and then diluted with water for injection so that the dose was 3 mg / kg.
- Adrenaline (Ad), angiotensin II (AT II), diltiazem, prazosin and labetalol were dissolved in water for injection and prepared to the following dosages.
- the drug was administered through an intravenous cannula, and then the drug solution in the cannula was completely pushed out with 0.2 mL of physiological saline supplemented with heparin (2 units / mL).
- Diltiazem (1 mg / kg), which is a calcium antagonist, decreased both blood pressure and heart rate, while blood pressure decreased to the same extent as GR103691, while the degree of heart rate decrease was considerably higher than that of GR103691. It was low (FIG. 6).
- AT II was administered after diltiazem administration, unlike the case of GR103691, the increase in blood pressure was suppressed (FIG. 6).
- GR103691 lowers blood pressure and that the blood pressure lowering effect is due to adrenergic ⁇ 1 receptor blockade. Further, it was suggested that GR103691 also has a ⁇ -blocking action.
Abstract
Disclosed is a prophylactic or therapeutic agent for hypertension, which comprises a biphenylcarboxamide compound represented by formula (1) [wherein R1 represents a hydrogen atom or a lower alkoxy group; R2 represents a hydrogen atom or a lower alkanoyl group; and n represents a number of 2 to 5] as an active ingredient.
Description
本発明は、高血圧症予防治療薬に関する。
The present invention relates to a drug for preventing and treating hypertension.
高血圧症は、肥満、高脂血症及び糖尿病と並んでメタボリックシンドロームと呼ばれる生活習慣病のひとつである。高血圧症自体は自覚症状等のないことが多いが、虚血性心疾患、脳卒中、腎不全などのリスクファクターであることから、血圧を正常範囲に維持することは極めて重要である。
高血圧症の治療は、高血圧症予防治療薬による薬物療法と食事療法が主に行なわれる。高血圧症予防治療薬としては、利尿薬、カルシウム拮抗薬、ＡＣＥ阻害薬、アンジオテンシンＩＩ受容体拮抗薬、β－ブロッカー等が、症状、原因などにより使い分けられている。ところが、これらの薬剤によって十分に血圧がコントロールできない患者もおり、さらに新たな高血圧症予防治療薬の開発が望まれている。 Hypertension is one of lifestyle-related diseases called metabolic syndrome along with obesity, hyperlipidemia and diabetes. Although hypertension itself often has no subjective symptoms, etc., it is a risk factor such as ischemic heart disease, stroke, and renal failure, so it is extremely important to maintain the blood pressure within the normal range.
Treatment of hypertension is mainly performed by pharmacotherapy and diet therapy with antihypertensive drugs. As antihypertensive drugs, diuretics, calcium antagonists, ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and the like are properly used depending on symptoms and causes. However, there are some patients whose blood pressure cannot be sufficiently controlled by these drugs, and further development of new drugs for preventing and treating hypertension is desired.
高血圧症の治療は、高血圧症予防治療薬による薬物療法と食事療法が主に行なわれる。高血圧症予防治療薬としては、利尿薬、カルシウム拮抗薬、ＡＣＥ阻害薬、アンジオテンシンＩＩ受容体拮抗薬、β－ブロッカー等が、症状、原因などにより使い分けられている。ところが、これらの薬剤によって十分に血圧がコントロールできない患者もおり、さらに新たな高血圧症予防治療薬の開発が望まれている。 Hypertension is one of lifestyle-related diseases called metabolic syndrome along with obesity, hyperlipidemia and diabetes. Although hypertension itself often has no subjective symptoms, etc., it is a risk factor such as ischemic heart disease, stroke, and renal failure, so it is extremely important to maintain the blood pressure within the normal range.
Treatment of hypertension is mainly performed by pharmacotherapy and diet therapy with antihypertensive drugs. As antihypertensive drugs, diuretics, calcium antagonists, ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and the like are properly used depending on symptoms and causes. However, there are some patients whose blood pressure cannot be sufficiently controlled by these drugs, and further development of new drugs for preventing and treating hypertension is desired.
一方、４’－アセチル－Ｎ－［４－［４－（２－メトキシフェニル）－１－ピペラジニル］ブチル］－［１，１’－ビフェニル］－４－カルボキサミド（ＧＲ１０３６９１）に代表されるビフェニルカルボキサミド化合物は、ドパミンＤ３受容体アンタゴニストとして市販されている（非特許文献１及び２）。また、このＧＲ１０３６９１は、α受容体、５－ＨＴ受容体にも親和性を有することが報告されている（非特許文献２）が、その作用が阻害作用なのか刺激作用なのかは明らかにされていない。
On the other hand, biphenylcarboxamide represented by 4′-acetyl-N- [4- [4- (2-methoxyphenyl) -1-piperazinyl] butyl]-[1,1′-biphenyl] -4-carboxamide (GR103691) The compound is commercially available as a dopamine D3 receptor antagonist (Non-patent Documents 1 and 2). Further, it has been reported that GR103691 also has an affinity for α receptors and 5-HT receptors (Non-patent Document 2), but it has been clarified whether the action is an inhibitory action or a stimulating action. Not.
本発明の課題は、新たな高血圧症予防治療薬を提供することにある。
An object of the present invention is to provide a new drug for preventing and treating hypertension.
そこで、本発明者らは、動物を用いて種々の化合物の血圧降下作用を検討したところ、全く意外にもドパミンＤ３受容体のアンタゴニストとして知られているビフェニルカルボキサミド化合物に優れた血圧降下作用があることを見出し、本発明を完成した。
Thus, the present inventors examined the blood pressure lowering action of various compounds using animals, and surprisingly, the biphenylcarboxamide compound known as an antagonist of dopamine D3 receptor has an excellent blood pressure lowering action. As a result, the present invention has been completed.
すなわち、本発明は、次式（１）
That is, the present invention provides the following formula (1)
（式中、Ｒ1は水素原子又は低級アルコキシ基を示し、Ｒ2は水素原子又は低級アルカノイル基を示し、ｎは２～５の数を示す）
で表されるビフェニルカルボキサミド化合物を有効成分とする高血圧症予防治療薬を提供するものである。
また、本発明は、上記式（１）で表されるビフェニルカルボキサミド化合物、及び薬学的に許容される担体を含有する高血圧症予防治療用医薬組成物を提供するものである。
また、本発明は、上記式（１）で表されるビフェニルカルボキサミド化合物の、高血圧症予防治療薬製造のための使用を提供するものである。
さらに、本発明は、上記式（１）で表されるビフェニルカルボキサミド化合物の有効量を投与することを特徴とする高血圧症予防治療方法を提供するものである。 (Wherein R 1 represents a hydrogen atom or a lower alkoxy group, R 2 represents a hydrogen atom or a lower alkanoyl group, and n represents a number of 2 to 5)
The antihypertensive agent for hypertension which uses the biphenyl carboxamide compound represented by these as an active ingredient is provided.
The present invention also provides a pharmaceutical composition for preventing and treating hypertension, comprising a biphenylcarboxamide compound represented by the above formula (1) and a pharmaceutically acceptable carrier.
The present invention also provides use of the biphenylcarboxamide compound represented by the above formula (1) for the production of a prophylactic and therapeutic agent for hypertension.
Furthermore, the present invention provides a method for preventing and treating hypertension, which comprises administering an effective amount of the biphenylcarboxamide compound represented by the above formula (1).
で表されるビフェニルカルボキサミド化合物を有効成分とする高血圧症予防治療薬を提供するものである。
また、本発明は、上記式（１）で表されるビフェニルカルボキサミド化合物、及び薬学的に許容される担体を含有する高血圧症予防治療用医薬組成物を提供するものである。
また、本発明は、上記式（１）で表されるビフェニルカルボキサミド化合物の、高血圧症予防治療薬製造のための使用を提供するものである。
さらに、本発明は、上記式（１）で表されるビフェニルカルボキサミド化合物の有効量を投与することを特徴とする高血圧症予防治療方法を提供するものである。 (Wherein R 1 represents a hydrogen atom or a lower alkoxy group, R 2 represents a hydrogen atom or a lower alkanoyl group, and n represents a number of 2 to 5)
The antihypertensive agent for hypertension which uses the biphenyl carboxamide compound represented by these as an active ingredient is provided.
The present invention also provides a pharmaceutical composition for preventing and treating hypertension, comprising a biphenylcarboxamide compound represented by the above formula (1) and a pharmaceutically acceptable carrier.
The present invention also provides use of the biphenylcarboxamide compound represented by the above formula (1) for the production of a prophylactic and therapeutic agent for hypertension.
Furthermore, the present invention provides a method for preventing and treating hypertension, which comprises administering an effective amount of the biphenylcarboxamide compound represented by the above formula (1).
式（１）の化合物は優れた血圧降下作用を示し、新たな高血圧症予防治療薬として有用である。
The compound of the formula (1) exhibits an excellent blood pressure lowering action and is useful as a new antihypertensive drug.
本発明の高血圧症予防治療薬の有効成分は、式（１）で表されるビフェニルカルボキサミド化合物である。式（１）中、Ｒ1で示される低級アルコキシ基としては、炭素数１～６のアルコキシ基、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロピルオキシ基、ブトキシ基等が挙げられるが、メトキシ基が特に好ましい。
The active ingredient of the antihypertensive drug of the present invention is a biphenylcarboxamide compound represented by the formula (1). In the formula (1), the lower alkoxy group represented by R 1 includes an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a butoxy group, and the like. Is particularly preferred.
式（１）中、Ｒ2で示される低級アルカノイル基としては、炭素数２～６のアルカノイル基、例えばアセチル基、プロピオニル基、ブチリル基等が挙げられるが、アセチル基が特に好ましい。
In the formula (1), the lower alkanoyl group represented by R 2 includes an alkanoyl group having 2 to 6 carbon atoms, such as an acetyl group, a propionyl group, and a butyryl group, and an acetyl group is particularly preferable.
式（１）中、ｎは２～５の数を示すが、３～５、特に４が好ましい。
In the formula (1), n represents a number of 2 to 5, but 3 to 5, particularly 4 is preferable.
式（１）中、Ｒ1がメトキシ基、Ｒ2がアセチル基、ｎが４である化合物がさらに好ましく、特に前記ＧＲ１０３６９１（４’－アセチル－Ｎ－［４－［４－（２－メトキシフェニル）－１－ピペラジニル］ブチル］－［１，１’－ビフェニル］－４－カルボキサミド）が好ましい。
In the formula (1), a compound in which R 1 is a methoxy group, R 2 is an acetyl group, and n is 4 is more preferable, especially GR103691 (4′-acetyl-N- [4- [4- (2-methoxyphenyl) ) -1-piperazinyl] butyl]-[1,1′-biphenyl] -4-carboxamide) is preferred.
式（１）の化合物は、それ自体公知であり、例えばＧＲ１０３６９１は、ドパミンＤ３受容体アンタゴニストとして市販されている。
The compound of formula (1) is known per se. For example, GR103691 is commercially available as a dopamine D3 receptor antagonist.
式（１）の化合物は、後記実施例に示すように、優れた血圧降下作用を示した。その血圧降下作用は主にアドレナリンα１受容体遮断によるものと考えられる。
従って、式（１）の化合物は、高血圧症予防治療薬として有用である。 The compound of the formula (1) showed an excellent blood pressure lowering action as shown in Examples described later. The blood pressure lowering effect is considered to be mainly due to adrenergic α1 receptor blockade.
Therefore, the compound of the formula (1) is useful as a therapeutic agent for preventing hypertension.
従って、式（１）の化合物は、高血圧症予防治療薬として有用である。 The compound of the formula (1) showed an excellent blood pressure lowering action as shown in Examples described later. The blood pressure lowering effect is considered to be mainly due to adrenergic α1 receptor blockade.
Therefore, the compound of the formula (1) is useful as a therapeutic agent for preventing hypertension.
本発明の医薬又は医薬組成物は、式（１）の化合物に賦形剤、結合剤、滑沢剤、崩壊剤、被覆剤、乳化剤、懸濁化剤、溶剤、安定化剤、吸収助剤、軟膏基剤等の１以上の薬学的に許容される担体を適宜添加し、常法により経口投与用、注射投与用、直腸内投与用、外用等の剤形に製剤化することによって得られる。
The medicament or pharmaceutical composition of the present invention comprises a compound of formula (1), an excipient, a binder, a lubricant, a disintegrant, a coating agent, an emulsifier, a suspending agent, a solvent, a stabilizer, an absorption aid. It is obtained by appropriately adding one or more pharmaceutically acceptable carriers such as an ointment base and formulating it into a dosage form for oral administration, for injection, for rectal administration, for external use, etc. by a conventional method. .
経口投与用の製剤としては、顆粒、錠剤、糖衣錠、カプセル剤、丸剤、液剤、乳剤、懸濁剤等が；注射投与用の製剤としては、静脈内注射、筋肉内注射、皮下注射、点滴注射用の製剤などが；直腸内投与用の製剤としては、坐薬軟カプセル等が好ましい。
本発明の医薬は上記の如き製剤として、ヒトを含む哺乳動物に投与することができる。
本発明の医薬は、式（１）の化合物として、１日当り約１～５００ｍｇ／ｋｇを１～４回投与するのが好ましい。 Preparations for oral administration include granules, tablets, dragees, capsules, pills, liquids, emulsions, suspensions, etc .; preparations for injection administration include intravenous injection, intramuscular injection, subcutaneous injection, infusion Preparations for injection and the like; As preparations for rectal administration, suppository soft capsules and the like are preferable.
The medicament of the present invention can be administered to mammals including humans as a preparation as described above.
The medicament of the present invention is preferably administered about 1 to 500 mg / kg as the compound of formula (1) 1 to 4 times per day.
本発明の医薬は上記の如き製剤として、ヒトを含む哺乳動物に投与することができる。
本発明の医薬は、式（１）の化合物として、１日当り約１～５００ｍｇ／ｋｇを１～４回投与するのが好ましい。 Preparations for oral administration include granules, tablets, dragees, capsules, pills, liquids, emulsions, suspensions, etc .; preparations for injection administration include intravenous injection, intramuscular injection, subcutaneous injection, infusion Preparations for injection and the like; As preparations for rectal administration, suppository soft capsules and the like are preferable.
The medicament of the present invention can be administered to mammals including humans as a preparation as described above.
The medicament of the present invention is preferably administered about 1 to 500 mg / kg as the compound of formula (1) 1 to 4 times per day.
次に実施例を挙げて、本発明をさらに詳細に説明するが、本発明はこれら実施例に何ら限定されるものではない。
Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
実施例１
（方法）
使用動物：１０～１１週齢のＷｉｓｔａｒ／ＳＴ雄性ラット
観血式血圧測定：麻酔下ラットの動脈に挿入したカニューレから直接動脈圧と心拍数を連続的に導出する観血式血圧測定法で行った。ウレタン６００ｍｇ／ｋｇとクロラロース６０ｍｇ／ｋｇを腹腔内注射し、十分麻酔がかかったことを確認したあと、ラットの腸骨動脈及び腸骨静脈を露出させ、それぞれ半切開しカニューレを挿入した。動脈カニューレは圧力センサーを介して血圧測定装置に接続し、血圧（ｍｍＨｇ）及び心拍数（回／分）をレコーダーに記録した。
薬物投与：すべての薬物は、投与量が体重１ｋｇあたり１ｍＬとなるように調製した。ＧＲ１０３６９１は５％酢酸で溶解させ、１ｍｏｌ／Ｌ ＮａＯＨでｐＨを約５に調節後、投与量が３ｍｇ／ｋｇになるように注射用水で希釈した。アドレナリン（Ａｄ）、アンギオテンシンＩＩ（ＡＴ ＩＩ）、ジルチアゼム、プラゾシン、ラベタロールは注射用水で溶解し下記の投与量に調製した。薬物は静脈カニューレから投与し、その後ヘパリン(２ｕｎｉｔ／ｍＬ)を加えた生理食塩水０．２ｍＬでカニューレ内の薬液を完全に押し出した。 Example 1
(Method)
Animals used: Wistar / ST male rat invasive blood pressure measurement at 10 to 11 weeks of age: invasive blood pressure measurement method that continuously derives arterial pressure and heart rate directly from the cannula inserted into the anesthetized rat artery It was. After injecting intraperitoneally with 600 mg / kg of urethane and 60 mg / kg of chloralose and confirming that anesthesia was sufficiently applied, the iliac arteries and iliac veins of the rats were exposed, each half-incised and cannulated. The arterial cannula was connected to a blood pressure measurement device via a pressure sensor, and blood pressure (mmHg) and heart rate (times / minute) were recorded on a recorder.
Drug administration: All drugs were prepared so that the dose was 1 mL per kg body weight. GR103691 was dissolved in 5% acetic acid, pH was adjusted to about 5 with 1 mol / L NaOH, and then diluted with water for injection so that the dose was 3 mg / kg. Adrenaline (Ad), angiotensin II (AT II), diltiazem, prazosin and labetalol were dissolved in water for injection and prepared to the following dosages. The drug was administered through an intravenous cannula, and then the drug solution in the cannula was completely pushed out with 0.2 mL of physiological saline supplemented with heparin (2 units / mL).
（方法）
使用動物：１０～１１週齢のＷｉｓｔａｒ／ＳＴ雄性ラット
観血式血圧測定：麻酔下ラットの動脈に挿入したカニューレから直接動脈圧と心拍数を連続的に導出する観血式血圧測定法で行った。ウレタン６００ｍｇ／ｋｇとクロラロース６０ｍｇ／ｋｇを腹腔内注射し、十分麻酔がかかったことを確認したあと、ラットの腸骨動脈及び腸骨静脈を露出させ、それぞれ半切開しカニューレを挿入した。動脈カニューレは圧力センサーを介して血圧測定装置に接続し、血圧（ｍｍＨｇ）及び心拍数（回／分）をレコーダーに記録した。
薬物投与：すべての薬物は、投与量が体重１ｋｇあたり１ｍＬとなるように調製した。ＧＲ１０３６９１は５％酢酸で溶解させ、１ｍｏｌ／Ｌ ＮａＯＨでｐＨを約５に調節後、投与量が３ｍｇ／ｋｇになるように注射用水で希釈した。アドレナリン（Ａｄ）、アンギオテンシンＩＩ（ＡＴ ＩＩ）、ジルチアゼム、プラゾシン、ラベタロールは注射用水で溶解し下記の投与量に調製した。薬物は静脈カニューレから投与し、その後ヘパリン(２ｕｎｉｔ／ｍＬ)を加えた生理食塩水０．２ｍＬでカニューレ内の薬液を完全に押し出した。 Example 1
(Method)
Animals used: Wistar / ST male rat invasive blood pressure measurement at 10 to 11 weeks of age: invasive blood pressure measurement method that continuously derives arterial pressure and heart rate directly from the cannula inserted into the anesthetized rat artery It was. After injecting intraperitoneally with 600 mg / kg of urethane and 60 mg / kg of chloralose and confirming that anesthesia was sufficiently applied, the iliac arteries and iliac veins of the rats were exposed, each half-incised and cannulated. The arterial cannula was connected to a blood pressure measurement device via a pressure sensor, and blood pressure (mmHg) and heart rate (times / minute) were recorded on a recorder.
Drug administration: All drugs were prepared so that the dose was 1 mL per kg body weight. GR103691 was dissolved in 5% acetic acid, pH was adjusted to about 5 with 1 mol / L NaOH, and then diluted with water for injection so that the dose was 3 mg / kg. Adrenaline (Ad), angiotensin II (AT II), diltiazem, prazosin and labetalol were dissolved in water for injection and prepared to the following dosages. The drug was administered through an intravenous cannula, and then the drug solution in the cannula was completely pushed out with 0.2 mL of physiological saline supplemented with heparin (2 units / mL).
（結果）
（１）ＧＲ１０３６９１（３ｍｇ／ｋｇ）は、単独で血圧及び心拍数を低下させた（図１）。
（２）アドレナリンα及びβ刺激作用を持つアドレナリン（Ａｄ）（１μｇ／ｋｇ）投与により、血圧は、著しく上昇した後、投与前より低下し、投与前に戻った（図２（Ａ））。これによりα及びβ刺激作用が見られることが確認されたので、同一のラットで、投与前の状態に戻ってしばらくおいた後、ＧＲ１０３６９１（３ｍｇ／ｋｇ）を投与したところ動脈圧及び心拍数は低下し、４分後にアドレナリン（Ａｄ）（１μｇ／ｋｇ）を投与してもアドレナリン（Ａｄ）単独で認められた血圧の変化は認められず、さらに４分後にアドレナリン（Ａｄ）（１０μｇ／ｋｇ）を投与しても血圧の変化は認められなかった（図２（Ｂ））。
（３）α遮断薬のプラゾシン（１ｍｇ／ｋｇ）を投与すると、血圧は低下したが心拍数は影響を受けなかった（図３）。また、プラゾシン投与後にアドレナリン（Ａｄ）を投与するとＡｄによる血圧上昇は、ＧＲ１０３６９１の場合と同様にほぼ完全に抑制されたが、心拍数は上昇が認められた（図３（Ｂ））。
（４）α、β遮断薬のラベタロール（３ｍｇ／ｋｇ）を投与すると血圧及び心拍数がともに低下し、ＧＲ１０３６９１単独の作用に類似した結果となった（図４）。
（５）アンジオテンシン（ＡＴ） ＩＩは、１及び１０μｇ／ｋｇの投与で用量依存的に血圧を上昇させ、心拍数をわずかに減少させた（図５（Ａ））。ＧＲ１０３６９１（３ｍｇ／ｋｇ）は、ＡＴ ＩＩによる血圧上昇に顕著な影響を及ぼさなかった（図５（Ｂ））。
（６）カルシウム拮抗薬であるジルチアゼム（１ｍｇ／ｋｇ）は、血圧、心拍数をともに低下させたが、血圧がＧＲ１０３６９１と同程度低下したのに対し、心拍数低下の程度はＧＲ１０３６９１に比較しかなり低かった（図６）。一方、ジルチアゼム投与後にＡＴ ＩＩを投与したところ、ＧＲ１０３６９１の場合とは異なり、血圧上昇を抑制した（図６）。 (result)
(1) GR103691 (3 mg / kg) alone decreased blood pressure and heart rate (FIG. 1).
(2) By administration of adrenaline (Ad) (1 μg / kg) having an effect of stimulating adrenaline α and β, the blood pressure significantly increased, then decreased from before administration, and returned to before administration (FIG. 2 (A)). As a result, it was confirmed that α and β stimulating effects were observed. Therefore, in the same rat, after returning to the pre-administration state and waiting for a while, when GR103691 (3 mg / kg) was administered, the arterial pressure and the heart rate were Even after administration of adrenaline (Ad) (1 μg / kg) after 4 minutes, there was no change in blood pressure observed with adrenaline (Ad) alone, and 4 minutes later, adrenaline (Ad) (10 μg / kg) No change in blood pressure was observed even after administration of (Fig. 2B).
(3) When α-blocker prazosin (1 mg / kg) was administered, blood pressure decreased, but heart rate was not affected (FIG. 3). In addition, when adrenaline (Ad) was administered after prazosin administration, the blood pressure increase due to Ad was almost completely suppressed as in GR103691, but an increase in heart rate was observed (FIG. 3 (B)).
(4) When α, β-blocker labetalol (3 mg / kg) was administered, both blood pressure and heart rate decreased, and the results were similar to those of GR103691 alone (FIG. 4).
(5) Angiotensin (AT) II increased blood pressure in a dose-dependent manner at doses of 1 and 10 μg / kg, and slightly decreased the heart rate (FIG. 5 (A)). GR103691 (3 mg / kg) did not significantly affect the blood pressure increase due to AT II (FIG. 5B).
(6) Diltiazem (1 mg / kg), which is a calcium antagonist, decreased both blood pressure and heart rate, while blood pressure decreased to the same extent as GR103691, while the degree of heart rate decrease was considerably higher than that of GR103691. It was low (FIG. 6). On the other hand, when AT II was administered after diltiazem administration, unlike the case of GR103691, the increase in blood pressure was suppressed (FIG. 6).
（１）ＧＲ１０３６９１（３ｍｇ／ｋｇ）は、単独で血圧及び心拍数を低下させた（図１）。
（２）アドレナリンα及びβ刺激作用を持つアドレナリン（Ａｄ）（１μｇ／ｋｇ）投与により、血圧は、著しく上昇した後、投与前より低下し、投与前に戻った（図２（Ａ））。これによりα及びβ刺激作用が見られることが確認されたので、同一のラットで、投与前の状態に戻ってしばらくおいた後、ＧＲ１０３６９１（３ｍｇ／ｋｇ）を投与したところ動脈圧及び心拍数は低下し、４分後にアドレナリン（Ａｄ）（１μｇ／ｋｇ）を投与してもアドレナリン（Ａｄ）単独で認められた血圧の変化は認められず、さらに４分後にアドレナリン（Ａｄ）（１０μｇ／ｋｇ）を投与しても血圧の変化は認められなかった（図２（Ｂ））。
（３）α遮断薬のプラゾシン（１ｍｇ／ｋｇ）を投与すると、血圧は低下したが心拍数は影響を受けなかった（図３）。また、プラゾシン投与後にアドレナリン（Ａｄ）を投与するとＡｄによる血圧上昇は、ＧＲ１０３６９１の場合と同様にほぼ完全に抑制されたが、心拍数は上昇が認められた（図３（Ｂ））。
（４）α、β遮断薬のラベタロール（３ｍｇ／ｋｇ）を投与すると血圧及び心拍数がともに低下し、ＧＲ１０３６９１単独の作用に類似した結果となった（図４）。
（５）アンジオテンシン（ＡＴ） ＩＩは、１及び１０μｇ／ｋｇの投与で用量依存的に血圧を上昇させ、心拍数をわずかに減少させた（図５（Ａ））。ＧＲ１０３６９１（３ｍｇ／ｋｇ）は、ＡＴ ＩＩによる血圧上昇に顕著な影響を及ぼさなかった（図５（Ｂ））。
（６）カルシウム拮抗薬であるジルチアゼム（１ｍｇ／ｋｇ）は、血圧、心拍数をともに低下させたが、血圧がＧＲ１０３６９１と同程度低下したのに対し、心拍数低下の程度はＧＲ１０３６９１に比較しかなり低かった（図６）。一方、ジルチアゼム投与後にＡＴ ＩＩを投与したところ、ＧＲ１０３６９１の場合とは異なり、血圧上昇を抑制した（図６）。 (result)
(1) GR103691 (3 mg / kg) alone decreased blood pressure and heart rate (FIG. 1).
(2) By administration of adrenaline (Ad) (1 μg / kg) having an effect of stimulating adrenaline α and β, the blood pressure significantly increased, then decreased from before administration, and returned to before administration (FIG. 2 (A)). As a result, it was confirmed that α and β stimulating effects were observed. Therefore, in the same rat, after returning to the pre-administration state and waiting for a while, when GR103691 (3 mg / kg) was administered, the arterial pressure and the heart rate were Even after administration of adrenaline (Ad) (1 μg / kg) after 4 minutes, there was no change in blood pressure observed with adrenaline (Ad) alone, and 4 minutes later, adrenaline (Ad) (10 μg / kg) No change in blood pressure was observed even after administration of (Fig. 2B).
(3) When α-blocker prazosin (1 mg / kg) was administered, blood pressure decreased, but heart rate was not affected (FIG. 3). In addition, when adrenaline (Ad) was administered after prazosin administration, the blood pressure increase due to Ad was almost completely suppressed as in GR103691, but an increase in heart rate was observed (FIG. 3 (B)).
(4) When α, β-blocker labetalol (3 mg / kg) was administered, both blood pressure and heart rate decreased, and the results were similar to those of GR103691 alone (FIG. 4).
(5) Angiotensin (AT) II increased blood pressure in a dose-dependent manner at doses of 1 and 10 μg / kg, and slightly decreased the heart rate (FIG. 5 (A)). GR103691 (3 mg / kg) did not significantly affect the blood pressure increase due to AT II (FIG. 5B).
(6) Diltiazem (1 mg / kg), which is a calcium antagonist, decreased both blood pressure and heart rate, while blood pressure decreased to the same extent as GR103691, while the degree of heart rate decrease was considerably higher than that of GR103691. It was low (FIG. 6). On the other hand, when AT II was administered after diltiazem administration, unlike the case of GR103691, the increase in blood pressure was suppressed (FIG. 6).
以上より、ＧＲ１０３６９１は血圧を低下させること、及び、血圧低下作用はアドレナリンα１受容体遮断によるものであることが明らかとなった。また、ＧＲ１０３６９１は、β遮断作用を併せ持つことが示唆された。
From the above, it has been clarified that GR103691 lowers blood pressure and that the blood pressure lowering effect is due to adrenergic α1 receptor blockade. Further, it was suggested that GR103691 also has a β-blocking action.
Claims (10)
- 次式（１）
で表されるビフェニルカルボキサミド化合物を有効成分とする高血圧症予防治療薬。 The following formula (1)
An antihypertensive drug comprising a biphenylcarboxamide compound represented by the formula: - Ｒ1が低級アルコキシ基であり、Ｒ2が低級アルカノイル基であり、ｎが４である請求項１記載の高血圧症予防治療薬。 The antihypertensive drug according to claim 1, wherein R 1 is a lower alkoxy group, R 2 is a lower alkanoyl group, and n is 4.
- Ｒ1がメトキシ基であり、Ｒ2がアセチル基であり、ｎが４である請求項１記載の高血圧症予防治療薬。 The antihypertensive agent according to claim 1, wherein R 1 is a methoxy group, R 2 is an acetyl group, and n is 4.
- 次式（１）
で表されるビフェニルカルボキサミド化合物、及び薬学的に許容される担体を含有する高血圧症予防治療用医薬組成物。 The following formula (1)
A pharmaceutical composition for preventing and treating hypertension, comprising a biphenylcarboxamide compound represented by the formula: and a pharmaceutically acceptable carrier. - 次式（１）
で表されるビフェニルカルボキサミド化合物の、高血圧症予防治療薬製造のための使用。 The following formula (1)
Use of a biphenylcarboxamide compound represented by the formula: - Ｒ1が低級アルコキシ基であり、Ｒ2が低級アルカノイル基であり、ｎが４である請求項５記載の使用。 The use according to claim 5, wherein R 1 is a lower alkoxy group, R 2 is a lower alkanoyl group, and n is 4.
- Ｒ1がメトキシ基であり、Ｒ2がアセチル基であり、ｎが４である請求項５記載の使用。 The use according to claim 5, wherein R 1 is a methoxy group, R 2 is an acetyl group, and n is 4.
- 次式（１）
で表されるビフェニルカルボキサミド化合物の有効量を投与することを特徴とする高血圧症予防治療方法。 The following formula (1)
A method for preventing and treating hypertension, which comprises administering an effective amount of a biphenylcarboxamide compound represented by the formula: - Ｒ1が低級アルコキシ基であり、Ｒ2が低級アルカノイル基であり、ｎが４である請求項８記載の予防治療方法。 The preventive treatment method according to claim 8, wherein R 1 is a lower alkoxy group, R 2 is a lower alkanoyl group, and n is 4.
- Ｒ1がメトキシ基であり、Ｒ2がアセチル基であり、ｎが４である請求項８記載の予防治療方法。 The prophylactic treatment method according to claim 8, wherein R 1 is a methoxy group, R 2 is an acetyl group, and n is 4.
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| JP2003513053A (en) * | 1999-11-04 | 2003-04-08 | アボット ゲーエムベーハー ウント カンパニー カーゲー | Use of dopamine D3 receptor agonists in the treatment of salt-dependent hypertension |
| WO2007148208A2 (en) * | 2006-06-22 | 2007-12-27 | Bioprojet | Carbonylated (aza) cyclohexanes as dopamine d3 receptor ligands |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2003513053A (en) * | 1999-11-04 | 2003-04-08 | アボット ゲーエムベーハー ウント カンパニー カーゲー | Use of dopamine D3 receptor agonists in the treatment of salt-dependent hypertension |
| WO2007148208A2 (en) * | 2006-06-22 | 2007-12-27 | Bioprojet | Carbonylated (aza) cyclohexanes as dopamine d3 receptor ligands |
Non-Patent Citations (6)
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| ASICO, L.D. ET AL.: "Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension", JOURNAL OF CLINICAL INVESTIGATION, vol. 102, no. 3, 1998, pages 493 - 498 * |
| BOECKLER, F. ET AL.: "Dopamine D3 receptor ligands - Recent advances in the control of subtype selectivity and intrinsic activity", BIOCHIMICA ET BIOPHYSICA ACTA - BIOMEMBRANES, vol. 1768, no. 4, 2007, pages 871 - 887 * |
| MUHLBAUER, B. ET AL.: "Dopamine D3 receptors in the rat kidney: role in physiology and pathophysiology", ACTA PHYSIOLOGICA SCANDINAVICA, vol. 168, no. 1, 2000, pages 219 - 223 * |
| MURRAY, P.J. ET AL.: "A Novel series of arylpiperazines with high affinity and selectivity for the dopamine D3 receptor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 5, no. 3, 1995, pages 219 - 222 * |
| TADORI, Y. ET AL.: "Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 597, no. 1-3, 2008, pages 27 - 33 * |
| ZENG, C. ET AL.: "D3 dopamine receptor and essential hypertension", CURRENT HYPERTENSION REVIEWS, vol. 2, no. 3, 2006, pages 247 - 253 * |
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