WO2010092811A1 - Agent prophylactique ou thérapeutique pour l'hypertension - Google Patents

Agent prophylactique ou thérapeutique pour l'hypertension Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen atom
formula
blood pressure
lower alkoxy
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.)
Ceased
Application number
PCT/JP2010/000830
Other languages
English (en)
Japanese (ja)
Inventor
久美子 石毛
芳久 伊藤
康弘 小菅
敦史 勝
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nihon University
Original Assignee
Nihon University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nihon University filed Critical Nihon University
Publication of WO2010092811A1 publication Critical patent/WO2010092811A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un agent prophylactique ou thérapeutique pour l'hypertension, comprenant un composé biphénylcarboxamide représenté par la formule (1) [dans laquelle R1 représente un atome d'hydrogène ou un groupe alcoxy inférieur ; R2 représente un atome d'hydrogène ou un groupe alcanoyle inférieur ; et n représente un nombre de 2 à 5] en tant qu'ingrédient actif.
PCT/JP2010/000830 2009-02-12 2010-02-10 Agent prophylactique ou thérapeutique pour l'hypertension Ceased WO2010092811A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-029497 2009-02-12
JP2009029497A JP2010184889A (ja) 2009-02-12 2009-02-12 高血圧症予防治療薬

Publications (1)

Publication Number Publication Date
WO2010092811A1 true WO2010092811A1 (fr) 2010-08-19

Family

ID=42561659

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/000830 Ceased WO2010092811A1 (fr) 2009-02-12 2010-02-10 Agent prophylactique ou thérapeutique pour l'hypertension

Country Status (2)

Country Link
JP (1) JP2010184889A (fr)
WO (1) WO2010092811A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003513053A (ja) * 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 塩依存性高血圧症の治療におけるドーパミンｄ３受容体アゴニストの使用
WO2007148208A2 (fr) * 2006-06-22 2007-12-27 Bioprojet Nouveau (aza) cyclohexanes carbonylés comme ligands récepteurs de la dopamine d3

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003513053A (ja) * 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 塩依存性高血圧症の治療におけるドーパミンｄ３受容体アゴニストの使用
WO2007148208A2 (fr) * 2006-06-22 2007-12-27 Bioprojet Nouveau (aza) cyclohexanes carbonylés comme ligands récepteurs de la dopamine d3

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
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 *

Also Published As

Publication number Publication date
JP2010184889A (ja) 2010-08-26

Similar Documents

Publication Publication Date Title
KR20160089516A (ko) 에테르 측쇄를 함유한 n-치환 이미다졸 카르복실산 에스테르 키랄 화합물, 제조 방법 및 용도
KR101516677B1 (ko) 지방성 간 질환의 치료용 의약 조성물
RU2632889C2 (ru) Метаболиты (1r-транс)-n-[[2-(2,3-дигидро-4-бензофуранил)циклопропил]-метил]пропанамида
JP2814600B2 (ja) 排尿障害治療剤
JPH04264030A (ja) 抗喘息剤
EP2172201A1 (fr) Composition pharmaceutique pour une amélioration du symptôme des voies urinaires inférieures associé à une prostatomégalie
WO2010092811A1 (fr) Agent prophylactique ou thérapeutique pour l'hypertension
AU2017204652B2 (en) Treatment of Type I and Type II diabetes
JP7601458B2 (ja) スフィンゴシン－１－リン酸受容体アゴニストの使用
RU2555760C2 (ru) Терапевтический агент против хронической боли
TWI357409B (en) Pharmaceutical composition for inhibiting vascular
CN1137686C (zh) 椎管狭窄的治疗药
JP4741131B2 (ja) 低血圧およびショックの治療または予防
KR20160035060A (ko) 비대성 심근병증을 치료하는 방법
CN1501802A (zh) 芳基乙烯磺酰胺衍生物的新用途
RU2850978C1 (ru) Применение агониста рецептора сфингозин-1-фосфата
TW201032805A (en) Pharmaceutical compositions comprising a compound having suppressive effect on nutrient digestion or absorption and a cyclohexanecarboxamide derivative
CN101234101A (zh) 预防和/或治疗肥胖症的药物
JP5142991B2 (ja) １−（３−クロロフェニル）−３−アルキルピペラジンを含む食欲障害治療用医薬組成物
JPH035425A (ja) 抗潰瘍剤
JP2005068141A (ja) Ｖｅｇｆ分泌亢進剤
US20040048776A1 (en) Medicament for preventive and therapeutic treatment of fibrosis
WO1998041199A1 (fr) Decongestionnant nasal ou oculaire
WO2004019926A1 (fr) Agent preventif et/ou curatif de l'insuffisance cardiaque
JP2005041801A (ja) 細胞移植療法後の予後改善剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10741091

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10741091

Country of ref document: EP

Kind code of ref document: A1