WO2013073382A1 - Médicament pour le traitement ou la prévention d'une néphropathie - Google Patents

Médicament pour le traitement ou la prévention d'une néphropathie Download PDF

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Publication number
WO2013073382A1
WO2013073382A1 PCT/JP2012/078346 JP2012078346W WO2013073382A1 WO 2013073382 A1 WO2013073382 A1 WO 2013073382A1 JP 2012078346 W JP2012078346 W JP 2012078346W WO 2013073382 A1 WO2013073382 A1 WO 2013073382A1
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Prior art keywords
renal
adrenergic receptor
compound
blocking action
receptor blocking
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PCT/JP2012/078346
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English (en)
Japanese (ja)
Inventor
秀伸 筒居
時人 雪村
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学校法人大谷学園
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Priority to JP2013544207A priority Critical patent/JP5958772B2/ja
Publication of WO2013073382A1 publication Critical patent/WO2013073382A1/fr

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic or prophylactic agent for renal disorders.
  • Renal disorder is a disease that causes a decrease in renal function or renal tissue, and laboratory findings include an increase in blood urea nitrogen (BUN) and serum creatinine and a marked decrease in glomerular filtration rate (GFR). Is recognized.
  • BUN blood urea nitrogen
  • GFR glomerular filtration rate
  • Non-Patent Documents 1-10 As the cause of the renal damage, ATP deficiency, generation of oxidative stress, increase of intracellular calcium concentration, activation of proteolytic enzyme, infiltration of neutrophils, loss of cell polarity, inflammatory cytokine and adhesion factor Increase of the renin-angiotensin system, involvement of endothelin, nitric oxide, and vasoactive substances such as prostacyclin, etc., and many studies have already been reported on the therapeutic effects on each of these. However, the therapeutic effect is limited and insufficient (see Non-Patent Documents 1-10).
  • examples of the renal disorder include those that develop due to shock associated with decreased blood pressure, cardiac output and renal blood flow due to bleeding, and those that develop after resumption of blood flow from an ischemic state such as during kidney transplantation.
  • no effective therapeutic or prophylactic agent has been found so far for such diseases.
  • An object of the present invention is to provide a pharmaceutical product that exhibits an excellent therapeutic or preventive effect on kidney damage based on a mechanism of action different from that of conventional products.
  • NA noradrenaline
  • a therapeutic or prophylactic agent for renal disorders comprising a compound having an ⁇ 2 adrenergic receptor blocking action as an active ingredient
  • the indolealkylamine derivative is yohimbic acid or a salt thereof or indolamine or a salt thereof which may be esterified
  • the renal disorder described in [1] above, wherein the compound having an ⁇ 2 adrenergic receptor blocking action is a compound having an ⁇ 2B adrenergic receptor blocking action (preferably a selective ⁇ 2B adrenergic receptor blocking action).
  • Therapeutic or preventive drugs [5] The therapeutic or prophylactic agent for renal injury according to the above [4], wherein the compound having an ⁇ 2B adrenergic receptor blocking action is an indazoylmethyl-1,4-benzodioxane derivative or a salt thereof, [6] The renal disorder described in [1] above, wherein the compound having an ⁇ 2 adrenergic receptor blocking action is a compound having an ⁇ 2C adrenergic receptor blocking action (preferably a selective ⁇ 2C adrenergic receptor blocking action).
  • the compound having an ⁇ 2 adrenergic receptor blocking action, a compound having an ⁇ 2B adrenergic receptor blocking action, or a compound having an ⁇ 2C adrenergic receptor blocking action of the present invention exhibits an excellent therapeutic or preventive effect on renal damage. .
  • the therapeutic or prophylactic agent for renal injury of the present invention is characterized by containing a compound having an ⁇ 2 adrenergic receptor blocking action as an active ingredient.
  • ⁇ 2 adrenergic receptor examples include ⁇ 2A , ⁇ 2B and ⁇ 2C subtypes.
  • ⁇ 2 adrenergic receptor blocking action of the compound of the present invention include non-selective ⁇ 2 adrenergic receptor blocking action, selective ⁇ 2A adrenergic receptor blocking action, selective ⁇ 2B adrenergic receptor blocking action and selection.
  • ⁇ 2C adrenergic receptor blocking action and the like are examples of the ⁇ 2 adrenergic receptor blocking action as an active ingredient.
  • the ⁇ 2 adrenergic receptor examples include ⁇ 2A , ⁇ 2B and ⁇ 2C subtypes.
  • ⁇ 2 adrenergic receptor blocking action of the compound of the present invention include non-selective ⁇ 2 a
  • a compound having a non-selective ⁇ 2 adrenergic receptor blocking action, a selective ⁇ 2B adrenergic receptor blocking action, or a selective ⁇ 2C adrenergic receptor blocking action from the viewpoint of having an excellent effect in the treatment or prevention of renal injury, etc. Is preferably used.
  • the compound having an ⁇ 2 adrenergic receptor blocking action is not limited to a known compound as long as the effect of the present invention is not hindered, and a wide range of compounds can be used.
  • yohimbic acid which may be esterified
  • a salt thereof, an indole alkylamine derivative such as indolamine, or an acid addition salt thereof can be used.
  • the indolealkylamine derivative is not particularly limited as long as it has an indolealkylamine skeleton and has an ⁇ 2 adrenergic receptor blocking action, so long as the effect of the present invention is not hindered.
  • Examples of the yohimbic acid that may be esterified include yohimbic acid lower (C 1-6 ) alkyl esters and salts thereof, such as yohimbine (17 ⁇ -hydroxy yohimban-16 ⁇ -carboxylic acid methyl ester) or acid addition salts thereof. And the like, salts with yohimbic acid or its base, laurorucic acid (17 ⁇ -Hydroxy-20 ⁇ -yohimban-16 ⁇ -carboxylic acid) which may be esterified, or an acid addition salt thereof.
  • yohimbic acid lower (C 1-6 ) alkyl esters and salts thereof such as yohimbine (17 ⁇ -hydroxy yohimban-16 ⁇ -carboxylic acid methyl ester) or acid addition salts thereof.
  • salts with yohimbic acid or its base such as laurorucic acid (17 ⁇ -Hydroxy-20 ⁇ -yohimban-16 ⁇ -carboxylic acid) which may be esterified, or an acid addition salt
  • the compound having an ⁇ 2B adrenergic receptor blocking action is not limited to known compounds as long as the effect of the present invention is not hindered, and a wide range of compounds can be used.
  • imyloxane (2- (1-Ethyl-2- indazoyl) methyl-1,4-benzodioxan hydrochloride) and other acid addition salts thereof;
  • ARC 239 (2- [2- (4- (2-Methoxyphenyl) piperazin-1- yl) ethyl] -4,4-dimethyl-1,3- (2H, 4H) -isoquinolindione dihydrochloride); piperazinyl isoquinoline derivatives;
  • Prazosin hydrochloride (1- (4-Amino-6,7-dimethoxy-2- quinazolinyl) -4- (2-furanylcarbonyl) piperazine hydrochloride) and the like, and indazoylmethyl-1,4-benzodiox
  • the indazoylmethyl-1,4-benzodioxane derivative, piperazinylisoquinoline derivative and piperazinylquinazoline derivative are respectively indazoylmethyl-1,4-benzodioxan skeleton, piperazinylisoquinoline skeleton, piperazinylquinazoline skeleton As long as it has an ⁇ 2B adrenergic receptor blocking action, the effect of the present invention is not particularly limited.
  • the compound having an ⁇ 2C adrenergic receptor blocking action is not limited to known compounds as long as the effects of the present invention are not hindered, and a wide range of compounds can be used.
  • piperazinylphenylacridinamine derivatives examples include N- [4- (4-Methyl-1-piperazinyl) phenyl] -9-acridinamine dihydrochloride, a benzofuroquinolidine derivative, MK-912 ((2S-trans) -1,3,4,5 ', 6, 6 ', 7,12b-Octahydro-1', 3'-dimethyl-spiro [2H-benzofuro [2,3-a] quinolizine-2,4 ′ (1′H) -pyrimidine] -2 ′ (3′H) -one hydrochloride hydrate).
  • the piperazinyl phenylacridinamine derivative and the benzofuroquinolidine derivative each have a piperazinylphenylacridinamine skeleton and a benzofuroquinolidine skeleton, and have an ⁇ 2C adrenergic receptor blocking action. If there is, it will not specifically limit unless the effect of this invention is prevented.
  • a compound that exhibits an ⁇ 2 adrenergic receptor blocking action in any of these methods is a compound used in the present invention.
  • Examples of the salt or acid addition salt of the compound include inorganic acid salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like, and organic acid salts with formic acid, acetic acid, propionic acid and the like.
  • Examples of the salt with a base include salts with metals such as sodium, potassium and calcium, and ammonium salts, and may form an inner salt.
  • the compound having an ⁇ 2 -adrenergic receptor blocking action of the present invention is produced at the site of injury in renal disorders of animals (for example, mammals such as rats, mice, pigs, cats, dogs, cows, horses, monkeys, humans). Inhibits the production of NA or the action of NA.
  • animals for example, mammals such as rats, mice, pigs, cats, dogs, cows, horses, monkeys, humans. Inhibits the production of NA or the action of NA.
  • the compounds of the present invention can effectively protect various organs associated with renal damage by blocking ⁇ 2 adrenergic receptors present in nerve endings and inflammatory cells, but are particularly prominent in the kidney. The effect will be recognized. Therefore, the compound having the blocking action of ⁇ 2 -adrenergic receptor of the present invention is useful as a pharmaceutical effective for treating or preventing various diseases and pathologies associated with renal disorders, that is, as an active ingredient of a therapeutic or preventive for renal failure. .
  • nephropathy includes a wide variety of diseases such as a decrease in renal function or a disorder of renal tissue, and includes various diseases such as acute ones and chronic ones. Examples thereof include renal dysfunction, renal failure, acute kidney injury, chronic kidney disease, renal ischemic injury, diabetic nephropathy and the like. Depending on the cause of acute kidney injury, prerenal acute renal failure due to decreased renal blood flow, renal acute renal failure with impaired renal parenchyma, post-renal acute renal failure due to urinary dysfunction after the kidney, etc. is there. Prerenal and postrenal acute renal failure can transition to renal acute renal failure.
  • Prerenal acute renal failure is cardiogenic shock (myocardial infarction, myocarditis, cardiac tamponade, etc.), sepsis, decreased circulating plasma volume (dehydration, bleeding, decreased intake, vomiting, diarrhea, heavy sweating, etc.) This is because renal blood flow is reduced by stenosis or occlusion of renal arteries, drugs (nonsteroidal anti-inflammatory analgesics, angiotensin converting enzyme inhibitors, etc.), etc.
  • Renal acute renal failure refers to vascular lesions, glomerular lesions (acute nephritis, glomerulonephritis, etc.), acute interstitial nephritis (drugs, infections, etc.), acute renal failure, acute tubular necrosis (Due to renal ischemia or tubule necrosis caused by nephrotoxic substances such as cisplatin, aminoglycoside, and contrast medium). Postrenal acute renal failure is due to urolithiasis, malignant tumor infiltration, prostate enlargement, prostate cancer, and the like.
  • Chronic kidney disease refers to, for example, renal disorder or a decrease in renal function that lasts for 3 months or more, and can be classified into stages 1 to 5.
  • the therapeutic or prophylactic agent for renal injury of the present invention is particularly a pathological condition in which renal ischemia or enhancement of renal catecholamine system is related to etiology or pathophysiology, such as acute renal injury, renal failure with renal ischemia reperfusion injury, septic kidney Preferred for the treatment or prevention of renal failure, acute renal failure with renal tubular necrosis, chronic kidney disease with chronic disease, renal ischemia reperfusion injury after renal transplantation or postoperative surgery such as renal thromboembolism, diabetic nephropathy Applied.
  • renal ischemia or enhancement of renal catecholamine system is related to etiology or pathophysiology, such as acute renal injury, renal failure with renal ischemia reperfusion injury, septic kidney Preferred for the treatment or prevention of renal failure, acute renal failure with renal tubular necrosis, chronic kidney disease with chronic disease, renal ischemia reperfusion injury after renal transplantation or postoperative surgery such as renal thromboembolism, diabetic nephropathy Applied.
  • the method for administering the therapeutic or prophylactic agent for renal disorder of the present invention is not particularly limited, and examples thereof include parenteral administration such as single / continuous infusion and transdermal absorption, oral administration, pre-administration, and post-administration.
  • the compound having a blocking action of ⁇ 2 -adrenergic receptor of the present invention may be administered as it is or as a pharmaceutical composition alone or in combination with other therapeutic agents or in combination with a carrier or excipient.
  • the carrier or excipient may be compatible with other components and has low toxicity.
  • the compound having an ⁇ 2 -adrenergic receptor blocking action of the present invention When used as an active ingredient, it is usually mixed with a pharmacologically acceptable carrier, excipient and / or other additives, and tableted. Oral or parenteral administration (intravenous, intramuscular, subcutaneous, other injection routes, etc.) as pharmaceutical compositions in dosage forms such as powders, granules and injections. Since the technology itself for producing pharmaceutical preparations for use in such applications has been sufficiently studied in the past, it may be followed in the present invention.
  • Ki values inhibition constants for each of the subtypes ( ⁇ 2A , ⁇ 2B, and ⁇ 2C ) are exemplified for some of the compounds having an ⁇ 2 adrenergic receptor blocking action according to the present invention.
  • these Ki values may reflect the strength of the ⁇ 2 adrenergic receptor blocking action of the compounds according to the present invention and the effectiveness and usefulness of the therapeutic effect and preventive effect on renal damage.
  • the Ki value for at least one subtype of ⁇ 2 adrenergic receptor is 500 or less, preferably 300 to 0.001, more preferably 150 to 0.01.
  • the therapeutic or prophylactic agent of the present invention is administered at an appropriate time for treating or preventing various diseases associated with renal disorders such as ischemic acute renal failure, and pathological conditions such as chronic kidney disease and acute renal disorder.
  • ischemic acute renal failure it can be administered between about 2 hours before reperfusion and about 2 hours after reperfusion.
  • the present invention suppresses the action or production of NA when administered with the ⁇ 2 -adrenergic receptor blocking action of the present invention, and unexpectedly various diseases and chronic kidney diseases associated with renal disorders such as ischemic acute renal failure.
  • the present inventors have found that it has an unexpectedly excellent effect in the treatment or prevention of pathological conditions such as acute kidney injury, and has been completed through further studies.
  • yohimbine yohimbine methyl ester
  • a low dose (10 to 100 ⁇ g / kg: for example, 0.6 to 6 mg for a person with a body weight of 60 kg) is administered.
  • a high dose (1 mg / kg or more: for example, 60 mg or more for a person with a body weight of 60 kg) is administered, the selective blocking effect of the ⁇ 2 receptor is reduced, and a psychological effect appears strongly.
  • the extreme amount of yohimbine is defined as 30 mg / time and 100 mg / day.
  • the appropriate dose of the compound having an ⁇ 2 -adrenergic receptor blocking action of the present invention is determined depending on the type and symptom of various diseases associated with renal disorders such as ischemic acute renal failure, chronic kidney disease, and acute renal disorder. It can be changed depending on administration route, sex difference, body weight and the like.
  • the daily dose of the compound having a blocking effect of the alpha 2 type adrenoceptors generally about 0.001 ⁇ 1000 mg / kg, preferably about 0.005 ⁇ 100 mg / kg Most preferably, it is 0.01 to 0.03 mg / kg.
  • the daily dose is usually about 0.0005-100 mg / kg, preferably about 0.001-10 mg / kg.
  • Administration can be performed once or divided into several times. When administered intravenously, continuous intravenous administration may be used.
  • the second component is an angiotensin converting enzyme inhibitor (captopril, ramipril, quinapril, benazepril, enalapril maleate, imidapril hydrochloride Salts, lisinopril hydrate, etc.), angiotensin receptor blockers (losartan potassium, candesartan cilexetil, valsartan, telmisartan, irbesartan, eprosartan, olmesartan, etc.), fibrate dyslipidemic drugs (bezafibrate, clofibrate) , Fenofibrate, etc.), HMG-CoA reductase inhibitors (pravastatin sodium, simvastatin, atorvastatin calcium hydrate, rosuvastatin calcium, etc.), provocol or reactive oxygen scavenger (bi
  • pentobarbital 50 mg / kg, ip
  • the atraumatic clip was then used to block the left renal arteriovenous blood flow, making the kidney ischemic. After 45 minutes, the clip was removed, blood flow was resumed, and the incision surface was sutured. Rats 24 hours after the end of the ischemia-reperfusion treatment were placed in a metabolic cage and urine collected for 5 hours. After completion of urine collection, blood collection and kidney extraction were performed under pentobarbital anesthesia. From the obtained blood and urine, blood urea nitrogen (BUN), plasma creatinine (Pcr), and creatinine clearance (Ccr) were measured as renal function parameters. From the obtained renal venous blood, the NA concentration in the renal venous plasma was measured. It was measured.
  • BUN blood urea nitrogen
  • Pcr plasma creatinine
  • Ccr creatinine clearance
  • Blood urea nitrogen is urea nitrogen B-Test Wako (Wako Pure Chemical Industries)
  • plasma and urine creatinine concentrations are Creatinine-Test Wako (Wako Pure Chemical Industries)
  • NA concentration in renal vein plasma is alumina.
  • NA was separated from plasma by an adsorption method and high performance liquid chromatography (HPLC), and then measured using an electrochemical detector.
  • 17 ⁇ -Hydroxyyohimban-16 ⁇ -carboxylic acid methyl ester hydrochloride was intravenously administered at a dose of 100 ⁇ g / kg 5 minutes before ischemia (drug administration group), and the control group was 0.9% physiological saline as a solvent. Was administered.
  • the group which performed only the right nephrectomy was made into the normal group.
  • control group showed a marked increase in BUN and Pcr and a significant decrease in Ccr compared to the normal group (Table 2, control group). It was remarkably improved by administration of 16 ⁇ -carboxylic acid methyl ester hydrochloride (Table 2, drug administration group). In addition, the increase in NA concentration in renal venous plasma after reperfusion observed in the control group was significantly suppressed by 17 ⁇ -Hydroxy- yohimban-16 ⁇ -carboxylic acid methyl ester hydrochloride (Table 3).
  • Example 2 2- (1-Ethyl-2-indazoyl) methyl-1,4-benzodioxan hydrochloride or N- [4- (4-Methyl-1-piperazinyl) phenyl] -9- for rat ischemic acute renal failure Evaluation of Renal Protection Effect of acridinamine dihydrochloride Renal ischemia reperfusion treatment was performed in the same manner as in Example 1 using Sprague-Dawley (SD) male rats (8 weeks old), and a renal injury model was prepared.
  • SD Sprague-Dawley
  • Renal dysfunction observed in the control group by renal ischemia-reperfusion treatment was 2- (1-Ethyl-2-indazoyl) methyl-1,4-benzodioxan hydrochloride or N- [4- (4-Methyl-1 -piperazinyl) phenyl] -9-acridinamine dihydrochloride was significantly improved (Table 4).
  • Example 3 Evaluation of the renal protective effect of 17 ⁇ -Hydroxyyohimban-16 ⁇ -carboxylic acid methyl ester hydrochloride or N- [4- (4-Methyl-1-piperazinyl) phenyl] -9-acridinamine dihydrochloride against cisplatin-induced renal injury -Dawley (SD) male rats (9 weeks old) were used.
  • Cisplatin was administered intravenously at a dose of 7.5 mg / kg.
  • 17 ⁇ -Hydroxyyohimban-16 ⁇ -carboxylic acid methyl ester hydrochloride is 0.1 mg / kg / day (drug A administration group), N- [4- (4-Methyl-1-piperazinyl) phenyl] -9-acridinamine dihydrochloride All were administered for 4 days at a rate of 3 mg / kg / day (drug B administration group).
  • a group administered with physiological saline was used as a control group.
  • a group not administered with cisplatin was defined as a normal group.
  • Urine was collected for 24 hours from the third day after cisplatin administration, and blood collection and kidney extraction were performed under pentobarbital anesthesia after completion of urine collection.
  • Blood urea nitrogen (BUN), plasma creatinine (Pcr), and creatinine clearance (Ccr) are measured as renal function parameters from the obtained blood and urine. From the obtained renal venous blood, the NA concentration in the renal venous plasma is measured. It was measured.
  • Renal dysfunction observed in the cisplatin-induced nephropathy group was 2- (1-Ethyl-2-indazoyl) methyl-1,4-benzodioxan hydrochloride or N- [4- (4-Methyl-1- Piperazinyl) phenyl] -9-acridinamine dihydrochloride was significantly improved (Table 5).
  • the increase in NA concentration in renal venous plasma after reperfusion observed in the control group was significantly suppressed by 17 ⁇ -Hydroxy- yohimban-16 ⁇ -carboxylic acid methyl ester hydrochloride (Table 6).
  • rat renal ischemia reperfusion treatment or cisplatin-induced renal injury increased NA levels in renal venous plasma, which plays an important role in the development and maintenance of renal ischemia-reperfusion injury or cisplatin-induced renal injury. It was suggested that he was playing.
  • Administration of ⁇ 2 adrenergic receptor or ⁇ 2C adrenergic receptor blocking compound suppresses renal venous plasma NA concentration increase due to renal ischemia reperfusion treatment or cisplatin-induced renal injury, resulting in renal injury Is thought to have improved.
  • a compound having the blocking action of the ⁇ 2 adrenergic receptor or ⁇ 2C adrenergic receptor of the present invention is additionally administered.
  • the purpose of chronic kidney disease treatment is to control the onset and progression of end-stage renal failure and cardiovascular disease.
  • the start time of treatment that is more troublesome than artificial dialysis in such patients is significantly delayed (for example, more than about half a year) Etc.) or can be eliminated.
  • Clinical trial 1 For patients with chronic kidney disease with mild to moderate decrease in estimated glomerular filtration rate, the primary endpoint was the rate of decrease in estimated glomerular filtration rate, and ⁇ 2 adrenergic receptor or ⁇ 2C adrenergic receptor Randomly divided into the administration group and non-administration group of the compound having a blocking action, and set as a double-blind comparison study. Comparison is made based on the presence of proteinuria, hypertension, and diabetes. It is considered that the decrease rate of the estimated glomerular filtration rate is significantly reduced in the administration group.
  • Clinical trial 2 For patients with moderate to severely decreased chronic glomerular filtration rate, the primary endpoint is the rate of dialysis induction over the 2-5 year observation period.
  • Example 4 Formulation example (tablet) After mixing yohimbine hydrochloride (17.24 g), mannitol (3187 g) and microcrystalline cellulose (663 g) uniformly in a fluid bed granulator, spray an aqueous solution of hydroxypropyl cellulose (132.6 g) in the machine. The mixture was granulated and then dried in the same machine. The obtained granulated product is crushed by a 1.5 mm ⁇ punching screen using a power mill to obtain a sized powder. To this sized powder (3,633 g), croscarmellose sodium (Ac-Di-Sol) (201.5 g) and magnesium stearate (40.3 g) are added and mixed to obtain granules for tableting.
  • croscarmellose sodium Ac-Di-Sol
  • magnesium stearate magnesium stearate
  • This granule is tableted using a 7.0 mm ⁇ punch with a tableting machine to give an uncoated tablet weighing 125 mg per tablet.
  • a film containing 0.5 mg yohimbine hydrochloride per tablet is obtained by spraying hydroxypropylmethylcellulose 2910 solution in which titanium oxide and yellow ferric oxide are dispersed in a film coating machine and polyethylene glycol 8000 is dissolved. Obtain about 25,000 tablets.
  • 1 to 3 tablets are orally administered to an adult patient at a time, 1 to 3 times daily.

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Abstract

La présente invention concerne un médicament pharmaceutique ayant un effet thérapeutique ou préventif supérieur contre une néphropathie. Le médicament pharmaceutique est un médicament pour le traitement ou la prévention d'une néphropathie, caractérisé en ce qu'il comprend en tant que substance active un composé ayant un effet bloquant de récepteur d'adrénaline α2.
PCT/JP2012/078346 2011-11-18 2012-11-01 Médicament pour le traitement ou la prévention d'une néphropathie WO2013073382A1 (fr)

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