JP5862897B2 - Pharmaceuticals used for the prevention or treatment of renal dysfunction - Google Patents

Description

  The present invention relates to a medicament for use in the prevention or treatment of renal dysfunction.

  The kidney is responsible for excretion of water, electrolytes, and metabolites (including foreign substances) in the blood, and maintaining the homeostasis of the body environment through regulation of body fluid volume, blood osmotic pressure, and acid-base balance It is a special organ. There are about 1 million nephrons in one kidney. In nephron, blood is filtered in the glomeruli, useful plasma components and water are reabsorbed from the filtrate in the tubules, and secretion and excretion in the tubules are performed. ing. This decline in kidney function reduces the homeostasis of the body environment and, if severe, results in death.

  Various indicators such as glomerular function, tubule function, renal blood flow, etc. are used for the renal function test. The glomerulus that filters blood plays a central role in the renal function and shows the function of the glomerulus. Filtration volume (hereinafter abbreviated as GFR) is considered to be one of the best indicators reflecting renal function.

  If GFR decreases due to glomerular damage and metabolites cannot be excreted sufficiently, renal failure occurs. However, glomeruli do not regenerate, so it is important to detect and treat kidney damage early. . However, it is often the case that subjective symptoms do not appear and the patient is left as it is until the disease stage has progressed considerably. For patients with chronic renal failure who have progressed to a point where conservative management is difficult, treatment by artificial dialysis is the main. In Japan, the dialysis population continues to increase.

Chronic kidney disease, including chronic renal failure among kidney diseases, has a certain period of time that suggests some kind of kidney damage or has a GFR below a certain value (60ml / min / 1.73m ^{2 in Japan} ). (3 months in Japan). For such chronic kidney disease, smoking cessation, moderate exercise, diet therapy, etc. are usually performed, and pharmacotherapy is one of the main complications of suppressing the progression of chronic kidney disease Antihypertensive drugs are sometimes used for the purpose of reducing the risk of cardiovascular diseases. However, the cure is difficult unless it is early or mild chronic kidney disease.

  On the other hand, in gout patients, it has been reported that a decrease in renal function can be suppressed by controlling uric acid production and blood concentration with allopurinol, a xanthine oxidase inhibitor (for example, Non-patent Document 1). In addition, allopurinol and febuxostat, which is another xanthine oxidase inhibitor, have an action of protecting renal function during ischemia reperfusion (Patent Document 1). In allopurinol, renal diseases of chronic kidney disease patients It has been reported that there is an effect of delaying the progress (Non-Patent Document 2). However, in the case of allopurinol, for example, in the Japanese package insert, “In patients with renal dysfunction, the excretion of this drug and its metabolites is delayed and high blood levels persist. Consider prolongation, especially if there are side effects in patients with renal insufficiency and may have serious outcomes and deaths have been reported. It is said that caution should be taken when administering to kidney disease patients (reduced renal function patients) (for example, Non-Patent Document 3), and is appropriate as a therapeutic agent for chronic kidney disease. Sex is questionable. Allopurinol and its main active metabolite, oxypurinol, are purine-like compounds, but administration of allopurinol inhibits xanthine oxidase and increases xanthine, and oxypurinol is excreted in the urine and is neutral. Xanthine and oxypurinol are less soluble than uric acid in urine, and kidney stones and urinary calculi containing these purines are also known to occur, and oxypurinol may be the main component of these stones. It has been reported (for example, Non-Patent Documents 4 and 5). Therefore, administration of a purine-like compound xanthine oxidase inhibitor such as allopurinol may cause purine-derived calculus formation and adversely affect renal function.

  The 1,2,4-triazole compound which is the compound of the present invention is a compound described in Patent Document 2, but the preventive or therapeutic effect of the compound on renal dysfunction is not known.

International Patent Publication International Publication Number WO96 / 31211 International Patent Publication International Publication Number WO03 / 064410

Arthritis Rheum. 18: 877-881 (1975) Clin. J. Am. Soc. Nephrol. 2010 Jun 10 (Epub) Physicians ’Desk Reference (51st edition, pp1194-1196 1997) N. Engl. J Med. 292: 626-627 (1975) Ann. Interm. Med. 92: 384-385 (1980)

  Medical satisfaction with pharmacotherapy for kidney diseases, particularly chronic kidney disease, is low, and the development of new drugs is desired. An object of the present invention is to provide a medicament for use in the prevention or treatment of renal dysfunction with few side effects.

  As a result of intensive studies to solve the above problems, the present inventors have found that the following compounds are useful for the prevention or treatment of renal dysfunction, and have completed the present invention.

〔上記式中、Ｒ^２は、非置換のピリジル基、又は置換基としてシアノ基、低級アルキル基、ハロゲン、低級アルコキシ基若しくは低級アルキルチオ基を有する置換ピリジル基を示す。Ｒ^１は、置換基としてハロゲン、シアノ基、若しくはフェニル基を有していてもよい、非置換若しくは置換ピリジル基、又はそれらピリジル基の相当するピリジンＮ−オキシド基、あるいは、置換基としてシアノ基若しくはニトロ基を有する置換フェニル基、又は該シアノ基、若しくはニトロ基のほかに、更に置換基として、置換若しくは非置換の低級アルコキシ基、Ｎ−低級アルキル置換ピペラジノ基、低級アルキルチオ基、フェニルチオ基、若しくは低級アルキルアミノ基を有する置換フェニル基を示す。但し、Ｒ^１は１つのシアノ基のみで置換されたフェニル基、又は、１つのニトロ基のみで置換されたフェニル基ではない。また、Ｒ^２が非置換のピリジル基、又は低級アルキル置換ピリジル基である場合、Ｒ^１は非置換のピリジル基、又は低級アルキル置換ピリジル基、あるいは、それらピリジル基の相当するピリジンＮ−オキシド基ではない。Ｒ^３は、水素、又はピバロイルオキシ置換低級アルキル基を示し、いずれも、一般式（１）で表される１，２，４−トリアゾール環の１つの窒素に結合している〕で表わされる、１，２，４−トリアゾール系化合物またはその医薬上許容され得る、水和物若しくは溶媒和物又はそれらの塩を有効成分として含有する、腎機能障害の予防又は治療に用いる医薬。
＜２＞前記一般式（１）において、Ｒ^２が、非置換のピリジル基、又は、置換基としてシアノ基、炭素数１から３の低級アルキル基、若しくはハロゲンを有する置換ピリジル基であり、Ｒ^１が、置換基としてハロゲン又はシアノ基を有していてもよい、非置換若しくは置換ピリジル基であり、Ｒ^３が水素原子である、＜１＞に記載の医薬。
＜３＞前記一般式（１）において、Ｒ^２が、非置換のピリジル基、又は、置換基として炭素数１から３の低級アルキル基若しくはハロゲンを有する置換ピリジル基であり、Ｒ^１が置換基としてシアノ基を有する置換ピリジル基であり、Ｒ^３が水素原子である、＜１＞に記載の医薬。
＜４＞有効成分が５−（２−シアノ−４−ピリジル）−３−（４−ピリジル）−１，２，４−トリアゾールである、＜３＞に記載の医薬。
＜５＞腎機能障害が腎不全又は慢性腎臓病である、＜１＞〜＜４＞のいずれかに記載の医薬。
＜６＞腎機能障害が糸球体ろ過量の低下を伴う疾患である、＜１＞〜＜４＞のいずれかに記載の医薬。That is, the present invention is as follows.
<1> The following general formula (1)

[In the above formula, R ² represents an unsubstituted pyridyl group or a substituted pyridyl group having a cyano group, a lower alkyl group, a halogen, a lower alkoxy group or a lower alkylthio group as a substituent. R ¹ may have a halogen, cyano group, or phenyl group as a substituent, an unsubstituted or substituted pyridyl group, or a pyridine N-oxide group corresponding to these pyridyl groups, or a cyano group as a substituent In addition to a substituted phenyl group having a nitro group, or the cyano group or nitro group, a substituted or unsubstituted lower alkoxy group, an N-lower alkyl-substituted piperazino group, a lower alkylthio group, a phenylthio group, Or the substituted phenyl group which has a lower alkylamino group is shown. However, R ¹ is not a phenyl group substituted with only one cyano group or a phenyl group substituted with only one nitro group. When R ² is an unsubstituted pyridyl group or a lower alkyl-substituted pyridyl group, R ¹ is an unsubstituted pyridyl group, a lower alkyl-substituted pyridyl group, or a pyridine N-oxide group corresponding to these pyridyl groups. is not. R ³ represents hydrogen or a pivaloyloxy-substituted lower alkyl group, each of which is bonded to one nitrogen of the 1,2,4-triazole ring represented by the general formula (1)]. , 2,4-triazole compound or a pharmaceutically acceptable hydrate or solvate thereof or a salt thereof as an active ingredient, used for the prevention or treatment of renal dysfunction.
<2> In the general formula (1), R ² is an unsubstituted pyridyl group, or a substituted pyridyl group having a cyano group, a lower alkyl group having 1 to 3 carbon atoms, or a halogen as a substituent; ¹ may have a halogen or cyano group as a substituent, an unsubstituted or substituted pyridyl group, R ³ is a hydrogen atom, a medicament according to <1>.
<3> In the general formula (1), R ² is an unsubstituted pyridyl group, or a substituted pyridyl group having a lower alkyl group having 1 to 3 carbon atoms or a halogen as a substituent, and R ¹ is a substituent. <1>, which is a substituted pyridyl group having a cyano group as R ³ is a hydrogen atom.
<4> The medicament according to <3>, wherein the active ingredient is 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole.
<5> The medicament according to any one of <1> to <4>, wherein the renal dysfunction is renal failure or chronic kidney disease.
<6> The medicament according to any one of <1> to <4>, wherein the renal dysfunction is a disease accompanied by a decrease in glomerular filtration rate.

  The present invention provides a medicament for use in the prevention or treatment of renal dysfunction. Although the compound which becomes an active ingredient of this invention is a compound which has a xanthine oxidase inhibitory effect, since it is not a purine analog, there is no fear that the kidney stone and urinary tract stone derived from purine will arise.

〔上記式中、Ｒ^２は、非置換のピリジル基、又は置換基としてシアノ基、低級アルキル基、ハロゲン、低級アルコキシ基若しくは低級アルキルチオ基を有する置換ピリジル基を示す。Ｒ^１は、置換基としてハロゲン、シアノ基、若しくはフェニル基を有していてもよい、非置換若しくは置換ピリジル基、又はそれらピリジル基の相当するピリジンＮ−オキシド基、あるいは、置換基としてシアノ基若しくはニトロ基を有する置換フェニル基、又は該シアノ基、若しくはニトロ基のほかに、更に置換基として、置換若しくは非置換の低級アルコキシ基、Ｎ−低級アルキル置換ピペラジノ基、低級アルキルチオ基、フェニルチオ基、若しくは低級アルキルアミノ基を有する置換フェニル基を示す。但し、Ｒ^１は１つのシアノ基のみで置換されたフェニル基、又は、１つのニトロ基のみで置換されたフェニル基ではない。また、Ｒ^２が非置換のピリジル基、又は低級アルキル置換ピリジル基である場合、Ｒ^１は非置換のピリジル基、又は低級アルキル置換ピリジル基、あるいは、それらピリジル基の相当するピリジンＮ−オキシド基ではない。Ｒ^３は、水素、又はピバロイルオキシ置換低級アルキル基を示し、いずれも、一般式（１）で表される１，２，４−トリアゾール環の１つの窒素に結合している〕で表わされる、１，２，４−トリアゾール系化合物またはその医薬上許容され得る、水和物若しくは溶媒和物又はそれらの塩。尚、一般式（１）中のハロゲンとしては、フッ素、塩素、臭素、ヨウ素が挙げられ、低級アルキル基としては、炭素数１から６の直鎖又は分岐鎖のアルキル基が、低級アルコキシ基としては、炭素数１から６の直鎖又は分岐鎖のアルコキシ基が、低級アルキルチオ基としては、炭素数１から６の直鎖又は分岐鎖のアルキルチオ基が、低級アルキルアミノ基としては、炭素数１から６の直鎖又は分岐鎖のアルキルアミノ基が挙げられる。Ｎ−低級アルキル置換ピペラジノ基としては、炭素数１から６の直鎖又は分岐鎖のアルキル基を置換基として有するＮ−置換ピペラジノ基が挙げられる。The medicament used for the prevention or treatment of renal dysfunction according to the present invention contains a compound represented by the following general formula (1) as an active ingredient. The said compound is a compound of international publication number WO03 / 064410, and a compound synthesis | combination can be implemented with reference to the said specification.

[In the above formula, R ² represents an unsubstituted pyridyl group or a substituted pyridyl group having a cyano group, a lower alkyl group, a halogen, a lower alkoxy group or a lower alkylthio group as a substituent. R ¹ may have a halogen, cyano group, or phenyl group as a substituent, an unsubstituted or substituted pyridyl group, or a pyridine N-oxide group corresponding to these pyridyl groups, or a cyano group as a substituent In addition to a substituted phenyl group having a nitro group, or the cyano group or nitro group, a substituted or unsubstituted lower alkoxy group, an N-lower alkyl-substituted piperazino group, a lower alkylthio group, a phenylthio group, Or the substituted phenyl group which has a lower alkylamino group is shown. However, R ¹ is not a phenyl group substituted with only one cyano group or a phenyl group substituted with only one nitro group. When R ² is an unsubstituted pyridyl group or a lower alkyl-substituted pyridyl group, R ¹ is an unsubstituted pyridyl group, a lower alkyl-substituted pyridyl group, or a pyridine N-oxide group corresponding to these pyridyl groups. is not. R ³ represents hydrogen or a pivaloyloxy-substituted lower alkyl group, each of which is bonded to one nitrogen of the 1,2,4-triazole ring represented by the general formula (1)]. , 2,4-triazole compounds, or pharmaceutically acceptable hydrates or solvates thereof, or salts thereof. The halogen in the general formula (1) includes fluorine, chlorine, bromine and iodine, and the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms as the lower alkoxy group. Is a linear or branched alkoxy group having 1 to 6 carbon atoms, a lower alkylthio group is a linear or branched alkylthio group having 1 to 6 carbon atoms, and a lower alkylamino group is a carbon number 1 To 6 linear or branched alkylamino groups. Examples of the N-lower alkyl-substituted piperazino group include an N-substituted piperazino group having a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent.

In the compound, in General Formula (1), R ² is an unsubstituted pyridyl group, or a substituted pyridyl group having a cyano group, a lower alkyl group having 1 to 3 carbon atoms, or a halogen as a substituent. R ¹ is an unsubstituted or substituted pyridyl group optionally having a halogen or a cyano group as a substituent, and a compound in which R ³ is a hydrogen atom is preferable. Among them, R ² is an unsubstituted pyridyl group, or a substituted pyridyl group having a lower alkyl group having 1 to 3 carbon atoms or halogen as a substituent, and R ¹ is a substituted pyridyl group having a cyano group as a substituent. Particularly preferred are compounds in which R ³ is a hydrogen atom. In addition, as a C1-C3 lower alkyl group, a methyl group or an ethyl group is preferable. As the halogen, chlorine is preferable.

  Specific examples include 3- (4-isobutoxy-3-nitrophenyl) -5- (2-methyl-4-pyridyl) -1,2,4-triazole, 3- (3-cyano-4-iso Butoxyphenyl) -5- (4-pyridyl) -1,2,4-triazole, 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole, 3- (2-methyl-4-pyridyl) -5- (3-cyano-4-isobutoxyphenyl) -1,2,4-triazole, 3- (2-methyl-4-pyridyl) -5- (3-nitro -4-methoxyphenyl) -1,2,4-triazole, 3- (2-methyl-4-pyridyl) -5- [3-cyano-4-{(2-methoxyethoxy) ethoxy} phenyl] -1, 2,4-triazole and the like can be mentioned.

  When the compound represented by the above general formula is used as a salt, it is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloride, sulfate, nitrate, phosphate, tartrate, succinate, citric acid Addition salt of inorganic or organic acid such as salt, maleate, fumarate, acetate, lactate, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, ethylenediamine salt, meglumine salt, dieta It can be used as an alkali salt with an inorganic or organic salt such as a nuramine salt or a tris salt.

  In addition, a compound having xanthine oxidase inhibitory action serves as a preventive or therapeutic agent for renal dysfunction. For example, such a compound group is described in WO92 / 9279, WO2010 / 030988, WO98 / 18765, and JP2000-1431, and not only the compound of the present invention but also other compounds having xanthine oxidase inhibitory activity In addition, the inventors have come to recognize that it is a preventive or therapeutic agent for renal dysfunction.

  In the present invention, renal dysfunction includes various renal diseases related to decreased or impaired renal function. One such kidney disease is identified as a kidney disease associated with a decrease in GFR and includes chronic kidney disease. More specifically, various glomerular diseases (acute nephritis syndrome, rapid progressive nephritis syndrome, recurrent (recurrent) / continuous hematuria, chronic nephritis syndrome, nephrotic syndrome, hereditary nephropathy (nephropathy), diffuse thread Glomerulonephritis, dense deposit disease, etc.), renal tubulointerstitial disease, renal failure, kidney stones / urinary tract stones, etc. In the morphological classification of glomerular disease, for example, primary glomerular disease (microscopic disease) Variant, focal glomerulosclerosis, membranous nephropathy, mesangial proliferative glomerulonephritis (IgA nephropathy, non-IgA nephropathy), membranous proliferative glomerulonephritis, diffuse sclerosing glomerulonephritis, etc.) Renal diseases based on systematic diseases include collagen disease kidney (scleroderma kidney, lupus nephritis, etc.), diabetic nephropathy, renal amyloidosis, purpura nephritis, renal gout, hereditary renal disease (inheritance) Nephritis, Alport syndrome, Fabry disease, etc.) It can Shimesuru. The medicament of the present invention can be used for prevention or treatment of primary and secondary renal diseases including glomerular lesions in transplanted kidneys including these renal diseases. GFR can be used as an index of the effect of prevention or treatment of these renal dysfunctions, and the effect can be confirmed as maintenance and / or improvement (increase) of GFR.

  As GFR, (1). Clearance of a renal function diagnostic substance (inulin and the like can be exemplified as a renal functional diagnostic substance, but is not limited to inulin), (2). Clearance of biological materials (creatinine and the like can be exemplified as biological materials, but are not limited to creatinine) and / or (3). Although it is possible to use a numerical value obtained by measuring the concentration of a biological substance in blood (serum or plasma may be used) (such as creatinine as a biological substance, but not limited to creatinine), The GFR measurement method is not limited to (1), (2), and (3).

  The administration form of the medicament of the present invention is not particularly limited, and examples thereof include oral preparations, injection preparations, and transdermal absorption preparations. It can also be administered alone or in combination with other drugs.

  In the case of solid preparations for oral use, tablets, coated tablets, granules, fine granules, powders, capsules, etc. can be prepared by conventional methods, and sugar, gelatin, and other substances that can be used for pharmaceuticals If it is of a shape, it can be appropriately coated if necessary. In addition, additives such as pharmaceutically acceptable excipients, binders, disintegrants, lubricants, colorants, and corrigents can be used in appropriate combinations as necessary.

  In the case of an injection, it can be in a dosage form for intravenous, subcutaneous, intramuscular, intradermal, or other sites that can be administered as an injection. The storage shape may be either solid or liquid. If necessary, additives such as pharmaceutically acceptable solubilizers, pH adjusters, buffers, suspending agents, stabilizers, tonicity agents, preservatives, etc. are used in appropriate combinations. be able to.

  The dosage of the medicament of the present invention is the degree of symptoms, the patient's age, sex, body weight, sensitivity difference, administration route, administration method, administration timing, administration interval, nature of pharmaceutical preparation, type of active ingredient, type of concomitant drug The dosage may vary depending on the dosage, combined use with other agents, etc., and is not particularly limited, but is usually about 0.1 to 5000 mg, preferably about 1 to 1000 mg, more preferably about 10 to 500 mg per day for an adult. It can be administered orally or parenterally in several or several times.

  Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these. As shown in the following examples, the medicament of the present invention can also be referred to as the pharmaceutical composition of the present invention.

Examples 1-3: Production of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole-containing uncoated tablets 5- (2-cyano-4-pyridyl)- After mixing 3- (4-pyridyl) -1,2,4-triazole, lactose hydrate, crystalline cellulose, croscarmellose calcium and hydroxypropyl cellulose in the component ratios of the formulation examples in Table 1, an appropriate amount of water was added. In addition, the mixture was granulated with stirring, and then dried using a fluidized bed granulation coating apparatus at an intake temperature of 80 ° C., an intake air volume of 20 m ³ / min, and an exhaust temperature of 40 ° C. The dried product was sized with a 30-mesh sieve, and then magnesium stearate was added and mixed in the composition ratio of the formulation example to obtain granules for tableting. This was tableted so as to have the mass shown in the prescription example per tablet to obtain an uncoated tablet.

Test Example 1: eGFR improving action in humans (8 weeks administration)
The transition of eGFR (estimated GFR) in humans was examined by the test method described below.
Test method: 186 subjects were administered 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole for a total of 8 weeks according to the dosage and schedule shown in Table 2. The eGFR was calculated from the serum creatinine concentration.

Test result 1: Table 3 shows the amount of change in eGFR after 2 weeks, 4 weeks and 8 weeks from the start of administration. As is clear from Table 3, the compound of the present invention has a significant eGFR improvement (eGFR increase) action, and is considered to have an inhibitory effect on a decrease in renal function and an effect to restore renal function. .

Test Example 2: eGFR improving action in humans (30 weeks administration)
The transition of eGFR (estimated GFR) in humans was examined by the test method described below.
Test method: 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole, 20 mg once a day for 2 weeks (initial I) 2 times a day 40 mg once a day for 4 weeks (initial II) from 2 weeks to 6 weeks after the start of administration, and 60 mg once a week for 24 weeks (maintenance period) from 6 to 30 weeks after the start of administration Is orally administered twice a day. However, if the serum uric acid level at 14 weeks after the start of administration (after 8 weeks of the maintenance phase) is 6.0 mg / dL or more, once every 12 weeks from the 18th week after the start of administration (after 12 weeks of the maintenance phase) to 30 weeks later 80 mg is orally administered twice a day. Based on the above schedule, administration was started with a schedule of administration to 240 subjects for a total of 30 weeks, and eGFR was calculated from the serum creatinine concentration.

Test result 2: Table 4 shows eGFR and the amount of change before and after the start of administration. As is apparent from Table 4, the compound of the present invention has a significant eGFR improvement (eGFR increase) action, and is considered to have an inhibitory effect on a decrease in renal function and an effect to restore renal function. .

Claims (3)

5- (2-cyano-4-pyridyl) -3- (4-pyridyl) -1,2,4-triazole or a pharmaceutically acceptable hydrate or solvate thereof or a salt thereof as an active ingredient A pharmaceutical used for preventing or treating renal dysfunction. The medicament according to claim 1, wherein the renal dysfunction is a disease accompanied by a decrease in glomerular filtration rate. The medicament according to claim 1 or 2, wherein the renal dysfunction is diabetic nephropathy.