JP2004123734A - Agent for renal failure containing oxaluric acid derivative - Google Patents
Agent for renal failure containing oxaluric acid derivative Download PDFInfo
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- JP2004123734A JP2004123734A JP2003316596A JP2003316596A JP2004123734A JP 2004123734 A JP2004123734 A JP 2004123734A JP 2003316596 A JP2003316596 A JP 2003316596A JP 2003316596 A JP2003316596 A JP 2003316596A JP 2004123734 A JP2004123734 A JP 2004123734A
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- renal failure
- agent
- acid derivative
- active ingredient
- oxalic acid
- Prior art date
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- 229940124423 agent for renal failure Drugs 0.000 title claims abstract description 11
- UWBHMRBRLOJJAA-UHFFFAOYSA-N oxaluric acid Chemical class NC(=O)NC(=O)C(O)=O UWBHMRBRLOJJAA-UHFFFAOYSA-N 0.000 title abstract 4
- 208000001647 Renal Insufficiency Diseases 0.000 claims abstract description 28
- 201000006370 kidney failure Diseases 0.000 claims abstract description 28
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 150000002912 oxalic acid derivatives Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 claims 1
- 208000033626 Renal failure acute Diseases 0.000 claims 1
- 201000011040 acute kidney failure Diseases 0.000 claims 1
- 208000012998 acute renal failure Diseases 0.000 claims 1
- 208000020832 chronic kidney disease Diseases 0.000 claims 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 24
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 229940109239 creatinine Drugs 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 239000008280 blood Substances 0.000 abstract description 6
- 210000004369 blood Anatomy 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 3
- 239000002253 acid Substances 0.000 description 9
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- 210000003734 kidney Anatomy 0.000 description 2
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- 230000003907 kidney function Effects 0.000 description 2
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- MOOKYOAHBSYSJR-UHFFFAOYSA-N 2-hexan-2-yloxy-2-oxoacetic acid Chemical compound CCCCC(C)OC(C(=O)O)=O MOOKYOAHBSYSJR-UHFFFAOYSA-N 0.000 description 1
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
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- 206010060891 General symptom Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
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- 238000011888 autopsy Methods 0.000 description 1
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- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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Abstract
Description
本発明はオキサルル酸誘導体又はその薬学的に許容される塩を有効成分として含有する腎不全用剤に関する。 The present invention relates to an agent for renal failure containing an oxalic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
日本における慢性透析患者数は２１万９千人（平成１３年末）で、年間増加数も約１万３千人に達してさらに増加傾向にあり、腎疾患の予防や早期発見、腎疾患の治療、腎不全の進行抑制、人工透析及び腎移植医療の整備と普及などに力が注がれている。本発明者らは、安全性が高く且つ腎不全用剤として有用な化合物を探求するうち、本発明オキサルル酸誘導体が、腎不全進展抑制作用を有することを見出し本発明を完成した。本発明オキサルル酸誘導体は、血糖低下作用を有することは知られていたが（特許文献１参照）、腎不全進展抑制作用を有することは新しい知見であった。 The number of chronic dialysis patients in Japan is 219,000 (end of 2001), and the annual increase is about 13,000, and it is increasing further. Prevention and early detection of kidney disease, treatment of kidney disease The focus is on controlling the progress of renal failure, and improving and disseminating medical dialysis and kidney transplantation. The present inventors have searched for a compound that is highly safe and useful as an agent for renal failure, and found that the oxalic acid derivative of the present invention has an inhibitory effect on the progress of renal failure, and completed the present invention. The oxalic acid derivative of the present invention was known to have a blood glucose lowering effect (see Patent Document 1), but it was a new finding that it had an effect of suppressing the progression of renal failure.
本発明の目的は、副作用が少なく且つ安全性の高い新規な腎不全用剤を提供することにある。 目的 An object of the present invention is to provide a novel agent for renal insufficiency with few side effects and high safety.
本発明者らはオキサルル酸誘導体について鋭意研究を行った結果、オキサルル酸誘導体が優れた腎不全進展抑制作用を有し、腎不全用剤として有用性が高いものであることを見出し本発明を完成した。 The present inventors have conducted intensive studies on oxalic acid derivatives and found that oxalic acid derivatives have an excellent inhibitory effect on renal failure progression and are highly useful as agents for renal failure, and completed the present invention. did.
腎不全の進展に伴う血中クレアチニン値の増加を本発明化合物は有意に抑制し、またラット単回投与毒性試験においても何等毒性は認められなかった。本発明化合物は優れた腎不全進展抑制作用を示し、且つ副作用が少なく安全性の高い化合物であり、長期投与が望まれる腎不全用剤として非常に有用性が高いものである。 (4) The compound of the present invention significantly suppressed the increase in the blood creatinine level associated with the progression of renal failure, and no toxicity was observed in a single dose toxicity test in rats. The compound of the present invention exhibits excellent inhibitory action on renal insufficiency, has few side effects and is highly safe, and is extremely useful as an agent for renal insufficiency for which long-term administration is desired.
本発明は、下記一般式（Ｉ）で表されるオキサルル酸誘導体又はその薬学的に許容される塩の少なくとも一種を有効成分として含有する腎不全用剤である。
上記一般式（Ｉ）においてＲ1、Ｒ2はそれぞれ同一若しくは異なって水素、アルキル基、好ましくは、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、t-ブチル、n-ペンチル、イソペンチル、neo-ペンチル、t-ペンチル、ヘキシル、ジメチルブチル、ヘプチル、オクチル、ノニル、デシル、ステアリル等の直鎖又は分枝状の炭素数１乃至２０のアルキル基、又はシクロアルキル基、好ましくはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロへプチル、シクロオクチル等の炭素数３乃至８のシクロアルキル基を表すか又はＲ1及びＲ2がこれらを結合する窒素原子と共に複素環、好ましくはアジリジノ、ピロリジノ、ピペリジノ、ピペラジノ、モルフォリノ等を形成する。Ｒ3は水素、アルキル基、好ましくはメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、t-ブチル、n-ペンチル、イソペンチル、ネオペンチル、t-ペンチル、ヘキシル、ジメチルブチル、ヘプチル、オクチル、ノニル、デシル、ステアリル等の直鎖又は分枝状の炭素数１乃至２０のアルキル基を表す。 In the general formula (I), R 1 and R 2 are the same or different and each is hydrogen, an alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, t-pentyl, hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl, stearyl, etc., a linear or branched alkyl group having 1 to 20 carbon atoms, or a cycloalkyl group Preferably represents a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, or a heterocyclic ring together with a nitrogen atom to which R 1 and R 2 bind, preferably Forms aziridino, pyrrolidino, piperidino, piperazino, morpholino and the like. R 3 is hydrogen, an alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, dimethylbutyl , Heptyl, octyl, nonyl, decyl, stearyl and the like, which represent a linear or branched alkyl group having 1 to 20 carbon atoms.
本発明化合物中、好ましい化合物は以下の通りである。
５−メチルオキサルル酸
５−エチルオキサルル酸
５−ｎ−ブチルオキサルル酸
５−イソブチルオキサルル酸
５−ｔ−ブチルオキサルル酸
５−ｎ−ヘキシルオキサルル酸
５−（１、３−ジメチルブチル）オキサルル酸
５−ｎ−デシルオキサルル酸
５−シクロペンチルオキサルル酸
５−シクロヘキシルオキサルル酸
５−メチルオキサルル酸アンモニウム塩
５−エチルオキサルル酸アンモニウム塩
５−メチルオキサルル酸メチルエステル
５−メチルオキサルル酸エチルエステル
５−ｎ−ブチルオキサルル酸メチルエステル
５−イソブチルオキサルル酸エチルエステル
５、５−ジメチルオキサルル酸メチルエステル
５、５−ジメチルオキサルル酸エチルエステル
５−シクロヘキシルオキサルル酸エチルエステル
５−シクロヘプチルオキサルル酸エチルエステル
Ｎ−（１−ピペリジルカルボニル）オキサム酸メチルエステル
Ｎ−（１−ピペリジルカルボニル）オキサム酸エチルエステル
５−メチルオキサルル酸ｎ−ブチルエステル
５−メチルオキサルル酸イソブチルエステル
５−メチルオキサルル酸ｎ−オクチルエステル
５−ｎ−ブチルオキサルル酸ｎ−ブチルエステル
５−シクロヘキシルオキサルル酸イソプロピルエステル
５−シクロヘキシルオキサルル酸ｎ−ブチルエステル
Among the compounds of the present invention, preferred compounds are as follows.
5-methyloxalate 5-ethyloxalate 5-n-butyloxalate 5-isobutyloxalate 5-t-butyloxalate 5-n-hexyloxalate 5- (1,3-dimethyl Butyl) oxalic acid 5-n-decyl oxalic acid 5-cyclopentyl oxalic acid 5-cyclohexyl oxalic acid 5-methyl oxalic acid ammonium salt 5-ethyl oxalic acid ammonium salt 5-methyl oxalic acid methyl ester 5-methyl oxalate Ethyl oleate 5-methyl methyl n-butyl oxalate 5-Ethyl ethyl isobutyl oxalate 5, Methyl 5-dimethyl oxalate 5, 5-Ethyl dimethyl oxalate 5-Ethyl cyclohexyl oxalate Ethyl 5-cycloheptyl oxalate Steroid N- (1-piperidylcarbonyl) oxamate methyl ester N- (1-piperidylcarbonyl) oxamate ethyl ester 5-methyloxalic acid n-butyl ester 5-methyloxalic acid isobutyl ester 5-methyloxalic acid n -Octyl ester 5-n-butyl oxalic acid n-butyl ester 5-cyclohexyl oxalic acid isopropyl ester 5-cyclohexyl oxalic acid n-butyl ester
本発明オキサルル酸誘導体は、前記一般式（Ｉ）で表される化合物の薬学的に許容される塩を包含し、例えば、ナトリウム、カリウム等のアルカリ金属、カルシウム、マグネシウム、バリウム等のアルカリ土類金属又はアルミニウム、亜鉛等との金属及びアンモニウムとの塩などが挙げられる。又、有機アミンや酸との塩であってもよい。これらの塩は公知の方法により遊離の本発明オキサルル酸誘導体より製造でき、或いは相互に変換することができる。 The oxalic acid derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the general formula (I), for example, an alkali metal such as sodium and potassium, and an alkaline earth such as calcium, magnesium and barium. Metals or salts with aluminum, zinc and the like, and salts with ammonium and the like can be mentioned. Further, a salt with an organic amine or an acid may be used. These salts can be produced from the free oxalic acid derivative of the present invention by known methods, or can be mutually converted.
また本発明化合物においてシス−トランス体、光学異性体、配座異性体等の立体異性体が存在する場合、或いは水和物や錯化合物の状態で存在する場合においても、本発明はそのいずれの立体異性体、水和物、錯化合物をも包含する。上記の本発明オキサルル酸誘導体及びその製造方法は特公平６−６０１５２号公報に開示されている。 Further, in the case where the compound of the present invention has a stereoisomer such as a cis-trans form, an optical isomer, a conformer, or a hydrate or a complex compound, the present invention relates to any of these. Stereoisomers, hydrates and complex compounds are also included. The above-mentioned oxalic acid derivative of the present invention and a method for producing the same are disclosed in JP-B-6-60152.
本発明化合物は、適当な医薬用の担体若しくは希釈剤と適宜組み合わせて医薬とすることができ、通常の如何なる方法によっても製剤化可能であり、錠剤、カプセル剤、粉末剤、液剤等の経口剤として、又は皮下、静脈内、筋肉内、直腸内、鼻腔内投与用の非経口剤として製剤化できる。処方にあたっては、本発明化合物をその薬学的に許容される塩の形で用いてもよく、本発明化合物を単独で若しくは適宜組み合わせて用いることができ、又、他の医薬活性成分との配合剤としてもよい。 The compound of the present invention can be used as a medicament by appropriately combining it with a suitable pharmaceutical carrier or diluent, and can be formulated by any usual method, and can be formulated into tablets, capsules, powders, liquids and other oral preparations. Or as a parenteral formulation for subcutaneous, intravenous, intramuscular, rectal, intranasal administration. In formulating, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, or a combination with other pharmaceutically active ingredients. It may be.
経口投与製剤には、そのまま或いは適当な添加剤、例えば乳糖、マンニット、トウモロコシデンプン、バレイショデンプン、クエン酸カルシウム等の慣用の賦形剤と共に、結晶セルロース、ヒドロキシプロピルセルロース等のセルロース誘導体、アラビアゴム、トウモロコシデンプン、ゼラチン等の結合剤、トウモロコシデンプン、バレイショデンプン、カルボキシメチルセルロースカルシウム等の崩壊剤、タルク、ステアリン酸マグネシウム等の滑沢剤、その他増量剤、湿潤化剤、緩衝剤、保存剤、香料等を適宜組み合わせて錠剤、散剤、顆粒剤或いはカプセル剤とすることができる。 For oral administration preparations, cellulose derivatives such as crystalline cellulose, hydroxypropylcellulose, gum arabic, as they are or with appropriate additives such as lactose, mannitol, corn starch, potato starch, calcium citrate, etc. , Binders such as corn starch, gelatin, disintegrants such as corn starch, potato starch, carboxymethylcellulose calcium, lubricants such as talc, magnesium stearate, other bulking agents, wetting agents, buffering agents, preservatives, fragrances Tablets, powders, granules or capsules can be prepared by appropriately combining the above.
また注射剤としては、注射用蒸留水、生理食塩水、ブドウ糖注射液等の水性溶剤、又は植物油、合成脂肪酸グリセリド、高級脂肪酸エステル、プロピレングリコール等の非水性溶剤の溶液、懸濁液若しくは乳化液とすることができ、必要に応じ溶解補助剤、等張化剤、懸濁化剤、乳化剤、安定剤、保存剤等の通常用いられる添加剤を適宜加えてもよい。 Examples of the injection include aqueous solvents such as distilled water for injection, physiological saline, and glucose injection, and non-aqueous solvents such as vegetable oils, synthetic fatty acid glycerides, higher fatty acid esters, and propylene glycol. If necessary, commonly used additives such as a solubilizing agent, a tonicity agent, a suspending agent, an emulsifier, a stabilizer, and a preservative may be appropriately added.
さらに疾患の種類や患者に応じて、その治療に最適な上記以外の剤型、例えば坐剤、吸入剤、エアゾール剤、シロップ剤、点眼剤、軟膏等の外用剤等に製剤化することができる。 Furthermore, depending on the type of the disease and the patient, it can be formulated into a dosage form other than the above, which is optimal for the treatment, for example, an external preparation such as a suppository, an inhalant, an aerosol, a syrup, an eye drop, an ointment or the like. .
本発明化合物の望ましい投与量は、投与対象、剤形、投与方法、投与期間等によって変わるが、所望の効果を得るには、一般に成人に対して有効成分量で一日に５０乃至５０００ｍｇ、好ましくは１００乃至３０００ｍｇ経口投与することができる。非経口投与（例えば注射剤）の場合は一般的に経口投与より少量で効果が期待できるため、例えば前記の経口投与量の３乃至１０分の１の用量レベルで十分と考えられる。 The desirable dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period and the like, but in order to obtain the desired effect, generally 50 to 5000 mg of an active ingredient per day for an adult is preferably used. Can be administered orally at 100 to 3000 mg. In the case of parenteral administration (for example, injection), the effect can be generally expected to be smaller than that of oral administration, so that, for example, a dose level of 3 to 1/10 of the above oral dose is considered to be sufficient.
前記一般式（Ｉ）で表される化合物を有効成分として含有する本発明腎不全用剤の好ましい実施態様を以下に挙げる。
（１）前記一般式（Ｉ）のＲ3が水素である化合物を有効成分として含有する腎不全用剤。
（２）上記（１）記載の化合物のうち、Ｒ2が水素である化合物を有効成分として含有する腎不全用剤。
（３）上記（２）記載の化合物のうち、Ｒ1がアルキル基である化合物を有効成分として含有する腎不全用剤。
（４）上記（３）記載の化合物のうち、Ｒ1がメチル基である化合物を有効成分として含有する腎不全用剤。
（５）５−メチルオキサルル酸又はその薬学的に許容される塩を有効成分として含有する腎不全用剤。
（６）５−メチルオキサルル酸又はその薬学的に許容される塩を有効成分として含有する腎不全進展抑制剤。
Preferred embodiments of the agent for renal failure of the present invention containing the compound represented by the general formula (I) as an active ingredient are described below.
(1) An agent for renal insufficiency comprising, as an active ingredient, a compound of the formula (I) wherein R 3 is hydrogen.
(2) An agent for renal insufficiency which comprises, as an active ingredient, a compound in which R 2 is hydrogen among the compounds described in the above (1).
(3) An agent for renal insufficiency comprising, as an active ingredient, a compound according to the above (2), wherein R 1 is an alkyl group.
(4) An agent for renal insufficiency comprising, as an active ingredient, a compound according to the above (3), wherein R 1 is a methyl group.
(5) An agent for renal failure comprising 5-methyloxalic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
(6) An agent for inhibiting progression of renal failure, comprising 5-methyloxalic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
実施例１．腎不全進展抑制作用
８週齢のウイスター系雄性ラットにアデニンを経口投与して腎不全モデル動物を作製した（腎と透析、１９９１年、臨時増刊号、４４０〜４４５頁及びNephron、４４巻、１９８６年、２３０〜２３４頁等を参照）。アデニン（２００ｍｇ／ｋｇ）を連日投与することによって、腎機能の指標となる血中クレアチニン値は徐々に上昇し、投与前の０．４４±０．０２ｍｇ／ｄＬから約３週間後には４．１２±０．５３ｍｇ／ｄＬに上昇した。また、クレアチニン・クリアランス（ｍＬ／ｋｇ／ｈｒ）の値は、３１５．３±１３．８から２５．７±４．４に低下し、腎機能は１０分の１程度に低下した。
このアデニン誘発腎不全ラットに、アデニン投与７日目から１７日間本発明化合物の５−メチルオキサルル酸１８．８ｍｇ／ｋｇ及び３７．５ｍｇ／ｋｇを連日経口投与した。被験薬投与前と投与後の血中クレアチニン値を比較し、腎不全進展に伴うクレアチニン増加（ΔＣｒ）に対する被験薬の抑制作用を調べた結果を図１に示す。試験は一群５匹のラットを用いて行い、平均値±標準誤差を求め、Dunnettの検定法によって発症対照群（Control）との有意差検定を行った（*; p<0.05）。
実施例２．単回投与毒性試験
The adenine-induced renal failure rats were orally administered daily with 18.8 mg / kg and 37.5 mg / kg of the compound of the present invention, 5-methyloxalic acid, for 17 days from the 7th day of adenine administration. FIG. 1 shows the results of comparing the blood creatinine level before and after administration of the test drug and examining the inhibitory effect of the test drug on creatinine increase (ΔCr) associated with the progression of renal failure. The test was performed using 5 rats per group, the mean value ± standard error was determined, and a significant difference test with the onset control group (Control) was performed by Dunnett's test method (*; p <0.05).
Embodiment 2. FIG. Single dose toxicity test
ＳＤ系ラット（６週齢、雄性・雌性各５匹）に７５乃至６００ｍｇ／ｋｇの５−メチルオキサルル酸を静脈内投与した。その結果、６００ｍｇ／ｋｇの投与量であっても、一般症状、体重、剖検所見に全く異常が認められず、勿論死亡例は全く無かった。 75-600 mg / kg of 5-methyloxalic acid was intravenously administered to SD rats (6 weeks old, 5 males and 5 females). As a result, even at a dose of 600 mg / kg, no abnormality was observed in general symptoms, body weight, and autopsy findings, and of course, no deaths occurred.
上記薬理試験の結果から明らかなように、本発明化合物は優れた腎不全進展抑制作用を示し、且つ副作用が少なく安全性の高い化合物であり、長期投与が望まれる腎不全用剤として非常に有用性が高いものである。 As is clear from the results of the above pharmacological tests, the compound of the present invention exhibits an excellent inhibitory effect on the progression of renal failure, and is a compound with low side effects and high safety, and is very useful as a renal failure agent for which long-term administration is desired. It is highly likely.
Claims (5)
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