JP2008179574A - Advanced glycation end product formation inhibitor with piperazine derivative as active ingredient - Google Patents

Advanced glycation end product formation inhibitor with piperazine derivative as active ingredient Download PDF

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JP2008179574A
JP2008179574A JP2007015423A JP2007015423A JP2008179574A JP 2008179574 A JP2008179574 A JP 2008179574A JP 2007015423 A JP2007015423 A JP 2007015423A JP 2007015423 A JP2007015423 A JP 2007015423A JP 2008179574 A JP2008179574 A JP 2008179574A
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age
formation inhibitor
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Takashi Nakagawa
隆 中川
Ryohei Sekimoto
亮平 堰本
Kazuhiro Onoki
和弘 小野木
Toshio Miyata
敏男 宮田
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Kowa Co Ltd
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a new AGE (advanced glycation end products) formation inhibitor having high AGE production inhibitory activity and useful as a prophylactic and/or curative agent for glomerular diseases, particularly as a pharmaceutical for preventing and/or treating diabetic nephropathy. <P>SOLUTION: The new AGE formation inhibitor comprises, as active ingredient, a compound represented by general formula (1) (wherein, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each H or a 1-6C alkoxy; and R<SP>5</SP>is H or a 1-6C alkyl), an acid addition salt thereof or a solvate thereof. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は糸球体病変における不可逆的蛋白修飾による糖尿病性腎症の発症又は進展に対する予防及び/又は治療に有用な薬剤に関する。   The present invention relates to a drug useful for the prevention and / or treatment of the onset or progression of diabetic nephropathy due to irreversible protein modification in glomerular lesions.

現在、本邦では糖尿病患者、糖尿病が疑われる患者及び糖尿病予備群が約2千万人存在するといわれている。糖尿病を起因とした合併症のうち、糖尿病性腎症の発症率は年々増加の推移をたどり、すでに慢性糸球体腎炎の発症率を上回り第一位となっている。   At present, it is said that there are about 20 million diabetic patients, suspected diabetic patients and pre-diabetes group in Japan. Among complications caused by diabetes, the incidence of diabetic nephropathy has been increasing year by year, already exceeding the incidence of chronic glomerulonephritis.

糖尿病性腎症が発症した場合における最大の問題点は、末期腎不全即ち透析への移行率が、非常に高いことにある。また、糖尿病性腎症による透析への移行は医療費高騰等の社会的に大きな問題となっている。そこで、糖尿病性腎症に関わる治療剤、又は予防を期待できる薬剤が強く望まれている。   The biggest problem when diabetic nephropathy develops is that the rate of transition to end-stage renal failure, that is, dialysis, is very high. Moreover, the shift to dialysis due to diabetic nephropathy has become a serious social problem such as a rise in medical costs. Therefore, a therapeutic agent related to diabetic nephropathy or a drug that can be expected to be prevented is strongly desired.

糖尿病性腎症の成因には、(1)遺伝的素因をはじめとして、(2)糸球体血行動態変化、(3)グリケーションの亢進やカルボニル・酸化ストレスにより生じた糖化最終産物(Advanced Glycation End Products(以下、「AGE」と称する))の蓄積、(4)Protein Kinase Cの活性化や、(5)ポリオール代謝の亢進など、様々な因子の関与が考えられている(非特許文献1、非特許文献2、非特許文献3、非特許文献4、非特許文献5)。   The pathogenesis of diabetic nephropathy includes (1) genetic predisposition, (2) changes in glomerular hemodynamics, (3) advanced glycation end product (advanced glycation end product caused by increased glycation and carbonyl / oxidative stress) The involvement of various factors such as accumulation of Products (hereinafter referred to as “AGE”), (4) activation of Protein Kinase C, and (5) enhancement of polyol metabolism are considered (Non-patent Document 1, Non-patent document 2, Non-patent document 3, Non-patent document 4, Non-patent document 5).

現在、糖尿病性腎症の治療現場では、糸球体血行動態の改善を主目的としたアンジオテンシン変換酵素阻害剤(以下、「ACE阻害剤」と称する)やアンジオテンシンIIの1型受容体拮抗剤(以下、「ARB」と称する)が汎用されており、基礎のみならず臨床的なevidenceが報告されている(非特許文献6、非特許文献7)。しかしながら、これらの多くは血圧降下剤として認可されており、糖尿病性腎症の治療剤としての認可はほとんどなされていない。単に、糖尿病性腎症の患者の多くは高血圧であることから、これらが汎用されているに過ぎない。なお、ACE阻害剤のタナトリル錠(塩酸イミダプリル)はI型糖尿病性腎症の治療剤として初めて認可されたものの、糖尿病性腎症に対する治療又は予防的作用を有する薬剤はほとんどなく、新規な薬剤の登場が切望されている。   Currently, in the treatment of diabetic nephropathy, angiotensin converting enzyme inhibitors (hereinafter referred to as “ACE inhibitors”) and angiotensin II type 1 receptor antagonists (hereinafter referred to as “ACE inhibitors”), which are mainly aimed at improving glomerular hemodynamics. , Referred to as “ARB”), and clinical evidence as well as basics have been reported (Non-Patent Document 6, Non-Patent Document 7). However, many of these have been approved as antihypertensive agents, and are hardly approved as therapeutic agents for diabetic nephropathy. Simply because many of the patients with diabetic nephropathy have high blood pressure, they are only widely used. Although the ACE inhibitor tanatril tablet (imidapril hydrochloride) was approved for the first time as a therapeutic agent for type I diabetic nephropathy, there are few drugs that have a therapeutic or prophylactic effect on diabetic nephropathy. Appearance is anxious.

そこで次の糖尿病性腎症の治療剤として、AGE形成阻害剤が注目を浴びている。AGEで修飾されたタンパクは腎循環動態、腎糸球体基底膜の濾過機構等、多数の腎機能に悪影響を及ぼし、また、AGE自身がメサンギウム細胞等の腎構成細胞に多数存在するAGE関連受容体(例えば、Receptor for AGE:RAGE)に作用して、サイトカインや増殖因子等の障害因子を産生させることが報告されている(非特許文献8)。従って、AGEの形成を抑制することは、糖尿病性腎症の進展抑制に繋がると考えられる。   Therefore, AGE formation inhibitors are attracting attention as therapeutic agents for the next diabetic nephropathy. AGE-modified proteins adversely affect many renal functions such as renal circulatory dynamics and the filtration mechanism of the glomerular basement membrane, and AGE-related receptors are present in many constitutive cells such as mesangial cells. (For example, receptor for AGE: RAGE) has been reported to produce disorder factors such as cytokines and growth factors (Non-patent Document 8). Therefore, suppressing the formation of AGE is thought to lead to the suppression of the progression of diabetic nephropathy.

アミノグアニジンは、反応性カルボニル化合物(3−デオキシグルコソン、メチルグリオキサールなど)の捕捉作用、酸素ラジカル(特に、ヒドロキシラジカル)の捕捉作用及び金属キレート形成作用により、AGEの形成を阻害すると考えられており、AGE阻害に基づく糖尿病性腎症の治療剤として、最初に本格的な研究がなされた化合物である。しかし、これはすでに臨床治験も終了したが、いまだ実用化には至っていない。(非特許文献9、非特許文献10、非特許文献11)。   Aminoguanidine is thought to inhibit the formation of AGEs by scavenging action of reactive carbonyl compounds (3-deoxyglucosone, methylglyoxal, etc.), scavenging action of oxygen radicals (particularly hydroxy radicals) and metal chelate forming action. It is a compound that was first fully studied as a therapeutic agent for diabetic nephropathy based on AGE inhibition. However, this clinical trial has already ended, but it has not yet been put into practical use. (Non-patent document 9, Non-patent document 10, Non-patent document 11).

また、その他のAGE形成阻害剤としてはアミノグアニジンの誘導体であるOPB−9195、LR−90、ALT−946、天然化合物及びその類縁体であるチアミン(ビタミンB)、チアミンピロリン酸、ベンフォチアミンなど幾つかの化合物が知られている(非特許文献12)が、いずれも実用化には至っていない。 Other AGE formation inhibitors include aminoguanidine derivatives OPB-9195, LR-90, ALT-946, natural compounds and their analogs thiamine (vitamin B 1 ), thiamine pyrophosphate, benfotiamine. Although some compounds are known (Non-patent Document 12), none of them have been put into practical use.

Cooper,ME.et al.;Lancet,352,213−219,1998.Cooper, ME. Et al. Lancet, 352, 213-219, 1998. 槙野博史;糖尿病性腎症 発症・進展機序と治療:80−121,1999年;診断と治療社Hirono Kanno; Diabetic nephropathy Onset and progression mechanism and treatment: 80-121, 1999; Diagnosis and treatment company Bohlender, J.et al.;Am. J. Physiol. Renal Physiol.,289,F645−F659,2005Bohlender, J. et al. Am. J. et al. Physiol. Renal Physiol. , 289, F645-F659, 2005 D, Jay.et al.;Free Radical Biology & Medicine,40,183−192,2006D, Jay. Et al. Free Radical Biology & Medicine, 40, 183-192, 2006; Vinik, A.;Expert Opin. Investig. Drugs,14(12),1547−1559,2005Vinik, A.A. Expert Opin. Investig. Drugs, 14 (12), 1547-1559, 2005. Masakuni,N.et al.;Jpn. J. Pharmacol.,85:416−422,2001Masakuni, N. et al. Jpn. J. et al. Pharmacol. 85: 416-422, 2001. Rossing, K.et al.;Diabetes Care.,28(9):2106−2112,2005Rossing, K.M. et al. Diabetes Care. 28 (9): 2106-21212, 2005. Locatelli, F.et al.;Nephrol.Dial.Transplant.,18(9):1716−25,2003Locelli, F. et al. Nephrol. Dial. Transplant. , 18 (9): 1716-25, 2003. Price,DL.et al.;J. Biol. Chem.,276,48967−48972,2001Price, DL. et al. J .; Biol. Chem. , 276, 48967-48972, 2001 Abdel−Rahman, E.et al.;Expert Opin. Investig. Drugs.,11(4):565−574、2002Abdel-Rahman, E. et al. Expert Opin. Investig. Drugs. 11 (4): 565-574, 2002. Mark E.et al.;Current Diabetes Reports.,4:441−446,2004Mark E. et al. Current Diabetes Reports. 4: 441-446, 2004 今泉勉 ほか;AGEs研究の最前線:209−217,2004年;メディカルレビュー社Tsutomu Imaizumi et al .; AGEs research front: 209-217, 2004; Medical Review

本発明は、新規なAGE形成阻害剤を提供することにある。AGE形成阻害剤は糸球体病変における不可逆的蛋白修飾による糖尿病性腎症の発症及び進展に対する予防又は治療に有用である。また、原疾患が糖尿病性腎症と診断されていない患者であっても、慢性糸球体腎炎や高血圧性腎症などの糸球体疾患により透析移行している患者の多くは血漿中のAGEが著しく増加しているという周知の事実から、AGE形成阻害剤は糖尿病性腎症のみならず、慢性糸球体腎炎や高血圧性腎症なども含めた糸球体疾患に対する予防又は治療に有用である。   The present invention is to provide a novel AGE formation inhibitor. AGE formation inhibitors are useful for the prevention or treatment of the onset and progression of diabetic nephropathy due to irreversible protein modification in glomerular lesions. Even in patients whose primary disease has not been diagnosed with diabetic nephropathy, many patients who have undergone dialysis due to glomerular diseases such as chronic glomerulonephritis and hypertensive nephropathy have markedly increased plasma AGE. Due to the well-known fact that it has increased, AGE formation inhibitors are useful not only for diabetic nephropathy but also for the prevention or treatment of glomerular diseases including chronic glomerulonephritis and hypertensive nephropathy.

上記実情に鑑み、本発明者らは、AGE形成阻害作用を持つ化合物を探索した結果、下記一般式(1)で表される化合物が、AGEの一種であるペントシジンを指標にしたin vitro系での阻害試験において、アミノグアニジンと比較して、強いAGE形成阻害作用を有することを見出し、本発明を完成するに至った。   In view of the above situation, as a result of searching for a compound having an AGE formation inhibitory activity, the present inventors have found that a compound represented by the following general formula (1) is an in vitro system using pentosidine, which is a kind of AGE as an index. In the inhibition test, it was found that it has a stronger AGE formation inhibitory action than aminoguanidine, and the present invention has been completed.

すなわち、本発明は次の一般式(1):   That is, the present invention provides the following general formula (1):

Figure 2008179574
Figure 2008179574

(式中、R、R、R及びRは同一又は異なって水素原子又はC1−6アルコキシ基を示し、Rは水素原子又はC1−6アルキル基を示す)で表される化合物、その酸付加塩又はそれらの溶媒和物を有効成分とするAGE形成阻害剤を提供するものである。 (Wherein R 1 , R 2 , R 3 and R 4 are the same or different and represent a hydrogen atom or a C 1-6 alkoxy group, and R 5 represents a hydrogen atom or a C 1-6 alkyl group). An AGE formation inhibitor comprising a compound, an acid addition salt thereof or a solvate thereof as an active ingredient.

また、本発明は、式(1)で表される化合物、その酸付加塩又はそれらの溶媒和物が2’−(1H−2−イミダゾリル)−5’−メトキシ−2−[4−(2,3,4−トリメトキシベンジル)ピペラジニル]アセトアニリド、その酸付加塩又はそれらの溶媒和物である上記記載のAGE形成阻害剤を提供するものである。   In the present invention, the compound represented by the formula (1), an acid addition salt thereof, or a solvate thereof is 2 ′-(1H-2-imidazolyl) -5′-methoxy-2- [4- (2 , 3,4-trimethoxybenzyl) piperazinyl] acetanilide, an acid addition salt thereof, or a solvate thereof, the above-mentioned AGE formation inhibitor is provided.

また、本発明は、一般式(1)で表されるAGE形成阻害剤を有効成分とする糸球体疾患の予防及び/又は治療剤を提供するものである。   In addition, the present invention provides a preventive and / or therapeutic agent for glomerular disease comprising an AGE formation inhibitor represented by the general formula (1) as an active ingredient.

さらに、本発明は、一般式(1)で表されるAGE形成阻害剤を有効成分とする糖尿病性腎症の予防及び/又は治療剤を提供するものである。   Furthermore, this invention provides the preventive and / or therapeutic agent of diabetic nephropathy which uses the AGE formation inhibitor represented by General formula (1) as an active ingredient.

後記実施例に記載するとおり、血液透析患者の血漿を用い、アミノグアニジン又は被検薬物を添加した評価において、被検薬物は、アミノグアニジンに比べ、優れたAGE形成阻害活性を示した。即ち、血液透析患者の血漿を用い、37℃、7日間、アミノグアニジン又は被検薬物を添加した系において認められた主要なAGEの一種であるペントシジンの抑制に対して、被検薬物の添加が、アミノグアニジン添加に比べ、強いペントシジン生成抑制作用を示した。
このように、本発明の一般式(1)で表される化合物、その酸付加塩又はそれらの溶媒和物は、優れたAGE形成阻害作用を有し、糸球体疾患の予防及び/又は治療剤、特に糖尿病性腎症の予防及び/又は治療剤として有用である。
As described in Examples below, the test drug showed superior AGE formation inhibitory activity as compared with aminoguanidine in the evaluation of aminoguanidine or test drug added using plasma of a hemodialysis patient. That is, for the suppression of pentosidine, which is one of the main AGEs observed in a system in which aminoguanidine or a test drug is added at 37 ° C. for 7 days using plasma of a hemodialysis patient, the addition of the test drug is Compared with the addition of aminoguanidine, it showed a stronger inhibitory effect on the formation of pentosidine.
As described above, the compound represented by the general formula (1) of the present invention, its acid addition salt, or a solvate thereof has an excellent AGE formation inhibitory action and is a prophylactic and / or therapeutic agent for glomerular diseases. In particular, it is useful as a preventive and / or therapeutic agent for diabetic nephropathy.

一般式(1):   General formula (1):

Figure 2008179574
Figure 2008179574

(式中、R、R、R及びRは同一又は異なって水素原子又はC1−6アルコキシ基を示し、Rは水素原子又はC1−6アルキル基を表す。)で表される化合物の置換基について以下に説明する。
式中、R、R、R及びRで示されるC1−6アルコキシ基としては直鎖、分岐鎖又は環状のC〜Cアルコキシ基が挙げられる。直鎖又は分岐鎖のC〜Cアルコキシ基としては、メトキシ基、エトキシ基、n−プロポキシ基、イソプロポキシ基、n−ブトキシ基、イソブトキシ基、sec−ブトキシ基、tert−ブトキシ基、n−ペンチルオキシ基、n−ヘキシルオキシ基等が挙げられる。また、環状のC〜Cアルコキシ基としては、シクロプロポキシ基、シクロブトキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基、シクロプロピルメトキシ基、シクロペンチルメトキシ基等が挙げられる。R、R、R及びRで示されるC1−6アルコキシ基としては直鎖のC〜Cアルコキシ基が好ましく、メトキシ基が特に好ましい。
、R及びRの置換位置は2,3,4,5,6位のいずれでもよいが、特に2,3,4位が好ましい。また、Rの置換位置は2,3,4,5,6位のいずれでもよいが、特に5位が好ましい。
一般式(1)中、Rで示されるC1−6アルキル基としては直鎖、分岐鎖又は環状のC〜Cアルキル基が挙げられる。直鎖又は分岐鎖のC〜Cアルキル基としては、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、n−ペンチル基、n−ヘキシル基等が挙げられる。環状のC〜Cアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロプロピルメチル基、シクロペンチルメチル基等が挙げられる。
一般式(1)中、イミダゾールの置換位置は2,3,4,5,6位のいずれでもよいが、特に2位が好ましい。
(Wherein R 1 , R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom or a C 1-6 alkoxy group, and R 5 represents a hydrogen atom or a C 1-6 alkyl group). The substituents of the compound to be prepared will be described below.
In the formula, examples of the C 1-6 alkoxy group represented by R 1 , R 2 , R 3 and R 4 include linear, branched or cyclic C 1 to C 6 alkoxy groups. The C 1 -C 6 alkoxy group linear or branched, methoxy group, ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, sec- butoxy group, tert- butoxy radical, n -A pentyloxy group, n-hexyloxy group, etc. are mentioned. Examples of the cyclic C 1 -C 6 alkoxy group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cyclopropylmethoxy group, and a cyclopentylmethoxy group. The C 1-6 alkoxy group represented by R 1 , R 2 , R 3 and R 4 is preferably a linear C 1 -C 6 alkoxy group, particularly preferably a methoxy group.
The substitution positions of R 1 , R 2 and R 3 may be any of the 2, 3, 4, 5 and 6 positions, but the 2, 3, 4 positions are particularly preferred. The substitution position of R 4 may be any of the 2, 3, 4 , 5, and 6 positions, but the 5 position is particularly preferable.
In the general formula (1), the C 1-6 alkyl group represented by R 5 includes a linear, branched or cyclic C 1 -C 6 alkyl group. Examples of the linear or branched C 1 -C 6 alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n- A pentyl group, n-hexyl group, etc. are mentioned. Examples of the cyclic C 1 -C 6 alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, and a cyclopentylmethyl group.
In the general formula (1), the substitution position of imidazole may be any of the 2, 3, 4, 5, and 6 positions, but the 2 position is particularly preferable.

本発明の具体的な化合物として、2’−(1H−2−イミダゾリル)−5’−メトキシ−2−[4−(2,3,4−トリメトキシベンジル)ピペラジニル]アセトアニリド、その酸付加塩又はそれらの溶媒和物を挙げることができる。   Specific compounds of the present invention include 2 ′-(1H-2-imidazolyl) -5′-methoxy-2- [4- (2,3,4-trimethoxybenzyl) piperazinyl] acetanilide, its acid addition salt or Those solvates can be mentioned.

一般式(1)で表される化合物の酸付加塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、リン酸塩のような鉱酸の酸付加塩;安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、p−トルエンスルホン酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、酢酸塩等の有機酸の酸付加塩が挙げられ、薬学上許容される塩であれば特に制限されない。   Examples of the acid addition salt of the compound represented by the general formula (1) include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; Organics such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, citrate, acetate, etc. Examples include acid addition salts of acids, and any salt that is pharmaceutically acceptable.

一般式(1)で表される化合物の溶媒和物としては、水和物等が挙げられる。   Examples of the solvate of the compound represented by the general formula (1) include hydrates.

一般式(1)で表される化合物に光学異性体が存在する場合は、すべての異性体単独のみならずそれらの混合物も本発明の範囲に含まれる。   When optical isomers exist in the compound represented by the general formula (1), not only all isomers alone but also mixtures thereof are included in the scope of the present invention.

本発明の一般式(1)で表される化合物は、文献(特開平3−141258号公報)に開示の方法あるいは類似の方法により製造することが出来る。すなわち、N−ベンジルピペラジン誘導体(2)をブロム酢酸エステル誘導体と反応し、化合物(3)を得る。化合物(3)は、加水分解してカルボン酸とした後、アンモニウム塩(4)とし、その後、アニリン誘導体(5)と縮合反応を行うことにより、一般式(1)で表される化合物を製造することができる。   The compound represented by the general formula (1) of the present invention can be produced by a method disclosed in the literature (Japanese Patent Laid-Open No. 3-141258) or a similar method. That is, the N-benzylpiperazine derivative (2) is reacted with a bromoacetate derivative to obtain a compound (3). The compound (3) is hydrolyzed to give a carboxylic acid, then converted to an ammonium salt (4), and then subjected to a condensation reaction with the aniline derivative (5) to produce a compound represented by the general formula (1). can do.

Figure 2008179574
Figure 2008179574

本発明の一般式(1)で表される化合物は、上記方法によって得られるが、さらに必要に応じて再結晶法、カラムクロマトグラフィー等の通常の精製手段を用いて精製することができる。また必要に応じて、常法によって前記した所望の酸付加塩又は溶媒和物にすることもできる。   The compound represented by the general formula (1) of the present invention can be obtained by the above-described method, and can be further purified by a usual purification means such as a recrystallization method or column chromatography, if necessary. If necessary, the desired acid addition salt or solvate described above can be obtained by a conventional method.

本発明の医薬組成物は、一般式(1)で表される化合物、若しくはその酸付加塩又はそれらの溶媒和物を含有するものであって、単独で用いてよいが、通常は薬学的に許容される担体、添加物等を配合して使用される。医薬組成物の投与形態は、特に限定されず、治療目的に応じて適宜選択できる。斯かる剤形としては、例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤等を挙げることができる。   The pharmaceutical composition of the present invention contains a compound represented by the general formula (1), or an acid addition salt thereof or a solvate thereof, and may be used alone, but usually pharmaceutically. Used in combination with acceptable carriers, additives and the like. The administration form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose of treatment. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections and the like.

これらの製剤は、その剤形に応じて製剤学上使用される賦形剤、崩壊剤、結合剤、滑沢剤、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤等の医薬品添加物と適宜混合、希釈又は溶解し、常法に従い製造することができる。   These preparations include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers used in pharmacology depending on the dosage form. It can be mixed with a pharmaceutical additive such as a dispersant, a stabilizer, a solubilizing agent, etc., appropriately mixed, diluted or dissolved, and manufactured according to a conventional method.

例えば、散剤の場合は、必須成分のほかに、必要に応じて適当な賦形剤、滑沢剤等を加えよく混和して調製すればよい。錠剤の場合は、必要に応じて適当な賦形剤、崩壊剤、結合剤、滑沢剤等を加え、常法に従い打錠して調製すればよい。また錠剤は必要に応じてコーティングを施し、フィルムコート錠、糖衣錠等にすることができる。   For example, in the case of powders, in addition to the essential components, an appropriate excipient, lubricant and the like may be added and mixed as necessary. In the case of a tablet, it may be prepared by adding an appropriate excipient, disintegrant, binder, lubricant, etc. as necessary, and tableting according to a conventional method. Tablets can be coated as necessary to form film-coated tablets, sugar-coated tablets, and the like.

また、注射剤の場合は、液剤(無菌水又は非水溶液)、乳剤及び懸濁剤の形態とすることができる。これらに用いられる非水担体、希釈剤、溶媒又はビヒクルとしては、例えばプロピレングリコール、ポリエチレングリコール、オリーブ油等の植物油、オレイン酸エチル等の注射可能な有機酸エステルが挙げられる。また、該組成物には防腐剤、湿潤剤、乳化剤、分散剤等の補助剤を適宜配合することができる。   In the case of an injection, it can be in the form of a solution (sterile water or non-aqueous solution), an emulsion and a suspension. Examples of the non-aqueous carrier, diluent, solvent, or vehicle used for these include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate. In addition, auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents can be appropriately blended in the composition.

本発明の一般式(1)で表される化合物の投与量は年齢、体重、症状、投与形態及び投与回数等によって異なるが、通常は成人に対して1日1〜1000mgを、1回又は数回に分けて経口投与又は非経口投与するのが好ましい。   The dose of the compound represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc., but usually 1 to 1000 mg per day is given once or several times per adult. It is preferable to administer orally or parenterally in divided doses.

以下、実施例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。   EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

実施例1
血液透析患者の血漿を用いてのAGE形成阻害作用
血液透析患者の血漿中AGE(指標:ペントシジン)濃度の測定はMiyataらの報告に従って実施した(Miyata,T.et al:J Am Soc Nephrol,13,2478−2487,2002)。血液透析患者の血漿0.9mLをアミノグアニジン又は被検薬物(特開平3−141258号公報の製造例1記載の方法に従い製造した2’−(1H−2−イミダゾリル)−5’−メトキシ−2−[4−(2,3,4−トリメトキシベンジル)ピペラジニル]アセトアニリド・3塩酸塩・1水和物)の存在下(添加量は0.1mL)で、37℃で7日間反応した。アミノグアニジン及び被検薬物の最終濃度は5.0mMとした。なお、アミノグアニジン又は被検薬物はジメチルスルフォキシド(DMSO)に溶解して使用した。DMSOの最終濃度は反応溶液1mL中、反応時における酸化反応に影響しない10%とした。7日間の反応後に、アミノグアニジン又は被検薬物を添加した血漿中のペントシジンの濃度を以下に示す方法で測定した。
Example 1
AGE formation inhibitory action using plasma of hemodialysis patients Plasma AGE (indicator: pentosidine) concentration in hemodialysis patients was measured according to the report of Miyata et al. (Miyata, T. et al: J Am Soc Nephrol, 13 2478-2487, 2002). 0.9 mL of plasma of hemodialysis patient was treated with aminoguanidine or a test drug (2 ′-(1H-2-imidazolyl) -5′-methoxy-2 produced according to the method described in Production Example 1 of JP-A-3-141258) -The reaction was carried out at 37 ° C for 7 days in the presence of [4- (2,3,4-trimethoxybenzyl) piperazinyl] acetanilide, trihydrochloride, monohydrate) (addition amount was 0.1 mL). The final concentration of aminoguanidine and test drug was 5.0 mM. Aminoguanidine or a test drug was dissolved in dimethyl sulfoxide (DMSO) and used. The final concentration of DMSO was 10% in 1 mL of the reaction solution, which did not affect the oxidation reaction during the reaction. After the reaction for 7 days, the concentration of pentosidine in plasma to which aminoguanidine or a test drug was added was measured by the method shown below.

反応溶液0.05mLに等量の10%トリクロロ酢酸(以下、「TCA」と称する)を加え、5000×g、5分間遠心した。上清を除去し、沈殿物を5%TCA0.3mLで洗い、その後凍結乾燥により乾燥させた。次いで、窒素条件下で6N塩酸0.1mLを添加し、110℃、16時間反応させ、乾燥物を加水分解した。引き続き、5N水酸化ナトリウム0.1mLと0.5Mリン酸緩衝液(pH7.4)0.2mLを添加し中和した。中和溶液は、口径0.5μmのフイルターを通し、リン酸緩衝液で希釈し、ペントシジン測定用サンプルを調製した。ペントシジン濃度の測定はMiyataらの方法に従って実施した。   An equal amount of 10% trichloroacetic acid (hereinafter referred to as “TCA”) was added to 0.05 mL of the reaction solution, and centrifuged at 5000 × g for 5 minutes. The supernatant was removed and the precipitate was washed with 0.3 mL of 5% TCA and then dried by lyophilization. Subsequently, 0.1N of 6N hydrochloric acid was added under nitrogen conditions and reacted at 110 ° C. for 16 hours to hydrolyze the dried product. Subsequently, 0.1 mL of 5N sodium hydroxide and 0.2 mL of 0.5M phosphate buffer (pH 7.4) were added for neutralization. The neutralized solution was passed through a filter having a diameter of 0.5 μm and diluted with a phosphate buffer to prepare a sample for measuring pentosidine. Pentosidine concentration was measured according to the method of Miyata et al.

表1に、被検薬物によるペントシジン形成阻害強度を、アミノグアニジンによる形成阻害強度を1.0とした場合における相対値として表した(形成阻害強度はコントロール群を対照においた。コントロール群にはDMSOのみ添加した)。
相対値=(被検薬物の形成阻害率)÷(アミノグアニジンの形成阻害率)
Table 1 shows the inhibition strength of pentosidine formation by the test drug as a relative value when the formation inhibition strength by aminoguanidine is 1.0 (the formation inhibition strength is in the control group. In the control group, DMSO was used). Only added).
Relative value = (test drug formation inhibition rate) ÷ (aminoguanidine formation inhibition rate)

アミノグアニジン及び被検薬物の反応中における最終濃度は5.0mMに固定した。 The final concentration during the reaction of aminoguanidine and the test drug was fixed at 5.0 mM.

被検薬物の相対値は、4.08と算出され、被検薬物はアミノグアニジンよりも強くペントシジン形成を阻害することがわかった。以上から、一般式(1)で表される本発明の化合物は、アミノグアニジンよりも強力なAGE形成阻害作用を有し、さらに強力な治療剤としての可能性が本実験結果より明らかとなった。   The relative value of the test drug was calculated to be 4.08, and it was found that the test drug inhibited pentosidine formation more strongly than aminoguanidine. As described above, the compound of the present invention represented by the general formula (1) has a stronger AGE formation inhibitory action than aminoguanidine, and the possibility as a more potent therapeutic agent has been clarified from the results of this experiment. .

Figure 2008179574
Figure 2008179574

Claims (4)

一般式(1)
Figure 2008179574
(式中、R、R、R及びRは同一又は異なって水素原子又はC1−6アルコキシ基を示し、Rは水素原子又はC1−6アルキル基を示す)で表される化合物、その酸付加塩又はそれらの溶媒和物を有効成分とするAGE形成阻害剤。
General formula (1)
Figure 2008179574
(Wherein R 1 , R 2 , R 3 and R 4 are the same or different and represent a hydrogen atom or a C 1-6 alkoxy group, and R 5 represents a hydrogen atom or a C 1-6 alkyl group). AGE formation inhibitors comprising as an active ingredient a compound, an acid addition salt thereof, or a solvate thereof.
一般式(1)で表される化合物、その酸付加塩又はそれらの溶媒和物が、2’−(1H−2−イミダゾリル)−5’−メトキシ−2−[4−(2,3,4−トリメトキシベンジル)ピペラジニル]アセトアニリド、その酸付加塩又はそれらの溶媒和物である請求項1記載のAGE形成阻害剤。 The compound represented by the general formula (1), an acid addition salt thereof, or a solvate thereof is 2 ′-(1H-2-imidazolyl) -5′-methoxy-2- [4- (2,3,4). The AGE formation inhibitor according to claim 1, which is -trimethoxybenzyl) piperazinyl] acetanilide, an acid addition salt thereof, or a solvate thereof. 請求項1または2記載のAGE形成阻害剤を有効成分とする糸球体疾患の予防及び/又は治療剤。 A prophylactic and / or therapeutic agent for glomerular disease comprising the AGE formation inhibitor according to claim 1 or 2 as an active ingredient. 糸球体疾患が、糖尿病性腎症である請求項3記載の予防及び/又は治療剤。 The prophylactic and / or therapeutic agent according to claim 3, wherein the glomerular disease is diabetic nephropathy.
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