JP2017128545A - Combination medicine - Google Patents
Combination medicine Download PDFInfo
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- JP2017128545A JP2017128545A JP2016010356A JP2016010356A JP2017128545A JP 2017128545 A JP2017128545 A JP 2017128545A JP 2016010356 A JP2016010356 A JP 2016010356A JP 2016010356 A JP2016010356 A JP 2016010356A JP 2017128545 A JP2017128545 A JP 2017128545A
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Abstract
Description
本発明は、ナトリウム依存性グルコース共輸送体1(Sodium−dependent glucose cotransporter 1。以下、「SGLT1」と記載することもある。)を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬、及びナトリウム依存性グルコース共輸送体2(Sodium−dependent glucose cotransporter 2。以下、「SGLT2」と記載することもある。)を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を組み合わせてなる医薬(以下、「併用医薬」と記載することもある)に関する。 The present invention relates to a compound that inhibits sodium-dependent glucose cotransporter 1 (hereinafter also referred to as “SGLT1”) or a pharmaceutically acceptable salt thereof as an active ingredient. And a compound that inhibits sodium-dependent glucose cotransporter 2 (hereinafter, sometimes referred to as “SGLT2”) or a pharmaceutically acceptable salt thereof. The present invention relates to a medicine comprising a medicine contained as an active ingredient in combination (hereinafter sometimes referred to as “concomitant medicine”).
糖尿病は肝臓、脂肪、筋肉でのインスリン感受性の低下及び膵臓でのインスリン分泌能の低下により、生体でのインスリンの作用が不足し慢性の高血糖を呈する疾患である。過食、肥満、運動不足などに伴いインスリン感受性が低下すると血糖値を正常に維持するため、代償的に膵β細胞からのインスリン分泌量が増加する。しかし、この状態が続くと膵β細胞が正常血糖値を維持するだけのインスリンを供給できなくなり、糖尿病が顕在化する。糖尿病が顕在化すると慢性的な高血糖となり、高血糖毒性により膵β細胞機能及び肝臓、脂肪、筋肉でのインスリン感受性がさらに低下し糖尿病が進展する。糖尿病は糖尿病性合併症の主要な因子として考えられており、高血糖を是正することが合併症の発症抑制に有効であると考えられる。 Diabetes mellitus is a disease that exhibits chronic hyperglycemia due to insufficient insulin action in the living body due to a decrease in insulin sensitivity in the liver, fat and muscle and a decrease in insulin secretion ability in the pancreas. When insulin sensitivity decreases due to overeating, obesity, lack of exercise, etc., the blood sugar level is maintained normally, so that the amount of insulin secretion from pancreatic β cells increases at a compensation. However, if this state continues, pancreatic β cells cannot supply insulin to maintain normal blood glucose level, and diabetes becomes apparent. When diabetes manifests, it becomes chronic hyperglycemia. Due to hyperglycemia toxicity, pancreatic β-cell function and insulin sensitivity in the liver, fat and muscle are further reduced, and diabetes progresses. Diabetes is considered as a major factor in diabetic complications, and correcting hyperglycemia is thought to be effective in suppressing the onset of complications.
糖尿病の治療は食事・運動療法が基本であるが、これらの方法で血糖コントロールが十分にできない場合は経口血糖降下薬による薬物治療が行われる。経口血糖降下薬としてはスルホニルウレア薬、ビグアナイド薬、α−グルコシダーゼ阻害薬、チアゾリジン薬、DPP4阻害薬などが挙げられ、これらは患者の病態に応じて適宜使用される。 Treatment of diabetes is based on diet / exercise therapy, but if these methods do not provide sufficient control of blood sugar, drug treatment with oral hypoglycemic drugs is performed. Examples of oral hypoglycemic agents include sulfonylurea drugs, biguanide drugs, α-glucosidase inhibitors, thiazolidine drugs, DPP4 inhibitors and the like, and these are used as appropriate depending on the patient's condition.
腎臓の近位尿細管に発現しているSGLT2は、糸球体でろ過されたグルコースの再吸収を担っていることが知られている。最近、SGLT2の活性を阻害することで余分なグルコースを体外に排出するというコンセプトに基づいたSGLT2阻害薬が開発され、インスリン作用を介さない血糖降下薬として臨床で使用されている(特許文献1)。 SGLT2 expressed in the proximal tubule of the kidney is known to be responsible for reabsorption of glucose filtered by the glomerulus. Recently, an SGLT2 inhibitor based on the concept of draining extra glucose out of the body by inhibiting the activity of SGLT2 has been developed and used clinically as a hypoglycemic agent that does not involve insulin action (Patent Document 1). .
小腸上皮に発現しているSGLT1は、小腸において、ナトリウムに依存したグルコ−ス又はガラクト−スの能動輸送を担っていることが知られており、SGLT1の活性を阻害することで食事由来の糖吸収を抑制し、糖尿病の予防または治療を行うことが期待される(特許文献2)。 SGLT1 expressed in the small intestine epithelium is known to be responsible for the active transport of glucose or galactose depending on sodium in the small intestine. By inhibiting the activity of SGLT1, sugars derived from diet It is expected to suppress absorption and prevent or treat diabetes (Patent Document 2).
糖尿病の治療においては、単剤で血糖コントロールが不十分な場合、作用メカニズムの異なる2種以上の医薬を組み合わせて使用することが知られている(特許文献3)。しかし、SGLT1を阻害する化合物を含有する医薬とSGLT2を阻害する化合物を含有する医薬を併用することにより、単独投与より優れた効果を示すという報告はこれまでにない。 In the treatment of diabetes, it is known that two or more kinds of medicaments having different action mechanisms are used in combination when blood glucose control is insufficient with a single agent (Patent Document 3). However, there has been no report that an effect superior to that of single administration is exhibited by using a medicine containing a compound that inhibits SGLT1 and a medicine containing a compound that inhibits SGLT2.
本発明は、糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療に有用な新たな医薬を提供することを目的とする。 An object of the present invention is to provide a new medicament useful for the prevention or treatment of diabetes, diabetes-related diseases, or diabetic complications.
本発明者らは、上記課題を達成すべく鋭意検討を重ねた結果、SGLT1を阻害する下記式[I]で表される化合物(以下、「化合物[I]」と記載することもある)、及びSGLT2を阻害する下記式[II]で表される化合物(以下、「化合物[II]」と記載することもある)を組み合わせてなる医薬が、優れた血糖値上昇抑制作用を有することを見出した。 As a result of intensive investigations to achieve the above-mentioned problems, the present inventors have obtained a compound represented by the following formula [I] that inhibits SGLT1 (hereinafter sometimes referred to as “compound [I]”), And a compound comprising a compound represented by the following formula [II] that inhibits SGLT2 (hereinafter sometimes referred to as “compound [II]”) has an excellent blood glucose level inhibitory action: It was.
すなわち、本発明は以下の通りである。
(1)SGLT1を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬、及びSGLT2を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を組み合わせてなる医薬を提供することである。
(2)SGLT1を阻害する化合物が下記式[I]で表される化合物である、(1)に記載の医薬を提供することである。
That is, the present invention is as follows.
(1) A medicine containing a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a medicine containing a compound that inhibits SGLT2 or a pharmaceutically acceptable salt thereof as an active ingredient It is to provide a combined medicine.
(2) To provide a medicament according to (1), wherein the compound that inhibits SGLT1 is a compound represented by the following formula [I].
(3)SGLT2を阻害する化合物が下記式[II]で表される化合物である、(1)に記載の医薬を提供することである。
(3) To provide the medicament according to (1), wherein the compound that inhibits SGLT2 is a compound represented by the following formula [II].
(4)SGLT1を阻害する化合物が上記式[I]で表される化合物であり、SGLT2を阻害する化合物が上記式[II]で表される化合物である、(1)に記載の医薬を提供することである。
(4) The pharmaceutical according to (1), wherein the compound that inhibits SGLT1 is a compound represented by the above formula [I], and the compound that inhibits SGLT2 is a compound represented by the above formula [II]. It is to be.
(5)血糖降下薬である、(1)から(4)のいずれかに記載の医薬を提供することである。
(6)糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬である、(1)から(4)のいずれかに記載の医薬を提供することである。
(5) To provide a medicament according to any one of (1) to (4), which is a hypoglycemic drug.
(6) To provide a medicament according to any one of (1) to (4), which is a preventive or therapeutic agent for diabetes, diabetes-related diseases, or diabetic complications.
(7)SGLT1を阻害する化合物又はその製薬学的に許容される塩とSGLT2を阻害する化合物又はその製薬学的に許容される塩が、別々の製剤として投与されることを特徴とする、(1)から(6)のいずれかに記載の医薬を提供することである。
(8)SGLT1を阻害する化合物又はその製薬学的に許容される塩とSGLT2を阻害する化合物又はその製薬学的に許容される塩が、一つの製剤中に配合され投与されることを特徴とする、(1)から(6)のいずれかに記載の医薬を提供することである。
(7) A compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof and a compound that inhibits SGLT2 or a pharmaceutically acceptable salt thereof are administered as separate preparations, It is to provide the medicament according to any one of 1) to (6).
(8) A compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof and a compound that inhibits SGLT2 or a pharmaceutically acceptable salt thereof are formulated and administered in one preparation. And providing the medicament according to any one of (1) to (6).
SGLT1を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬、及びSGLT2を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を組み合わせてなる、本発明の併用医薬は、SGLT1を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬、又はSGLT2を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を単独で投与した場合の効果よりも、優れた血糖値上昇抑制作用を有する。したがって、本発明により、糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療に有用な新たな医薬を提供することが可能となった。 Combining a drug containing a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a medicine containing a compound that inhibits SGLT2 or a pharmaceutically acceptable salt thereof as an active ingredient The pharmaceutical composition of the present invention comprises a compound containing SGLT1 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, or a compound inhibiting SGLT2 or a pharmaceutically acceptable salt thereof as an active ingredient As compared with the effect when administered alone as a pharmaceutical, it has a superior blood glucose level inhibitory action. Therefore, according to the present invention, it has become possible to provide a new medicine useful for the prevention or treatment of diabetes, diabetes-related diseases, or diabetic complications.
以下に、本願明細書において記載する記号、用語等の意義を説明するとともに、本発明を詳細に説明するが、本発明は例示されたものに特に限定されない。 Hereinafter, the meanings of symbols, terms, and the like described in the present specification will be described and the present invention will be described in detail. However, the present invention is not particularly limited to those illustrated.
本願明細書における「糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬」とは、一般的に用いられているか、または現在開発中である糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防用の医薬又は治療用の医薬の総称を示す。
本願明細書における「糖尿病」とは、1型糖尿病、2型糖尿病、特定の原因によるその他の型の糖尿病を包含する。
本願明細書における「糖尿病関連疾患」とは、肥満、高インスリン血症、糖代謝異常、耐糖能異常、高脂質血症、高コレステロール血症、脂質代謝異常、高血圧、うっ血性心不全、浮腫、高尿酸血症、痛風、非アルコール性脂肪性肝疾患、非アルコール性脂肪肝炎などがあげられる。
本願明細書における「糖尿病性合併症」とは、急性合併症及び慢性合併症に分類される。急性合併症には、高血糖(ケトアシドーシスなど)、感染症(皮膚、軟部組織、胆道系、呼吸系、尿路感染など)などがあげられる。慢性合併症には、細小血管症(腎症、網膜症)、動脈硬化症(アテローム性動脈硬化症、心筋梗塞、脳梗塞、下肢動脈閉塞など)、神経障害(感覚神経、運動神経、自律神経など)、足壊疽などがあげられる。
As used herein, the term “diabetes, diabetes-related disease, or diabetic complication preventive or therapeutic agent” is commonly used or is currently being developed for diabetes, diabetes-related disease, or diabetic complications. The generic name of the preventive drug or therapeutic drug is shown.
As used herein, “diabetes” includes type 1 diabetes, type 2 diabetes, and other types of diabetes due to specific causes.
As used herein, “diabetes-related disease” includes obesity, hyperinsulinemia, glucose metabolism disorder, glucose tolerance disorder, hyperlipidemia, hypercholesterolemia, lipid metabolism disorder, hypertension, congestive heart failure, edema, high Examples include uricemia, gout, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis.
As used herein, “diabetic complications” is classified into acute complications and chronic complications. Acute complications include hyperglycemia (such as ketoacidosis) and infections (such as skin, soft tissue, biliary system, respiratory system, urinary tract infection). Chronic complications include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb arterial occlusion, etc.), neuropathy (sensory, motor, autonomic) Etc.) and foot gangrene.
本明細書における「血糖値上昇抑制作用」とは、血漿中グルコース濃度(血糖値)を低く維持する作用を意味する。本作用により、例えば、食後の血糖値を低く維持することができる。
また、「血糖降下薬」とは、「血糖値上昇抑制作用」を有する医薬を意味する。例えば、血糖降下薬としては、前述のように、スルホニルウレア薬、ビグアナイド薬、α−グルコシダーゼ阻害薬、チアゾリジン薬、DPP4阻害薬が挙げられ、また、SGLT1阻害薬やSGLT2阻害薬も挙げられる。
The “blood glucose level increase inhibitory effect” in the present specification means an effect of maintaining a low plasma glucose concentration (blood glucose level). With this action, for example, the blood glucose level after a meal can be kept low.
In addition, the “hypoglycemic agent” means a medicine having a “suppressing effect on increase in blood glucose level”. For example, as described above, the hypoglycemic drug includes a sulfonylurea drug, a biguanide drug, an α-glucosidase inhibitor, a thiazolidine drug, and a DPP4 inhibitor, and also includes an SGLT1 inhibitor and an SGLT2 inhibitor.
本願明細書における「SGLT1を阻害する化合物」としては、例えば、以下の化合物が挙げられる。 Examples of the “compound that inhibits SGLT1” in the present specification include the following compounds.
(i)国際公開第WO2007/136116号に記載の、下記一般式[III−1]で表される化合物、 (I) a compound represented by the following general formula [III-1] described in International Publication No. WO2007 / 136116,
(ii)国際公開第WO2008/001864号に記載の、下記一般式[III−2]で表される化合物、 (Ii) a compound represented by the following general formula [III-2] described in International Publication No. WO2008 / 001864,
(iii)国際公開第WO2008/072726号に記載の、下記に表される化合物:
(1S)−1,5−アンヒドロ−1−[4−メチル−5−(4−メチルベンジル)−2−ヒドロキシフェニル]−1−チオ−D−グルシトール、
(1S)−1,5−アンヒドロ−1−[5−(4-メトキシベンジル)−4−メチル−2−ヒドロキシフェニル]−1−チオ−D−グルシトール、
(1S)−1,5−アンヒドロ−1−[5−(4-エチルベンジル)−2−ヒドロキシ−4−メチルフェニル]−1−チオ−D−グルシトール、
(1S)−1,5−アンヒドロ−1−[2−ヒドロキシ−4−メチル−5−[4−(メチルスルファニル)ベンジル]フェニル]−1−チオ−D−グルシトール、
(1S)−1,5−アンヒドロ−1−[4−クロロ−2−ヒドロキシ−5−(4−メチルベンジル)フェニル]−1−チオ−D−グルシトール、
(1S)−1,5−アンヒドロ−1−[4−クロロ−2−ヒドロキシ−5−(4−エチルベンジル)フェニル]−1−チオ−D−グルシトール、
(1S)−1,5−アンヒドロ−1−[4−クロロ−2−ヒドロキシ−5−(4−メトキシベンジル)フェニル]−1−チオ−D−グルシトール、
(Iii) The following compounds described in International Publication No. WO2008 / 072726:
(1S) -1,5-anhydro-1- [4-methyl-5- (4-methylbenzyl) -2-hydroxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [5- (4-methoxybenzyl) -4-methyl-2-hydroxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [5- (4-ethylbenzyl) -2-hydroxy-4-methylphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [2-hydroxy-4-methyl-5- [4- (methylsulfanyl) benzyl] phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-2-hydroxy-5- (4-methylbenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-2-hydroxy-5- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-2-hydroxy-5- (4-methoxybenzyl) phenyl] -1-thio-D-glucitol,
(iv)国際公開第WO2010/095768号に記載の、下記一般式[III−3]で表される化合物、 (Iv) a compound represented by the following general formula [III-3] described in International Publication No. WO2010 / 095768,
なお、前述の式[I]で表される化合物は、上記一般式[III−3]で表される化合物のうちの1つである。
In addition, the compound represented by the above-mentioned formula [I] is one of the compounds represented by the above general formula [III-3].
(v)国際公開第WO2012/023582号に記載の、下記一般式[III−4]で表される化合物、 (V) a compound represented by the following general formula [III-4] described in International Publication No. WO2012 / 023582;
(vi)国際公開第WO2012/023600号に記載の、下記式[III−5]で表される(E)−N−(1−アミノ−2-メチル−1−オキソプロパン−2−イル)−4−(4−(2−イソプロピル−4−メトキシ−5−((2S,3R,4R,5S,6R)−3,4,5−トリヒドロキシ−6−(ヒドロキシメチル)テトラヒドロ−2H−ピラン−2−イル)ベンジル)−3−メチルフェニル)−2,2−ジメチルブタ−3−エンアミド、 (Vi) (E) -N- (1-amino-2-methyl-1-oxopropan-2-yl)-represented by the following formula [III-5] described in International Publication No. WO2012 / 023600 4- (4- (2-Isopropyl-4-methoxy-5-((2S, 3R, 4R, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran- 2-yl) benzyl) -3-methylphenyl) -2,2-dimethylbut-3-enamide,
(vii)国際公開第WO2004/014932号に記載の、下記一般式[III−6]で表される化合物、 (Vii) a compound represented by the following general formula [III-6] described in International Publication No. WO2004 / 014932,
(viii)国際公開第WO2004/018491号に記載の、下記一般式[III−7]で表される化合物、 (Viii) a compound represented by the following general formula [III-7] described in International Publication No. WO 2004/018491,
(ix)国際公開第WO2004/019958号に記載の、下記一般式[III−8]で表される化合物、 (Ix) a compound represented by the following general formula [III-8] described in International Publication No. WO2004 / 019958,
(x)国際公開第WO2009/084531号及び国際公開第WO2009/128421号に記載の、3−(3−{4−[3−(β−D−グルコピラノシルオキシ)−5−イソプロピル−1H−ピラゾール−4−イルメチル]−3−メチルフェノキシ}プロピルアミノ)−2,2−ジメチルプロピオンアミド、
(xi)国際公開第WO2004/050122号に記載の、5−ヒドロキシ−3−メチル−2−{4−[3−(3−ピリジルメチル)ウレイド]ベンジル}フェニル β−D−グルコピラノシド、及び3−(β−D−グルコピラノシルオキシ)−4−{[4−(2−グアニジノエトキシ)−2−メチルフェニル]メチル}−5−イソプロピル−1H−ピラゾール、
(X) 3- (3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H described in International Publication No. WO2009 / 084531 and International Publication No. WO2009 / 128421. -Pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2,2-dimethylpropionamide,
(Xi) 5-hydroxy-3-methyl-2- {4- [3- (3-pyridylmethyl) ureido] benzyl} phenyl β-D-glucopyranoside, as described in International Publication No. WO 2004/050122, and 3- (Β-D-glucopyranosyloxy) -4-{[4- (2-guanidinoethoxy) -2-methylphenyl] methyl} -5-isopropyl-1H-pyrazole,
(xii)国際公開第WO2008/016132号に記載の、下記一般式[III−9]で表される化合物、 (Xii) a compound represented by the following general formula [III-9] described in International Publication No. WO2008 / 016132,
(xiii)国際公開第WO2005/121161号に記載の、下記一般式[III−10]で表される化合物、 (Xiii) a compound represented by the following general formula [III-10] described in International Publication No. WO2005 / 121161,
(xiv)国際公開第WO2008/042688号に記載の、下記一般式[III−11]で表される化合物。 (Xiv) A compound represented by the following general formula [III-11] described in International Publication No. WO2008 / 042688.
当該「SGLT1を阻害する化合物」は、製薬学的に許容される塩を形成してもよく、また、水和物をはじめ、各種溶媒和物を形成してもよい。 The “compound inhibiting SGLT1” may form a pharmaceutically acceptable salt, and may form various solvates including hydrates.
SGLT1を阻害する好ましい化合物としては、例えば、
前記(iv)で挙げた国際公開第WO2010/095768号に記載の、式[I]で表される化合物(1S)−1,5−アンヒドロ−1−[5−(4−{(1E)−4−[(1−{[2−(ジメチルアミノ)エチル]アミノ}−2−メチル−1−オキソプロパン−2−イル)アミノ]−3,3−ジメチル−4−オキソブタ−1−エン−1−イル}ベンジル)−2−メトキシ−4−(プロパン−2−イル)フェニル]−D−グルシトール)や
前記(vi)国際公開第WO2012/023600号に記載の、式[III−5]で表される化合物(E)−N−(1−アミノ−2-メチル−1−オキソプロパン−2−イル)−4−(4−(2−イソプロピル−4−メトキシ−5−((2S,3R,4R,5S,6R)−3,4,5−トリヒドロキシ−6−(ヒドロキシメチル)テトラヒドロ−2H−ピラン−2−イル)ベンジル)−3−メチルフェニル)−2,2−ジメチルブタ−3−エンアミド、
前記(x)で挙げた国際公開第WO2009/084531号及び国際公開第WO2009/128421号に記載の、式[III−12]で表される化合物3−(3−{4−[3−(β−D−グルコピラノシルオキシ)−5−イソプロピル−1H−ピラゾール−4−イルメチル]−3−メチルフェノキシ}プロピルアミノ)−2,2−ジメチルプロピオンアミドが挙げられる。
As a preferable compound that inhibits SGLT1, for example,
Compound (1S) -1,5-anhydro-1- [5- (4-{(1E)-represented by the formula [I] described in International Publication No. WO2010 / 095768 mentioned in (iv) above) 4-[(1-{[2- (dimethylamino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-ene-1 -Yl} benzyl) -2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol) and the formula (III-5) described in (vi) International Publication No. WO2012 / 023600. Compound (E) -N- (1-amino-2-methyl-1-oxopropan-2-yl) -4- (4- (2-isopropyl-4-methoxy-5-((2S, 3R, 4R, 5S, 6R) -3,4,5-trihydroxy-6- ( Dorokishimechiru) tetrahydro -2H- pyran-2-yl) benzyl) -3-methyl-phenyl) -2,2-dimethyl-but-3-enamide,
Compound 3- (3- {4- [3- (β) represented by formula [III-12] described in International Publication No. WO2009 / 084531 and International Publication No. WO2009 / 128421 mentioned in (x) above -D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino) -2,2-dimethylpropionamide.
SGLT1を阻害するより好ましい化合物としては、式[I]で表される化合物(1S)−1,5−アンヒドロ−1−[5−(4−{(1E)−4−[(1−{[2−(ジメチルアミノ)エチル]アミノ}−2−メチル−1−オキソプロパン−2−イル)アミノ]−3,3−ジメチル−4−オキソブタ−1−エン−1−イル}ベンジル)−2−メトキシ−4−(プロパン−2−イル)フェニル]−D−グルシトール)が挙げられる。 As a more preferred compound that inhibits SGLT1, the compound represented by the formula [I] (1S) -1,5-anhydro-1- [5- (4-{(1E) -4-[(1-{[ 2- (dimethylamino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} benzyl) -2- Methoxy-4- (propan-2-yl) phenyl] -D-glucitol).
本願明細書における「SGLT2を阻害する化合物」としては、例えば、以下の化合物が挙げられる。 Examples of the “compound that inhibits SGLT2” in the present specification include the following compounds.
(i)国際公開第WO2006/073197号に記載の、下記一般式[IV−1]で表される化合物、 (I) a compound represented by the following general formula [IV-1] described in International Publication No. WO2006 / 073197,
(なお、式[IV−1]中の置換基R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、A、Ar1、及びAr2の定義は、国際公開第WO2006/073197号の記載による。)
なお、上記式[II]で表される化合物は、上記一般式[IV−1]で表される化合物のうちの1つである。
(Note that the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , A, Ar 1 , and Ar in the formula [IV-1] ( The definition of 2 is based on the description of International Publication No. WO2006 / 073197.)
The compound represented by the above formula [II] is one of the compounds represented by the above general formula [IV-1].
(ii)国際公開第WO2004/080990号に記載の、下記一般式[IV−2]で表される化合物、 (Ii) a compound represented by the following general formula [IV-2] described in International Publication No. WO2004 / 080990,
(なお、式[IV−2]中の置換基R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、A、B、及びXの定義は、国際公開第WO2004/080990号の記載による。)
(In the formula [IV-2], the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , A, B, And X are defined by the description of International Publication No. WO 2004/080990.)
(iii)国際公開第WO2006/080421号に記載の、下記一般式[IV−3]で表される化合物、 (Iii) a compound represented by the following general formula [IV-3] described in International Publication No. WO2006 / 080421,
(なお、式[IV−3]中の置換基R1、R2、R3、R4、Ar1、Q、n、及びAの定義は、国際公開第WO2006/080421号号の記載による。)
(The definitions of the substituents R 1 , R 2 , R 3 , R 4 , Ar 1 , Q, n, and A in the formula [IV-3] are as described in International Publication No. WO 2006/080421. )
(iv)国際公開第WO03/099836号に記載の、下記式[IV−4]で表される化合物、 (Iv) a compound represented by the following formula [IV-4] described in International Publication No. WO03 / 099836,
(v)国際公開第WO2005/012326号に記載の、下記一般式[IV−5]で表される化合物、 (V) a compound represented by the following general formula [IV-5] described in International Publication No. WO2005 / 012326,
(なお、式[IV−5]中の置換基A、B、X、及びYの定義は、国際公開第WO2005/012326号の記載による。)
(The definitions of substituents A, B, X, and Y in formula [IV-5] are as described in International Publication No. WO2005 / 012326.)
(vi)国際公開第WO2005/092877号に記載の、下記一般式[IV−6]で表される化合物、 (Vi) a compound represented by the following general formula [IV-6] described in International Publication No. WO2005 / 092877,
(なお、式[IV−6]中の置換基R1、R2、R3、R4、R5、R6、R7a、R7b、及びR7cの定義は、国際公開第WO2005/092877号の記載による。)
(Note that the definitions of substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b , and R 7c in formula [IV-6] are defined in International Publication No. WO2005 / 092877. (According to the description of the issue)
当該「SGLT2を阻害する化合物」は、製薬学的に許容される塩を形成してもよく、また、水和物をはじめ、各種溶媒和物を形成してもよい。 The “compound inhibiting SGLT2” may form a pharmaceutically acceptable salt, and may form various solvates including hydrates.
SGLT2を阻害する好ましい化合物としては、例えば、
前記(i)で挙げた国際公開第WO2006/073197号に記載の、式[II]で表される化合物(1S)−1,5−アンヒドロ−1−[5−(4−エトキシベンジル)−2−メトキシ−4−メチルフェニル]−1−チオ−D−グルシトール、
前記(ii)で挙げた国際公開第WO2004/080990号に記載の、式[IV−6]で表される化合物(1S)−1,5−アンヒドロ−1−C−{3−[(1−ベンゾチオフェン−2−イル)メチル]−4−フルオロフェニル}−D−グルシトール、
前記(iii)で挙げた国際公開第WO2006/080421号に記載の、式[IV−7]で表される化合物(1S,3’R,4’S,5’S,6’R)−6−[(4−エチルフェニル)メチル]−6’−(ヒドロキシメチル)−3’,4’,5’,6’−テトラヒドロ−3H−スピロ[2−ベンゾフラン−1,2’−ピラン]−3’,4’,5’−トリオール、
前記(iv)で挙げた国際公開第WO03/099836号に記載の、式[IV−8]で表される化合物(1S)−1,5−アンヒドロ−1−C−{4−クロロ−3−[(4-エトキシフェニル)メチル]フェニル}−D−グルシトール、
前記(v)で挙げた国際公開第WO2005/012326号に記載の、式[IV−9]で表される化合物(1S)−1,5−アンヒドロ−1−C−(3{[5−(4−フルオロフェニル)チオフェン−2−イル]メチル}−4−メチルフェニル)−D−グルシトール、
前記(vi)で挙げた国際公開第WO2005/092877号に記載の、式[IV−10]で表される化合物(1S)−1,5−アンヒドロ−1−C−{4−クロロ−3−[(4−{[(3S)−オキソラン−3−イル]オキシ}フェニル)メチル]フェニル}−D−グルシトールが挙げられる。
As a preferable compound that inhibits SGLT2, for example,
Compound (1S) -1,5-anhydro-1- [5- (4-ethoxybenzyl) -2 represented by the formula [II] described in International Publication No. WO2006 / 073197 mentioned in (i) above -Methoxy-4-methylphenyl] -1-thio-D-glucitol,
Compound (1S) -1,5-anhydro-1-C- {3-[(1- (1S) -1,5-anhydro-1-C- (III) described in International Publication No. WO 2004/080990 mentioned in (ii) above Benzothiophen-2-yl) methyl] -4-fluorophenyl} -D-glucitol,
Compound (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6 represented by formula [IV-7] described in International Publication No. WO2006 / 080421 listed in (iii) above -[(4-Ethylphenyl) methyl] -6 '-(hydroxymethyl) -3', 4 ', 5', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol,
Compound (1S) -1,5-anhydro-1-C- {4-chloro-3- represented by the formula [IV-8] described in International Publication No. WO03 / 099836 mentioned in (iv) above [(4-ethoxyphenyl) methyl] phenyl} -D-glucitol,
Compound (1S) -1,5-anhydro-1-C- (3 {[5- (3) represented by the formula [IV-9] described in International Publication No. WO2005 / 012326 mentioned in (v) above 4-fluorophenyl) thiophen-2-yl] methyl} -4-methylphenyl) -D-glucitol,
Compound (1S) -1,5-anhydro-1-C- {4-chloro-3- represented by the formula [IV-10] described in International Publication No. WO2005 / 092877 mentioned in (vi) above And [(4-{[(3S) -oxolan-3-yl] oxy} phenyl) methyl] phenyl} -D-glucitol.
SGLT2を阻害するより好ましい化合物としては、式[II]で表される化合物(1S)−1,5−アンヒドロ−1−[5−(4−エトキシベンジル)−2−メトキシ−4−メチルフェニル]−1−チオ−D−グルシトールが挙げられる。 As a more preferable compound that inhibits SGLT2, the compound represented by the formula [II] (1S) -1,5-anhydro-1- [5- (4-ethoxybenzyl) -2-methoxy-4-methylphenyl] Examples include -1-thio-D-glucitol.
本願明細書における「塩」としては、SGLT1を阻害する化合物、又はSGLT2を阻害する化合物と製薬学的に許容される塩を形成するものであれば特に限定されないが、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩、硫酸塩、硝酸塩のような鉱酸塩、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、トリフルオロメタンスルホン酸塩のようなスルホン酸塩、シュウ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、コハク酸塩、酢酸塩、安息香酸塩、マンデル酸塩、アスコルビン酸塩、乳酸塩、グルコン酸塩、リンゴ酸塩、フマル酸、モノセバシン酸のような有機酸塩等の酸付加塩、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩、又は、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩のような無機塩若しくはアンモニウム塩、トリエチルアミン塩、ジイソプロピルアミン塩、シクロヘキシルアミン塩のような有機塩基との塩が挙げられる。なお、塩には、含水塩が含まれる。 The “salt” in the present specification is not particularly limited as long as it forms a pharmaceutically acceptable salt with a compound that inhibits SGLT1 or a compound that inhibits SGLT2. Hydronate, hydroiodide, phosphate, sulfate, nitrate such as nitrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfone Sulfonates such as acid salts, oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbate, lactate, gluconate, Acid addition salts such as malate, fumaric acid, organic acid salt such as monosebacic acid, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate Amino acid salts such as, or salts with organic bases such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, inorganic salts or ammonium salts, triethylamine salts, diisopropylamine salts, cyclohexylamine salts. It is done. The salt includes a hydrated salt.
本願明細書における「SGLT1を阻害する化合物」及び「SGLT2を阻害する化合物」は、不斉中心を持つことがあり、その場合種々の光学異性体が存在する。したがって、本発明の化合物は、(R)および(S)の別々の光学活性体として、およびラセミ体又は(RS)混合物として存在し得る。また、不斉中心を2個以上持つ化合物の場合には、さらにそれぞれの光学異性によるジアステレオマーも存在する。本発明の化合物は、これらすべての型を、任意の割合で含むものも含む。そして、ジアステレオマーは、当業者によく知られた方法、例えば分別結晶法等によって分離することができ、また、光学活性体はこの目的のためによく知られた有機化学的手法によって得ることができる。また、本発明の化合物には、シス体、トランス体等の幾何異性体が存在することがある。本発明の化合物は、それらの異性体、及びそれらの異性体を任意の割合で含んだものも含む。 The “compound that inhibits SGLT1” and the “compound that inhibits SGLT2” in this specification may have an asymmetric center, and in this case, various optical isomers exist. Thus, the compounds of the present invention may exist as separate optically active forms of (R) and (S) and as racemates or (RS) mixtures. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. Diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active substances can be obtained by organic chemical methods well known for this purpose. Can do. The compound of the present invention may have geometric isomers such as cis isomer and trans isomer. The compound of the present invention includes those isomers and those containing these isomers in an arbitrary ratio.
SGLT1を阻害する化合物の、SGLT1に対する阻害活性は、公知の方法によって測定することができる。 The inhibitory activity against SGLT1 of a compound that inhibits SGLT1 can be measured by a known method.
SGLT2を阻害する化合物の、SGLT2に対する阻害活性も、公知の方法によって測定することができる。 The inhibitory activity against SGLT2 of a compound that inhibits SGLT2 can also be measured by a known method.
よって、本発明の属する技術の分野における通常の知識を有する者であれば、前述の公知の測定方法を用いることにより、いかなる化合物についても、そのSGLT1に対する阻害活性を測定し、SGLT1を阻害する化合物を同定することができる。
同様に、いかなる化合物についても、そのSGLT2に対する阻害活性を測定し、SGLT2を阻害する化合物を同定することができる
Therefore, a person who has ordinary knowledge in the technical field to which the present invention belongs can measure the inhibitory activity against SGLT1 and inhibit SGLT1 for any compound by using the above-mentioned known measurement method. Can be identified.
Similarly, for any compound, its inhibitory activity against SGLT2 can be measured to identify a compound that inhibits SGLT2.
以下に、本発明にかかる「併用医薬」が糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症を予防又は治療する医薬として有用であることを示す試験例を記載する(試験例1)。該試験において使用した化合物は、上記式[I]で表される化合物((1S)−1,5−アンヒドロ−1−[5−(4−{(1E)−4−[(1−{[2−(ジメチルアミノ)エチル]アミノ}−2−メチル−1−オキソプロパン−2−イル)アミノ]−3,3−ジメチル−4−オキソブタ−1−エン−1−イル}ベンジル)−2−メトキシ−4−(プロパン−2−イル)フェニル]−D−グルシトール)、及び上記式[II]で表される化合物((1S)−1,5−アンヒドロ−1−[5−(4−エトキシベンジル)−2−メトキシ−4−メチルフェニル]−1−チオ−D−グルシトール)である。 Hereinafter, test examples showing that the “combination drug” according to the present invention is useful as a drug for preventing or treating diabetes, diabetes-related diseases, or diabetic complications will be described (Test Example 1). The compound used in the test was a compound represented by the above formula [I] ((1S) -1,5-anhydro-1- [5- (4-{(1E) -4-[(1-{[ 2- (dimethylamino) ethyl] amino} -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl} benzyl) -2- Methoxy-4- (propan-2-yl) phenyl] -D-glucitol) and the compound represented by the above formula [II] ((1S) -1,5-anhydro-1- [5- (4-ethoxy) Benzyl) -2-methoxy-4-methylphenyl] -1-thio-D-glucitol).
上記式[I]で表される化合物は、国際公開第WO2010/095768号のExample 15−2で既に開示された化合物であり、当該文献に記載の方法により得ることができる。また、該化合物の結晶は、国際公開第WO2012/023598号に記載の方法により得ることができる。 The compound represented by the above formula [I] is a compound already disclosed in Example 15-2 of International Publication No. WO2010 / 095768, and can be obtained by the method described in the document. Moreover, the crystal | crystallization of this compound can be obtained by the method as described in international publication WO2012 / 023598.
上記式[II]で表される化合物は、国際公開第WO2006/073197号の実施例7で既に開示された化合物であり、当該文献に記載の方法により得ることができる。 The compound represented by the above formula [II] is a compound already disclosed in Example 7 of International Publication No. WO2006 / 073197, and can be obtained by the method described in the document.
本発明の糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬は、様々な方法によって製造することが可能であり、例えば、前述の文献に記載の方法によって製造することができる。 The preventive or therapeutic agent for diabetes, diabetes-related diseases, or diabetic complications of the present invention can be produced by various methods, for example, by the methods described in the aforementioned literature.
本発明に係る併用医薬は、有効成分であるSGLT1を阻害する化合物及びSGLT2を阻害する化合物を単一の製剤(配合剤)、または別々に製剤化して得られる2種以上の製剤(併用剤)とすることができる。
これらの有効成分を別々に製剤化して2種以上の製剤とする場合には、個々の製剤を同時または一定の時間間隔を空けて投与することが可能である。また、これらの場合、どちらを先に投与しても構わない。当該2種以上の製剤は、1日にそれぞれ異なる回数で投与することもできる。これらの有効成分を別々に製剤化して2種以上の製剤とした場合には、個々の製剤を異なる経路で投与することもできる。
The combination drug according to the present invention comprises a compound that inhibits SGLT1 as an active ingredient and a compound that inhibits SGLT2 in a single preparation (compound) or two or more preparations (combination drugs) obtained separately. It can be.
When these active ingredients are separately formulated into two or more preparations, the individual preparations can be administered simultaneously or at a certain time interval. In these cases, either may be administered first. The two or more types of preparations can be administered at different times each day. When these active ingredients are formulated separately into two or more preparations, the individual preparations can be administered by different routes.
これらの有効成分を別々に製剤化して2種の製剤とする場合は、同時に、または極めて短い間隔で投与する場合もあり、例えば、市販されている医薬の添付文書や販売パンフレット等の文書に、それぞれを併用する旨を記載するのが好ましい。
また、これらの有効成分を別々に製剤化して2種の製剤からなるキットの形態とすることも好ましい。
When these active ingredients are formulated separately into two types of preparations, they may be administered at the same time or at extremely short intervals. For example, in documents such as package inserts or sales brochures of commercially available drugs, It is preferable to describe that both are used together.
It is also preferable to formulate these active ingredients separately to form a kit comprising two types of preparations.
本発明の糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬について、含有するSGLT1を阻害する化合物又はその製薬学的に許容される塩、及びSGLT2を阻害する化合物又はその製薬学的に許容される塩は、単独に、又は薬学的あるいは薬剤学的に許容される添加剤と共に投与することができる。
添加剤としては、常用の賦形剤又は希釈剤、そして、必要に応じて一般に使用される結合剤、崩壊剤、潤滑剤、被覆剤、糖衣剤、pH調整剤、溶解剤又は水性若しくは非水性溶媒を使用することができる。具体的には、水、乳糖、デキストロース、フラクトース、ショ糖、ソルビトール、マンニトール、ポリエチレングリコール、プロピレングリコール、デンプン、コーンスターチ、ガム、ゼラチン、アルギネート、ケイ酸カルシウム、リン酸カルシウム、セルロース、水シロップ、メチルセルロース、ポリビニルピロリドン、アルキルパラヒドロキシベンゾエート、タルク、ステアリン酸、ステアリン酸マグネシウム、寒天、ペクチン、アラビアゴム、グリセリン、ゴマ油、オリーブ油、大豆油カカオバター、エチレングリコール、低粘度ヒドロキシプロピルセルロース(HPC−L)、微結晶セルロース、カルボキシメチルセルロース(CMC)、カルボキシメチルセルロースナトリウム(CMC−Na)等やその他常用されるものを挙げることができる。
About the preventive or therapeutic agent of diabetes of this invention, diabetes related disease, or diabetic complication, the compound which inhibits SGLT1, or its pharmaceutically acceptable salt, and the compound which inhibits SGLT2, or its pharmaceutical Can be administered alone or in combination with pharmaceutically or pharmaceutically acceptable additives.
Additives include commonly used excipients or diluents, and commonly used binders, disintegrants, lubricants, coating agents, dragees, pH adjusters, solubilizers, or aqueous or non-aqueous additives. A solvent can be used. Specifically, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinyl Pyrrolidone, alkyl parahydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil cocoa butter, ethylene glycol, low viscosity hydroxypropyl cellulose (HPC-L), microcrystal Examples include cellulose, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), and other commonly used ones. Door can be.
本発明の糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬は、固体組成物、液体組成物及びその他の組成物のいずれの形態でもよく、必要に応じて最適のものが選択される。 The preventive or therapeutic agent for diabetes, diabetes-related diseases, or diabetic complications of the present invention may be in the form of a solid composition, liquid composition, or other composition, and the optimal one is selected as necessary. The
本発明の糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬について、含有するSGLT1を阻害する化合物又はその製薬学的に許容される塩、及びSGLT2を阻害する化合物又はその製薬学的に許容される塩に、前記の添加剤を添加し、常用の製剤技術によって、錠剤、丸剤、カプセル剤、顆粒剤、粉剤、散剤、液剤、乳剤、懸濁剤、注射剤等に調製する事ができる。 About the preventive or therapeutic agent of diabetes of this invention, diabetes related disease, or diabetic complication, the compound which inhibits SGLT1, or its pharmaceutically acceptable salt, and the compound which inhibits SGLT2, or its pharmaceutical Add the above-mentioned additives to the salts acceptable to the above, and prepare tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, etc. by conventional formulation techniques I can do things.
また、本発明の糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬について、含有するSGLT1を阻害する化合物又はその製薬学的に許容される塩、及びSGLT2を阻害する化合物又はその製薬学的に許容される塩は、α、β若しくはγ−シクロデキストリン又はメチル化シクロデキストリン等と包接化合物を形成させて製剤化することができる。 In addition, for the preventive or therapeutic agent for diabetes, diabetes-related diseases, or diabetic complications of the present invention, a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof, a compound that inhibits SGLT2, or a pharmaceutical thereof Chemically acceptable salts can be formulated by forming an inclusion compound with α, β or γ-cyclodextrin or methylated cyclodextrin.
本発明の糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療薬の投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、例えば、成人の糖尿病患者に経口投与する場合、SGLT1を阻害する化合物又はその製薬学的に許容される塩、SGLT2を阻害する化合物又はその製薬学的に許容される塩を、それぞれ通常1回量として0.01mg〜1000mg、好ましくは1mg〜200mgであり、この量を1日1回〜3回投与するのが望ましい。 The dosage of the preventive or therapeutic agent for diabetes, diabetes-related diseases, or diabetic complications of the present invention varies depending on the administration subject, administration route, target disease, symptoms, etc., but is orally administered to adult diabetic patients, for example. In this case, a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof, a compound that inhibits SGLT2 or a pharmaceutically acceptable salt thereof, each usually in a single dose of 0.01 mg to 1000 mg, preferably 1 mg It is desirable to administer this amount once to three times a day.
本発明により、糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症を予防又は治療する新規な医薬を提供することができる。本発明にかかる併用医薬は、SGLT1阻害作用を有し、消化管からの糖吸収を抑制することにより食後の急激な血糖値の上昇を抑制することができる。また、SGLT2阻害作用も有し、腎臓において糖の再吸収を抑制することにより過剰な糖を体外へ排泄することもできる。したがって、本発明は過剰な膵β細胞からのインスリン分泌を伴わず高血糖を是正することにより、糖尿病を治療し、膵β細胞の負担を軽減して糖尿病の進展を抑制することができる。 According to the present invention, a novel medicament for preventing or treating diabetes, diabetes-related diseases, or diabetic complications can be provided. The concomitant drug according to the present invention has an SGLT1 inhibitory action, and can suppress a rapid increase in blood glucose level after a meal by suppressing sugar absorption from the digestive tract. It also has an SGLT2 inhibitory action, and it can excrete excess sugar outside the body by suppressing reabsorption of sugar in the kidney. Therefore, the present invention corrects hyperglycemia without insulin secretion from excessive pancreatic β cells, thereby treating diabetes, reducing the burden on pancreatic β cells, and suppressing the progression of diabetes.
SGLT1を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬、及びSGLT2を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する糖尿病の予防又は治療薬を組み合わせてなる、本発明の併用医薬は、SGLT1を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬、又はSGLT2を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を単独で投与した場合の効果よりも、優れた血糖値上昇抑制作用を有し、有用性が高い。 Pharmaceuticals containing SGLT1 inhibiting compound or pharmaceutically acceptable salt thereof as active ingredient, and prevention or treatment of diabetes containing SGLT2 inhibiting compound or pharmaceutically acceptable salt as active ingredient The combination drug of the present invention, which is a combination of drugs, is a drug containing a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof as an active ingredient, or a compound that inhibits SGLT2 or a pharmaceutically acceptable drug thereof. It has a superior blood glucose level inhibitory action and higher utility than the effect of administering a pharmaceutical containing a salt as an active ingredient alone.
以下に、試験例及び製剤例を挙げて、本発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to test examples and formulation examples, but the present invention is not limited thereto.
化合物[I]及び化合物[II]を組み合わせてなる医薬の血糖値上昇抑制作用を、以下の試験例1により説明する。 The inhibitory action on the increase in blood glucose level of a pharmaceutical comprising a combination of compound [I] and compound [II] will be described by the following Test Example 1.
試験例1
ストレプトゾトシン誘発糖尿病モデルラットにおける血糖値上昇抑制作用確認試験
(1)糖尿病モデルラットの作製
6週齢のSD/IGSラット(日本チャールスリバー株式会社,雄性)について約17
時間の絶食後、ストレプトゾトシン(STZ)50mg/kgを尾静脈内投与し、糖尿病モデルラットを作製した。同様に1.25mmol/Lクエン酸生理食塩液1mL/kgを尾静脈内投与し、正常対照ラットを作製した。STZまたは1.25mmol/Lクエン酸生理食塩液投与1週後(7週齢)、経口グルコース負荷試験に供した。
(2)経口グルコース負荷試験
約19時間絶食させたラットに0.5%カルボキシメチルセルロース(CMC)水溶液に懸濁した化合物[II](1mg/kg)または0.5%CMC水溶液を経口投与した。その30分後に0.5%メチルセルロース(MC)水溶液に溶解した化合物[I]
(0.5及び1mg/kg)または0.5%MC水溶液を経口投与し、直後にグルコース溶液(2g/kg)を経口投与した。グルコース投与前(0時間)及び投与後0.25、0.5、1、1.5、2時間の計6点で採血した。グルコース負荷前の血漿中グルコース(PG)濃度を基準としたグルコース負荷後2時間までのPG濃度-時間曲線下面積(ΔPG AUC0-2h)を指標にしてグルコース負荷後の血糖値上昇に対する化合物[I]及び化合物[II]の併用効果を検討した。
Test example 1
Test for confirming inhibitory effect on blood glucose level in streptozotocin-induced diabetic model rats (1) Preparation of diabetic model rats About 17 about 6-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male)
After fasting for time, streptozotocin (STZ) 50 mg / kg was administered into the tail vein to prepare diabetic model rats. Similarly, 1.25 mmol / L citrate physiological saline 1 mL / kg was administered into the tail vein to produce normal control rats. One week after administration of STZ or 1.25 mmol / L citrate physiological saline (7 weeks old), it was subjected to an oral glucose tolerance test.
(2) Oral glucose tolerance test Rats fasted for about 19 hours were orally administered Compound [II] (1 mg / kg) or 0.5% CMC aqueous solution suspended in 0.5% carboxymethylcellulose (CMC) aqueous solution. Compound [I] dissolved in 0.5% methylcellulose (MC) aqueous solution 30 minutes later
(0.5 and 1 mg / kg) or 0.5% MC aqueous solution was orally administered, and immediately thereafter, a glucose solution (2 g / kg) was orally administered. Blood was collected at a total of 6 points before glucose administration (0 hour) and after administration, 0.25, 0.5, 1, 1.5, and 2 hours. A compound for an increase in blood glucose level after glucose loading using as an index the area under the PG concentration-time curve (ΔPG AUC 0-2h ) up to 2 hours after glucose loading based on the plasma glucose (PG) concentration before glucose loading [ The combined effect of I] and compound [II] was examined.
試験結果を表1に示す。 The test results are shown in Table 1.
*** p<0.001(正常対照群に対するWelchのt検定)
化合物[I]の主効果 F(2,36)=30.44 p<0.001、
化合物[II]の主効果 F(1,36)=52.38 p<0.001、
交互作用 F(2,36)=1.03 有意差なし(二元配置分散分析)
*** p <0.001 (Welch t-test against normal control group)
Main effect of compound [I] F (2,36) = 30.44 p <0.001,
Main effect of compound [II] F (1,36) = 52.38 p <0.001,
Interaction F (2,36) = 1.03 No significant difference (two-way analysis of variance)
化合物[I]及び化合物[II]の併用投与により、糖尿病モデルであるSTZラットの血糖値の上昇が抑制された。このとき、化合物[I]の単独投与による血糖値上昇抑制作用よりも併用投与による血糖値上昇抑制作用が優れていた。また、同様に、化合物[II]の単独投与による血糖値上昇抑制作用よりも併用投与による血糖値上昇抑制作用も優れていた。この結果により、化合物[I]及び化合物[II]の併用投与が、糖尿病に対して、より有用であることが示された。 The combined administration of Compound [I] and Compound [II] suppressed the increase in blood glucose level in STZ rats, which is a diabetes model. At this time, the blood glucose level increase inhibitory effect by combined administration was superior to the blood glucose level increase inhibitory effect by single administration of Compound [I]. Similarly, the blood glucose level increase inhibitory effect of the combined administration was superior to the blood glucose level increase inhibitory effect of the compound [II] administered alone. This result showed that the combined administration of compound [I] and compound [II] is more useful for diabetes.
以下に、本発明の併用医薬の製剤例を示す。 Below, the formulation example of the combined use medicine of this invention is shown.
製剤例1
以下の成分を含有する顆粒剤を製造する。
(処方)
成分 式[I]で表される化合物 3.3mg
式[II]で表される化合物 6.6mg
乳糖 700.1mg
コーンスターチ 274 mg
HPC−L 16 mg
1000 mg
Formulation Example 1
A granule containing the following ingredients is produced.
(Prescription)
Ingredient Compound represented by formula [I] 3.3mg
Compound represented by formula [II] 6.6 mg
Lactose 700.1mg
Corn starch 274 mg
HPC-L 16 mg
1000 mg
(製法)
式[I]で表される化合物、式[II]で表される化合物、及び乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらをV型混合機にて混合する。混合末に低粘度ヒドロキシプロピルセルロース(HPC−L)水溶液を添加し、練合、造粒(押し出し造粒 孔径0.5〜1mm)した後、乾燥する。得られた乾燥顆粒を振動ふるい(12/60メッシュ)で篩過し顆粒剤を得る。
(Manufacturing method)
The compound represented by the formula [I], the compound represented by the formula [II], and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated (extruded granulation, pore diameter: 0.5 to 1 mm), and then dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.
製剤例2
以下の成分を含有するカプセル充填用散剤を製造する。
成分 式[I]で表される化合物 3.3mg
式[II]で表される化合物 6.6mg
乳糖 79.1mg
コーンスターチ 10 mg
ステアリン酸マグネシウム 1 mg
100 mg
Formulation Example 2
A powder for capsule filling containing the following components is produced.
Ingredient Compound represented by formula [I] 3.3mg
Compound represented by formula [II] 6.6 mg
Lactose 79.1mg
Corn starch 10 mg
Magnesium stearate 1 mg
100 mg
(製法)
式[I]で表される化合物、式[II]で表される化合物、及び乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらとステアリン酸マグネシウムをV型混合機にて混合する。10倍散100mgを5号硬ゼラチンカプセルに充填する。
(Manufacturing method)
The compound represented by the formula [I], the compound represented by the formula [II], and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.
製剤例3
以下の成分を含有するカプセル充填用顆粒剤を製造する。
成分 式[I]で表される化合物 5mg
式[II]で表される化合物 10mg
乳糖 90mg
コーンスターチ 42mg
HPC−L 3mg
150mg
Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Component Compound represented by formula [I] 5 mg
Compound represented by formula [II] 10 mg
Lactose 90mg
Cornstarch 42mg
HPC-L 3mg
150mg
(製法)
式[I]で表される化合物、式[II]で表される化合物、及び乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらをV型混合機にて混合する。混合末に低粘度ヒドロキシプロピルセルロース(HPC−L)水溶液を添加し、練合、造粒した後、乾燥する。得られた乾燥顆粒を振動ふるい(12/60メッシュ)で篩過し整粒し、その150mgを4号硬ゼラチンカプセルに充填する。
(Manufacturing method)
The compound represented by the formula [I], the compound represented by the formula [II], and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated, and then dried. The obtained dried granule is sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg thereof is filled into a No. 4 hard gelatin capsule.
製剤例4
以下の成分を含有する錠剤を製造する。
成分 式[I]で表される化合物 3.3mg
式[II]で表される化合物 6.6mg
乳糖 90.1mg
微結晶セルロース 30 mg
ステアリン酸マグネシウム 5 mg
CMC−Na 15 mg
150 mg
Formulation Example 4
A tablet containing the following ingredients is produced.
Ingredient Compound represented by formula [I] 3.3mg
Compound represented by formula [II] 6.6 mg
Lactose 90.1mg
Microcrystalline cellulose 30 mg
Magnesium stearate 5 mg
CMC-Na 15 mg
150 mg
(製法)
式[I]で表される化合物、式[II]で表される化合物、及び乳糖と微結晶セルロース、CMC−Na(カルボキシメチルセルロース ナトリウム塩)を60メッシュのふるいに通し、混合する。混合末にステアリン酸マグネシウムを添加し、製剤用混合末を得る。本混合末を直打し150mgの錠剤を得る。
(Manufacturing method)
The compound represented by the formula [I], the compound represented by the formula [II], lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.
SGLT1を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬、及びSGLT2を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を組み合わせてなる、本発明の医薬は、優れた血糖値上昇抑制作用を有する。したがって、本発明により、糖尿病、糖尿病関連疾患、若しくは糖尿病性合併症の予防又は治療に有用な医薬を提供することが可能となり、更なる医薬品産業の発達が期待される。 Combining a drug containing a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a medicine containing a compound that inhibits SGLT2 or a pharmaceutically acceptable salt thereof as an active ingredient The medicament of the present invention has an excellent inhibitory effect on increase in blood glucose level. Therefore, according to the present invention, it is possible to provide a drug useful for the prevention or treatment of diabetes, diabetes-related diseases, or diabetic complications, and further development of the pharmaceutical industry is expected.
Claims (4)
SGLT2を阻害する化合物又はその製薬学的に許容される塩を有効成分として含有する医薬
を組み合わせてなる医薬。 Combining a drug containing a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a medicine containing a compound that inhibits SGLT2 or a pharmaceutically acceptable salt thereof as an active ingredient Medicine.
SGLT2を阻害する化合物が下記式[II]で表される化合物である
請求項1に記載の医薬。
The compound that inhibits SGLT1 is a compound represented by the following formula [I],
The pharmaceutical according to claim 1, wherein the compound that inhibits SGLT2 is a compound represented by the following formula [II].
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CN114450011A (en) * | 2019-05-31 | 2022-05-06 | 阿沃林特有限公司 | Compositions and methods for treating metabolic disorders |
EP3976053A4 (en) * | 2019-05-31 | 2022-11-23 | Avolynt | Compositions and methods for treating metabolic disease |
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