WO2015178683A1 - Pharmaceutical composition comprising p-glycoprotein inhibitor and p-glycoprotein substrate drug - Google Patents

Pharmaceutical composition comprising p-glycoprotein inhibitor and p-glycoprotein substrate drug Download PDF

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WO2015178683A1
WO2015178683A1 PCT/KR2015/005053 KR2015005053W WO2015178683A1 WO 2015178683 A1 WO2015178683 A1 WO 2015178683A1 KR 2015005053 W KR2015005053 W KR 2015005053W WO 2015178683 A1 WO2015178683 A1 WO 2015178683A1
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glycoprotein
drug
dabigatran
pharmaceutical composition
substrate
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PCT/KR2015/005053
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French (fr)
Korean (ko)
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장영길
이재헌
이재구
최경진
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한미정밀화학주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • compositions comprising inhibitors of P-glycoproteins and substrate drugs of P-glycoproteins
  • the present invention relates to pharmaceutical compositions comprising inhibitors of P-glycoproteins and substrate drugs of P-glycoproteins.
  • Dabigatran etexilate Product name Pradaxa, Pradaxa
  • Pradaxa is a thrombin inhibitor that is effective in preventing postoperative deep vein thrombosis, stroke, and atrial fibrillation and stroke, especially atriai fibrillation.
  • AF is the first oral anticoagulant drug released worldwide in about 60 years after warfarin. Compared with warfarin, this drug has little drug interaction, a relatively wide range of treatment, and does not require anti-ungogenic activity monitoring.
  • dabigatran is a relatively safe drug with relatively low gastrointestinal bleeding or intracranial hemorrhage compared to warfarin (Souffi OTffi MR e: Eng: J. of Med). ⁇ 3; DOI: DOI: 10.1056 / NEJMpl302834).
  • the dabigat duct etexilate is a prodrug with very low solubility and is a substrate of P-glycoprotein, which inhibits its absorption by p-glycoprotein in the intestinal tract and thus oral bioavailability. Only about%. As demonstrated by this low oral bioavailability, only a portion of dabigatran etexilate is absorbed from the digestive tract and the remainder remains in the GI tract and is eventually excreted in feces. Two-thirds are converted to active dabigatran by gut esterase (Jay Desai et al., Trombo Haemost. 10 (2), 205-12 (2013); see FIG. 1).
  • dabigatran etexilate When oral intake of tran etexilate, dabigatran etexilate, a substrate of P-glycoprotein, is absorbed from the digestive tract and transported through the gut wall into the blood vessels, where some dabigatran etexilate is released from the MONO—After being converted to prodrugs, blood vessels are transformed into blood vessels, dabigatran. Dabigatran etexilate is excreted back into the lumen by the P-glycoprotein at the barrier, consequently the substrate of the p-glycoprotein. Therefore, limited absorption of dabigatran occurs and thus lowers bioavailability.
  • dabigatran an anticoagulant active agent
  • the lumen of the gastrointestinal tract rather than in blood vessels, hemorrhage in the lesion. Therefore, it is necessary to reduce the exposure of dabigatran in the gastrointestinal tract, since the amount of dabigatran remaining in the gastrointestinal tract is a major factor in the degree of bleeding.
  • an object of the present invention is to provide a pharmaceutical composition that enhances the pharmacological effect of the substrate drug of P-glycoprotein, including dabigatran, enjoys side effects, and can effectively administer the drug in a small amount.
  • the present invention provides an inhibitor of P-glycoprotein and
  • a pharmaceutical composition comprising a substrate drug of P-glycoprotein.
  • the pharmaceutical compositions of the present invention can reduce the side effects of drugs caused by P-glycoprotein and activity, and further provide equivalent pharmacological effects using smaller amounts of drugs.
  • the combination of P-glycoprotein substrate drug dabigatran etexilate and P-glycoprotein inhibitor tetrazole derivatives can significantly increase the bioavailability of dabigatran etexilay S.
  • Reduction of the amount of use of the same level of bioavailability can significantly reduce the residual amount of dabigatran in the gastrointestinal tract.
  • this reduces the amount of drug exposure in the gastrointestinal tract, thereby reducing the risk of bleeding, a fatal drawback for patients taking conventional dabigatran etexilate.
  • Figure 1 is a schematic diagram showing the path of absorption of dabigatran etexilate by P-glycoprotein in the gastrointestinal tract.
  • the present invention provides a pharmaceutical composition comprising an inhibitor of P-glycoprotein and a substrate drug of P-glycoprotein.
  • inhibitors of the P-glycoprotein used in the composition of the present invention include tetrazole derivatives of the general formula (1) or pharmaceutically acceptable salts thereof:
  • Tetrazole derivatives of Formula 1 are known as effective P-glycoprotein inhibitors (see US Pat. No. 7,625,926) and can be readily prepared according to known methods. Can be. Pharmaceutically acceptable salts of the tetrazole derivatives include all salt forms prepared using organic or inorganic acids.
  • a substance known as a third generation p-glycoprotein inhibitor such as LY 335979, XR 9576, OC 144-093, quercetin, Rutin, etc. J. Pharm. Pharmaceut. Sci., 12 (1): 46-78, 2009) or combinations thereof.
  • P-glycoprotein is a substance that causes multi-drug resistance (MDR) of cancer cells and is a transporter (excretion transporter) involved in the excretion of many drugs. They are distributed in the human body such as kidney, liver and brain barrier. Especially, P-glycoprotein in small intestine epithelium is reversed from digestive tract absorption. do.
  • MDR multi-drug resistance
  • p-glycoprotein inhibitors such as verapamil or cyclosporine
  • side effects such as hypotension or immunosuppression are present in clinical trials. Cancer Res., 41, 1967-1972, 1981. Therefore, such pharmacologically substances can not be used with the substrate drug of the P-glycoprotein of the present invention, such as dabigatran etexilate.
  • substrate drug of the P-glycoprotein of the present invention such as dabigatran etexilate.
  • Substrate drugs of P-glycoproteins used in the compositions of the present invention include dabigatran, Apixaban, Rivaroxaban, naproxen, celecoxib, Meloxicam ), Clarithromycine, clopidogrel, aspirin, duloxetine, silodosine, pharmaceutically acceptable precursors thereof, pharmaceuticals thereof It can be selected from the group consisting of acceptable salts, and combinations thereof.
  • the substrate drug of the p ⁇ glycoprotein is Dabigatran etexilate of Formula 2 or a pharmaceutically acceptable salt thereof:
  • Preferred examples of the pharmaceutically acceptable salt of dabigatran etexilate include, but are not limited to, dabigatran etexilate mesylate.
  • the substrate drug of the P-glycoprotein may be used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents, based on the P-glycoprotein inhibitor.
  • the pharmaceutical compositions of the present invention may further comprise pharmaceutically acceptable additives such as carriers, excipients and the like.
  • the pharmaceutical compositions of the present invention may be formulated in a variety of oral dosage forms. The inventors have found a way to reduce exposure of dabigatran to the gastrointestinal tract.
  • dabigatran etexilate is a P-glycoprotein substrate
  • administration of dabigatran etexilate or a pharmaceutically acceptable salt thereof with a P-glycoprotein inhibitor results in the gastrointestinal tract of dabigatran.
  • the inventors of the present invention have determined that they will be able to enjoy the exposure at.
  • the pharmaceutical compositions of the present invention may exhibit an improved effect of reducing the dosage of P-glycoprotein matrix drugs, or reducing drug exposure in the gastrointestinal tract, and reducing gastrointestinal related side effects such as ulcers.
  • the rats were administered dabigatran etexilate mesylate with or without P-glycoprotein inhibitor and examined the dabigatran concentration in the gastrointestinal tract, P- It was confirmed that the concentration of dabigatran in the gastrointestinal tract was lower than in the case of using the glycoprotein inhibitor. From these results, it can be inferred that co-administration of P-glycoprotein inhibitors and P-glycoprotein substrate drugs can reduce bleeding in vulnerable lesions.
  • the present invention provides a method for lowering gastrointestinal bleeding, which is not a substrate drug of P-glycoprotein in a subject, comprising administering an inhibitor of P-glycoprotein and a substrate drug of P-glycoprotein to a subject in need thereof. To provide.
  • the present invention provides a method for lowering ulcers caused by substrate drugs of P-glycoprotein in a subject, comprising administering P-glycoproteins and inhibitors and substrate drugs of P-glycoprotein to a subject in need thereof.
  • Preparation Example 1 N- (2- (2- (4- (2- (6, gdimethoxy-3,4-dihydroisoquinolin-2 (1H) -yl) ethyl) phenyl) -2H-tetrazol Preparation of -5-yl) -4,5-dimethoxyphenyl) -4-oxo-4H-chromen-2-carboxamide (tetrazole derivative of formula 1) 2- (2- (4- (2- (6,7-dimethoxy— 3,4-dihydroisoquinolin-2 (1H) -yl) ethyl) phenyl) -2H-tetrazol-5-yl) 0.85 g of -4,5-dimethoxybenzeneamine and 0.
  • Preparation Example 3 Preparation of dabigatran etexilate mesylate (DAEM) 20 g of dabigatran etexilate (4chembiogenix) was added to 112 mL of acetone and then dissolved by stirring at about 40-50 ° C. The dissolved reaction solution was slowly cooled to about 30-36 ° C. On the other hand, a solution of 3.5 g of mesylic acid (MSA) dissolved in 10 mL of acetone was slowly added to the reaction solution for 15 to 40 minutes while maintaining 30 to 36 ° C. The reaction liquid 26-3
  • MSA mesylic acid
  • Example 2 Concentration and pharmacokinetic characterization of P-glycoprotein substrate drugs in the small and large intestine according to the combination of p—glycoprotein inhibitors and P-glycoprotein substrate drugs
  • the concentrations of p-glycoprotein substrate drugs in the small and large intestine following the combination of P-glycoprotein inhibitors and P-glycoprotein substrate drugs were analyzed.
  • DAEM dabigatran etexilate mesylate
  • DAEM dabigatran etexilate mesylate
  • the control group administered with dabigatran etexilate mesylate alone had a high concentration with dabigatran in the small and large intestine
  • the experimental group co-administered with dabigatran etexylate mesylate and tetrazole derivatives. Showed a relatively low dabigatran concentration.
  • the results show that co-administration of P-glycoprotein inhibitors and P-glycoprotein substrate drugs can lower gastrointestinal side effects caused by P-glycoprotein substrate drugs.

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Abstract

The present invention relates to a pharmaceutical composition comprising a p-glycoprotein inhibitor and a p-glycoprotein substrate drug. The pharmaceutical composition of the present invention reduces side effects of the drug caused by activity of p-glycoprotein, and further may provide an equivalent pharmacological effect using a smaller amount of the drug. In particular, use of dabigatran etexilate, a p-glycoprotein substrate drug, with tetrazole derivative, a p-glycoprotein inhibitor, can significantly increase the bioavailability of dabigatran etexilate, and consequently the remaining amount of dabigatran etexilate in the gastrointestinal tract may be significantly reduced as the drug has the same level of bioavailability despite a reduction in the amount thereof. Also, because of the above reasons, the dosage of the drug in the gastrointestinal tract is reduced, and so the pharmaceutical composition of the present invention can reduce the risk of bleeding, a fatal drawback for patients taking a conventional dabigatran etexilate.

Description

명세서  Specification
P-당단백질의 저해제 및 P-당단백질의 기질 약물을포함하는 약제학적 조성물 발명의 분야 본 발명은 P-당단백질의 저해제 및 P-당단꿱질의 기질 약물을 포함하는 약제학적 조성물에 관한 것이다. 발명의 배경 다비가트란 에텍실레이트 (제품명 Pradaxa, 프라닥사)는 수술 후 심부정맥 혈전증， 뇌졸중， 및 심방 세동이 았는 환자와 뇌졸중을 예방하는데 효능이 있는 트롬빈 억제제로서， 특히 심빙^세동 (atriai fibrillation, AF) 환자의 뇌졸중 예방에 있어서는 와파린 아후 약 60여년 만에 전세계적으로 출시된 최초의 경구용 항웅 고제이다. 이 약물은 와파린에 비해 약물 간 상호작용이 거의 없고， 치료 범위가 비 H적 넓으며, 항웅고 작용 모니터링이 필요하지 않다는 장점도 있다.  Pharmaceutical compositions comprising inhibitors of P-glycoproteins and substrate drugs of P-glycoproteins The present invention relates to pharmaceutical compositions comprising inhibitors of P-glycoproteins and substrate drugs of P-glycoproteins. Background of the Invention Dabigatran etexilate (Product name Pradaxa, Pradaxa) is a thrombin inhibitor that is effective in preventing postoperative deep vein thrombosis, stroke, and atrial fibrillation and stroke, especially atriai fibrillation. , AF) is the first oral anticoagulant drug released worldwide in about 60 years after warfarin. Compared with warfarin, this drug has little drug interaction, a relatively wide range of treatment, and does not require anti-ungogenic activity monitoring.
하기 표 1에서 보는 바와 같이, 다비가트란은 와파린에 비하여 위장관 출 혈이나 두개내 출혈 (Intracranial hemorrhage)이 상대적으로 낮아 상당히 안전한 약물인 것으로 알려졌다 (Souffi¥OTffi MR e ：， Eng: J. of Med:; ^3； DOI:DOI: 10.1056/NEJMpl302834). ,  As shown in Table 1, dabigatran is a relatively safe drug with relatively low gastrointestinal bleeding or intracranial hemorrhage compared to warfarin (Souffi OTffi MR e: Eng: J. of Med). ^ 3; DOI: DOI: 10.1056 / NEJMpl302834). ,
〈표 1>  <Table 1>
다비가트란 및 와파린의 위장관 출혈 및 두개내 출혈에 대한 RE-LY 임 상시험 (기년， 여성 36.7%)  RE-LY clinical study of gastrointestinal bleeding and intracranial hemorrhage of dabigatran and warfarin (36.7% of women in the year)
Figure imgf000003_0001
그러나, 다른 한편으로 표 2에서 보는바와 같이， RE-LY 임상시험 결과와 정반대로， 다비가트란이 와파린에 비하여 위장관 출혈을 2배 이상 야기하며, 특 히 출혈에 의한 사망도 2배 가량 높은 것으로 보고되었다 (American College of Cardiology 2013 Scientific Sessions; March 1Ό. 2013； San Francisco, CA. Abstract 914-8).
Figure imgf000003_0001
On the other hand, as shown in Table 2, contrary to the results of the RE-LY study, dabigatran causes more than twice as much gastrointestinal bleeding as warfarin, and in particular, the death from bleeding is about twice as high. Reported (American College of Cardiology 2013 Scientific Sessions; March 1 ′. 2013; San Francisco, CA.Abstract 914-8).
〈표 2〉  <Table 2>
FDA에 보고된 와파린 및 다비가트란의 부작용  Side effects of warfarin and dabigatran reported to the FDA
Figure imgf000004_0001
다비가트관 에텍실레이트는 전구약물 (prodrug)로서 용해도가 무척 낮을 뿐만 아니라 P-당단백질의 기질 (substrate)이어서 장관 내의 p-당단백질에 의하여 이의 흡수가 저해되고ᅳ 그에 따라 경구 생체이용률이 6% 정도에 불과하다. 이와 같이 낮은 경구 생체이용률에서 알 수 있듯이， 다비가트란 에텍실레이트는 일부만 소화관에서 흡수되고， 그 나머지는 위장관 (GI tract)에 남아 결국 대변으로 배출되는데， 이러한 경로를 거치는 증에 전구꺅물의 3분의 2가 소화관 께스터레이츠 (gut esterase)에 의해 활성체인 다비가트란으로 전환된다 (Jay Desai 등， Trombo Haemost. 10(2), 205-12(2013)； 도 1 참조) · 다비가트란 에텍실레이트를 경구 섭취하면， P-당단백질의 기질인 다비가트란 에텍실레이트가 소화관에서 흡수되어 장벽 (gut wall)을 거쳐 혈관으로 이송되는데, 이때 일부 다비가트란 에텍실레이트가 장벽에서 모노—전구약물로 전환된 후 혈관으로 «·어가 활성체인 다비가트란으로 바뀌고, 또 일부 다비가트란 에텍실레이트는 p-당단백질의 기질인 연유로 장벽에 있는 P-당단백질에 의해 다시 루멘으로 _배출된다. 따라서， 다비가트란의 흡수가 제한적으로 일어나고 그에 따라 생체이용를이 낮아지게 되며, 특히 항응고작용을 하는 활성체인 다비가트란이 혈관이 아닌 위장관의 루멘 (lumen) 내에 대부분 존재하게 됨에 따라 취약한 병소 (lesion)에서 출혈을 일으키는 원인으로 작용할 수 았다. 따라서 위장관에 다비가트란 잔류량이 어느 정도 노출되어 느냐가 출혈 정도에 주요한 인자이므로, 위장관에서의 다비가트란의 노출량을 감소시킬 필요가 있다.
Figure imgf000004_0001
The dabigat duct etexilate is a prodrug with very low solubility and is a substrate of P-glycoprotein, which inhibits its absorption by p-glycoprotein in the intestinal tract and thus oral bioavailability. Only about%. As demonstrated by this low oral bioavailability, only a portion of dabigatran etexilate is absorbed from the digestive tract and the remainder remains in the GI tract and is eventually excreted in feces. Two-thirds are converted to active dabigatran by gut esterase (Jay Desai et al., Trombo Haemost. 10 (2), 205-12 (2013); see FIG. 1). When oral intake of tran etexilate, dabigatran etexilate, a substrate of P-glycoprotein, is absorbed from the digestive tract and transported through the gut wall into the blood vessels, where some dabigatran etexilate is released from the MONO—After being converted to prodrugs, blood vessels are transformed into blood vessels, dabigatran. Dabigatran etexilate is excreted back into the lumen by the P-glycoprotein at the barrier, consequently the substrate of the p-glycoprotein. Therefore, limited absorption of dabigatran occurs and thus lowers bioavailability. Especially, since dabigatran, an anticoagulant active agent, is mostly present in the lumen of the gastrointestinal tract rather than in blood vessels, hemorrhage in the lesion). Therefore, it is necessary to reduce the exposure of dabigatran in the gastrointestinal tract, since the amount of dabigatran remaining in the gastrointestinal tract is a major factor in the degree of bleeding.
발명의 요약 Summary of the Invention
따라서， 본 발명의 목적은 다비가트란을 비롯한 P-당단백질의 기질 약물의 체내 약리 효과를 높이고 부작용을 즐이며， 상기 약물을 적은 양으로 유효하게 투여할 수밌는 약제학적 조성물을 제공하는 것이다. Accordingly, an object of the present invention is to provide a pharmaceutical composition that enhances the pharmacological effect of the substrate drug of P-glycoprotein, including dabigatran, enjoys side effects, and can effectively administer the drug in a small amount.
상기 목적을 달성하기 위해， 본 발명은 P-당단백질의 저해제 및 In order to achieve the above object, the present invention provides an inhibitor of P-glycoprotein and
P-당단백질의 기질 약물을 포함하는 약제학적 조성물을 제공한다. 본 발명의 약제학적 조성물은 P-당단백질와 활성에 의하여 발생하는 약물의 부작용을 줄이고， 나아가 더 적은 양의 약물을 사용하여 동등한 약리 효과를 제공할 수 있다. 특히， P-당단백질 기질 약물인 다비가트란 에텍실레이트와 P-당단백질 저해제인 테트라졸 유도체를 함께 사용하면 다비가트란 에텍실레이 S의 생체이용를을 현저히 증가시킬 수 있으며， 그 결과 상가 약물의 사용량을 줄여도동일 수준의 생체이용률을 갖게 되어 위장관에서의 다비가트란의 잔류량을 .현저히 줄일 수 있다. 또한， 이 때문에 위장관에서의 약물 노출량이 적어져 종래 다비가트란 에텍실레이트를 복용하는 환자의 치명적인 단점인 출혈 위험을 감소시킬 수 있다. Provided is a pharmaceutical composition comprising a substrate drug of P-glycoprotein. The pharmaceutical compositions of the present invention can reduce the side effects of drugs caused by P-glycoprotein and activity, and further provide equivalent pharmacological effects using smaller amounts of drugs. In particular, the combination of P-glycoprotein substrate drug dabigatran etexilate and P-glycoprotein inhibitor tetrazole derivatives can significantly increase the bioavailability of dabigatran etexilay S. Reduction of the amount of use of the same level of bioavailability can significantly reduce the residual amount of dabigatran in the gastrointestinal tract. In addition, this reduces the amount of drug exposure in the gastrointestinal tract, thereby reducing the risk of bleeding, a fatal drawback for patients taking conventional dabigatran etexilate.
도면의 간단한설명 도 1은 위장관에서 P-당단백질에 의하여 다비가트란 에텍실레이트가 흡수되는 경로를 나타낸 모식도이다. Brief description of the drawings Figure 1 is a schematic diagram showing the path of absorption of dabigatran etexilate by P-glycoprotein in the gastrointestinal tract.
도 2는 랫트에 다비가트란 (-♦-) 단독 투여; 다비가트란 에텍실레이트 메실산염 (DAEM, -·-) 단독 투여; 및 DAEM과 테트라졸 유도체의 병용 투여 (-A-)시 시간 경과에 따른 다비가트란의 혈장내 농도를 나타낸 그래프이다. 도 3은 랫트에 다비가트란 에텍실레이트 메실산염 (DAEM) 단독 투여; 및 DAEM과 테트라졸 유도체의 병용 투여시 시간 경과에 따른 소장 및 대장에서의 다비가트란꾀 농도를 나타낸 그래프이다. 발명의 상세한설명 본 발명은 P-당단백질의 저해제 및 P-당단백질의 기질 약물을 포함하는 약제학적 조성물을 제공한다.  2 shows administration of dabigatran (-♦-) alone to rats; Administration of dabigatran etexilate mesylate (DAEM, -.-) alone; And plasma concentrations of dabigatran over time upon co-administration of DAEM and tetrazole derivatives (-A-). Figure 3 administration of dabigatran etexilate mesylate (DAEM) alone to rats; And dabigatranchi concentration in the small intestine and the large intestine over time when co-administration of DAEM and tetrazole derivatives. DETAILED DESCRIPTION The present invention provides a pharmaceutical composition comprising an inhibitor of P-glycoprotein and a substrate drug of P-glycoprotein.
<P-당단백질와 저해제〉 P-glycoproteins and Inhibitors
본 발명의 조성물에 사용되는 P-당단백질의 저해제의 바람직한 예는 하기 화학식 1의 테트라졸 유도체 또는 이의 약제학적으로 허용가능한 염을 들 수 있 다：  Preferred examples of inhibitors of the P-glycoprotein used in the composition of the present invention include tetrazole derivatives of the general formula (1) or pharmaceutically acceptable salts thereof:
Figure imgf000006_0001
Figure imgf000006_0001
상기 화학식 1의 테트라졸 유도체는 효과적인 P-당단백질 저해제로 알려 져 있으며 (미국 특허 계 7,625,926호 참조), 공지의 방법에 따라 용이하게 제조될 수 있다. 상기 테트라졸 유도체의 약제학적으로 허용가능한 염은， 유기산 또는 무기산을 이용하여 제조된 염 형태를 모두 포함한다. Tetrazole derivatives of Formula 1 are known as effective P-glycoprotein inhibitors (see US Pat. No. 7,625,926) and can be readily prepared according to known methods. Can be. Pharmaceutically acceptable salts of the tetrazole derivatives include all salt forms prepared using organic or inorganic acids.
또한， 본 발명의 다른 실시 양태에서， P-당단백질 저해제로서， LY 335979， XR 9576, OC 144-093， 쿼세틴 (quercetin), 루틴 (Rutin) 등과 같은 3세대 p-당단 백질 저해제로 알려진 물질 (J. Pharm. Pharmaceut. Sci., 12(1)： 46-78, 2009) 또 는 이들의 흔합물이 사용될 수 있다. 、  Further, in another embodiment of the present invention, as a P-glycoprotein inhibitor, a substance known as a third generation p-glycoprotein inhibitor such as LY 335979, XR 9576, OC 144-093, quercetin, Rutin, etc. J. Pharm. Pharmaceut. Sci., 12 (1): 46-78, 2009) or combinations thereof. 、
P-당단백질은 암세포의 다제내성 (MDR: Multi-drug resistance)의 원인이 되는 물질로서， 많은 약물의 배설에 관여하는 트랜스포터 (배설수송담체)이다. 이 들은 신장， 간장， 뇌장벽 등 인체 내에 분포되어 았으며, 특히 소장상피에 존재하 는 P-당단백질은 소화관 흡수와는 역방향으로， 즉 혈관 쪽에서 소화관 내로 약물 을 배설시켜 장관에서의 약물 흡수를 방해한다. P-glycoprotein is a substance that causes multi-drug resistance (MDR) of cancer cells and is a transporter (excretion transporter) involved in the excretion of many drugs. They are distributed in the human body such as kidney, liver and brain barrier. Especially, P-glycoprotein in small intestine epithelium is reversed from digestive tract absorption. do.
한편, 베라파밀 (Verapamil) 또는 사이클로스포린 (cyclosporine) 같은 p- 당단백질 저해제는 그 자체가 강력한 약리작용을 지니고 있어서 이들 약물과 함 께 사용할 경우 혈압강하 또는 면역억제와 같은 부작용이 임상시 나타나는 문제 점이 있다 (Cancer Res., 41, 1967-1972, 1981). 따라서 이러한 약리작용아 있는 물질은， 본 발명의 P-당단백질의 기질 약물， 예컨대 다비가트란 에텍실레이트와 함께 사용할 수 없다. <p-당단백질의 기질 약물〉  On the other hand, p-glycoprotein inhibitors, such as verapamil or cyclosporine, have strong pharmacological effects in themselves, and when used with these drugs, side effects such as hypotension or immunosuppression are present in clinical trials. Cancer Res., 41, 1967-1972, 1981). Therefore, such pharmacologically substances can not be used with the substrate drug of the P-glycoprotein of the present invention, such as dabigatran etexilate. <substrate drug of p-glycoprotein>
본 발명의 조성물에 사용되는 P-당단백질의 기질 약물은 다비가트란 (dabigatran), 아픽사반 (Apixaban), 리바록사반 (Rivaroxaban), 나프록센， 샐레콕 시브 (celecoxib), 멜록시캄 (Meloxicam), 클래리스로마이신 (Clarithromycine), 클 로피도그텔 (Clopidogrel), 아스피린 (Aspirin), 둘록세틴 (Duloxetine), 실로도신 (Silodosin), 이들의 약제학적으로 허용가 ^한 전구물질, 이들의 약제학적으로 허 용가능한 염， 및 이들의 흔합물로 이루어진 군으로부터 선택될 수 있다.  Substrate drugs of P-glycoproteins used in the compositions of the present invention include dabigatran, Apixaban, Rivaroxaban, naproxen, celecoxib, Meloxicam ), Clarithromycine, clopidogrel, aspirin, duloxetine, silodosine, pharmaceutically acceptable precursors thereof, pharmaceuticals thereof It can be selected from the group consisting of acceptable salts, and combinations thereof.
본 발명의 바람직한 구현예에서 상기 pᅳ당단백질의 기질 약물은 하기 화 학식 2의 다비가트란 에텍실레이트 또는 이의 약제학적으로 허용가능한 염일 수 있다: In a preferred embodiment of the present invention, the substrate drug of the p \ glycoprotein is Dabigatran etexilate of Formula 2 or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
Figure imgf000008_0001
상기 다비가트란 에텍실레이트의 약제학적으로 허용가능한 염의 바람직한 예로는 다비가트란 에텍실레이트 메실산염을 들 수 있으나， 이에 제한되지 않는 다.  Preferred examples of the pharmaceutically acceptable salt of dabigatran etexilate include, but are not limited to, dabigatran etexilate mesylate.
본 발명의 약제학적 조성물에서， 상기 P-당단백질의 기질 약물은 P-당단 백질 저해제를 기준으로 0.1 내지 10 당량비, 바람직하게는 0.5 내지 5 당량비로 사용될 수 있다. 전술한 상기 2종의 활성 성분 외에도， 본 발명의 꺅제학적 조성물은， 약제 학적으로 허용가능한 첨가제, 예컨대 담체， 부형제 등을 추가로 포함할수 있다. 또한, 본 발명의 약제학적 조성물은 다양한 경구 투여 형태로 제형화될 수 있다. 본 발명자들은 다비가트란의 위장관에서의 노출을 줄일 수 있는 방안에. 관해 연구하던 중, 다비가트란 에텍실레이트가 P-당단백질 기질임을 고려하여， 다비가트란 에텍실레이트 또는 이의 약제학적으로 허용가능한 염을 P-당단백질 저해제와 함께 투여하면 다비가트란의 위장관에서의 노출량을 즐일 수 있을 것으 로 판단하고 본 발명을 개발하게 되었다.  In the pharmaceutical composition of the present invention, the substrate drug of the P-glycoprotein may be used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents, based on the P-glycoprotein inhibitor. In addition to the two active ingredients described above, the pharmaceutical compositions of the present invention may further comprise pharmaceutically acceptable additives such as carriers, excipients and the like. In addition, the pharmaceutical compositions of the present invention may be formulated in a variety of oral dosage forms. The inventors have found a way to reduce exposure of dabigatran to the gastrointestinal tract. During the study, considering that dabigatran etexilate is a P-glycoprotein substrate, administration of dabigatran etexilate or a pharmaceutically acceptable salt thereof with a P-glycoprotein inhibitor results in the gastrointestinal tract of dabigatran. The inventors of the present invention have determined that they will be able to enjoy the exposure at.
선행 연구에 의하면， 다비가트란 에텍실레이트를 11 Omg 용량으로 하루 2 회 복용한 환자에서의 주요 장출혈위험이 와파린과 비슷하였으나， 75mg 저용량 으로 하루. 2회 복용할—경우에는 장출혈 위험이 보고되지 않았다 (Jay Desai 등, Trombo Haemost. 10(2), 205-12(2013)). 이러한 결과는다비가트란을 75mg의 저용량으로도 l lOmg의 고용량과 유사한 효력을 나타낼 수만 있다면 그만큼 장 출혈위험을 혁신적으로 낮출 수 있다는 의미로서 그 시사하는 바가크다. 본 발명의 약제학적 조성물은 P-당단백질 기질 약물의 투여 용량을 줄이 거나， 위장관에서의 약물 노출을 줄여， 위장관 관련 부작용， 예컨대 궤양을 줄이 는 개선된 효과를 나타낼 수 있다. According to a previous study, dabigatran etexilate was dosed at 11 Omg 2 times a day. The major intestinal bleeding risk was similar to that of warfarin in single doses, but at 75 mg daily. Two doses—no risk of intestinal bleeding was reported (Jay Desai et al., Trombo Haemost. 10 (2), 205-12 (2013)). These findings suggest that if a low dose of 75 mg of vigatran can be as effective as a high dose of lOmg, the risk of intestinal bleeding can be significantly lowered. The pharmaceutical compositions of the present invention may exhibit an improved effect of reducing the dosage of P-glycoprotein matrix drugs, or reducing drug exposure in the gastrointestinal tract, and reducing gastrointestinal related side effects such as ulcers.
본 발명에 따른 실험 결과에 따르면， 랫트를 대상으로 P-당단백질 저해제 를 사용하거나 사용하지 않은 상태로 다비가트란 에텍실레이트 메실산염을 투여 하고 위장관에서의 다비가트란 농도를 살펴본 결과， P-당단백질 저해제를 사용한 경우가그렇지 않은 경우에 비해 위장관에서의 다비가트란의 농도가낮음을 확인 하였다. 이 결과로부터 P-당단백질 저해제와 P-당단백질 기질 약물의 병용 투여 가 취약한 병소 (lesion)에서의 출혈사례를 낮출 수 있음을 유추할수 있다. 또한, 본 발명은 P-당단백질의 저해제 및 P-당단백질의 기질 약물을 이를 필요로 하는 대상에게 투여하는 것을 포함하는， 대상에서의 P-당단백질의 기질 약물로 _안한 위장관 출혈을 낮추는 방법을 제공한다.  According to the experimental results according to the present invention, the rats were administered dabigatran etexilate mesylate with or without P-glycoprotein inhibitor and examined the dabigatran concentration in the gastrointestinal tract, P- It was confirmed that the concentration of dabigatran in the gastrointestinal tract was lower than in the case of using the glycoprotein inhibitor. From these results, it can be inferred that co-administration of P-glycoprotein inhibitors and P-glycoprotein substrate drugs can reduce bleeding in vulnerable lesions. In addition, the present invention provides a method for lowering gastrointestinal bleeding, which is not a substrate drug of P-glycoprotein in a subject, comprising administering an inhibitor of P-glycoprotein and a substrate drug of P-glycoprotein to a subject in need thereof. To provide.
나아가， P-당단백질와 저해제 및 P-당단백질의 기질 약물을 이를 필요로 하는 대상에게 투여하는 것을 포함하는， 대상에서의 P-당단백질의 기질 약물로 인한 궤양을 낮추는 방법을 제공한다. 제조예 1: N-(2-(2-(4-(2-(6,그디메록시 -3，4-디하이드로이소퀴놀린 -2(1H)-일)에틸)페닐) -2H-테트라졸 -5-일) -4,5-디메특시페닐 )-4-옥소 -4H-크로 멘 -2-카르복사마드 (화학식 1의 테트라졸유도체)의 제조 2-(2-(4-(2-(6，7-디메톡시— 3,4-디하이드로이소퀴놀린 -2(1H)-일)에틸)페 닐) -2H-테트라졸 -5-일) -4,5-디메톡시벤젠아민 0.85g 및 4-옥소 -4H-크로멘 -2-카보티오산 S—벤조티아졸 -2—일 에스테르 0.75g을 디클로로메탄 5 mL에 첨 가한 후 상온에서 12시간 동안 교반하여 반웅시켰다. 반웅이 완료후， 상기 반 '웅 용액을 증류수 50 mL로 세척하고 유기층을 황산 마그네슘으로 건조시킨 후 감압여과 및 감압증류하여 잔사를 얻었다. 얻어진 잔사를 컬럼 크로마토그래피로 분리 정제하여 표제화합물 (l.Og)을 수득하였다. 제조예 2. N-(2-(2-(4-(2-(6,7-디메특시 -3,4-디하이드로이소퀴놀린 -2(1H)-일)에틸)페닐) -2H-테트라졸 -5-일) -4，5-디메톡시페닐 )-4-옥소— 4H-크로 멘 -2-카르복사미드 메탄설포네이트 (화학식 1의 테트라졸 유도체와 메탄설폰산 염)의 제조 Furthermore, the present invention provides a method for lowering ulcers caused by substrate drugs of P-glycoprotein in a subject, comprising administering P-glycoproteins and inhibitors and substrate drugs of P-glycoprotein to a subject in need thereof. Preparation Example 1 N- (2- (2- (4- (2- (6, gdimethoxy-3,4-dihydroisoquinolin-2 (1H) -yl) ethyl) phenyl) -2H-tetrazol Preparation of -5-yl) -4,5-dimethoxyphenyl) -4-oxo-4H-chromen-2-carboxamide (tetrazole derivative of formula 1) 2- (2- (4- (2- (6,7-dimethoxy— 3,4-dihydroisoquinolin-2 (1H) -yl) ethyl) phenyl) -2H-tetrazol-5-yl) 0.85 g of -4,5-dimethoxybenzeneamine and 0.75 g of 4-oxo-4H-chromen-2-carbothioic acid S-benzothiazol-2-yl ester were added to 5 mL of dichloromethane, followed by 12 at room temperature. Stirred for hours to react. After banung is complete, then washing the anti 'grand solution with distilled water to 50 mL and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure and filtration under reduced pressure to obtain a residue. The obtained residue was separated and purified by column chromatography to give the title compound (l.Og). Preparation Example 2.N- (2- (2- (4- (2- (6,7-Dimethic-3 -3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) phenyl) -2H- Tetrazol-5-yl) -4,5-dimethoxyphenyl) -4-oxo—4H-chromen-2-carboxamide methanesulfonate (Tetrazole Derivative and Methanesulfonic Acid Salt of Formula 1)
N-(2-(2-(4-(2-(6,7-디메록시 -3,4-디하이드로이소퀴놀린 -2(1Ή)—일)에 탈)페닐) -2Η-테트라졸 -5-일) -4,5-디메록시페날 )-4-옥소 -4Η-크로멘 -2-카르복 사미드 1.4g을 에틸아세테이트 3 mL에 첨가한후， 여기에 메탄설폰산 0.2g을 첨 가하여 12사간 동안 교반하였다. 생성된 고체를 여과하고 에틸아세테이트로 세척 한후 건조하여 표쩨화합물 (1.2g)을 수득하였다. 제조예 3: 다비가트란에텍실레이트 메실산염 (DAEM)의 제조 다비가트란 에텍실레이트 (4chembiogenix) 20g을 아세톤 112 mL에 첨가 한 다음， 약 40~50°C에서 교반하여 용해시켰다. 상기 용해된 반웅액을 약 30~36 °C까지 서서히 냉각시켰다. 함편， 메실산 (MSA) 3.5g을 아세톤 10 mL에 녹 인 용액을 30~36°C를 유지하면서 상기 반웅액에 15~40분 동안 서서히 투입하 였다. 상기 반웅액을 26-3N- (2- (2- (4- (2- (6,7-dimethoxy-3,4-dihydroisoquinolin-2 (1))-yl))) phenyl) -2Η-tetrazol-5 -Yl) -4,5-dimethoxyphenal) -4-oxo -4Η-chromen-2-carboxamide 1.4 g was added to 3 mL of ethyl acetate, and 0.2 g of methanesulfonic acid was added thereto. Stir for 12 hours. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (1.2 g). Preparation Example 3: Preparation of dabigatran etexilate mesylate (DAEM) 20 g of dabigatran etexilate (4chembiogenix) was added to 112 mL of acetone and then dissolved by stirring at about 40-50 ° C. The dissolved reaction solution was slowly cooled to about 30-36 ° C. On the other hand, a solution of 3.5 g of mesylic acid (MSA) dissolved in 10 mL of acetone was slowly added to the reaction solution for 15 to 40 minutes while maintaining 30 to 36 ° C. The reaction liquid 26-3
3 °C로 유자하면서 40 60분간 교반한후 다시 17~23°C로 넁각하여 40 60분 동 안 교반하였다. 이어서, 얻어진ᅵ 반웅액 (모액)을 여과하고 여과된 결정을 아세톤And citron to 3 ° C After stirring for 40 60 minutes and again nyaenggak to 17 ~ 23 ° C 40 60 minutes under It was not stirred. Subsequently, the obtained reaction liquid (mother liquor) was filtered and the filtered crystals were acetone
60 mL로 세척하였다. 이후， 수득한 결정을 약 4CTC에서 훈풍 건조하여 표제화합 물 l9.6g (수율: 85.3%)을 수득하였다. Wash with 60 mL. Then, the warm air flow and drying the obtained crystals in about 4CTC title compounds l .6g 9 (yield: 85.3%) was obtained.
순: £: 99.3% by HPLC  Net: £: 99.3% by HPLC
DSC의 흡열피크: 179 °C 실시예 1: P-당단백질 저해제 및 P-당단백질 기질 약물의 병용에 따른 생 체이용률 비교 P-당단백질 저해제 및 P-당단백질 기질 약물의 병용에 따른 P-당단백질 기질 약물의 생체이용률을 살펴보았다. 구체적으로， 랫트 3마리에 각각 다비가트 란 (4chembiogenix) 단독， 제조예 3에서 제조된 다비가트란 에텍실레이트 메실산 염 (DAEM) 단독， 및 DAEM과 테트라졸 유도체 (제조예 2)의 조합을 경구 투여한 후, 다비가트란와 시간 경과에 따른 혈장내 농도를 측정하였다. Endothermic Peak of DSC: 179 ° C Example 1 Comparison of Bioavailability with Combination of P-Glycoprotein Inhibitor and P-Glycoprotein Substrate Drug P-Glycoprotein Inhibitor with P-Glycoprotein Substrate The bioavailability of glycoprotein matrix drugs was examined. Specifically, three rats each had dabigatran (4chembiogenix) alone, dabigatran etexilate mesylate salt (DAEM) prepared in Preparation Example 3 alone, and a combination of DAEM and tetrazole derivative (Preparation Example 2). After oral administration, plasma concentrations were measured with dabigatran and over time.
비히클 (Vehicle)은 PEG40Q, 트휜 20 및 증류수의 혼합물 (1/1/8; v/V/v)을 사용하였고, 다비가트란 단독은 0.5 mg/kg, 다바가트란 에텍실레이트 메실산염은 다비가트란 에텍실레이트를 기준으로 10 mg/kg으로 사용하였고, 테트라졸 유도 체는 테트라졸 유도체: 증류수 /프로필렌글리콜: HCl=70:30:0.02(v/v/v)의 흔합물 로서 20 mg/kg를 사용하였다.  The vehicle used a mixture of PEG40Q, TRUB 20 and distilled water (1/1/8; v / V / v), 0.5 mg / kg of dabigatran alone, and dabgatran etexilate mesylate It was used at 10 mg / kg based on Gatran etexilate, and the tetrazole derivative was 20 mg as a mixture of tetrazole derivatives: distilled water / propylene glycol: HCl = 70: 30: 0.02 (v / v / v). / kg was used.
상기 실험 결과를 도 2에 나타내었다. 도 2에서 보는 바와 같이， 다비가 트란 에텍실레이트 메실산염과 테트라졸 유도체의 병용 투여는 다비가트란 에텍 실레이: 메실산염 단독후여 및 다비가트란 단독 투여에 비해 랫트에서 더 높은 혈장농도를 나타내었다.  The experimental results are shown in FIG. 2. As shown in Figure 2, the combination administration of dabiga tran etexilate mesylate and tetrazole derivatives showed higher plasma concentrations in rats as compared to dabigatran etexisil: mesylate alone and dabigatran alone. It was.
또한， P—당단백질 저해제 및 P-당단백질 기질 약물의 병용에 따른 랫트에 서의 곡선하면적 (AUC0-24), 최대 혈장 농도 (Cmax), 반감기 및 생체이용률 (BA)을 분석하였다. 상기 결과를 표 3에 나타내었다. In addition, the curve of the enemy on standing rats according to the combined use of P- glycoprotein inhibitors and the P- substrate protein per drug were analyzed (AUC 0 24), the maximum plasma concentration (C max), half-life and bioavailability (BA) . The results are shown in Table 3.
<표 3>
Figure imgf000012_0001
상기 표 3에서 보는 바와 같이， 다비가트란 에텍실레이트 메실산염 단독 투여시 생체이용률은 9.7%인데 반해， 테트라졸 유도체와 병용 투여시 생체이용 률은 21.5%로서， 병용 투여시 2배 이상증가된 수치를 보여 주었다. 실시예 2: p—당단백질 저해제 및 P-당단백질 기질 약물의 병용에 따른 소 장 및 대장에서의 P-당단백질기질 약물의 농도 및 약동학적 특성 분석 TABLE 3
Figure imgf000012_0001
As shown in Table 3, the bioavailability of the dabigatran etexilate mesylate alone is 9.7%, whereas the bioavailability of the tetrazole derivatives in combination with 21.5%, more than doubled in combination Showed figures. Example 2: Concentration and pharmacokinetic characterization of P-glycoprotein substrate drugs in the small and large intestine according to the combination of p—glycoprotein inhibitors and P-glycoprotein substrate drugs
P-당단백질 저해제 및 P-당단백질 기질 약물의 병용에 따른 소장 및 대 장에서의 p—당단백질 기질 약물의 농도를 분석하였다. The concentrations of p-glycoprotein substrate drugs in the small and large intestine following the combination of P-glycoprotein inhibitors and P-glycoprotein substrate drugs were analyzed.
구체적으로, 대조군의 경우 랫트 (n=3)에 다비가트란 에텍실레이트 메실산 염 (DAEM) 10.0 mg/kg (다비가트란으로서)을 경구 투여하였고， 실험군의 경우 랫 트 (n=3)에 다비가트란 에텍실레이트 메실산염 5.0 mg/kg 및 테트라졸 유도체 (제 조예 2) 20.0 mg/kg을 병용하여 경구 투여한 후， 소장 (SI) 및 대장 (LI)에서의 다 비가트란 농도를 측정하였다.  Specifically, rats (n = 3) were orally administered dabigatran etexilate mesylate (DAEM) 10.0 mg / kg (as dabigatran) in the control group, and rats (n = 3) in the experimental group. After oral administration of 5.0 mg / kg of dabigatran etexilate mesylate and 20.0 mg / kg of a tetrazole derivative (Preparation Example 2), the concentration of dabigatran in the small intestine (SI) and the large intestine (LI) was determined. Measured.
상기 결과를 도 3에 나타내었다.  The results are shown in FIG. 3.
도 3에서 보는 바와 같이, 다비가트란 에텍실레이트 메실산염을 단독 투 여한 대조군은 소장 및 대장에서 다비가트란와농도가높은 반면， 다비가트란 에 텍실레이트 메실산염 및 테트라졸 유도체를 병용 투여한 실험군은 상대적으로 낮 은 다비가트란 농도를 나타내었다. 상기 결과는 P-당단백질 저해제 및 P-당단백 질 기질 약물의 병용 투여가 P-당단백질 기질 약물로 인한 위장관 부작용을 낮 출 수 있음을 보여준다. 한편， P-당단백질 저해제 및 P-당단백질 기질 약물의 병용에 따른랫트의 소장 및 대장에서의 곡선하면적 (AUC0-24), 최대 혈장 농도， 반감기 및 를을 분석하였다. 상기 결과를표 4에 나타내었다. As shown in FIG. 3, the control group administered with dabigatran etexilate mesylate alone had a high concentration with dabigatran in the small and large intestine, while the experimental group co-administered with dabigatran etexylate mesylate and tetrazole derivatives. Showed a relatively low dabigatran concentration. The results show that co-administration of P-glycoprotein inhibitors and P-glycoprotein substrate drugs can lower gastrointestinal side effects caused by P-glycoprotein substrate drugs. On the other hand, the rat according to the combination of P-glycoprotein inhibitor and P-glycoprotein substrate drug If the curve in the small intestine and colon ever-analyzed for (AUC 0 24), maximum plasma concentration, half-life and. The results are shown in Table 4.
〈표 4>  <Table 4>
Figure imgf000013_0001
상기 표 4에서 보는 바와 같이， 다비가트란 에텍실레이트 메실산염 및 테트라졸 유도체를 병용 투여한실험군의 경우 투여량이 대조군에 비해 적음에도 불구하고 대조군과 유사한 수준의 생체이용률을 나타내었다. 상기 결과는 P-당단백질 저해제 및 P-당단백질 기질 꺅물의 병용 투여함으로써 P-당단백질 기질 약물을 적은 양으로 사용함에도 불구하고 우수한 약리 JL과를 달성할 수 있고， 이에 따라 약물의 부작용을 줄일 수 있음을 보여준다. '
Figure imgf000013_0001
As shown in Table 4, the experimental group co-administered with dabigatran etexilate mesylate and tetrazole derivatives showed a similar level of bioavailability as the control group, although the dosage was smaller than that of the control group. The results show that the combination of a P-glycoprotein inhibitor and a P-glycoprotein substrate product can achieve excellent pharmacological JL despite the small amount of P-glycoprotein substrate drug, thereby reducing side effects of the drug. Shows that it can. '

Claims

허청구범위: 청구항 1. P-당단빡질의 저해제; 및 P-당단백질의 기질 약물을 포함하는 약제학적 조성물. 청구항 2. 제 1항에 있어서， 상기 P-당단백질의 쩌해제가 하기 화학식 1의 테트라졸 유도체 또는 이의 약제학적으로 허용가능한 염인 것을 특징으로 하는， 약제학적 조성물: Claims: Claim 1. Inhibitors of P-glycoprotein; And a substrate drug of P-glycoprotein. 2. The pharmaceutical composition of claim 1, wherein the inhibitor of the P-glycoprotein is a tetrazole derivative of Formula 1 or a pharmaceutically acceptable salt thereof:
<화학식 1> <Formula 1>
Figure imgf000014_0001
Figure imgf000014_0001
청구항 3. 겨 11항에 있어서， 상기 P-당단백질의 기질 약물이 다비가트란 (dabigatran), 아픽사반 (Apixaban), 리바록사반 (Rivaroxaban), 나프록센， 샐레콕시브 (celecoxib) 멜록시캄 (Meloxicam), 클래리스로마이신 (Clarithromycine)， 클로피도그텔 (Clopidogrel), 아스피린 (Aspirin), 둘록세틴 (Duloxetine), 실로도신 (Silodosin), 이들의 약제학적으로 허용가능한 전구물질， 이들의 약제학적으로 허용가능한 염， 및 이들의 흔합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는， 약제학적 조성물. ' 청구항 4. 제 3항에 있어서, 상기 P-당단백질의 기질 약물0 3. The drug substance of claim 11, wherein the substrate drug of P-glycoprotein is dabigatran, Apixaban, Rivaroxaban, naproxen, celecoxib meloxycamp (Meloxicam), clarithromycine, clopidogrel, aspirin, duloxetine, silodosin, pharmaceutically acceptable precursors thereof, medicaments thereof A pharmaceutical composition, characterized in that it is selected from the group consisting of pharmaceutically acceptable salts, and combinations thereof. '4. The method of claim 3, wherein the substrate of the P- glycoprotein drug 0
에텍실레이트 메실산염인 것을 특징으로 하는， 약제학적 조성물. 청구항 5. pᅳ당단백질의 저해제 및 P-당단백질의 기질 약물을 이를 필요로 하는 대상에게 투여하는 것을 포함하는， 대상에서의 P-당단백질의 기질 약물로 인한 위장관 출혈을 낮추는 방법. Pharmaceutical composition, characterized in that the etexilate mesylate. 5. A method of lowering gastrointestinal bleeding caused by a substrate drug of P-glycoprotein in a subject, comprising administering an inhibitor of p \ glycoprotein and a substrate drug of P-glycoprotein to the subject in need thereof.
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