KR20030095729A - PHARMACEUTICAL COMPOSITION FOR INHIBITING THE ACTIVITY OF PROTEIN TYROSINE PHOSPHATASE 1B COMPRISING 2-[5-(3-CARBOXY-4-CHLORO-PHENYL)-FURAN-2-YLMETHYLENE]-3-OXO-2,3-DIHYDRO-5H-THIAZOLO[3,2-a]PYRIMIDINE-6-CARBOXYLIC ACID ETHYL ESTER DERIVATIVES - Google Patents
PHARMACEUTICAL COMPOSITION FOR INHIBITING THE ACTIVITY OF PROTEIN TYROSINE PHOSPHATASE 1B COMPRISING 2-[5-(3-CARBOXY-4-CHLORO-PHENYL)-FURAN-2-YLMETHYLENE]-3-OXO-2,3-DIHYDRO-5H-THIAZOLO[3,2-a]PYRIMIDINE-6-CARBOXYLIC ACID ETHYL ESTER DERIVATIVES Download PDFInfo
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Abstract
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본 발명은 단백질 티로신 포스파타제 1B(protein tyrosine phosphatase 1B, PTP1B)의 활성을 억제할 수 있는 화합물을 포함하는 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition comprising a compound capable of inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B).
세포 신호 전달(cellular signal transduction)은 외부자극을 세포 내부에 연결시켜서 다양한 세포 내 과정을 조절하는 세포내의 중추적인 기작이다. 신호 전달에서 중요한 생화학적 기작 중의 하나가 단백질의 티로신(tyrosine) 잔기에서의 가역적인 인산화(reversible phophorylation)인데, 이러한 단백질의 인산화 상태에 따라 단백질의 구조(conformation), 활성도, 세포 내 위치 등이 영향을 받게 되며, 단백질의 인산화 상태는 단백질 티로신 키나아제(protein tyrosine kinases,PTKs)와 단백질 티로신 포스파타제(protein tyrosine phosphatase, PTPs)의 상호작용을 통해서 조절된다.Cellular signal transduction is the central mechanism within cells that regulates various intracellular processes by connecting external stimuli to cells inside. One of the important biochemical mechanisms in signal transduction is the reversible phophorylation of tyrosine residues in proteins, which influence the protein's conformation, activity, and cellular location. Phosphorylation of proteins is regulated through the interaction of protein tyrosine kinases (PTKs) and protein tyrosine phosphatase (PTPs).
일반적으로 수용체(receptor)를 통한 세포의 기능 조절은 수용체 자체에 내재되어 있는 티로신 키나아제 또는 수용체에 결합되어 있는 다른 티로신 키나아제에 의해서 이루어진다(Darnell 등,Science,264: 1415-1421(1994); Heldin,Cell,80: 213-223(1995) 및 Pawson,Nature.373: 573-580(1995)). 단백질 티로신 키나아제는 크게 세포막에 존재하는 수용체 단백질 키나아제와 세포내에 존재하는 세포질 단백질 티로신 키나아제(cytoplasmic protein tyrosin kinase)의 두 부류로 구분된다(Taylor 등,Ann. Rev. Cell Biol.,8: 429-62(1992)). 표피 성장 인자 수용체(epidermal growth factor receptor, EGFR)나 혈소판-유래 성장 인자 수용체(platelet-derived growth factor receptor, PDGFR)와 같은 많은 수용체 단백질 티로신 키나아제들은 리간드의 결합에 의해 올리고머화되고 수용체의 세포질 내 부분의 특정한 티로신 잔기에 자가 인산화를 일으킨다(Schlessinger 및 Ulrich,Neuron,9: 383-91(1992) 및 Heldin,Cell,80;213-223(1995)).In general, regulation of cellular function through receptors is achieved by tyrosine kinases inherent in the receptor itself or by other tyrosine kinases bound to the receptor (Darnell et al., Science , 264 : 1415-1421 (1994); Heldin, Cell , 80 : 213-223 (1995) and Pawson, Nature . 373 : 573-580 (1995). Protein tyrosine kinases are largely divided into two classes: receptor protein kinases in cell membranes and cytoplasmic protein tyrosin kinases in cells (Taylor et al . , Ann. Rev. Cell Biol. , 8 : 429-62). (1992). Many receptor protein tyrosine kinases, such as epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor (PDGFR), are oligomerized by binding of ligands and part of the cytoplasm of the receptor. Autophosphorylation of specific tyrosine residues of Schlesinger and Ulrich, Neuron , 9 : 383-91 (1992) and Heldin, Cell , 80; 213-223 (1995).
PTPs는 인산화된 단백질의 티로신 잔기에서 탈인산화 역할을 하며, 막관통(transmembrane) 효소 및 세포질 효소로 분류될 수 있는데, PTPs의 활성 중심 부위는 대략 230개의 아미노산으로 구성되어 있고 고도로 보존되어 있으며, 서열번호: 1의 [I/V]HCXAGXXR[S/T]G의 공통 모티프(concensus motif)로 이루어져 있다. PTPs의 기질로는 포스포티로신 잔기를 포함하는 PTKs나 PTKs의 기질이 있다(Hunter,Cell,58: 1013-16(1989); Fischer 등,Science,253: 401-6(1991);Saito 및 Streuli,Cell Growth and Differentiation,2: 59-65(1991); 및 Pot 및 Dixon,Biochem. Biophys. Acta,1136: 35-43(1992)).PTPs dephosphorylate at tyrosine residues in phosphorylated proteins and can be classified as transmembrane enzymes and cytoplasmic enzymes. The active central region of PTPs consists of approximately 230 amino acids and is highly conserved and sequenced. It consists of the consensus motif of [I / V] HCXAGXXR [S / T] G of No. 1. Substrates of PTPs include PTKs containing phosphotyrosine residues or substrates of PTKs (Hunter, Cell , 58 : 1013-16 (1989); Fischer et al., Science , 253 : 401-6 (1991); Saito and Streuli , Cell Growth and Differentiation , 2 : 59-65 (1991); and Pot and Dixon, Biochem. Biophys. Acta , 1136 : 35-43 (1992)).
세포질 PTPs(cytoplasmic PTPs, CPTPs)들은 일반적으로 몇 가지 모듈 보존 도메인(modular conserved domain) 옆에 위치하는 하나의 활성부위를 갖고 있다. 예를 들면, 조혈세포 CPTP인 PTP1C는 포스포티로신을 포함하는 짧은 펩티드 모티프를 인식하는 두 개의 Src-상동성(homology) 2(SH2) 부분이 특징적이다. 일반적으로 이러한 모듈 보존 부분은 단백질의 세포 내 위치에 영향을 끼친다. SH2를 포함하는 단백질들은 활성화된 수용체와 세포질 인단백질의 포스포티로신에 결합할 수 있다. SH3라고 알려진 다른 보존 도메인은 프롤린을 많이 포함하는 부분을 갖는 단백질에 결합한다. 또한 플렉스트린-상동성(Pleckstrin-homology, PH) 도메인이라고 불리우는 세 번째 형태도 알려져 있다. 이들 모듈 도메인은 CPTKs와 CPTPs 뿐 아니라 Grbs(growth factor receptor bound)와 같은 비-촉매성 어댑터(non-catalytic adapter)에서도 발견되는데, 이들은 신호 전달 과정의 요소들간의 단백질-단백질 상호작용을 조절한다(Skolnik 등,Cell,65: 83-90(1991) 및 Pawson, Nature 373:573-580(1995)).Cytoplasmic PTPs (CPTPs) generally have an active site located next to several modular conserved domains. For example, PTP1C, a hematopoietic cell CPTP, is characterized by two Src-homology 2 (SH2) moieties that recognize short peptide motifs comprising phosphotyrosine. In general, this module conserved portion affects the intracellular location of the protein. Proteins containing SH2 can bind to activated receptors and phosphotyrosine of cytoplasmic phosphoproteins. Another conserved domain, known as SH3, binds to a protein having a high proline-containing portion. There is also a third form known as the Pleckstrin-homology (PH) domain. These module domains are found in CPTKs and CPTPs as well as non-catalytic adapters such as growth factor receptor bound (Gbs), which regulate protein-protein interactions between elements of the signal transduction process. Skolnik et al., Cell , 65 : 83-90 (1991) and Pawson, Nature 373: 573-580 (1995)).
수용체 소단위, 키나아제, 포스파타제, 어댑터 분자(adapter molecule)로 구성되는 다단백질 신호 결합체는 이러한 도메인들과 다른 결합부위 사이의 특정하고 동적인 상호작용을 통해 아세포성 구역(subcellular compartment)을 구성한다. 그러한 신호 결합체는 리간드가 결합된 수용체로부터 유래되는 세포 외부의 신호를 합쳐서 세포 안 또는 핵 안의 다른 부위에 위치한 다음 단계의 신호 결합체나 단백질에 그 신호를 전달한다(Koch 등,Science,252: 668-674(1991); Pawson,Nature,373: 573-580(1994); Mauro 등,Trends Biochem Sci.,19: 151-155(1994); 및 Cohen 등,Cell,80: 237-248(1995))Multiprotein signal binders, which consist of receptor subunits, kinases, phosphatase, and adapter molecules, make up the subcellular compartment through specific and dynamic interactions between these domains and other binding sites. Such signal binders combine signals from outside the cell derived from the receptor to which the ligand is bound and deliver the signal to the next level of signal receptor or protein located elsewhere in the cell or in the nucleus (Koch et al., Science , 252 : 668-). 674 (1991); Pawson, Nature , 373 : 573-580 (1994); Mauro et al ., Trends Biochem Sci ., 19 : 151-155 (1994); and Cohen et al., Cell , 80 : 237-248 (1995))
정상적인 세포성장과 분화에서 필요한 티로신의 인산화의 수위는 PTKs와 PTPs의 조화로운 활동에 의해 조절된다. 세포내의 상황에 따라 이러한 두 형태의 효소들은 신호전달 과정동안 서로 반대로 작용하거나 돕기도 한다. 이 효소들 사이의 불균형은 정상적인 세포 작용을 손상시켜 신진대사의 장애와 세포의 변형을 초래할 수 있다. 예를 들면, PTK인 인슐린 수용체에 결합되어 있는 인슐린은 글루코스 수송, 글리코겐과 지방의 합성, DNA의 합성, 세포분화와 같은 신진대사와 성장에 다양한 영향을 끼치는 일들을 유발한다. 인슐린의 부족현상이나 그 신호변환의 결여 상태인 당뇨는 인슐린 신호체계 중의 어느 부분에서 이상현상이 발생함으로써 나타난다(Olefsky, in Cecil Textbook of Medicine 18th Ed.,2: 1360-81(1988)).The level of tyrosine phosphorylation required for normal cell growth and differentiation is regulated by the harmonious activity of PTKs and PTPs. Depending on the situation in the cell, these two types of enzymes may act or help each other during signaling. Imbalances between these enzymes can impair normal cellular function, leading to metabolic disorders and cell transformation. For example, insulin, which is bound to the insulin receptor, PTK, causes various effects on metabolism and growth, such as glucose transport, synthesis of glycogen and fat, synthesis of DNA, and cell differentiation. Diabetes, a lack of insulin or a lack of signal transduction, is caused by abnormalities in some parts of the insulin signaling system (Olefsky, in Cecil Textbook of Medicine 18th Ed., 2 : 1360-81 (1988)).
그러나, 신호변환 과정 중에서의 티로신 포스파타제의 직접적인 역할은 잘 알려져 있지 않다. PTPs는 인간 질병에서 어떤 역할을 하는 것으로 추측되는데, 예를 들어, PTP1C를 코딩하는 유전자에서의 돌연변이화는 심각한 면역결핍과 자가면역 질병으로 고통받는 쥐에서 좀먹은(moth-eaten) 표현형을 일으키며(Schultz 등,Cell,73: 1445-1454(1993)), 항-PTP1D 항체의 주입에 의한 PTP1D의 활성도 감소는 인슐린이나 EGF에 의해 야기되는 유사분열발생(mitogenesis)을 막는 것으로 보인다(Xiao 등,J. Biol. Chem.,269: 21244-21248(1994)).However, the direct role of tyrosine phosphatase in the signal transduction process is not well known. PTPs are thought to play a role in human disease, for example, mutations in genes encoding PTP1C cause a moth-eaten phenotype in mice suffering from severe immunodeficiency and autoimmune diseases ( Schultz et al., Cell , 73 : 1445-1454 (1993)), decreased PTP1D activity by infusion of anti-PTP1D antibodies appears to prevent mitogenesis caused by insulin or EGF (Xiao et al., J.). Biol.Chem . , 269 : 21244-21248 (1994)).
PTP1B는 인슐린 신호전달에서 음성 조절(negative regulation)을 담당하고 있다. 케네디(Kennedy) 및 라마찬드란(Ramachandran)은 최근 PTP1B 유전자가 결여된 쥐는 인슐린에 대해 민감한 성질을 보인다고 보고한 바 있다(Elchevly 등,Science,283: 1544(1999)). 즉, 쥐에게 인슐린을 투여하였을 때 간과 근육 세포에서 인슐린 수용체의 인산화가 증가하고 오래 지속된다는 사실을 보였는데, 이는 PTP1B가 활성화된 인슐린 수용체의 탈인산화에서 결정적인 역할을 하므로 이 효소의 억제가 타입 2 당뇨의 치료에 매우 효과적이라는 것을 보여준다. PTP1B와 당뇨병과의 관계는 동물 실험 등을 통해 여러 논문 등에 나와 있고 전세계적으로 유망한 타겟(taget)으로 알려져 있다(Elchevly 등.,Science,283: 1544(1999) 및Science's Stke, 57: 1-4(2000)).PTP1B is responsible for negative regulation of insulin signaling. Kennedy and Ramachandran recently reported that mice lacking the PTP1B gene are sensitive to insulin (Elchevly et al., Science , 283 : 1544 (1999)). In other words, when insulin was administered to rats, it was shown that the phosphorylation of insulin receptors in the liver and muscle cells increased and persisted, which inhibits the enzyme because PTP1B plays a critical role in the dephosphorylation of activated insulin receptors. It is shown to be very effective in the treatment of diabetes. The relationship between PTP1B and diabetes has been shown in several papers, including through animal studies, and is known worldwide as a promising target (Elchevly et al., Science , 283 : 1544 (1999) and Science's Stke, 57 : 1-4). (2000)).
이에 본 발명자들은 비만 및 당뇨병을 치료 및 예방할 수 있는 화합물을 개발하기 위해 계속 연구를 진행하던 중 구조화학 유전체학 라이브러리를 통하여 단백질 티로신 포스파타제 1B의 활성을 억제할 수 있는 화합물을 발견함으로써 본 발명을 완성하였다.Therefore, the present inventors completed the present invention by finding a compound that can inhibit the activity of the protein tyrosine phosphatase 1B through the structural chemical genomics library while continuing to develop a compound that can treat and prevent obesity and diabetes. .
본 발명의 목적은 단백질 티로신 포스파타제 1B(protein tyrosine phosphatase 1B, PTP1B)의 활성을 억제할 수 있는 약학 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition capable of inhibiting the activity of protein tyrosine phosphatase 1B (protein tyrosine phosphatase 1B, PTP1B).
상기 목적을 달성하기 위해, 본 발명에서는 하기 화학식 1의 화합물, 그의 약학적으로 허용되는 염, 수화물, 용매화물 또는 이성체를 함유하는 단백질 티로신 포스파타제 1B(protein tyrosine phosphatase 1B, PTP1B) 저해용 조성물을 제공한다:In order to achieve the above object, the present invention provides a composition for inhibiting protein tyrosine phosphatase 1B (PTP1B) containing a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof do:
화학식 1Formula 1
상기식에서,In the above formula,
R1은 할로겐, 알킬옥시, 알킬, 아미노, 알킬 아미노, 카복실산 또는 아미드로 치환되거나 치환되지 않은 방향족기 또는 질소, 황 또는 산소-함유 헤테로 사이클릭 방향족기이고,R 1 is an aromatic group or a nitrogen, sulfur or oxygen-containing heterocyclic aromatic group, substituted or unsubstituted with halogen, alkyloxy, alkyl, amino, alkyl amino, carboxylic acid or amide,
R2는 C1-C5알킬 또는 할로겐, 알킬옥시, 알킬, 아미노, 알킬 아미노, 카복실산 또는 아미드로 치환되거나 치환되지 않은 방향족기 또는 질소, 황 또는 산소-함유 헤테로 사이클릭 방향족기이다.R 2 is an aromatic group or a nitrogen, sulfur or oxygen-containing heterocyclic aromatic group substituted or unsubstituted with C 1 -C 5 alkyl or halogen, alkyloxy, alkyl, amino, alkyl amino, carboxylic acid or amide.
본 발명의 화학식 1의 화합물은 단백질 티로신 포스파타제에 대한 구조화학 유전체학 라이브러리를 구축함으로써 수득할 수 있다. 구조화학 유전체학 라이브러리는 단백질의 활성부위가 약이 될 수 있는 화학물질들을 인식하는 과정을 3차원구조에 근거하여 연구하는 구조화학 유전체학에 바탕을 둔 기술로서 우선 단백질들의 활성부위 구조를 분석하여 비슷한 활성부위를 가지는 단백질들을 모아 단백질군으로 묶은 다음, 각각의 단백질군에 대해 선택적으로 결합할 수 있는 화합물들을 가상공간에서의 약효검색법(virtual screening)을 사용하여 선정한 후 화합물 라이브러리의 형태로 모아둔 것이다. 따라서 이러한 방법을 이용함으로써 이미 대응하는 화합물 라이브러리를 확보하고 있는 단백질들이 표적이 되는 경우에는 매우 빠른 속도로 선도물질을 확보할 수 있다는 장점이 있다.Compounds of formula (1) of the present invention can be obtained by building a structural chemical genomics library for protein tyrosine phosphatase. Structural chemistry genomics library is a technique based on structural chemistry genomics that studies the process of recognizing chemicals that can be active parts of proteins based on three-dimensional structure. By collecting proteins with sites and grouping them into protein groups, compounds that can selectively bind to each protein group are selected using virtual screening and collected in the form of a compound library. . Therefore, the use of this method has the advantage that it is possible to secure the leading material at a very high speed when the proteins that already have a corresponding compound library is targeted.
구체적으로, 본 발명의 화학식 1의 화합물은, 첫 번째 단계에서는, 확보가 가능한 단백질 티로신 포스파타제들의 3차원 구조들을 모두 모아서 이들을 활성부위의 구조에 따라 분류한다. 주로 PDB(protein data bank)에서 단백질의 3차원 구조정보를 획득하거나, 필요에 따라서는 구조 유전체학 연구를 수행하여 3차원 구조를 확보할 수 있다. 이어서 새로운 화합물이 직접 접촉하는 부위를 정하고 이 접촉에 관여할 수 있는 아미노산 및 새로운 화합물의 이차구조를 파악한다. 대부분의 경우 유사 단백질 종에 속하는 각 단백질들의 활성부위는 거의 동일한 부분을 포함하고 있다. 이 경우 화합물의 골격(backbone) 뿐만 아니라 관련된 잔기의 측쇄 종류 및 배향도가 거의 같은 경우를 의미한다. 또한, 각 단백질 마다 다른 구조를 가지고 있는데 이런 구조적 차이들은 새로운 화합물의 선택성을 높일 때 이용할 수 있다.Specifically, in the first step, the compound of Formula 1 collects all three-dimensional structures of protein tyrosine phosphatase that can be obtained and classifies them according to the structure of the active site. Mainly, three-dimensional structure information of a protein is obtained from a protein data bank (PDB), or structural genomics studies can be performed if necessary. The site where the new compound is in direct contact is then identified and the secondary structure of the new compound and the amino acids that may be involved in the contact are identified. In most cases, the active sites of proteins belonging to similar protein species contain almost identical parts. In this case, it means the case where the backbone of the compound as well as the side chain type and orientation of related residues are almost the same. In addition, each protein has a different structure, which can be used to increase the selectivity of new compounds.
두 번째 단계에서는 단백질 활성부위의 공통적인 구조를 인식하는 화학구조들을 가상공간에서의 약효검색 방법(Virtual screening,in silicoHTS)을 이용하여 컴퓨터상에서 선별한다. 이 기술은 단백질의 활성부위에 결합할 수 있는 물질들을 도킹(docking) 실험을 통하여 고속으로 확인하는 기술로서 상기 약효검색을 수행하여 확보된 라이브러리(library)를 단백질의 3차 구조에 대해 컴퓨터상에서 고속의 결합 시험을 수행한 다음, 상기 확보한 단백질 활성부위 구조 데이터베이스의 항목들에 속한 단백질들에 결합이 가능한 물질들을 선별해 낸다. 이 과정에서 이 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르가 단백질 티로신 포스파타제들의 활성부위에 나타나는 공통구조를 인식할 수 있음을 확인할 수 있다.In the second step, chemical structures that recognize common structures of protein active sites are screened on a computer using virtual screening ( in silico HTS). This technique is a technology to identify substances that can bind to the active site of proteins at high speed through docking experiments. After performing the binding test, the materials capable of binding to proteins belonging to the items of the obtained protein active site structure database are screened. In the process this 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -3-oxo-2,3-dihydro-5H-thiazolo [3,2-a ] It can be seen that the pyrimidine-6-carboxylic acid ethyl ester can recognize the common structure of the active site of the protein tyrosine phosphatase.
이어서, 마지막 단계로서 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르가 포함된 화합물들을 수집함으로써 화학식 1의 화합물을 수득할 수 있다.Then, as a final step, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -3-oxo-2,3-dihydro-5H-thiazolo [3,2- a] The compound of formula 1 can be obtained by collecting the compounds containing pyrimidine-6-carboxylic acid ethyl ester.
화학식 1의 화합물 중 바람직한 것은 R1이 할로겐, C1-C3알킬옥시, C1-C3알킬 또는 알킬 아미노로 치환되거나 치환되지 않은 페닐기, C1-C3알킬옥시로 치환되거나 치환되지 않은 나프틸기 또는 황-함유 헤테로 사이클릭 방향족기이고, R2가 C1-C5알킬 또는 페닐기인 화합물이다.Preferred among the compounds of the formula (1) are phenyl groups in which R 1 is substituted or unsubstituted with halogen, C 1 -C 3 alkyloxy, C 1 -C 3 alkyl or alkyl amino, substituted or unsubstituted with C 1 -C 3 alkyloxy A naphthyl group or a sulfur-containing heterocyclic aromatic group, and R 2 is a C 1 -C 5 alkyl or phenyl group.
본 발명의 화학식 1의 화합물 중 더욱 바람직한 것은 하기 화합물들이다:More preferred among the compounds of formula 1 of the present invention are the following compounds:
2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(2-메톡시-카프탈렌-1-일)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (2-methoxy-caphthalen-1-yl) -7-methyl-3-oxo-2 , 3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester
2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-티오펜-2-일-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -7-methyl-3-oxo-5-thiophen-2-yl-2,3-dihydro-5H -Thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester
2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(4-에톡시-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (4-ethoxy-phenyl) -7-methyl-3-oxo-2,3-dihydro -5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester
2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(4-디메틸아미노-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (4-dimethylamino-phenyl) -7-methyl-3-oxo-2,3-dihydro -5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester
2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(2,5-디메톡시-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (2,5-dimethoxy-phenyl) -7-methyl-3-oxo-2,3- Dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester
2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-페닐-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -7-methyl-3-oxo-5-phenyl-2,3-dihydro-5H-thiazolo [3 , 2-a] pyrimidine-6-carboxylic acid ethyl ester
2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-p-토릴-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -7-methyl-3-oxo-5-p-tolyl-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester
본 발명의 화학식 1의 화합물은 그 구조 내에 비대칭 탄소 중심을 가질 수 있으므로, 개개의 에나티오머 또는 부분입체이성체로 존재할 수 있고, 라세미체를 포함한 이들의 혼합물로 존재할 수 있으며, 이러한 이성체 또는 이들의 혼합물 역시 본 발명의 범위에 포함된다.Compounds of formula (I) of the present invention may have asymmetric carbon centers in their structure, and therefore may exist as individual enantiomers or diastereomers, and as mixtures thereof, including racemates, such isomers or these Mixtures of are also included within the scope of the present invention.
본 발명에 따른 화합물은 또한 약제학적으로 허용되는 염을 형성할 수 있다. 이러한 약제학적으로 허용되는 염에는 알칼리금속 수산화물 (예: 수산화나트륨, 수산화칼륨), 알칼리금속 중탄산염(예: 중탄산나트륨, 중탄산칼륨), 알칼리금속 탄산염(예: 탄산 나트륨, 탄산 칼륨, 탄산 칼슘)등과 같은 무기염기와 1차, 2차 3차 아민 아미노산과 같은 유기염기가 포함된다.The compounds according to the invention can also form pharmaceutically acceptable salts. These pharmaceutically acceptable salts include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, calcium carbonate), and the like. The same inorganic base and organic base such as primary and secondary tertiary amine amino acids are included.
본 발명의 화합물들은 또한 용매화물, 특히 수화물의 형태일 수 있다. 수화는 상기 화합물을 분리하는 동안 일어날 수 있거나, 또는 화합물의 흡습성으로 인해 시간이 경과함에 따라 일어날 수 있다.The compounds of the invention may also be in the form of solvates, in particular hydrates. Hydration may occur during separation of the compound, or may occur over time due to the hygroscopicity of the compound.
본 발명의 화학식 1의 화합물은 비만 또는 당뇨병과 관련된 효소인 단백질티로신 포스파타제 1B의 활성을 억제시키며, 15μM 이하의 IC50값을 나타낸다.The compound of formula 1 of the present invention inhibits the activity of protein tyrosine phosphatase 1B, an enzyme associated with obesity or diabetes, and exhibits an IC 50 value of 15 μM or less.
이에 따라, 본 발명에서는 화학식 1의 화합물, 그의 약학적으로 허용되는 염, 수화물, 용매화물 또는 이성체를 유효성분으로 하고 약제학적으로 허용되는 담체를 포함하는 PTP1B 저해제, 또는 비만 또는 당뇨병 치료 또는 예방용 조성물이 제공된다. 이 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화할 수 있다. 경구 투여용 제형으로는 예를 들면 정제, 캅셀제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다. 또한 비경구 투여용 제형의 대표적인 것은 주사용 제형으로 등장성 수용액 또는 현탁액이 바람직하다.Accordingly, in the present invention, a PTP1B inhibitor comprising a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient and a pharmaceutically acceptable carrier, or for treating or preventing obesity or diabetes A composition is provided. The composition can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, capsules, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), glidants ( Examples: silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its Disintegrants or boiling mixtures such as sodium salts and / or absorbents, colorants, flavors, and sweeteners. The formulations may be prepared by conventional mixing, granulating or coating methods. Also representative of parenteral formulations are injectable formulations, preferably aqueous isotonic solutions or suspensions.
상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법에 따라 제제화할 수 있다.The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure and other therapeutically useful substances and may be formulated according to conventional methods. have.
본 발명의 약학 조성물은 목적하는 바에 따라 정맥내, 근육내 등의 경로를 통해 비경구 투여하거나 경구 투여할 수 있으며, 화학식 1 화합물은 하루에 체중 1 ㎏당 0.01 내지 100 ㎎, 바람직하게는 0.1 내지 50 ㎎의 양을 1회 내지 수회로 나누어 투여할 수 있다. 특정 환자에 대한 투여용량 수준은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법 및 배설 그리고 약제 혼합 및 질환의 중증도에 따라 변화시킬 수 있다.The pharmaceutical composition of the present invention can be parenterally or orally administered via a route such as intravenous, intramuscular, etc. as desired, and the compound of formula 1 is 0.01 to 100 mg per kg of body weight per day, preferably 0.1 to The amount of 50 mg may be administered in one to several portions. Dosage levels for a particular patient may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, method and excretion, drug combination and severity of the disease.
이하 하기 실시예에 의하여 본 발명을 좀더 상세하게 설명하고자 한다. 단. 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. only. The following examples are only for illustrating the present invention, but the scope of the present invention is not limited thereto.
실시예 1: PTP1B 억제 화합물의 선별Example 1 Screening of PTP1B Inhibitory Compounds
(단계 1) PTP1B 활성부위 구조 분석(Step 1) PTP1B active site structure analysis
PDB(protein data bank)에서 단백질 티로신 포스파타제의 3차원 구조정보들을 모두 모아서 SGI 사의 옥탄(Octane) 컴퓨터에서 아셀리스(Accelys)사의 인사이트 프로그램(Insight program)을 이용하여 이들을 활성부위의 구조에 따라 분류하였다. 그리고 같은 컴퓨터와 프로그램을 사용하여 활성부위의 아미노산 잔기들과 이차구조를 분석하고 새로운 화합물이 직접 접촉할 경우 PTP의 활성을 억제할 수 있는 부위를 결정하였다.All three-dimensional structural information of protein tyrosine phosphatase in the PDB (protein data bank) was collected and classified according to the structure of the active site by using the Acelys Insight program on the Octane computer of SGI. . The same computer and program were used to analyze the amino acid residues and secondary structures of the active sites, and to determine the sites that would inhibit the activity of PTP when new compounds were in direct contact.
(단계 2) PTP1B의 활성부위를 인식하는 화합물의 선별(Step 2) Selection of compounds that recognize the active site of PTP1B
이어서, PTP1B의 활성부위를 인식하는 화학구조(입수처: MDL사 ACD 스크리닝 데이터 베이스)들을 가상공간에서의 약효검색 방법(Virtual screening,in silicoHTS)을 이용하여 컴퓨터상에서 선별하였다(노성구,정밀화학 2001,59, 49(2001)). 즉, 아셀리스사의 루디(Ludi) 프로그램을 사용하여, 확보된 가상공간의 화합물 라이브러리(library)를 단백질의 3차 구조에 대해 컴퓨터상에서 고속의 결합 시험을 수행하였다. 이 과정에서 화학식 1의 구조 중 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르 부위가 PTP1B의 활성부위를 인식할 수 있음을 확인하였다.Then, the chemical structure of recognizing the active site of PTP1B (available destination: MDL four ACD screening database) the were selected on the computer using the drug screening methods of the virtual space (Virtual screening, in silico HTS) (noseonggu, Fine Chemicals 2001 , 59 , 49 (2001). That is, a high-speed binding test was carried out on a computer for the tertiary structure of the protein in the compound library of the secured virtual space using the Rudy program of Acelis. 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -3-oxo-2,3-dihydro-5H-thiazolo [3 , 2-a] pyrimidine-6-carboxylic acid ethyl ester moiety was able to recognize the active site of PTP1B.
마지막 단계로 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르가 포함된 화합물들을 수집하므로써 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(2-메톡시-카프탈렌-1-일)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-티오펜-2-일-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(4-에톡시-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(4-디메틸아미노-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(2,5-디메톡시-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-페 닐-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르 및 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-p-토릴-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르 화합물을 수득하였다. 상기 화합물들은 스펙스(Specs)사와 켐디브(ChemDiv)사로부터 입수할 수 있다.The final step was 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (2-methoxy-capphthalene by collecting compounds containing pyrimidine-6-carboxylic acid ethyl ester -1-yl) -7-methyl-3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester, 2- [5- (3-carboxy 4-chloro-phenyl) -furan-2-ylmethylene] -7-methyl-3-oxo-5-thiophen-2-yl-2,3-dihydro-5H-thiazolo [3,2-a ] Pyrimidine-6-carboxylic acid ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (4-ethoxy-phenyl) -7-methyl- 3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan- 2-ylmethylene] -5- (4-dimethylamino-phenyl) -7-methyl-3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid Ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (2,5-dimethoxy-phenyl) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene]- 7-Methyl-3-oxo-5-phenyl-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester and 2- [5- (3-carboxy- 4-Chloro-phenyl) -furan-2-ylmethylene] -7-methyl-3-oxo-5-p-tolyl-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine- 6-carboxylic acid ethyl ester compound was obtained. The compounds are available from Specs and ChemDiv.
실시예 2 : PTP1B 활성 억제능 분석Example 2 Analysis of Inhibitory Activity of PTP1B
PTP1B의 활성 억제능 실험은 나오히토(Naohito) 등의 방법(JBC,271: 29422(1996))을 변형하여 수행하였다. PTP1B는 유전자 재조합 기술에 의해 제조된 인간 PTP1B를 사용하였다(Iversen 등,JBC,275: 10300(2000)).The activity inhibitory activity of PTP1B was carried out by modifying the method of Naohito et al. ( JBC , 271 : 29422 (1996)). PTP1B used human PTP1B prepared by genetic recombination technology (Iversen et al., JBC , 275 : 10300 (2000)).
상기 실시예 1에서 수득된 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸 렌]-5-(2-메톡시-카프탈렌-1-일)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-티오펜-2-일-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(4-에톡시-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(4-디메틸아미노-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-5-(2,5-디메톡시-페닐)-7-메틸-3-옥소-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르, 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-페닐-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르 및 2-[5-(3-카복시-4-클로로-페닐)-푸란-2-일메틸렌]-7-메틸-3-옥소-5-p-토릴-2,3-디하이드로-5H-티아졸로[3,2-a]피리미딘-6-카복실산 에틸 에스테르를 각각 디메틸설폭사이드(DMSO)에 용해시킨 다음, 효소 반응액인 1 mM EDTA 및 2 mM DTT가 포함된 50 mM 구연산 완충용액(pH 6.0)에 5 %농도(v/v)로 첨가하였다. 여기에 PTP1B 100nM 및 기질로서 pNPP(para-nitrophenyl phosphate) 10 mM을 첨가하여 상온에서 30분 반응시킨 후 UV-분광계를 이용하여 405 nm에서 흡광도의 감소를 측정하였다. 효소 저해능은 시험 화합물이 없는 상태에서의 흡광도에 대한 시험화합물의 흡광 정도를 백분율로 표시하였으며 50 %의 효소 활성을 저해하는 각 시험 화합물의 농도를 IC50로 결정하였다. 상기 화합물들은 15 μM이하의 IC50값을 나타내었다.2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (2-methoxy-caphthalen-1-yl) -7 obtained in Example 1 above -Methyl-3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -Furan-2-ylmethylene] -7-methyl-3-oxo-5-thiophen-2-yl-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid Ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (4-ethoxy-phenyl) -7-methyl-3-oxo-2,3 -Dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5 -(4-dimethylamino-phenyl) -7-methyl-3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -5- (2,5-dimethoxy-phenyl) -7-methyl-3-oxo-2,3-dihydro-5H- Thiazolo [3,2-a] pyrimidine-6-carboxylic acid Ethyl ester, 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -7-methyl-3-oxo-5-phenyl-2,3-dihydro-5H-thia Solo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester and 2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -7-methyl-3-oxo- 5-p-tolyl-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester was dissolved in dimethylsulfoxide (DMSO), respectively, and the enzyme reaction solution 1 To 50 mM citric acid buffer (pH 6.0) containing mM EDTA and 2 mM DTT was added at a 5% concentration (v / v). After 100 nM of PTP1B and 10 mM of pNPP (para-nitrophenyl phosphate) as a substrate were added and reacted at room temperature for 30 minutes, the decrease in absorbance was measured at 405 nm using a UV-spectrometer. Enzyme inhibition capacity was expressed as a percentage of the absorbance of the test compound to the absorbance in the absence of the test compound, and the concentration of each test compound that inhibited 50% of enzyme activity was determined as IC 50 . The compounds showed IC 50 values of 15 μM or less.
본 발명의 화학식 1의 화합물은 단백질 티로신 포스파타제 1B의 활성을 억제시키므로 비만 및 당뇨병의 치료 또는 예방용 약학 조성물로 유용하게 사용될 수 있다.Since the compound of Formula 1 of the present invention inhibits the activity of protein tyrosine phosphatase 1B, it may be usefully used as a pharmaceutical composition for the treatment or prevention of obesity and diabetes.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010077680A3 (en) * | 2008-12-08 | 2010-10-14 | Vm Discovery Inc. | Compositions of protein receptor tyrosine kinase inhibitors |
| US8999992B2 (en) | 2013-03-15 | 2015-04-07 | Vm Pharma Llc | Crystalline forms of tryosine kinase inhibitors and their salts |
| US10301271B2 (en) | 2014-09-17 | 2019-05-28 | Purdue Pharma L.P. | Crystalline forms of tyrosine kinase inhibitors and their salts |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010077680A3 (en) * | 2008-12-08 | 2010-10-14 | Vm Discovery Inc. | Compositions of protein receptor tyrosine kinase inhibitors |
| JP2012511054A (en) * | 2008-12-08 | 2012-05-17 | ブイエム ファーマ エルエルシー | Composition of protein receptor tyrosine kinase inhibitor |
| US8809530B1 (en) | 2008-12-08 | 2014-08-19 | Vm Pharma Llc | Compositions of protein receptor tyrosine kinase inhibitors |
| US9040508B2 (en) | 2008-12-08 | 2015-05-26 | Vm Pharma Llc | Compositions of protein receptor tyrosine kinase inhibitors |
| US9738659B2 (en) | 2008-12-08 | 2017-08-22 | Purdue Pharma L.P. | Compositions of protein receptor tyrosine kinase inhibitors |
| US8999992B2 (en) | 2013-03-15 | 2015-04-07 | Vm Pharma Llc | Crystalline forms of tryosine kinase inhibitors and their salts |
| US9388146B2 (en) | 2013-03-15 | 2016-07-12 | Purdue Pharma L.P. | Crystalline forms of tyrosine kinase inhibitors and their salts |
| US9718794B2 (en) | 2013-03-15 | 2017-08-01 | Purdue Pharma L.P. | Crystalline forms of tyrosine kinase inhibitors and their salts |
| US9993473B2 (en) | 2013-03-15 | 2018-06-12 | Purdue Pharma L.P. | Crystalline forms of tyrosine kinase inhibitors and their salts |
| US10124002B2 (en) | 2013-03-15 | 2018-11-13 | Purdue Pharma, L.P. | Crystalline forms of tyrosine kinase inhibitors and their salts |
| US10301271B2 (en) | 2014-09-17 | 2019-05-28 | Purdue Pharma L.P. | Crystalline forms of tyrosine kinase inhibitors and their salts |
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