• 专利附录
  • 专利说明
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  • 类似技术
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  • 优先权
    • 专利摘要:
    The present invention relates to a pharmaceutical composition comprising a compound of formula (1) capable of inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the pharmaceutical composition of the present invention effectively inhibits the activity of PTP1B PTP1B inhibitor Or as a pharmaceutical composition for the treatment or prevention of obesity or diabetes. In the above formula, R 1 is an aromatic group substituted or unsubstituted with halogen, alkyloxy, alkyl, amino, alkyl amino, carboxylic acid or amide or a nitrogen, sulfur or oxygen-containing heterocyclic aromatic group. 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.
    公开号:KR20030095729A
    申请号:KR1020020033282
    申请日:2002-06-14
    公开日:2003-12-24
    发明作者:노성구；김진환；이태규；전영호；황광연；조중명
    申请人:크리스탈지노믹스(주)；
    IPC主号:
    专利说明:

    2- [5- (3-carboxy-4-chloro-phenyl) -furan-2-ylmethylene] -3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine- 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}
    [1] The present invention relates to a pharmaceutical composition comprising a compound capable of inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B).
    [2] 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).
    [3] 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).
    [4] 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)).
    [5] 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)).
    [6] 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))
    [7] 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)).
    [8] 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)).
    [9] 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)).
    [10] 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. .
    [11] 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).
    [12] 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:
    [13] Formula 1
    [14]
    [15] In the above formula,
    [16] 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,
    [17] 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.
    [18] 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.
    [19] 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.
    [20] 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.
    [21] 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.
    [22] 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.
    [23] More preferred among the compounds of formula 1 of the present invention are the following compounds:
    [24] 2- [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
    [25]
    [26] 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
    [27]
    [28] 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
    [29]
    [30] 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
    [31]
    [32] 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
    [33]
    [34] 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
    [35]
    [36] 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
    [37]
    [38] 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.
    [39] 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.
    [40] 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.
    [41] 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.
    [42] 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.
    [43] 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.
    [44] 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.
    [45] 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.
    [46] Example 1 Screening of PTP1B Inhibitory Compounds
    [47] (Step 1) PTP1B active site structure analysis
    [48] 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.
    [49] (Step 2) Selection of compounds that recognize the active site of PTP1B
    [50] 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.
    [51] 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.
    [52] Example 2 Analysis of Inhibitory Activity of PTP1B
    [53] 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)).
    [54] 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.
    [55] 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.
    权利要求:
    Claims (4)
    [1" claim-type="Currently amended] A composition for inhibiting protein tyrosine phosphatase 1B containing a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof:
    Formula 1

    In the above formula,
    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,
    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.
    [2" claim-type="Currently amended] The method of claim 1,
    In formula 1 R 1 is halogen, C 1 -C 3 alkyloxy, C 1 -C 3 alkyl substituted by amino or alkyl or unsubstituted phenyl group, C 1 -C 3 alkyloxy which is optionally substituted with a naphthyl group or a sulfur A composition comprising a compound containing a -containing heterocyclic aromatic group and R 2 is a C 1 -C 5 alkyl or phenyl group.
    [3" claim-type="Currently amended] The method of claim 1,
    A composition containing a compound selected from the group consisting of:
    2- [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-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-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-thia Jolo [3,2-a] pyrimidine-6-carboxylic acid ethyl ester.
    [4" claim-type="Currently amended] The method of claim 1,
    A composition, which is used for the treatment or prevention of obesity or diabetes.
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2002-06-14|Application filed by 크리스탈지노믹스(주)
    2002-06-14|Priority to KR1020020033282A
    2003-12-24|Publication of KR20030095729A
    优先权:
    申请号 | 申请日 | 专利标题
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