CN101792440B - Quinazolinone derivatives, preparation and application thereof - Google Patents
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- 0 COc(cccc1)c1N1C(S*)=Nc2ccc(*)cc2C1=O Chemical compound COc(cccc1)c1N1C(S*)=Nc2ccc(*)cc2C1=O 0.000 description 3
- LGGATXSKBLNSEZ-UHFFFAOYSA-N CCC(Nc(c(Cl)ccc1)c1[N+]([O-])=O)=O Chemical compound CCC(Nc(c(Cl)ccc1)c1[N+]([O-])=O)=O LGGATXSKBLNSEZ-UHFFFAOYSA-N 0.000 description 1
- VCVUMBWLSGNGFA-UHFFFAOYSA-N CCC(Nc(cccc1)c1Cl)=O Chemical compound CCC(Nc(cccc1)c1Cl)=O VCVUMBWLSGNGFA-UHFFFAOYSA-N 0.000 description 1
- ZTHRQJQJODGZHV-UHFFFAOYSA-N CCC(Nc1ccccc1)=O Chemical compound CCC(Nc1ccccc1)=O ZTHRQJQJODGZHV-UHFFFAOYSA-N 0.000 description 1
- JFBWPNPKYAZQHA-UHFFFAOYSA-N CCC(Nc1nc(OC)cc(OC)n1)=O Chemical compound CCC(Nc1nc(OC)cc(OC)n1)=O JFBWPNPKYAZQHA-UHFFFAOYSA-N 0.000 description 1
- VONWPEXRCLHKRJ-UHFFFAOYSA-N O=C(CCl)Nc1ccccc1 Chemical compound O=C(CCl)Nc1ccccc1 VONWPEXRCLHKRJ-UHFFFAOYSA-N 0.000 description 1
- LSDJRBFOXKCGFY-UHFFFAOYSA-N O=C(CCl)Nc1ncc[s]1 Chemical compound O=C(CCl)Nc1ncc[s]1 LSDJRBFOXKCGFY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses quinazolinone derivatives, preparation and application thereof, and belongs to the technical fields of medicaments, preparation and application thereof. The application means that the quinazolinone derivatives serve as protein-tyrosine-phosphatase 1B (PTP1B for short) inhibitors. The quinazolinone derivatives are prepared by taking 2-amino-5-iodobenzoic acid or o-aminobenzoic acid as a raw material and performing cyclization reaction on the raw material and 2-methoxyphenylthioisocyanate; and then performing substitution reaction on the reaction product and various halogenated reagents. The derivatives have remarkable PTP1B inhibiting activity, and are particularly suitable to be used as potential anti-diabetic medicaments.
Description
Technical field
The present invention relates to a class Quinazol derivative and preparation and application, use and be meant the inhibitor as protein-tyrosine-phosphatase 1B (being called for short PTP1B), the technical field that belongs to medicine and preparation thereof and use.
Background technology
Diabetes are one group of clinical syndromes that caused by the h and E factor interaction, are a kind of chronic diseases, do not take place when enough Regular Insulin or human body can't effectively utilize the Regular Insulin that is produced when pancreas produces.Diabetes and complication thereof have become the worldwide public health problem of serious threat human health.
Generally diabetes are divided into two classes at present, type i diabetes (insulin-dependent diabetes mellitus, IDDM) with type ii diabetes (non insulin dependent diabetes, NIDDM).90% belongs to type ii diabetes among the diabetic subject all over the world, and type ii diabetes is called non insulin dependent diabetes or adult's morbidity in the past, is the result that human body can't effectively utilize Regular Insulin.The World Health Organization (WHO) estimates that the whole world has 1.8 hundred million people to suffer from diabetes at present approximately, and this numeral will be doubled more than one times to the year two thousand thirty probably.
Obesity be meant the body fat overheap and (or) distribute unusually, be a kind of multifactorial chronic metabolic disease, suspend etc. closely related with many chronic diseases such as hypertension, dyslipidemias, diabetes, hyperlipidaemia, breathing sleep.Though the cause of disease of obesity and pathogenesis also are not fully aware of, insulin resistant is that its topmost pathogenesis is extensively admitted.
Diabetes and obesity all are the healthy endocrine regulation metabolism class diseases of serious harm people, the insulin sensitivity reduction that often is accompanied by in the insulin sensitivity tissue is an insulin resistant, reason is insulin signaling signal weakening or disorder in conduction, thereby causes the glycolipid metabolism dysequilibrium in muscle, liver, the fatty tissue.
An important regulatory mechanism is to insulin receptor (insulinreceptor in the insulin signaling pathway, IR), IRS (insulin receptor substrate, IRS) and the protein tyrosine phosphataseization of other downstream molecules carry out reversible adjusting (White MF, Kahn CR.J Biol Chem 1996,269,1).Protein tyrosine phosphatase is the posttranslational modification mode that a kind of important conditioning signal is transduceed.The phosphorylation of tyrosine is the reversible dynamic process in vivo, its phosphorylation and dephosphorylation are respectively by protein tyrosine kinase (protein tyrosinekinases, PTKs) and protein-tyrosine-phosphatase (protein tyrosine phosphatases PTPs) regulates.The feature of type ii diabetes is the opposing to insulin action of insulin sensitivity tissue such as skeletal muscle, liver, fatty tissue, and insulin signaling weakens in its conduction path or blocks is its direct factor.Regular Insulin is subunit's intrinsic PTKs activity in the activated receptor born of the same parents by combining with the outer subunit of its IR born of the same parents, cause tyrosine residues autophosphorylation crucial in the adjustment structure territory, thereby activate the PTKs activity of I subunit, contain the joint albumen of SH2 structural domain such as the SH2 binding site that IRS is enrolled into IR then, PI3K is activated subsequently, then PKB, the GLUT4 in the carbohydrate metabolism path of downstream further is activated, and intravital glycolipid metabolism is activated.A plurality of links of PTPs effect and this path, as with autophosphorylation activatory IR dephosphorylation, thereby reduce the activity of receptor kinase, or with the protein-tyrosine residue dephosphorylation among IRS IRS-1, IRS-2, the Shc etc., thereby the negative regulation insulin signaling pathway.The active imbalance of PTKs glucose-6-phosphate dehydrogenase may be the reason that causes the type ii diabetes insulin resistant in specific PTPs and the insulin signaling pathway.Therefore, suppress its activity, strengthen and the prolongation insulin signaling, become the new way of more and more valued treatment type ii diabetes by the inhibitor of seeking selectively acting PTPs in this path.
Protein-tyrosine-phosphatase 1B (protein tyrosine phosphatase 1B, PTP1B) be to be purified the earliest and the protein-tyrosine-phosphatase of definite biological characteristics, the about 50kDa of total length, at C art end one section amino acid whose hydrophobic fragment of 35 of can be cut is arranged, this fragment is responsible for PTP1B is positioned on the endoplasmic reticulum, then with receptor type kinases IR, EGFR (epidermal growth factor receptor) and PDGFR (platelet-derived growthfactor receptor) interact, make its dephosphorylation (Boute N, et al.Science 2002,295 (5560), 1708).PTP1B all has expression in multiple tissue, particularly at the target tissue of Regular Insulin such as liver, muscle, fat etc.It is found that recently PTP1B can be by reducing insulin signaling (Kenner KA to the dephosphorylation effect of IR, IRS, et al.J BiolChem 1996,271,19810), by suppressing the activity of PTP1B, help to improve the susceptibility of peripheral tissues to Regular Insulin; In addition, PTP1B also can make leptin receptor associated kinase JAK2 dephosphorylation inactivation, can not produce leptin and reply, thereby cause leptin opposing (ZabolotnyJM, et al.Dev Cell 2002,2,489), thus the PTP1B inhibitor in the treatment of diabetes and obesity, wide prospect is arranged.
Animal experiment shows, the mouse of PTP1B disappearance is owing to increase or prolonged the phosphorylation level of IR in muscle and liver organization, and makes its susceptibility enhancing to Regular Insulin, obviously reduce level (the Elchebly M of triglyceride level in the body, et al.Science 1999,283,1544; Klaman LD, et al.Mol Cell Biol 2000,20,5479); The relevant simultaneously mouse that studies show that the PTP1B disappearance is owing to the enhancing to leptin susceptibility, and energy expenditure increases, so the obesity that high lipid food is caused has good resistant function (Zabolotny LD, et al.Dev Cell 2002,2,489; Cheng A, et al.Dev Cell 2002,2,497).Along with the progress of the Human Genome Project, aspect genetics more and more evidences show PTP1B and type ii diabetes and fat relevant (Echwald SM, et al.Diabetes 2002,51 (1), 1; Di Paoia R, et al.Am J Hum Genet 2002,70 (3), 806), so the PTP1B inhibitor is treatment diabetes and obesity potential medicine.
The research of PTP1B selective depressant has obtained certain progress, but is confined to some peptide classes or class peptide compounds mostly, for example based on inhibitor EEDE (F2PMP) M (Ki=7.2nM), the Glu-F of the dephosphorylized substrate sequences Design of PTP1B
2PMP-F
2PMP (IC
50=40nM), though these peptide inhibitors have the active and higher selectivity of stronger inhibition, they are that the fact of peptide class phosphate cpd makes it be difficult to become drug candidate compound.Recently, a series of non-peptide class non-phosphorylating compound class PTP1B inhibitor are in the news, and they have certain selectivity, the more important thing is, the some of them compound has remarkable effect to glucose and insulin level in the reduction ob/ob mice plasma.
Quinazolinones is that a class has the active nitrogen-containing heterocycle compound of good biological, it is at antitumor (Melin C, et al.J Med Chem 2000,43,1910), anti-inflammatory (Chao Q, et al.J Med Chem 1999,42,860), hypertension (Allen EE, et al.Bioorg MedChem Lett 1993,3,293) and antibiotic (Kung PP, et al.J Med Chem 1999,42,705) etc. the aspect all demonstrates good activity, the bibliographical information Quinazol derivative also can be as antagonist (Rudolph J, the et al.J Med Chem 2007,50 of growth hormone-releasing peptide acceptor (Ghrelin receptor) in addition in addition, 5202) effect that, has potential treatment diabetes and obesity.Quinazolinones is the focus of pharmaceutical chemistry research always, and commercial example has treatment colorectal carcinoma new drug Raltitrexed (Raltitrexed), disinfectant use in agriculture fluquinconazole (Fluquinconazole) etc.Therefore be guide's thing with the quinazolinones, the active compound at different mechanism of action of exploitation possesses good pharmacokinetic property probably and becomes the property of medicine.
Summary of the invention
By PTP1B is suppressed screening active ingredients, PTP1B suppresses active to find to have preferably by a kind of quinazolinones.
The objective of the invention is to release a class Quinazol derivative, it is characterized in that, have the structure shown in the following general structure:
In the formula, R
1Be H or I, work as R
1When being H, R
2Be respectively
The title of described derivative is respectively WLH-409, WLH-424, WLH-417, WLH-495, WLH-496, WLH-402, WLH-451, WLH-479, WLH-322, WLH-324 or WLH-396, works as R
1When being I, R
2Be respectively
The title of described derivative is respectively WLH-535, WLH-550, WLH-558, WLH-621, WLH-622, WLH-528, WLH-577, WLH-605, WLH-448, WLH-450 or WLH-522.
Another object of the present invention is to provide the preparation method of this analog derivative.To achieve these goals, the present invention by the following technical solutions.With 2-amino-5-iodo-benzoic acid or anthranilic acid as raw material and 2-p-methoxy-phenyl isothiocyanic acid ester generation annulation, obtain a class Quinazol derivative with various halogenating agent generation substitution reactions then, this analog derivative has remarkable PTP1B and suppresses active.
Now describe technical scheme of the present invention in detail, a kind of method of preparation one class Quinazol derivative is characterized in that, the concrete operations step:
The first step prepares the quinazolinone intermediate by condensation reaction
8.6g～16.6g anthranilic acid or 2-amino-5-iodo-benzoic acid, 10.4g 2-p-methoxy-phenyl isothiocyanic acid ester is dissolved in the 50mL dehydrated alcohol, refluxes 10 hours, be cooled to room temperature, filter filter cake 10mL sherwood oil drip washing, the drip washing of 10mL saturated sodium bicarbonate solution, the anhydrous EtOH drip washing of 10mL, drying, obtain quinazolinone intermediate crude product, 200-300 order purification by silica gel column chromatography gets 4.7g～7.0g quinazolinone intermediate, productive rate 26%～30%.
Second step prepared Quinazol derivative by substitution reaction
0.23g the quinazolinone intermediate of～0.32g, 0.06g～0.2g halohydrocarbon, 0.24g NaI, 0.22g K
2CO
3Be dissolved in 70mL acetone; backflow 7h removes solvent under reduced pressure under the nitrogen protection, adds the 20mL saturated aqueous common salt; the 100mL dichloromethane extraction; the 50mL water washing, organic layer anhydrous sodium sulfate drying, 200-300 order purification by silica gel column chromatography; get 0.1g～0.35g Quinazol derivative, productive rate 40%～70%.
Below be the reaction skeleton symbol relevant with this preparation method:
Another object of the present invention provides the potential application that described derivative is made antidiabetic medicine.
The invention has the advantages that with 2-amino-5-iodo-benzoic acid or anthranilic acid as raw material and 2-p-methoxy-phenyl isothiocyanic acid ester generation annulation, then with various halogenating agent generation substitution reactions, prepared a class and had remarkable PTP1B and suppress active Quinazol derivative, be expected to have good pharmacokinetic property and the antidiabetic medicine guide thing that becomes the property of medicine as exploitation.
Embodiment
Now describe technical scheme of the present invention in conjunction with the embodiments in detail.All embodiment operate in strict accordance with above-mentioned preparation method's operation steps.
Embodiment one: the preparation of WB-409
In the first step, 8.6g2-amino-5-iodo-benzoic acid, 10.4g 2-p-methoxy-phenyl isothiocyanic acid ester, be dissolved in the 50mL dehydrated alcohol, refluxed 10 hours, be cooled to room temperature, filter, filter cake 10mL sherwood oil drip washing, the drip washing of 10mL saturated sodium bicarbonate solution, the anhydrous EtOH drip washing of 10mL, dry, obtain quinazolinone intermediate crude product, 200-300 order purification by silica gel column chromatography, eluent are the mixed solvent of methylene dichloride and methyl alcohol, the mixed solvent ratio is a methylene dichloride: methyl alcohol=100: 1, get 5.4g quinazolinone intermediate, productive rate 30%, this compound
1H NMR (DMSO, 500MHz): δ=13.11 (brs, 1H), 8.18 (d, J=2.0Hz, 1H), 8.05 (dd, J=2.0,4.2Hz, 1H), 7.39-7.42 (m, 1H), 7.23 (m, J=9.0Hz, 1H), 7.21 (dd, J=1.5,7.5Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 7.02 (t, J=8.0Hz, 1H), 3.71 (s, 3H);
In second step, the quinazolinone intermediate of 0.23g, the 0.13g halogenating agent, halogenating agent is
0.24g NaI, 0.22g K
2CO
3, be dissolved in 70mL acetone, backflow 7h under the nitrogen protection; remove solvent under reduced pressure, add the 20ml saturated aqueous common salt, the 100ml dichloromethane extraction; the 50mL water washing; the organic layer anhydrous sodium sulfate drying, 200-300 order purification by silica gel column chromatography, eluent are the mixed solvent of methylene dichloride and methyl alcohol; the mixed solvent ratio is a methylene dichloride: methyl alcohol=100: 1; get 0.16g Quinazol derivative WLH-409, productive rate 50%, this compound
1H NMR (CDCl
3, 500MHz): δ=8.23 (d, J=8.0Hz, 1H), 7.70 (m, 1H), 7.56 (d, J=8.0Hz, 1H), 7.48 (m, 1H), 7.31 (m, 1H), 7.26 (d, J=7.0Hz, 1H), 7.05 (s, 2H), 4.21 (d, J=14.5Hz, 1H), 4.07 (d, J=15.0Hz, 1H), 3.79 (s, 3H), 3.55 (m, 4H), 1.60 (m, 4H), 1.50 (m, 2H).
Embodiment two: the preparation of WLH-535
In the first step, 16.6g anthranilic acid, 10.4g 2-p-methoxy-phenyl isothiocyanic acid ester, be dissolved in the 50mL dehydrated alcohol, refluxed 10 hours, be cooled to room temperature, filter, filter cake 10mL sherwood oil drip washing, the drip washing of 10mL saturated sodium bicarbonate solution, the anhydrous EtOH drip washing of 10mL, dry, obtain quinazolinone intermediate crude product, 200-300 order purification by silica gel column chromatography, eluent are the mixed solvent of methylene dichloride and methyl alcohol, the mixed solvent ratio is a methylene dichloride: methyl alcohol=100: 1, get 6.7g quinazolinone intermediate, productive rate 26%, this compound
1H NMR (DMSO, 500MHz): δ=13.11 (brs, 1H), 8.18 (d, J=2.0Hz, 1H), 8.05 (dd, J=2.0,4.2Hz, 1H), 7.39-7.42 (m, 1H), 7.23 (d, J=9.0,1H), 7.21 (dd, J=1.5,7.5Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 7.02 (t, J=7.5Hz, 1H), 3.71 (s, 3H);
In second step, the quinazolinone intermediate of 0.33g, the 0.13g halogenating agent, halogenating agent is
0.24g NaI, 0.22g K
2CO
3, be dissolved in 70mL acetone, backflow 7h under the nitrogen protection; remove solvent under reduced pressure, add the 20ml saturated aqueous common salt, the 100ml dichloromethane extraction; the 50mL water washing; the organic layer anhydrous sodium sulfate drying, 200-300 order purification by silica gel column chromatography, eluent are the mixed solvent of methylene dichloride and methyl alcohol; the mixed solvent ratio is a methylene dichloride: methyl alcohol=100: 1; get 0.27g Quinazol derivative WLH-535, productive rate 63%, this compound
1H NMR (CDCl
3, 500MHz): δ=8.56 (d, J=2.2Hz, 1H), 7.81 (dd, J=2.2,8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.30 (d, J=8.7Hz, 1H), 7.18 (d, J=10.0Hz, 2H), 4.02 (s, 2H), 3.56-2.58 (m, 4H), 1.68 (m, 4H), 1.57 (m, 2H).
Except following difference, embodiment three to embodiment 12 is all identical with embodiment one.
Embodiment three: the preparation of WLH-424
In second step, halogenating agent is
Add-on is 0.14g, and productive rate is 65%, this derivative
1H NMR (CDCl
3, 500MHz): δ=11.52 (brs, 1H), 8.27 (d, J=5.0Hz, 1H), 7.82 (d, J=5.0Hz, 2H), 7.54 (t, J=10.0Hz, 1H), 7.47 (t, J=15.0Hz, 1H), 7.43 (m, 1H), 7.25 (s, 1H), 7.09 (t, J=10.0Hz, 1H), 6.98-6.97 (s, 1H), 4.02 (d, J=15Hz, 1H), 3.89 (d, J=15.0Hz, 1H), 3.82 (s, 3H).
Embodiment four: the preparation of WLH-417
In second step, halogenating agent is
Add-on is 0.14g, and productive rate is 69%, this derivative
1H NMR (CDCl
3, 500MHz): δ=9.80 (brs, 1H), 8.29 (d, J=6.0Hz, 1H), 7.80 (d, J=6.0Hz, 1H), 7.70 (d, J=6.0Hz, 1H), 7.44-7.52 (m, 1H), 7.25 (t, J=6.0Hz, 3H), 7.07-7.12 (m, 3H), 3.93 (d, J=12.0Hz, 1H), 3.77 (d, J=12.0Hz, 1H), 3.77 (s, 1H).
Embodiment five: the preparation of WLH-495
In second step, halogenating agent is
Add-on is 0.20g, and productive rate is 40%, this derivative
1H NMR (CDCl
3, 500MHz): δ=10.05 (brs, 1H), 8.31 (d, J=5.0Hz, 1H), 7.82 (t, 1H), 7.68 (d, J=8.0Hz, 1H), 7.49 (m, 2H), 7.34 (m, 4H), 7.25 (d, J=4.0Hz, 1H), 7.07 (m, 2H), 3.94 (d, J=14.5Hz, 1H), 3.73 (d, J=14.5Hz, 1H), 3.78 (s, 3H).
Embodiment six: the preparation of WLH-496
In second step, halogenating agent is
Add-on is 0.20g, and productive rate is 52%, this derivative
1H NMR (CDCl
3, 500MHz): δ=9.90 (brs, 1H), 8.27 (d, J=8.0Hz, 1H), 7.81 (m,, 1H), 7.76 (d, J=3.5Hz, 2H), 7.61 (dd, J=0.75,4.0Hz, 1H), 7.53-7.56 (m, 1H), and 7.44-7.47 (m, 1H), 7.27-7.30 (m, 2H), 7.09-7.14 (m, 2H), 3.99 (d, J=14.5Hz, 1H), 3.92 (d, J=14.5,1H), 3.80 (s, 3H).
Embodiment seven: the preparation of WLH-402
In second step, halogenating agent is
Add-on is 0.12g, and productive rate is 62%, this derivative
1H NMR (CDC13,500MHz): δ=8.22 (d, J=8.0Hz, 1H), 8.10 (d, J=7.5Hz, 1H), 7.61 (m, 2H), 7.52 (m, 3H), 7.32 (m, 2H), 7.09 (m, 2H), 4.70 (d, J=16.0Hz, 1H), 4.47 (d, J=16.5Hz, 1H), 3.82 (s, 3H).
Embodiment eight: the preparation of WLH-451
In second step, halogenating agent is
Add-on is 0.16g, and productive rate is 65%, this derivative
1H NMR (CDCl
3, 500MHz): δ=9.31 (brs, 1H), 8.27 (t, 2H), 7.75 (t, J=5.6Hz, 1H), 7.70 (d, J=7.4Hz, 1H), 7.52 (t, J=Hz, 3H), 7.43 (t, J=Hz, 2H), 7.24-7.29 (m, 3H), 7.08-7.13 (m, 2H), 7.00 (t, J=Hz, 1H), 4.05 (d, J=14.8Hz, 1H), 3.97 (d, J=14.5Hz, 1H), 3.77 (s, 3H).
Embodiment nine: the preparation of WLH-479
In second step, halogenating agent is
Add-on is 0.19g, and productive rate is 60%, this derivative
1H NMR (CDCl
3, 500MHz): δ=8.28 (d, J=7.5Hz, 1H), 7.80 (brs, 1H), 7.72 (t, J=7.7Hz, 1H), 7.53 (t, J=8.5Hz, 1H), 7.44 (t, J=7.5,1H), 7.29 (m, 1H), 7.10-7.14 (m, 2H), 5.78 (s, 1H), 3.90 (s, 6H), 3.82 (s, 3H).
Embodiment ten: the preparation of WLH-322
In second step, halogenating agent is
Add-on is 0.095g, and productive rate is 59%, this derivative
1H NMR (CDCl
3, 300MHz): δ=8.24 (d, J=3.0Hz, 1H), 7.73 (m, 1H), 7.64 (d, J=6.0Hz, 1H), 7.52 (m, 1H), 7.40 (m, 1H), 7.07-7.12 (m, 2H), 6.69 (t, J=6.0Hz, 1H), 5.03-5.04 (m, 2H), 3.80 (s, 3H).
Embodiment 11: the preparation of WLH-324
In second step, halogenating agent is
Add-on is 0.097g, and productive rate is 50%, this derivative
1H NMR (CDCl
3, 300MHz): δ=8.23 (t, J=4.7Hz, 1H), 7.70-7.74 (m, 1H), 7.60 (d, J=6.0Hz, 1H), 7.48-7.52 (m, 1H), 7.36 (t, J=5.5Hz, 1H), 7.23-7.25 (m, 1H), 7.06-7.23 (m, 2H), 5.88-5.98 (m, 1H), 5.26-5.31 (m, 1H), 5.10-5.13 (m, 1H), 3.79-3.88 (s, 5H).
Embodiment 12: the preparation of WLH-396
In second step, halogenating agent is
Add-on is 0.15g, and productive rate is 41%, this derivative
1H NMR (CDCl
3, 300MHz): δ=8.26 (t, J=6.0Hz, 1H), 7.71 (t, J=6.0Hz, 1H), 7.62 (d, J=6.0Hz, 1H), 7.50 (t, J=6.0Hz, 1H), 7.37 (t, J=6.0Hz, 1H), 7.26 (d, J=3.0Hz, 1H), 7.08-7.14 (m, 2H), 3.81 (s, 3H), 3.16 (t, J=6.0Hz, 2H), 1.70 (t, J=4.5Hz, 2H), 1.30-1.47 (m, 10H), 0.89 (m, 3H).
Embodiment 13 to embodiment 22 is all identical with embodiment two except following difference.
Embodiment 13: the preparation of WLH-550
In second step, halogenating agent is
Add-on is 0.14g, and productive rate is 56%, this derivative
1HNMR (CDCl
3, 500MHz): δ=11.34 (brs, 1H), 8.61 (s, 1H), 8.09 (d, J=8.5Hz, 1H), 7.55-7.59 (m, 2H), 7.45 (d, J=3.5Hz, 1H), 7.26-7.28 (m, 1H), 7.11-7.15 (m, 2H), 6.99 (d, J=3.5Hz, 1H), 4.03 (d, J=15.0Hz, 1H), 3.90 (d, J=15.0Hz, 1H), 3.85 (s, 3H).
Embodiment 14: the preparation of WLH-558
In second step, halogenating agent is
Add-on is 0.14g, and productive rate is 54%, this derivative
1H NMR (CDCl
3, 300MHz): δ=10.33 (brs, 1H), 8.33 (s, 1H), 8.10 (d, J=6.0Hz, 1H), 7.57 (s, 3H), 7.42 (d, J=5.4Hz, 1H), 7.30-7.36 (m, 4H), 7.14 (s, 1H), 7.05 (s, 1H), 4.07 (s, 2H), 3.76 (s, 3H).
Embodiment 15: the preparation of WLH-621
In second step, halogenating agent is
Add-on is 0.20g, and productive rate is 64%, this derivative
1H NMR (CDCl
3, 500MHz): δ=9.74 (brs, 1H), 8.61 (d, J=2.0Hz, 1H), and 8.07-8.09 (m, 1H), 7.52-7.53 (m, 1H), 7.37-7.42 (m, 3H), 7.37-7.32 (m, 1H), 7.30-7.22 (m, 1H), 7.10-7.07 (m, 2H), 3.93 (d, J=14.5Hz, 1H), 3.74 (d, J=14.5Hz, 1H), 3.76 (s, 3H).
Embodiment 16: the preparation of WLH-622
In second step, halogenating agent is
Add-on is 0.20g, and productive rate is 40%, this derivative
1H NMR (CDCl
3, 500MHz): δ=9.74 (brs, 1H), 8.58 (d, J=2.0Hz, 1H), 8.01 (dd, J=10.0,8.0Hz, 1H), 7.81 (dd, J=1.0,8.5Hz, 1H), 7.62 (dd, J=10.0,8.0Hz, 1H), 7.54-7.57 (m, 2H), 7.49 (d, J=8.5Hz, 1H), 7.25-7.31 (m, 2H), 7.09-7.14 (m, 2H), 3.96 (d, J=14.5Hz, 1H), 3.91 (d, J=14.5Hz, 1H), 3.80 (s, 3H).
Embodiment 17: the preparation of WLH-528
In second step, halogenating agent is
Add-on is 0.12g, and productive rate is 50%, this derivative
1H NMR (CDCl
3, 500MHz): δ=8.54 (d, J=2.0Hz, 1H), 8.08-8.09 (m, 2H), 7.87 (dd, J=2.0,9.0Hz, 1H), 7.64 (t, J=7.5Hz, 1H), and 7.53-7.56 (m, 3H), 7.31 (dd, J=1.5,8.0Hz, 1H), and 7.10-7.15 (m, 2H), 6.97 (d, J=9.0Hz, 1H), 4.68 (d, J=16.0Hz, 1H), 4.45 (d, J=16.0Hz, 1H), 3.82 (s, 3H).
Embodiment 18: the preparation of WLH-577
In second step, halogenating agent is
Add-on is 0.16g, and productive rate is 59%, this derivative
1H NMR (CDCl
3, 500MHz): δ=9.17 (brs, 1H), 8.58 (s, 1H), 8.27 (d, J=8.1Hz, 1H), 8.00 (d, J=8.4Hz, 1H), 7.53 (t, J=Hz, 1H), 7.43 (d, J=8.7Hz, 1H), 7.24-7.30 (m, 2H), 7.08-7.13 (m, 3H), 7.01-7.04 (t, J=Hz, 1H), 4.02 (d, J=14.7Hz, 1H), 3.94 (d, J=14.8Hz, 1H), 3.77 (s, 3H).
Embodiment 19: the preparation of WLH-605
In second step, halogenating agent is
Add-on is 0.19g, and productive rate is 70%, this derivative
1H NMR (CDCl
3, 500MHz): δ=8.57 (d, J=1.9Hz, 1H), 7.96 (dd, J=2.0,10.3Hz, 1H), 7.53 (m, 1H), 7.45 (brs, 1H), 7.26-7.25 (m, 1H), 7.08-7.12 (m, 2H), 5.78 (s, 1H), 3.90 (s, 6H), 3.80 (s, 3H).
Embodiment 20: the preparation of WLH-448
In second step, halogenating agent is
Add-on is 0.095g, and productive rate is 44%, this derivative
1H NMR (CDCl
3, 500MHz):, δ=8.55 (brs, 1H), 7.98 (d, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.38 (d, J=9.0Hz, 1H), 7.23 (m, 1H), 7.07-7.11 (m, 1H), 6.63 (t, J=6.5Hz, 1H), 5.04 (d, J=6.5Hz, 2H), 3.80 (s, 3H).
Embodiment 21: the preparation of WLH-450
In second step, halogenating agent is
Add-on is 0.097g, and productive rate is 50%, this derivative
1H NMR (CDCl
3, 300MHz): δ=8.54 (s, 1H), 7.95 (d, J=6.2Hz, 1H), 7.48 (d, J=5.6Hz, 1H), 7.33 (d, J=6.0Hz, 1H), 7.21 (t, J=6.1Hz, 1H), 7.05 (t, J=7.3Hz, 1H), 5.90-5.91 (m, 1H), 5.25 (d, J=7.5Hz, 1H), 5.10 (d, J=7.5Hz, 1H), 3.78 (s, 3H).
Embodiment 22: the preparation of WLH-522
In second step, halogenating agent is
Add-on is 0.15g, and productive rate is 61%, this derivative
1H NMR (CDCl
3, 500MHz) δ=8.55 (s, 1H), 7.96 (d, J=8.5Hz, 1H), 7.5 (t, 1H), 7.33 (d, J=8.5Hz, 1H), 7.22 (d, J=7.5Hz, 1H), 7.07 (m, 2H), 3.79 (s, 3H), 3.10 (m, 2H), 1.63 (m, 2H), 1.37 (m, 2H), 1.26 (m, 8H), 0.86 (m, 3H).
Embodiment 23: the PTP1B of Quinazol derivative suppresses active testing
1. test philosophy: utilize molecular biology method at intestinal bacteria system expression hPTP1B catalyst structure domain, the phosphatide key of hPTP1B recombinant protein energy hydrolysis substrate pNPP after purified, the product that obtains has very strong photoabsorption at the 410nm place, and variation that therefore can be by directly detecting 410nm place's photoabsorption is with the activity change of observation enzyme and the compound inhibition situation to enzymic activity.The survey live body of standard is as follows: 50mM Mops, PH 7.0,1mM EDTA, 2mM DTT, 2mM PNPP, 2% DMSO, 40nM hPTP1B.
2. observation index: the dynamic measurement wavelength is the photoabsorption at 410nm place, and the time is 3min, and the slope of its kinetic curve first order reaction is as the activity index of enzyme.
3. sample test: 1, the 1mg sample is dissolved among the 200 μ L DMSO.Get in the A2-H11 sample well that 20 μ L join 96 hole polypropylene boards, add 80 μ L DMSO then, as motherboard.2, get 2 μ L samples with Biomek 2000 automatic sample adding systems and join in the counter sample hole of 96 hole polystyrene plates, as the daughter board of screening usefulness.3, adding 2 μ L DMSO among A1-D1, the E12-H12 contrasts as a hundred per cent enzymic activity.4, the positive control (by four concentration of 10 μ L/mL twices dilution) that adds 2 μ L different concns among A12-D12, the E1-H1.5, A1-H12 adds 88 μ L Assay mix respectively.6, A1-H12 adds 10 μ L hPTP1B respectively.7, measure 410nm place's photoabsorption on SpectraMAX 340, the time is 3min.8, data are output as text, open in the Excel mode then, with the Vmax value of A1-D1, E12-H12 on average as 100% enzyme activity.Compound is tried to achieve by following formula the inhibiting rate of PTP1B:
Inhibiting rate (%)=(each screen holes Vmax value/blank V of 1-
MaxMean value) * 100%
4. test result: The selection result is to the percent inhibition of enzymic activity when compound concentrations is 20 μ g/mL; suppress activity and be higher than at 50% o'clock; screening draws IC50, positive control 4-[4-(4-oxalyl group-Phenoxymethyl)-benzyloxy routinely]-IC of benzoylformic acid (4-[4-(4-oxalyl-phenoxymethyl)-benzyloxy]-phenyl-oxo-acetic acid)
50Be 5.4 μ M[Christopher T.Seto, et al.J.Med.Chem.2002,45,3946.].
4-[4-(4-oxalyl group-Phenoxymethyl)-benzyloxy]-benzoylformic acid
Each test compounds suppresses the IC of PTP1B
50Value sees the following form:
Quinazol derivative suppresses the activity data of PTP1B
Derivative of the present invention is a kind of protein-tyrosine-phosphatase 1B (being called for short PTP1B) inhibitor, the suitable especially potential antidiabetic medicine of doing.
Claims (3)
1. a class Quinazol derivative is characterized in that, has the structure shown in the following general structure:
In the formula, R
1Be H or I,
Work as R
1When being H, R
2Be respectively
Or
The title of described derivative is respectively WLH-424, WLH-417, WLH-496, WLH-479 or WLH-396,
Work as R
1When being I, R
2Be respectively
The title of described derivative is respectively WLH-550, WLH-558, WLH-621, WLH-622, WLH-577, WLH-605, WLH-448 or WLH-522.
2. a method for preparing the described Quinazol derivative of claim 1 is characterized in that, the concrete operations step:
The first step prepares the quinazolinone intermediate by condensation reaction
8.6g～16.6g anthranilic acid or 2-amino-5-iodo-benzoic acid, 10.4g 2-p-methoxy-phenyl isothiocyanic acid ester is dissolved in the 50mL dehydrated alcohol, refluxes 10 hours, be cooled to room temperature, filter filter cake 10mL sherwood oil drip washing, the drip washing of 10mL saturated sodium bicarbonate solution, the anhydrous EtOH drip washing of 10mL, drying, obtain quinazolinone intermediate crude product, 200-300 order purification by silica gel column chromatography gets 4.7g～7.0g quinazolinone intermediate, productive rate 26%～30%;
Second step prepared Quinazol derivative by substitution reaction
0.23g the quinazolinone intermediate of～0.32g, 0.06g～0.2g halohydrocarbon, the general molecular formula of this halohydrocarbon is R
2X, wherein, R
2Connotation described identical with claim 1, X is Cl or Br, 0.24g NaI, 0.22g K
2CO
3Be dissolved in 70mL acetone; backflow 7h removes solvent under reduced pressure under the nitrogen protection, adds the 20mL saturated aqueous common salt; the 100mL dichloromethane extraction; the 50mL water washing, organic layer anhydrous sodium sulfate drying, 200-300 order purification by silica gel column chromatography; obtain the described Quinazol derivative of 0.1g～0.35g claim 1, productive rate 40%～70%.
3. the application of the described derivative of claim 1 is characterized in that, prepares antidiabetic medicine with described derivative.
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