CN103183606B - A kind of 4,4'-bis-substituted benzophenone compounds and preparation method thereof - Google Patents
A kind of 4,4'-bis-substituted benzophenone compounds and preparation method thereof Download PDFInfo
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- CN103183606B CN103183606B CN201210583177.XA CN201210583177A CN103183606B CN 103183606 B CN103183606 B CN 103183606B CN 201210583177 A CN201210583177 A CN 201210583177A CN 103183606 B CN103183606 B CN 103183606B
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- DPHUGDBPIGROCP-YRNVUSSQSA-N CC(C)COc(cc1)ccc1C(c(cc1)cc(/C=C/C(OC)=O)c1O)=O Chemical compound CC(C)COc(cc1)ccc1C(c(cc1)cc(/C=C/C(OC)=O)c1O)=O DPHUGDBPIGROCP-YRNVUSSQSA-N 0.000 description 1
- IXOKIWZMTKUQKC-UHFFFAOYSA-N CC(C)COc(cc1)ccc1C(c(cc1)cc(CCC(O)=O)c1OCC(C)C)=O Chemical compound CC(C)COc(cc1)ccc1C(c(cc1)cc(CCC(O)=O)c1OCC(C)C)=O IXOKIWZMTKUQKC-UHFFFAOYSA-N 0.000 description 1
- AAKCIHDTNRKPCF-UHFFFAOYSA-N CC(C)COc(cc1)ccc1C(c(cc1)cc(CCC(OC)=O)c1O)=O Chemical compound CC(C)COc(cc1)ccc1C(c(cc1)cc(CCC(OC)=O)c1O)=O AAKCIHDTNRKPCF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides class 4,4 ' two substituted benzophenone compounds, there is the structure shown in following formula I:This compound can suppress AP 1 albumen and the activity of NDM 1 albumen well, and it is for the IC of NDM 1 albumen50Value is 52.93 ± 11.86 μMs.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to a kind of 4,4 '-two substituted benzophenone compounds, system
Preparation Method, biological activity and application thereof.
Background technology
Along with the further investigation to the disease such as rheumatoid arthritis and cancer, cell signalling is in drug research
Role is increasingly important.Novel anti-inflammatory medicine all lays particular emphasis on design micromolecular compound and acts on various passage, so that its
Effect to target spot has higher selectivity.AP-1 albumen plays conclusive as transcription factor in cell signalling
Effect.Strong being activated by platelet derived growth factor (PDGF), so including that c-Fos, c-Jun become of activity energy due to AP-1
Member plays important role at interior AP-1 protein family in cell increases, and has determined DNA sequence 5-TGAGTCA-
3 ' is AP-1 binding site.It addition, AP-1 is the most relevant with the response of cytometaplasia, immunity and inflammatory factor, this means that AP-
1 albumen can involve various disease.So designing the little molecule of 3D drug effect with synthesis based on AP-1-DNA complex and it being entered
The change of row three dimensional structure, such as, change a series of AP-1 inhibitor pair that the rigidity of compound, hydrophobicity, hydrophilic etc. obtain
It is significantly in the treatment various important diseases including rheumatoid arthritis, cancer.As this year is just reported
Anticarcinogen 2-thiazole-3H-quinazoline-4-one derivatives acts on the multiple passages such as NF-kB and AP-1, and the treatment of cancer is risen by it
Key effect.
In sum, by the three-dimensional knot having been found that the lead compound benzophenone derivates acting on AP-1 albumen
Structure carries out transformation and modifies and synthesized, and is carrying out drug efficacy study, thus assessment determined and act on the three of AP-1 albumen
Dimension avtive spot, and then design the Medicine small molecule that selectivity more high activity is higher.Additionally by the change to avtive spot
Design can explore the required model of molecule really acting on AP-1 albumen, is transformed and can screen on its essential group
Go out the clinical medicine molecule of the more symptom of a trend.
NDM-1 is a kind of novel metal-beta-lactamase, is that in August, 2010 may be in India's New Delhi sense according to patient
Dye is by its named New Delhi metal-beta-lactamase (New Delhi metallo-β-lactamase-1).Novel metal-
The NDM-1 gene that beta-lactamase carries is on plasmid, and drug resistance gram-negative bacteria is shown by force by the antibacterial with NDM-1 gene
Other all of antibiotic almost all can be produced in addition to antibiotic polymyxin, tigecycline by big antibacterial action at present
Drug resistance.The antibacterial carrying NDM-1 gene mainly causes the infections relatings such as urinary tract, pulmonary, wound, blood flow and conduit, finds
Having, at various countries worldwide, the report that case infects less than one month, so causing people's extensive concern, therefore developing
The medicine of suppression NDM-1 activity is most important.
Dividing with protein sequence according to ribose, NDM-1 adheres to Type B separately, and it is a kind of metalloenzyme, and its active site is metal
Ion, so having to rely on divalent metal Zn+ catalysis activity occurs.The present invention is found by high-flux medicaments sifting
The lead compound compound of formula I of the resisting rheumatoid arthritis T-5224 being in the clinical second phase has certain suppression to NDM-1
Effect, and show good albumen inhibitory action and biostatic activity, this is by the NDM-1 again and again occurred in recent years
The patient infected brings Gospel.Further investigation can develop the NDM-1 inhibitor of novel parent nucleus, super for prevention or treatment
Antibacterial infects, such as urinary tract, pulmonary, wound infection level.
Summary of the invention
The lead compound compound of formula I of the present invention compound T-5224 to having been enter into clinical three phases carries out high flux sieve
Choosing, pharmacologically active result shows, this compound has obvious inhibitory action to NDM-1 albumen, its may be used for prevention or
Treatment superbacteria infects, such as urinary tract, pulmonary infection.
The invention provides a kind of 4,4 '-two substituted benzophenone analog, its chemical name be 3-(2-isobutoxy-
5-(4-isobutyl oxygen benzoyl) phenyl) propanoic acid, there is the structure shown in following formula I, thus be hereinafter sometimes referred to simply as Formulas I
Compound:
The invention provides the preparation method of above-mentioned compound of formula I, comprise the following steps:
Step a. makes Formula II compound
Aldehyde and further sodium chlorite oxidation reaction generation formula III compound is reacted into through first step manganese dioxide
Step b. formula III compound is carried out with phenyl isobutyl ether under the conditions of lewis acid phosphorus pentoxide and methanesulfonic acid
F-K reaction generates formula IV compound
Step c. formula IV compound carries out lactone ring-opening reaction production V compound under the conditions of Feldalat NM
Step d. Formula V compound 5%Pd/C carries out the reduction reaction production of double bond under sodium formate and acetic acid effect
VI compound
Step e. Formula IV compound carries out Williamson reaction under mild alkaline conditions and generates ether VII
Step f. Formula VII compound is hydrolyzed in NaOH-methanol system and reacts production I.
The invention provides compound of formula I application in prevention or treatment NDM-1 catch.Compound of formula I energy
Enough significantly inhibit growth and the activity of NDM-1 albumen, such that it is able to prevention or treatment NDM-1 catch.
The invention provides compound of formula I application in the medicine that preparation prevention or treatment NDM-1 catch.
The compound of formula I of the present invention can suppress survival and the growth of NDM-1 albumen, its IC effectively50Value is 52.93 ±
11.86 μMs, it may be used for prevention or treatment NDM-1 catches, such as infections relatings such as urinary tract, pulmonary, wound, conduits.
Detailed description of the invention
It is further described with feature the most to various aspects of the present invention.
Pharmacologically active part
Measure cytoactive and include following several step:
Step 1): the NDM-1 (diluting with albumen buffer) of 50nM is joined 100 μ l/ hole in 96 microwell plates.Then add
Entering the various concentration dissolved is 100mM medicine, 2 μ l/ holes.Vibration, after incubated at room 1min, every hole adds 50 μ l, 600 μMs
Substrate react.Surveyed once every 6 seconds, survey 25 times altogether.Drawing curve, taking negative control slope of curve maximum value is
V0, is Vi at drug profile maximum slope, then this enzyme residual activity mark (NDM-1activity)=Vi/V0.Residual activity is more
Low, represent that the suppression of compound for protein activity is the strongest.Residual activity mark (i.e. suppression ratio is higher than 70%) within 0.3 when enzyme
Time, the IC50 value of this medicine will be measured further.
Step 2): primary dcreening operation have the compound of obvious inhibiting effect carry out proportional diluted, altogether dilution 11 in the ratio of 1: 2
Concentraton gradient.Ultimate density is followed successively by 1316,658,329,164.5,82.2,41.1,20.6,10.3,5.1,2.6,1.3 μMs.
Then carrying out the IC50 value detection of compound, detection method ibid, finally carries out curve plotting, and abscissa is drug level pair
Number, vertical coordinate is the residual activity of enzyme.With data processing software Graphpad Prism 5.0, Excel2007 is carried out at data
Reason, mapping, obtain IC50Value.
The following example is only used for illustrating the present invention, limits the invention never in any form.
Embodiment 1 3-(2-isobutoxy-5-(4-isobutyl oxygen benzoyl) phenyl) propanoic acid
Take two mouthfuls of round-bottomed flasks of 50ml, at room temperature, be sequentially added into 3-(2-isobutoxy-5-(4-isobutyl oxygen benzoyl
Base) phenyl) methyl propionate (Formula VII compound) (1g, 2.51mmol), prepare before 20%NaOH (mass fraction,
1.5g) and methanol (4ml), it is heated to 60 DEG C to react 2 hours.After question response terminates, reactant liquor use water (12ml) is diluted, and
With 6M HCl regulation reaction solution to PH 1, sucking filtration obtains solid and obtains white solid 0.9g, productivity with water (2 × 50ml) washing
It is 93%.
1H-NMR (400MHz, CDCl3): δ 1.04 (6H, d, J=6.6Hz), 1.07 (6H, d, J=6.8Hz), 2.06-
2.22 (2H, m), 2.71 (2H, t, J=7.7Hz), 3.00 (2H, t, J=7.7Hz), 3.80 (2H, d, J=6.4Hz), 3.82
(2H, d, J=6.6Hz), 6.87 (1H, d, J=8.5Hz), 6.95 (2H, d, J=8.8Hz), 7.66 (1H, d, J=2.2Hz),
7.69 (1H, dd, J=8.5,2.2Hz), 7.76 (2H, d, J=8.8Hz)；
MS:m/z 397 (M-H)-, 399 (M+H)+；
Anal.(C24H30O5) C, H.
Embodiment 2 initiation material 3-(2-isobutoxy-5-(4-isobutoxy benzyl) phenyl) methyl propionate (Formula VII
Compound) preparation
Step 1.1: formula III compound
Taking 500ml there-necked flask, 30ml water is added dropwise in 62.5% sulphuric acid (152ml) prepared before, and adds 6-
Methylcoumarin (25g, 0.156mol) and chlorobenzene (25ml), at 70-90 DEG C, add points for 8 times manganese dioxide (35g,
0.4026mol), in dropping 62.5% sulphuric acid (20ml), finish, control temperature at 80-90 DEG C, react 1h.Question response is complete
After, cooling system is to room temperature, and adds water (150ml), is added dropwise over 25% ammonia (43ml), is subsequently adding EtOAc under ice bath
(50ml), butanone (100ml), sucking filtration, and with butanone (3 × 50ml) filter wash cake to canescence, extract and separate obtains organic layer, continue
With butanone (2 × 20ml) wash water layer, merge organic layer, after rotation is evaporated off butanone, in system, add DMSO (15ml), HCl
(8ml), and at 15-40 DEG C, it is added dropwise over 25% sodium chlorite (55ml), finishes, stir 30min at a temperature of keeping being somebody's turn to do, continuing
Continue and at being warming up to 74-80 DEG C, stir 15min.After question response is complete, it is cooled to room temperature, separates to obtain organic layer.Organic layer adds
Enter water (125ml), at 30-40 DEG C, be added dropwise over 25% ammonia (20ml), make solution PH arrive 10, separate aqueous layer.In water layer
Continuously add DMSO (70ml), be added dropwise over HCl (16ml) at 30-40 DEG C, be continuously heating to 65-75 DEG C and be added dropwise over HCl
(15ml), mutually synthermal stirring 30min is kept, cooling, overnight, obtain 14.8g yellow solid, productivity is 50%.
1H-NMR (400MHz, DMSO-d6) δ: 6.59 (1H, d, J=9.6Hz), 7.49 (1H, d, J=8.6Hz), 8.12
(1H, dd, J=8.6,1.9Hz), 8.20 (1H, d, J=9.6Hz), 8.36 (1H, d, J=1.9Hz), 13.22 (1H, br s)；
MS:m/z189 (M-H)-, 191 (M+H)+；
Anal.(C10H6O4) C, H.
Step 1.2:6-(4-isobutoxy benzoyl)-2H-.alpha.-5:6-benzopyran (formula IV compound)
Take 100ml there-necked flask, be sequentially added into phosphorus pentoxide (0.7g, 4.932mmol), methanesulfonic acid (5ml), be warming up to
70-80 DEG C of reaction 1h.Continuously add the formula III compound (1.7g, 8.945mmol) that step 1.1 obtains, chlorobenzene (0.2ml), and
It is added dropwise over phenyl isobutyl ether (1.4g, 9.327mmol) at 70-80 DEG C, finishes, keep 70-80 DEG C of reaction 3h.Question response is complete
Quan Hou, cooling system, to room temperature, adds butanone (10ml), water (5ml), is added dropwise over 25% ammonia (7ml), is warming up to 65-75
DEG C separate to obtain organic layer, in gained organic layer, continuously add butanone (3ml), water (4ml), and 25% ammonia (0.5ml), heat up
Separating to obtain organic layer at 65-75 DEG C, organic layer concentrates, and obtains white by residue through silica gel column chromatography (PE: EA=20: 1) purification
Color solid 1.8g, productivity is 65%.
1H-NMR (400MHz, CDCl3) δ: 1.08 (6H, d, J=6.8Hz), 2.16 (1H, m), 3.84 (2H, d, J=
6.8Hz), 6.52 (1H, d, J=9.6Hz), 7.01 (2H, q, J=2Hz), 7.44 (1H, d, J=8Hz), 7.77 (1H, d, J=
9.6Hz), 7.82 (2H, d, J=8.4Hz), 7.98 (2H, d, J=1.6Hz)；
MS:m/z323 (M+H)+；
Anal.(C20H18O4) C, H.
Step 1.3:(E)-3-(2-hydroxyl-5-(4-isobutoxy benzoyl) phenyl) acrylic acid methyl ester. (Formula V chemical combination
Thing)
Take 100ml single port flask, be sequentially added into 28% Feldalat NM (721mg, 13.34mmol), the formula that step 1.2 obtains
IV compound (560mg, 1.739mmol), methanol (2ml), it is heated to reflux 3h.After question response is complete, ice bath cooling reactant, to
Ice bath system adds water (7ml), and with 6M HCl regulation PH to the 1-2. then system of cooling adds the EtOAc of cooling
(10ml), organic layer is separated to obtain.Concentrated, by residue through silica gel column chromatography (PE: EA=10: 1) purification, obtain white solid
540mg, productivity is 88%.
1H-NMR (400MHz, DMSO-d6) δ: 1.01 (6H, d, J=6.4Hz), 2.08 (1H, m), 3.72 (3H, s), 3.86
(2H, d, J=6.4Hz), 6.66 (1H, d, J=16Hz), 7.07 (3H, t, J=8.8Hz), 7.64 (1H, d, J=2.4Hz),
7.71 (2H, d, J=8.8Hz), 7.84 (1H, s), 7.94 (1H, d, J=2Hz), 11.21 (1H, s)；
MS:m/z 353 (M-H)-, 355 (M+H)+；
Anal.(C21H22O5) C, H.
Step 1.4:3-(2-hydroxyl-5-(4-isobutoxy benzoyl) phenyl) methyl propionate (Formula IV compound)
Take 100ml single port flask, be sequentially added into the Formula V compound (430mg, 1.21mmol) that step 1.3 obtains, acetic acid
(430mg), sodium formate (430mg, 6.32mmol), isopropanol (3.2ml), 5%Pd/C (110mg)-H2O (0.9ml), 45-50
DEG C reaction 5h.After band reaction completely, cooling reactant liquor, to 25-35 DEG C, adds kieselguhr (500mg), stirs 10min, and sucking filtration is also
With isopropanol (3 × 10ml), H2O (3 × 5ml) filter wash cake, gained filtrate adds EtOAc (15ml) and extracts to obtain organic layer, concentrates
Obtain yellow oily liquid 390mg, productivity 91%.
1H-NMR (400MHz, CDCl3) δ: 1.05 (6H, d, J=6.8Hz), 2.06-2.18 (1H, m), 2.76 (2H, t, J
=6.3Hz), 2.95 (2H, t, J=6.3Hz), 3.72 (3H, s), 3.80 (2H, d, J=6.6Hz), 6.94 (1H, d, J=
8.3Hz), 6.95 (2H, d, J=8.7Hz), 7.58 (1H, dd, J=8.4,2Hz), 7.63 (1H, d, J=2.2Hz), 7.76
(2H, d, J=8.8Hz), 7.95 (1H, br s)；
MS:m/z 355 (M-H)-, 357 (M+H)+；
Anal.(C21H24O5) C, H.
Step 1.5:3-(2-isobutoxy-5-(4-isobutoxy benzoyl) phenyl) methyl propionate (Formula VII chemical combination
Thing)
Take 100ml there-necked flask, be sequentially added into the Formula IV compound (240mg, 0.0674mmol) that step 1.4 obtains,
K2CO3(100mg), isobutyl bromide (300mg, 2.205mmol), DMF (3ml), it is warming up to 90-100 DEG C, reacts 1h.Question response is complete
Quan Hou, is cooled to room temperature, extracts to obtain organic layer with EtOAc (3 × 5ml), and gained organic layer uses H successively2O (3ml), saturated common salt
Water (3ml) washs, and gained organic layer is dried through anhydrous magnesium sulfate, filters, and concentrates, by residue through silica gel column chromatography (PE: EA=
20: 1) purification, obtains the title compound of 230mg, and for white solid, productivity is 85.2%.
1H-NMR (400MHz, DMSO-d6) δ: 1.05 (6H, d, J=6.8Hz), 1.08 (6H, d, J=6.6Hz), 2.06-
2.22 (4H, m), 2.56 (2H, t, J=7.7Hz), 3.02 (2H, t, J=7.7Hz), 3.80 (2H, d, J=6.6Hz), 3.83
(2H, d, J=6.3Hz), 6.90 (1H, d, J=8.8Hz), 6.96 (2H, d, J=8.5Hz), 7.09 (1H, d, J=9.6Hz),
7.62-7.70 (2H, m), 7.78 (2H, d, J=8.5Hz)；
MS:m/z 413 (M+H)+；
Anal.(C25H32O5) C, H.
According to above-described embodiment, it will be appreciated that the compounds of this invention can effectively suppress the survival of NDM-1 albumen and growth.This
Invention compound may be used for prevention or treatment NDM-1 bacterial infective diseases, such as urinary tract, pulmonary, wound infection.
Claims (1)
1.4,4'-bis-substituted benzophenone compounds answering in the medicine that preparation prevention or treatment NDM-1 catch
With, described 4,4'-bis-substituted benzophenone compounds there is the structure shown in following formula I:
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| CN201210583177.XA CN103183606B (en) | 2011-12-28 | 2012-12-27 | A kind of 4,4'-bis-substituted benzophenone compounds and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102285931A (en) * | 2006-02-21 | 2011-12-21 | 富山化学工业株式会社 | Process for production of 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-bezisoxazol-6-yl)methoxy]phenyl]propionate ester and intermediate for the process |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102285931A (en) * | 2006-02-21 | 2011-12-21 | 富山化学工业株式会社 | Process for production of 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-bezisoxazol-6-yl)methoxy]phenyl]propionate ester and intermediate for the process |
Non-Patent Citations (2)
| Title |
|---|
| AP-1信号传导通路细胞模型的建立;关冰;《中国优秀博硕士学位论文全文数据库(硕士)基础科学辑》;20061115(第11期);前言第15行 * |
| Discovery of Nonpeptidic Small-Molecule AP-1 Inhibitors: Lead Hopping Based on a Three-Dimensional Pharmacophore Model;Keiichi Tsuchida et al.,;《J. Med. Chem.》;20051201;第49卷(第1期);第80页摘要,第82页table 1 * |
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