CN103113353B - Triazole compounds, medical composition thereof and preparation and application of triazole compounds - Google Patents
Triazole compounds, medical composition thereof and preparation and application of triazole compounds Download PDFInfo
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Abstract
The invention provides triazole compounds hlyc60, hlyc67, hlyc68 and hlyc69 as Wnt signal path agonists, a medical composition with the triazole compounds as active components, a preparation method of the triazole compounds, and application of the compounds provided by the invention in preparation of medicines for adjusting Wnt signal path, medicines for preventing and treating classical Wnt signal path related diseases and stem cell amplifying medicines.
Description
Technical field
The invention belongs to field of pharmacology, be specifically related to triazole compound, as Wnt signal path agonist, its pharmaceutical composition and its preparation method and its application in pharmacy.
Background technology
Wnt signal transduction pathway be a class at the conservative signal transduction pathway of organism evolutionary process camber, regulate numerous vital movement processes of controlling.In animal body early development, a series of critical events such as the formation of Wnt signal deciding dorso ventral axis, germinal layer foundation, body segment differentiation, tissue or organ formation, and directly controlling propagation, differentiation, polarization, apoptosis and the isocellular destiny of anti-apoptosis.Tens members of Wnt albumen have participated in different signal transduction pathways by the receptor acting from different on cytolemma.These approach are mainly divided into the classical Wnt signal transduction path (Wnt/ β-catenin approach) that depends on β-catenin/TCF transcription complex and the non-classical Wnt signal transduction pathway (Wnt/Ca that does not rely on β-catenin/TCF transcription complex
2+approach and Wnt/JNK approach)
Because Wnt/ β-catenin signal pathway and numerous cancer and disease have relation, so regulate Wnt/ β-catenin signal pathway out of control to can be used as fine means for the treatment of with Wnt/ β-catenin signal pathway relative disease, but the research of present stage does not also have anything significantly to make progress.For example, the pathological process of alzheimer's disease is accompanied by the abnormal inactivation of Wnt/ β-catenin signal transduction pathway.The Presenilins that Ahl tribulus sea silent sickness is closely related can form complex body with β-catenin and GSK3.So be expected to for providing new effective way with its relative disease for the molecular targeted targeted therapy of this signal pathway.In addition, in stem cell, Wnt signal transduction pathway also plays a part to maintain stem cell versatility, so regulate this signal pathway to be expected to provide new effective ways for the application of stem cell.
Summary of the invention
The object of the present invention is to provide new Wnt signal pathway activator and preparation method thereof and application.
First the present invention provides a series of compounds, and its structural formula is:
The present invention further provides the preparation method of this compounds, its syntheti c route is:
Preparation method of the present invention comprises the following steps:
1) take narcissine (Lycorine) is methylated and is prepared intermediate 1 separated product with Hofmann degradation by N-as starting raw material;
2) compound 1 is prepared intermediate 3 separated product by two Oxymethylenes of degrading;
3) make intermediate 1 hydro-reduction obtain product compound 2.
4) compound 2 is prepared intermediate 4 separated product by two Oxymethylenes of degrading;
5) compound 3,4 carries out alkylated reaction with propine bromine respectively and prepares compound 5,6 separated product
6) compound 5,6 carries out Click with intermediate 7 respectively and reacts preparation hlyc60, hlyc67 separated product;
7) utilize diacetyl oxide to obtain hlyc68, hlyc69 separated product to hlyc 60 with hlyc67 acetylize.
8) take 2-bromine ethylamine hydrobromide (2-Bromoethylamine hydrobromide) prepares compound 5 separated product as starting raw material and sodium azide (sodium azide) nucleophilic substitution.
The present invention also provides described Compound I and the purposes of Compound I I in preparing canonical Wnt signal pathway agonist.
Further, described canonical Wnt signal pathway agonist can activate the reporter gene of canonical Wnt signal pathway or the expression activity of goal gene.
The present invention also provides the application of above-claimed cpd in preparing medicine:
The application of described compound in preparing canonical Wnt signal pathway agonist.Described canonical Wnt signal pathway agonist can activate the reporter gene of canonical Wnt signal pathway or the expression activity of goal gene.
The application of described compound in the medicine of preparation prevention or the treatment caused disease of abnormal inactivation or imbalance by canonical Wnt signal pathway.
Described compound needs specificity to activate the application in the disease of canonical Wnt signal pathway or the medicine of imbalance in preparation;
The application of described compound in preparation stem cell number amplification medicine.
In described application, described disease is: senile dementia, rheumatic arthritis, osteoporosis or zebra fish grow deficiency disorder.
" disease or imbalance " herein comprises any illness that can benefit from processing of the present invention.It is including, but not limited to various chronic and acute imbalance or diseases.At one, preferably in embodiment, described disease or imbalance are senile dementia, rheumatic arthritis or osteoporosis.At another, preferably in embodiment, described disease or imbalance comprise hematopoietic stem cell transplantation.
Further, described medicine is selected from following arbitrary: senile dementia, rheumatic arthritis medicine, osteoporosis agents, hematopoietic stem cell transplantation medicine, stem cell versatility maintain medicine or zebra fish developmental regulation medicine.
The present invention further provides a kind of for prevent or treat by the abnormal inactivation of canonical Wnt signal pathway, caused or for needing specificity to activate the disease of canonical Wnt signal pathway or the pharmaceutical composition of imbalance: contain and treat the Compound I of significant quantity or Compound I I and acceptable vehicle pharmaceutically.
Term " comprises " and refers to that " containing " and “ You ﹍ form ", the composition that for example " comprises " X can consist of X completely, or can contain the material outside X, for example X-Y.Term used herein " treatment significant quantity " refers to therapeutical agent treatment, alleviates or prevent the amount of target disease or situation, or shows the amount of detectable treatment or preventive effect.This effect for example can detect by chemical labeling or antigen levels.Result for the treatment of also comprises alleviating of physiological symptom.The build and the healthy state that for the accurate effective dose of a certain object, depend on this object, the therapeutical agent that the character of illness or degree and selection give and/or the combination of therapeutical agent.Therefore it is useless, specifying in advance significant quantity accurately.Yet, for certain given symptom, can determine this significant quantity with normal experiment, clinicist can judge.
Described pharmaceutically acceptable vehicle (or vehicle) refers to be used for the treatment of the vehicle of agent administration, and itself and consumption thereof should not induce the individuality of accepting said composition to produce harmful antibody, and after administration, there is no undue toxicity.Pharmaceutically acceptable vehicle generally includes the preparation subsidiary of nontoxic solid, semisolid or liquid filling agent, thinner, lapping or any general type.Suitable vehicle includes but are not limited to water, glucose, glycerine, salt solution, ethanol or its combination.Described vehicle also includes other reagent as the adjuvant of wetting agent or emulsifying agent, pH buffer reagent or enhancing preparation effect.Other materials can add as required as antioxidant, wetting Agent for Printing Inks, viscosity stabilizer and similar reagents.Liposome is also included within the definition of pharmaceutically acceptable vehicle.
Conventionally, pharmaceutical composition can be made to injectable agent, for example liquor or suspension; Also can be made into before injection, be applicable to allocating in solution or suspension, the solid form of liquid vehicle.
Compound of the present invention can be used for preparation and regulates the medicine of canonical Wnt signal pathway and can be used for studying canonical Wnt signal pathway.The present invention also provides new thinking for screening regulates the medicine of medicine, prevention and the treatment canonical Wnt signal pathway relative disease of Wnt signal pathway, the application of research Wnt signal pathway in stem cell.
The present invention, through further investigation, finds that compound hlyc60, hlyc67, hlyc68 and hlyc69 can be with a kind of form deexcitation canonical Wnt signal pathways that depends on acceptor first.Due to canonical Wnt signal pathway and various diseases, senile dementia for example, the growth of rheumatic arthritis, osteoporosis and regulation and control hemopoietic stem cell is relevant, therefore find that this compounds can be with a kind of form deexcitation canonical Wnt signal pathway that depends on acceptor, for developing new medicine, treat these diseases new thinking is provided.
Accompanying drawing explanation
Fig. 1: the synthetic schemes of the compounds of this invention;
Fig. 2: compound hlyc60, hlyc67, hlyc68 and the hlyc69 active result that affects on canonical Wnt signal pathway reporter gene TOPFlash: dye TOPFlash reporter gene at HEK293T transit cell and add respectively the hlyc60 of certain concentration after 18 hours, hlyc67, Wnt3a conditioned medium or the control medium of hlyc68 and hlyc69 and solvent control DMSO.Collecting cell examining report gene activity after 6 hours.
Embodiment
Below in conjunction with accompanying drawing, by the embodiment of the present invention, further illustrate essentiality content of the present invention, but with this, do not limit the present invention.Should be appreciated that, these embodiment are only for the present invention is described but not limit the scope of the invention.The specific experiment method that embodiment adopts and experiment condition are this area ordinary method and condition, or manufacturer method and the condition of recommending.Unless otherwise defined, identical with known to scientific words and those skilled in the art of specialty used in literary composition.
In the following examples, following compound and intermediate characterize by liquid chromatography-mass spectrography (LC-MS) and nucleus magnetic resonance (NMR), and the initial substance and the reagent that in the described compound of preparation, use can be buied or prepare by method known to those skilled in the art from supplier.General synthetic route only for example understands and can synthesize the method for the compounds of this invention by it below, and for reference to those skilled in the art of the disclosure of invention, the multiple modification of described synthetic route be can work it out and take a hint.
Unless otherwise indicated, in the present invention, disclosed experimental technique, detection method, preparation method all adopt the routine techniques of organic chemistry, analytical chemistry, cell cultures, recombinant DNA technology and the association area of the art routine.These technology are existing perfect explanation in existing document, specifically can be referring to MOLECULAR CLONING such as Sambrook: A LABORATORY MANUAL, Second edition, Cold Spring Harbor Laboratory Press, 1989 and Third edition, 2001; Ausubel etc., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, 1987 and periodic updates; The series METHODS IN ENZYMOLOGY, Academic Press, San Diego; Wolffe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998; METHODS IN ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic Press, San Diego, 1999; With METHODS IN MOLECULAR BIOLOGY, Vol.119, Chromatin Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999 etc.
Embodiment 1
The preparation of the compounds of this invention:
Synthetic route is as shown in Figure 1:
(1) take Lycorine prepares intermediate 1:5-methyl-4-vinyl-5,6-dihydro-[1,3 as raw material] dioxolo[4,5-j] phenanthridine:
Narcissine (Lycorine) (28.7mg, 0.1mmol) dissolves solution to N, N-dimethyl formamide (DMF) (5mL) in, add methyl iodide (MeI) (17.0mg, 0.12mmol), stirring reaction 12h at 50 ℃, underpressure distillation is directly used in next step reaction after going out solvent, under nitrogen protection condition, compound (the 30.2mg that upper step is made, 0.1mmol) solvent in the trimethyl carbinol (t-BuOH) (5mL) in, back flow reaction 4h after adding potassium tert.-butoxide (t-BuOK) (30mg), after finishing, reaction adds ammonium chloride solution, then add extracted with diethyl ether 2 times (2 * 10ml), then with 2 times (2 * 10ml) of ammonium chloride solution washing, with saturated common salt water washing 2 times (2 * 10ml), organic layer is with using anhydrous magnesium sulfate drying after saturated common salt washing, decompression is used silica gel chromatography column purification (ethyl acetate/petroleum ether 200:1 after removing volatile solvent, R
f=0.23), obtain intermediate 1,21.2mg, yield 80%.
NMR, MS analysis confirmation product:
1H?NMR?(400?MHz,?CDCl
3)?δ:?7.58?(d,?J?=?7.7?Hz,?1H),?7.47?(d,?J?=?7.7?Hz,?1H),?7.26?(dt,?J?=?10.7,?7.1?Hz,?2H),?7.16?(t,?J?=?7.7?Hz,?1H),?6.72?(s,?1H),?5.99?(s,?2H),?5.75?(d,?J?=?17.8?Hz,?1H),?5.32?(d,?J?=?11.1?Hz,?1H),?4.03?(s,?2H),?2.51?(s,?3H);?
13C?NMR?(100?MHz,?CDCl
3)?δ:?147.4?(C),?145.1?(C),?133.4?(CH),?133.2?(C),?129.2?(C),?126.4?(C),?125.8?(C),?124.9?(CH),?124.3?(CH),?122.7?(CH),?114.3?(CH
2),?107.1?(CH),?103.6?(CH),?100.9?(CH
2),?54.8?(CH
2),?41.5?(CH),?EIMS?m/z:?266?[M+H]
+.
(2) prepare compound 2:N-methyl-4-ethyl-5 from 1 further of intermediate, 6-dihydro-8,9-bis-Oxymethylenes-phenanthridines (4-ethyl-5-methyl-5,6-dihydro-[1,3] dioxolo[4,5-j] phenanthridine)
Under nitrogen protection condition; intermediate 1(26.5mg; 0.1mmol) be dissolved in methylene dichloride (5mL); then add to 10% Pd/C (30mg); in nitrogen atmosphere, react 30h; reaction finishes rear filtration, and filtrate decompression is used silica gel chromatography column purification (ethyl acetate/petroleum ether 200:1, R after removing volatile solvent
f=0.21), obtain compound 2.Yellow solid 26.8mg, yield 95%.Product m.p.(fusing point) 179-180 ° C.
NMR, MS analysis confirmation product:
1H?NMR?(400?MHz,?MeOD)?δ:?7.51?(t,?J?=?8.4?Hz,?1H),?7.28?(d,?J?=?6.4?Hz,?2H),?7.20?(t,?J?=?7.9?Hz,?2H),?6.75?(s,?1H),?6.01?(s,?1H),?4.01?(s,?2H),?2.83?(q,?J?=?7.5?Hz,?2H),?2.50?(s,?3H),?1.32?(dd,?J?=?15.7,?8.2?Hz,?3H)；
13C?NMR?(100?MHz,?CDCl
3)?δ:?147.3?(C),?147.1?(C),?145.4?(C),?139.4?(C),?129.3?(C),?127.7?(CH),?126.6?(C),?126.3?(C),?124.6?(CH),?121.0?(CH),?107.2?(CH),?103.7?(CH),?100.9?(CH
2),?55.2?(CH
2),?41.02?(CH),?23.1?(CH
2),?14.8?(CH
3),?HREIMS?m/z?217.1261?[M]
+?(calcd?for?C
17H
17NO
2,?267.1259).
(3) from compound 1, prepare intermediate 3:4-ethenyl-5-methyl-5,6-dihydrophenanthridine-8,9-diol, under-78 ℃ of conditions, is dissolved into methylene dichloride (CH at compound 1 (26mg, 0.1mmol)
2cl
2) (2mL) in, add boron tribromide (BBr
3) (49.4mg, 0.2mmol) reaction 2h, after finishing, reaction adds sodium hydrogen carbonate solution, then add extracted with diethyl ether 2 times (2 * 10ml), then with 2 times (2 * 10ml) of sodium hydrogen carbonate solution washing, with saturated common salt water washing 2 times (2 * 10ml), organic layer is rear with anhydrous magnesium sulfate drying with saturated common salt washing, decompression is used silica gel chromatography column purification (ethyl acetate/petroleum ether 1:1, R after removing volatile solvent
f=0.22), obtain intermediate 3, yellow solid 16.8mg, yield 74%.
NMR, MS analysis confirmation product:
1H?NMR?(400?MHz,?DMSO)?δ?7.59-7.49?(m,?2H),?7.41?(d,?J?=?7.6?Hz,?1H),?7.19?–?7.08?(m,?2H),?6.65?(s,?1H),?5.76?(d,?J?=?17.9?Hz,?1H),?5.27?(d,?J?=?11.4?Hz,?1H),?4.23?(s,?2H),?3.87?(s,?3H);
?13C?NMR?(150?MHz,?DMSO)?δ?153.39?(C),?149.58?(C),?138.22?(CH),?133.15?(CH),?132.75?(C),?132.05?(C),?131.04?(C),?128.92?(CH),?125.57?(C),?123.98?(CH),?118.65?(C),?118.39?(CH
2),?113.46?(CH),?107.33?(CH),?62.34?(CH
2),?50.72?(CH
3);?HREIMS?m/z?253.1109?[M]
+?(calcd?for?C
16H
15NO
2,?253.1103).
(4) from compound 2s, prepare intermediate 4:4-ethyl-5-methyl-5,6-dihydrophenanthridine-8,9-diol, under-78 ℃ of conditions, is dissolved into methylene dichloride (CH at compound 2 (26.7mg, 0.1mmol)
2cl
2) (2mL) in, add boron tribromide (BBr
3) (49.4mg, 0.2mmol) reaction 2h, after finishing, reaction adds sodium hydrogen carbonate solution, then add extracted with diethyl ether 2 times (2 * 10ml), then with 2 times (2 * 10ml) of sodium hydrogen carbonate solution washing, with saturated common salt water washing 2 times (2 * 10ml), organic layer is rear with anhydrous magnesium sulfate drying with saturated common salt washing, decompression is used silica gel chromatography column purification (ethyl acetate/petroleum ether 1:1, R after removing volatile solvent
f=0.22), obtain intermediate 4, yellow solid 17.9mg, yield 70%.
NMR, MS analysis confirmation product:
1H?NMR?(400?MHz,?CDCl
3)?δ:?7.46?(d,?J?=?7.1?Hz,?1H),?7.27?(d,?J?=?2.7?Hz,?1H),?7.17-7.11?(m,?2H),?6.75?(s,?1H),?3.96?(s,?2H),?2.79?(q,?J?=?7.5?Hz,2H),?2.47?(s,?3H),?1.28?(dd,?J?=?14.7,?7.1?Hz,?3H)；
13C?NMR?(100?MHz,?CDCl
3)?δ:?143.8?(C),?143.0?(C),?139.4?(C),?129.0?(C),?127.6?(CH),?125.7?(C),?125.5?(C),?124.7?(CH),?120.9?(CH),?113.8?(CH),?113.4?(C),?110.4?(CH),?54.6?(CH
2),?41.2?(CH
3),?23.1?(CH
2),?14.8?(CH
3);?EIMS?m/z:?256?[M+H]
+?.
(5) from intermediate 3s, prepare intermediate 5:4-ethenyl-5-methyl-8,9-bis (prop-2-ynyloxy)-5,6-dihydrophenanthridine:
Under nitrogen protection condition, intermediate 3(24.8mg, 0.1mmol) be dissolved in THF(5mL) in, then add sodium hydride (NaH)
?(180mg, 0.3mmol, 40%) and propine bromine (3-bromoprop-1-yne) (14mg, 0.3mmol, 80%), under room temperature, react 8 hours, after finishing, reaction adds ammonium chloride solution, then add extracted with diethyl ether 2 times (2 * 10ml), then with 2 times (2 * 10ml) of ammonium chloride solution washing, with saturated common salt water washing 2 times (2 * 10ml), organic layer is rear with anhydrous magnesium sulfate drying with saturated common salt washing, decompression is used silica gel chromatography column purification (ethyl acetate/petroleum ether 200:1, R after removing volatile solvent
f=0.21), obtain intermediate 5, yellow solid 25.6mg, yield 82%.
NMR, MS analysis confirmation product:
1H?NMR?(400?MHz,?CDCl
3)?δ?7.62?(s,?1H),?7.48?(d,?J?=?12.4?Hz,?2H),?7.24-7.14?(m,?2H),?6.92?(s,?1H),?5.75?(d,?J?=?19.0?Hz,?1H),?5.32?(d,?J?=?10.6?Hz,?1H),?4.88?–?4.77?(m,?4H),?4.06?(s,?2H),?2.56?(s,1H),?2.55?(s,?1H),?2.52?(s,?3H);?
13C?NMR?(151?MHz,?CDCl
3)?δ?159.12?(C),?156.17?(C),?146.12?(C),?139.32?(CH),?133.72?(CH),?129.17?(C),?127.56?(C),?124.57?(CH),?123.30?(CH),?120.88?(C),?118.76?(C),?114.12?(CH
2),?110.63?(CH),?106.21?(CH),?80.14?(C),?80.09?(C),?76.42?(CH),?76.36?(CH),?64.78?(CH
2),?64.71?(CH
2),?58.83?(CH
2),?42.68?(CH
3);?HREIMS?m/z?329.1420?[M]
+?(calcd?for?C
22H
19NO
2,?329.1416).
(6) from intermediate 4s, prepare intermediate 6:4-ethyl-5-methyl-8,9-bis (prop-2-ynyloxy)-5,6-dihydrophenanthridine
Under nitrogen protection condition, intermediate 4(25.5mg, 0.1mmol) be dissolved in THF(5mL) in, then add sodium hydride (NaH)
?(180mg, 0.3mmol, 40%) and propine bromine (3-bromoprop-1-yne) (14mg, 0.3mmol, 80%), under room temperature, react 8 hours, after finishing, reaction adds ammonium chloride solution, then add extracted with diethyl ether 2 times (2 * 10ml), then with 2 times (2 * 10ml) of ammonium chloride solution washing, with saturated common salt water washing 2 times (2 * 10ml), organic layer is rear with anhydrous magnesium sulfate drying with saturated common salt washing, decompression is used silica gel chromatography column purification (ethyl acetate/petroleum ether 200:1, R after removing volatile solvent
f=0.21), obtain intermediate 6, yellow solid 26.4mg, yield 80%.
NMR, MS analysis confirmation product:
1H?NMR?(400?MHz,?CDCl
3)?δ?
1H?NMR?(400?MHz,?CDCl
3)?δ?7.54?(d,?J?=?6.9?Hz,?1H),?7.46?(s,?1H),?7.23?–?7.12?(m,?2H),?6.91?(s,?1H),?4.83?(s,?2H),?4.80?(s,?2H),?4.02?(s,?2H),?3.09?–?2.99?(m,?2H),?2.86?–?2.74?(m,?2H),?2.47?(s,?3H),?1.29?–?1.17?(m,?3H);?；
13C?NMR?(100?MHz,?CDCl
3)?δ:?147.4?(C),?146.8?(C),?145.6?(C),?139.5?(C),?128.9?(C),?127.9?(CH),?126.8?(C),?126.3?(C),?124.6?(CH),?121.0?(CH),?113.1?(CH),?110.5?(CH),?78.6?(C),?78.4?(C),?75.9?(CH),?75.8?(CH),?57.2?(CH
2),?56.9?(CH
2),?54.8?(CH
2),?41.31?(CH
3),?23.1?(CH
2),?14.8?(CH
3);?ESIMS?m/z:?330[M-H]
-.
(7) prepare compound 7:2-Azidoethylamine
2-bromine ethylamine hydrobromide (2-Bromoethylamine hydrobromide) (500 mg, 2.44 mmol) and sodium azide (sodium azide) (475.9 mg, 7.32 mmol) are dissolved into H
2in O (2 mL), under 75 ° of C, then stirring reaction 21 h are cooled to 0 ° of C, add potassium hydroxide (KOH) (800 mg) and Et
2o (2 mL), extracted with diethyl ether 2 times (2 * 10ml) for water layer, organic layer is with using anhydrous magnesium sulfate drying after saturated common salt washing, and decompression is used silica gel chromatography column purification (chloroform/methanol 20:1, R after removing volatile solvent
f=0.21), obtain compound 5, yellow liquid 171 mg, 1.99 mmol, yield 82%.
NMR analysis confirmation product:
1H?NMR?(400?MHz,?CDCl
3)?δ:?1.27?(s,?2?H,?NH2),?2.80–2.84?(m,?2?H,?CH
2N
3),?3.30?(t,?J?=?5.7?Hz,?2?H,?CH
2NH
2)；
13C?NMR?(100?MHz,?CDCl3)?δ:?41.2?(CH
2NH
2),?54.6?(CH
2N
3)。
(8) prepare compound hlyc60:4-ethyl-5-methyl-8,9-bis (prop-2-tri-azole-ethylamineoxy)-5,6-dihydrophenanthridine
Compound 6(33.1mg, 0.1mmol) with compound 7(30.1mg, 0.4mmol) be dissolved to tBuOH(5mL) in, sodium ascorbate (sodium ascorbate) (19.8mg, 0.1mmol) and copper sulfate (1.8mg, 0.01) add water (2mL), then the aqueous solution is added in t-BuOH solution, at 50 ℃, stirring reaction is 12 hours, and underpressure distillation is used silica gel chromatography column purification (chloroform/methanol 25:1, R after removing solvent
f=0.23), obtain compound hlyc60, yellow solid 57.3mg, yield 60%.m.p.?196-197?°C。
NMR, MS analysis confirmation product:
1H?NMR?(400?MHz,?CDCl
3)?δ:?7.78?(m,?1H),?7.51–7.41?(m,?3H),?7.15–7.08?(m,?3H),?5.23–5.16?(m,?8H),?4.52–4.43?(m,?2H),?4.42?(s,?1H),?3.50?(s,?2H),?3.45?(s,?2H),?2.78?(d,?J?=?8?Hz,?2H),?2.44?(s,?3H),?1.27?(t,?J?=?8.0?Hz,?3H)；
13C?NMR?(100?MHz,?CDCl
3)?δ:?147.17?(C),?144.05?(C),?139.44?(C),?135.99?(C),?134.83?(CH),?134.03?(C),?128.80?(C),?128.44?(C),?124.75?(CH),?124.51?(CH),?121.62?(CH),?121.55?(CH),?115.64?(C),?115.55?(C),?110.23?(CH),?109.84?(CH),?64.27?(CH
2),?63.26?(CH
2),?54.96?(CH
2),?50.78?(CH
2),?50.61?(CH
2),?41.65?(CH
3),?40.29?(CH
2),?39.41?(CH
2),?29.91?(CH
2),?15.27?(CH
3);?HREIMS?m/z?503.2741?[M]+?(calcd?for?C
26H
33N
9O
2,?503.2757).
(9) prepare compound hlyc68:4-ethyl-5-methyl-8,9-bis (prop-2-tri-azole-ethanediamideoxy)-5,6-dihydrophenanthridine
Compound hlyc60(50mg, 0.1mmol at 0 ℃) be dissolved in pyridine (5mL), add under diacetyl oxide (100 μ L) normal temperature stirring reaction 12 hours, add saturated NaHCO
3solution is used silica gel chromatography column purification (chloroform/methanol 9:1, R after regulating reaction solution pH 8-9 underpressure distillation to remove organic solvent
f=0.34), obtain compound hlyc68, yellow solid 46.3mg, yield 62%.
NMR, MS analysis confirmation product:
1H?NMR?(500?MHz,?CDCl
3?)?δ?7.99?(s,?1H),?7.89?–?7.81?(m,?2H),?7.47?(s,?1H),?7.32-7.29?(m,?2H),?7.13?(dd,?J?=?16.0,?3.7?Hz,?1H),?5.56?–?5.42?(m,?3H),?5.41-5.12?(m,?5H),?4.58-4.43?(m,?2H),?3.80?–?3.64?(m,?4H),?2.79?(m,?2H),?2.68?(s,?3H),?1.92?(s,?3H),?1.90?(s,?3H),?1.25?(m,?3H);?
13C?NMR?(125?MHz,?CDCl
3)?δ?172.2,?171.9,?149.7,?149.4,?146.1,?142.9,?142.6,?130.7,?129.3,?126.1,?125.1,?124.8,?124.4,?122.7,?122.0,?121.9,?112.6,?110.9,?56.2,?56.0,?51.4,?50.4,?50.3,?39.8,?36.8,?36.3,?28.6,?27.1,?26.9,?14.1.HREIMS?m/z?587.2960?[M]+?(calcd?for?C
30H
37N
9O
4,?587.2969).
(10) prepare compound hlyc67:4-ethenyl-5-methyl-8,9-bis (prop-2-tri-azole-ethylamineoxy)-5,6-dihydrophenanthridine
Compound 5(33.1mg, 0.1mmol) with compound 7(30.1mg, 0.4mmol) be dissolved to tBuOH(5mL) in, sodium ascorbate (sodium ascorbate) (19.8mg, 0.1mmol) and copper sulfate (1.8mg, 0.01) add water (2mL), then the aqueous solution is added in t-BuOH solution, at 50 ℃, stirring reaction is 12 hours, and underpressure distillation is used silica gel chromatography column purification (chloroform/methanol 25:1, R after removing solvent
f=0.46), obtain compound hlyc67, yellow solid 56.1mg, yield 57%.
NMR, MS analysis confirmation product:
1H?NMR?(500?MHz,?CDCl
3?)?δ?7.92?(s,?1H),?7.88?–?7.84?(m,?1H),?7.61?(s,?1H),?7.44?–?7.27?(m,?2H),?7.19?–?7.12?(m,?2H),?6.97?–?6.88?(m,?1H),?5.81?–?5.73?(m,?1H),?5.68?–?5.51?(m,?5H),?5.19?(s,?2H),?5.11?(s,?2H),?4.94?(s,?1H),?4.67?(s,?1H),?3.33?–?3.21?(m,?4H),?2.77?(s,?3H);?
13C?NMR?(125?MHz,?CDCl
3?)?δ?150.4,?148.1,?146.6,?144.1,?143.9,?137.7,?128.2,?126.1,?125.9,?125.3,?125.1,?124.1,?123.3,?123.0,?115.3,?115.1,?113.8,?111.1,?59.1,?58.8,?52.4,?52.2,?49.1,?40.3,?40.2,?39.9;?HREIMS?m/z?501.2613?[M]
+?(calcd?for?C
26H
31N
9O
2,?501.2601).
(11) prepare compound hlyc69:4-ethenyl5-methyl-8,9-bis (prop-2-tri-azole-ethanediamideoxy)-5,6-dihydrophenanthridine
Compound hlyc67(51mg, 0.1mmol at 0 ℃) be dissolved in pyridine (5mL), add under diacetyl oxide (100 μ L) normal temperature stirring reaction 12 hours, add saturated NaHCO
3solution is used silica gel chromatography column purification (chloroform/methanol 12:1, R after regulating reaction solution pH 8-9 underpressure distillation to remove organic solvent
f=0.44), obtain compound hlyc69, yellow solid 48.1mg, yield 61%.
NMR, MS analysis confirmation product:
1H?NMR?(500?MHz,?CDCl
3?)?δ?7.93?–?7.91?(m,?1H),?7.86?(s,?1H),?7.69?(s,?1H),?7.51?–?7.37?(m,?2H),?7.28?–?7.15?(m,?2H),?6.91?–?6.84?(m,?1H),?5.88?–?5.79?(m,?1H),?5.62?–?5.50?(m,?5H),?5.14?(s,?2H),?5.10?(s,?2H),?4.76?(s,?1H),?4.62?(s,?1H),?3.67?–?3.54?(m,?4H),?2.98?(s,?3H),?1.94?(s,?3H),?1.91?(s,?3H);
?13C?NMR?(125?MHz,?CDCl
3?)?δ?174.3,?174.2,?150.1,?148.9,?146.4,?143.8,?143.6,?138.7,?128.6,?126.8,?125.8,?125.2,?125.0,?122.8,?121.3,?121.1,?116.4,?115.1,?112.6,?111.0,?55.70,?55.6,?50.7,?51.4,?51.3,?39.8,?36.8,?36.6,?22.4,?22.1;?HREIMS?m/z?585.2821?[M]
+?(calcd?for?C
30H
35N
9O
4,?585.2812).
Embodiment 2:
Embodiment 1 gained compound activates the active result of Wnt signal path as table 1.
Table 1 compound activates the active result of Wnt signal path
| Sample title | The compound concentration that synergistic activation Wnt reporter gene is one times |
| HLYC-60 | 1.25μM |
| HLYC-67 | 2.5μM |
| HLYC-68 | 1.25μM |
| HLYC-69 | 5μM |
Experimental result:
Compound hlyc60, hlyc67, hlyc68 and hlyc69 can activate to depend on the form of Wnt3a acceptor the Reporter System of canonical Wnt signal pathway.
The present invention utilizes the Reporter System SCREENED COMPOUND of canonical Wnt signal pathway.Find compound hlyc60, hlyc67, hlyc68 and hlyc69 can work in coordination with the Reporter System (Fig. 1) of the activation canonical Wnt signal pathway of Wnt3a dose-dependently.
Embodiment 3:
The compound combination medicinal tablet of embodiment 1:
The compound of the embodiment of the present invention 1 is as the preparation of the drug regimen tablet of effective constituent: use the compound of embodiment 1 as active constituents of medicine, described in use table 2, vehicle is as the adjunct ingredient of preparing medicinal composition tablet, proportionally proportioning is made the tablet samples of every compound medicine composition 5 ~ 60mg that contains embodiment 1, and table 2 provides the formula rate of conventional tablet:
Bulk drug and the accessory formula of the compound combination medicinal tablet of table 2 embodiment of the present invention 1
The method that the compound of the embodiment of some amount 1 and vehicle auxiliary material is prepared into various dose tablet formulation is that several vehicle auxiliary materials are evenly mixed with bulk drug, add 1% sodium cellulose glycolate solution to make in right amount soft material, the granulation of sieving, wet grain is dried and is sieved whole, adds Magnesium Stearate and talcum powder mix rear compressing tablet and get final product.
Embodiment 4:
Compound combination pharmaceutical dosage form-capsule of embodiment 1:
The compound that contains embodiment 1 is as the preparation of the drug regimen capsule preparations of effective constituent: use the compound sample of embodiment 1 as active constituents of medicine, in use table 3, several vehicle are as the adjunct ingredient of preparing medicinal composition tablet, proportionally proportioning is made the capsule preparations of the compound medicine composition 5 ~ 50mg that contains embodiment 1 in every capsules, and table 3 provides the formula rate of conventional capsule preparation:
Bulk drug and the accessory formula of the compound combination pharmaceutical capsule preparation of table 3 embodiment 1
The method that the compound sample of the embodiment of some amount 1 and vehicle auxiliary material is prepared into capsule preparations is: the compound of several vehicle auxiliary materials and embodiment 1 is even, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dry the whole grain that sieves, add Magnesium Stearate to mix, insert capsule and make; Or do not use granulation step, and directly the compound of embodiment 1 is mixed with several vehicle auxiliary materials, after sieving, directly incapsulate and make.
Embodiment 5:
By the method for embodiment 1, first make the compounds of this invention, injection liquid assistant agent used, injects respectively water routinely, essence filter, and injection liquid is made in embedding sterilizing.
Embodiment 6:
By the method for embodiment 1, first make the compounds of this invention, it is dissolved in respectively in sterile water for injection, stirring makes molten, with aseptic suction funnel, filter, more aseptic essence filter, being sub-packed in 2 ampoules, after frozen drying, aseptic sealing by fusing obtains powder injection.
The medicine of the compound that use contains embodiment 1 is the various medicines that use the compound contain embodiment 1 to manufacture as active constituents of medicine.
The dosage scope of the compound sample of embodiment 1, is used the compound composition of embodiment 1 as active constituents of medicine, and every day, dosage feature was within the scope of 5 ~ 200mg.
Above embodiment is for embodiment disclosed by the invention being described, can not being interpreted as limitation of the present invention.In addition, in various modifications listed herein and invention, the variation of method, composition, is apparent to those skilled in the art without departing from the scope and spirit in the present invention.Although the present invention has been carried out to concrete description in conjunction with multiple concrete preferred embodiment of the present invention, should be appreciated that the present invention should not only limit to these specific embodiments.In fact, various as above concerning those skilled in the art apparent modification obtain invention and all should comprise within the scope of the invention.
Claims (9)
1. triazole compound hlyc60, hlyc67, hlyc68, the hlyc69 shown in following structural formula,
2. the hlyc60 of compound shown in claim 1, hlyc67, the preparation method of hlyc68 and hlyc69, comprises the steps:
1) take narcissine (Lycorine) is methylated and is prepared intermediate 1 separated product with Hofmann degradation by N-as starting raw material;
2) compound 1 is prepared intermediate 3 separated product by two Oxymethylenes of degrading;
3) make intermediate 1 hydro-reduction obtain product compound 2 separated product;
4) compound 2 is prepared intermediate 4 separated product by two Oxymethylenes of degrading;
5) compound 3,4 carries out alkylated reaction with propine bromine respectively and prepares compound 5,6 separated product;
6) compound 5,6 respectively with intermediate 7 carry out Click react preparation hlyc60, hlyc67;
7) utilize diacetyl oxide to obtain hlyc68, hlyc69 separated product to hlyc60 and hlyc67 acetylize;
8) take 2-bromine ethylamine hydrobromide (2-Bromoethylamine hydrobromide) prepares compound 7 separated product as starting raw material and sodium azide (sodium azide) nucleophilic substitution.
3. the application of compound in preparing canonical Wnt signal pathway agonist described in claim 1.
4. application as claimed in claim 4, is characterized in that, described canonical Wnt signal pathway agonist can activate the reporter gene of canonical Wnt signal pathway or the expression activity of goal gene.
5. the application of compound in the medicine of preparation prevention or the treatment caused disease of abnormal inactivation or imbalance by canonical Wnt signal pathway described in claim 1.
6. described in claim 1, compound needs specificity to activate the application in the disease of canonical Wnt signal pathway or the medicine of imbalance in preparation.
7. the application of compound in preparation stem cell number amplification medicine described in claim 1.
8. the application as described in claim 6 or 7, is characterized in that, described disease is: senile dementia, rheumatic arthritis, osteoporosis or zebra fish grow deficiency disorder.
For prevent or treat by the abnormal inactivation of canonical Wnt signal pathway, caused or for needing specificity to activate the disease of canonical Wnt signal pathway or a pharmaceutical composition for imbalance, contain compound and pharmaceutically acceptable carrier described in the claim 1 for the treatment of significant quantity.
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| PCT/CN2014/072697 WO2014131368A1 (en) | 2013-03-01 | 2014-02-28 | Phenanthridine derivatives, preparation methods therefor and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102105464A (en) * | 2008-05-27 | 2011-06-22 | 德克萨斯大学系统董事会 | Wnt protein signalling inhibitors |
| CN102369187A (en) * | 2009-03-02 | 2012-03-07 | Irm责任有限公司 | N- (hetero)aryl, 2- (hetero)aryl-substituted acetamides for use as wnt signaling modulators |
| CN102595899A (en) * | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | Indazoles as WNT/B-catenin signaling pathway inhibitors and therapeutic uses thereof |
| CN102595900A (en) * | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102105464A (en) * | 2008-05-27 | 2011-06-22 | 德克萨斯大学系统董事会 | Wnt protein signalling inhibitors |
| CN102369187A (en) * | 2009-03-02 | 2012-03-07 | Irm责任有限公司 | N- (hetero)aryl, 2- (hetero)aryl-substituted acetamides for use as wnt signaling modulators |
| CN102595899A (en) * | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | Indazoles as WNT/B-catenin signaling pathway inhibitors and therapeutic uses thereof |
| CN102595900A (en) * | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
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