Embodiment
Below in conjunction with accompanying drawing, further illustrate essentiality content of the present invention by the embodiment 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 concrete experimental technique 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.Below general synthetic route only for example understand and can synthesize the method for the compounds of this invention by it, 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), at 50 ℃ of lower stirring reaction 12h, underpressure distillation is directly used in next step reaction after going out solvent, under the 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), reaction adds ammonium chloride solution after finishing, 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 after the saturated common salt washing, using anhydrous magnesium sulfate drying, 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 the nitrogen protection condition; intermediate 1(26.5mg; 0.1mmol) be dissolved in methylene dichloride (5mL); then add to 10% Pd/C (30mg); react 30h in nitrogen atmosphere; reaction is filtered after finishing, 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) prepare intermediate 3:4-ethenyl-5-methyl-5 from the compound 1,6-dihydrophenanthridine-8,9-diol, under-78 ℃ of conditions, be 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, reaction adds sodium hydrogen carbonate solution after finishing, 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 with after the saturated common salt washing, using anhydrous magnesium sulfate drying, 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) prepare intermediate 4:4-ethyl-5-methyl-5 from the compound 2s, 6-dihydrophenanthridine-8,9-diol, under-78 ℃ of conditions, be 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, reaction adds sodium hydrogen carbonate solution after finishing, 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 with after the saturated common salt washing, using anhydrous magnesium sulfate drying, 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) prepare intermediate 5:4-ethenyl-5-methyl-8 from the intermediate 3s, 9-bis (prop-2-ynyloxy)-5,6-dihydrophenanthridine:
Under the 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, reaction is 8 hours, reaction adds ammonium chloride solution after finishing, 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 after the saturated common salt washing, using anhydrous magnesium sulfate drying, 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) prepare intermediate 6:4-ethyl-5-methyl-8 from the intermediate 4s, 9-bis (prop-2-ynyloxy)-5,6-dihydrophenanthridine
Under the 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, reaction is 8 hours, reaction adds ammonium chloride solution after finishing, 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 after the saturated common salt washing, using anhydrous magnesium sulfate drying, 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 after the saturated common salt washing, using anhydrous magnesium sulfate drying, 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) and 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, 50 ℃ of lower stirring reactions 12 hours, underpressure distillation removes after solvent with silica gel chromatography column purification (chloroform/methanol 25:1, R
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
0 ℃ of lower compound hlyc60(50mg, 0.1mmol) be dissolved in pyridine (5mL), add under diacetyl oxide (100 μ L) normal temperature stirring reaction 12 hours, add saturated NaHCO
3solution conditioned reaction liquid pH 8-9 underpressure distillation is used silica gel chromatography column purification (chloroform/methanol 9:1, R after removing 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) and 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, 50 ℃ of lower stirring reactions 12 hours, underpressure distillation removes after solvent with silica gel chromatography column purification (chloroform/methanol 25:1, R
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
0 ℃ of lower compound hlyc67(51mg, 0.1mmol) be dissolved in pyridine (5mL), add under diacetyl oxide (100 μ L) normal temperature stirring reaction 12 hours, add saturated NaHCO
3solution conditioned reaction liquid pH 8-9 underpressure distillation is used silica gel chromatography column purification (chloroform/methanol 12:1, R after removing 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
The 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 with the form that depends on the Wnt3a acceptor 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, the described vehicle of use table 2 is as the adjunct ingredient for preparing the 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 to the 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 for preparing the 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 to 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:
Method by embodiment 1 first makes the compounds of this invention, and injection liquid assistant agent used, inject respectively water routinely, the essence filter, and injection liquid is made in the embedding sterilizing.
Embodiment 6:
Method by embodiment 1 first makes the compounds of this invention, and it is dissolved in respectively in sterile water for injection, and 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, used the compound composition of embodiment 1 as active constituents of medicine, and every day, the dosage feature was in 5 ~ 200mg scope.
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, be apparent to those skilled in the art without departing from the scope and spirit in the present invention.Although in conjunction with multiple concrete preferred embodiment of the present invention, the present invention has been carried out to concrete description, 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.