CN107129497A - The Sophoridine analog derivative of one class containing mustargen and its production and use - Google Patents
The Sophoridine analog derivative of one class containing mustargen and its production and use Download PDFInfo
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- CN107129497A CN107129497A CN201710319723.1A CN201710319723A CN107129497A CN 107129497 A CN107129497 A CN 107129497A CN 201710319723 A CN201710319723 A CN 201710319723A CN 107129497 A CN107129497 A CN 107129497A
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- 0 [*-]C(C(CC1)N(CCC[C@@]2C3)[C@@]2[C@]1C(CCCCOC(N(CCCl)CCCl)=O)N3S(c([s]1)ccc1Cl)(=O)=O)=C Chemical compound [*-]C(C(CC1)N(CCC[C@@]2C3)[C@@]2[C@]1C(CCCCOC(N(CCCl)CCCl)=O)N3S(c([s]1)ccc1Cl)(=O)=O)=C 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention belongs to antitumor action technical field of pharmaceuticals, there is provided the Sophoridine analog derivative of the class with structure shown in formula I containing mustargen and its production and use and its pharmaceutically acceptable salt, wherein R1, X, Y, n as used in the description.The invention further relates to the preparation method of above-claimed cpd, and also disclose using the compound or its pharmaceutically acceptable salt as the pharmaceutical composition of active effective ingredient, and they are being used as the application in terms of antineoplastic.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a class newly be used for the compound of tumour or treatment of cancer, it is special
Not being related to a class has Sophoridine analog derivative containing mustargen of antitumor activity and preparation method thereof, and such compound exists
Application in terms of being particularly as medicine for tumour or treatment of cancer.
Technical background
Sophoridine is that a kind of isolated kuh-seng type alkaloid is extracted from legume Sophora alopecuroide, Alkaloid tool
There is quinolizidine structure, find it to solid tumor sarcoma 180 (S180), cervical carcinoma, Lewis lungs from LI XUEMEI professor in 1977
Since many animals such as cancer transplantable tumor has stable antitumaous effect, Sophoridine has been subjected to pharmaceutical research for many years, in succession
There is multidigit researcher to confirm that Sophoridine equally has stable Inhibit proliferaton to stomach cancer cell, liver cancer cells, colon adenocarcinoma cell
Effect.Compound light-yellow sophora root injection is ratified to be used for and other antineoplastics such as vinorelbine, cis-platinum and purple in nineteen ninety-five by CFDA
The therapeutic alliance non-small cell lung cancer such as China fir alcohol, liver cancer and stomach cancer etc..The injection Main Ingredients and Appearance be oxymatrine, matrine and
Sophoridine, belongs to quinoxyl pyridine class natural products, and wherein Sophoridine was ratified to be used to treat pernicious nourishing in 2005 by CFDA
Type tumour, its mechanism of action can suppress Topo I activity, prevent DNA duplication, transcription, restructuring, influence the cell cycle, effectively
Suppress cancer cell multiplication.Sophoridine shows such as structural versatility that highly dissoluble and good medicine generation are dynamic as new chemical entities
The druggability characteristic such as mechanics, and abundance, toxic side effect are small.But Sophoridine antitumor activity is limited, and polarity is larger, water-soluble
Property it is strong, be allowed to that clinic can not be widely used in.
Based on this, the mustargen group of high activity is successfully incorporated into Sophoridine skeleton by the present invention, synthesizes serial new
The Sophoridine analog derivative of type, for treatment of cancer.
The content of the invention
It is an object of the present invention to disclose the Sophoridine analog derivative containing mustargen of a class new structure and its medicinal
Salt.
It is another object of the present invention to disclose the preparation of Sophoridine analog derivative and its pharmaceutical salts of the class containing mustargen
Method.
Another object of the present invention is that disclosure is with the Sophoridine analog derivative and its medicine containing mustargen of a class new construction
With the pharmaceutical composition that salt is main active ingredient.
A further object of the invention is, discloses Sophoridine analog derivative and its pharmaceutical salts of the class containing mustargen as anti-
Application in terms of tumour medicine.
In conjunction with the object of the invention, present invention is described in detail.
Present invention relates particularly to the compound of structure shown in formula I or its pharmaceutically acceptable salt, stereoisomer：
Wherein：
X is the hetero atoms such as O, S or N；
N is equal to 1 or 2；
R1For fatty carbonic acyl radical, fragrant carbonic acyl radical, fatty sulfonyl, fragrant sulfonyl, aromatic heterocycle sulfonyl, fatty phosphorus
Acyl group, fragrant phosphoryl, benzyl or substituted benzyl, heteroaromatic benzyl or substitution heteroaromatic benzyl, olefin alkylation, alkynes alkyl；
Y isOr
Wherein R2For hydrogen, C1-4Straight or branched alkyl, cycloalkyl group, alkylene, olefin alkylation, alkynes base, alkynes
Alkyl, aromatic ring or substitution aromatic ring, heteroaromatic or substitution heteroaromatic, benzyl or substituted benzyl, heteroaromatic benzyl or substitution heteroaromatic
Benzyl.
According to the type I compound of the present invention, wherein the compound of the formula I is selected from：
Wherein：
R1, X, Y, n definition it is identical with the definition of formula (I).
Type I compound pharmaceutically acceptable salt of the present invention refers to：Compound and inorganic acid, organic acid into salt, wherein it is preferred that：
Hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate,
Mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate,
Taurate, gluconate, amino-acid salt.
The syntheti c route of a compounds of formula I is as follows：
12-N substitution Chinese scholartree determine acetoacetic ester (III), dichloromethane, chloroform, acetonitrile, DMF, DMSO, ethyl acetate,
In acetone or THF equal solvents, and the reducing agent such as sodium borohydride, Lithium Aluminium Hydride, diisobutyl aluminium hydride, palladium carbon, red aluminum solution ,-
10~100 DEG C of reactions, are made key intermediate II.Intermediate II is again with mustargen formyl chloride in dichloromethane, chloroform, second
In nitrile, DMF, DMSO, ethyl acetate, acetone or THF equal solvents, in triethylamine, pyridine, potassium carbonate, sodium acid carbonate, bicarbonate
In the presence of the acid binding agents such as potassium, sodium hydroxide or lithium hydroxide, the a-1 of target compound I is made in -10~100 DEG C of reactions.
Intermediate II is again with mustargen sulfonic acid chloride in dichloromethane, chloroform, acetonitrile, DMF, DMSO, ethyl acetate, acetone
Or in THF equal solvents-, tied up in triethylamine, pyridine, potassium carbonate, sodium acid carbonate, saleratus, sodium hydroxide or lithium hydroxide etc.
In the presence of sour agent, the a-2 of target compound I is made in 10~100 DEG C of reactions.
Intermediate II is again with substituted mustargen phosphoryl chloride phosphorus oxychloride in dichloromethane, chloroform, acetonitrile, DMF, DMSO, acetic acid second
In ester, acetone or THF equal solvents, in triethylamine, pyridine, potassium carbonate, sodium acid carbonate, saleratus, sodium hydroxide or hydroxide
In the presence of the acid binding agents such as lithium, the a-3 of target compound I is made in -10~100 DEG C of reactions.
The preparation method of the b compounds of formula I is with a of formula I.
The obtained various compounds of reaction or by products therefrom be dissolved in acetone, methanol, ethanol, isopropanol, ether, DMF or
Inorganic acid, organic acid are added dropwise in DMSO pharmaceutically acceptable salt is made.
Various compounds are specifically dissolved in one kind in ether, DMF, acetone, methanol, ethanol, ethyl acetate or DMSO,
In ethereal HCI is added dropwise under ice-water bath to pH=2, hydrochloride is made；Or various compounds are dissolved in ether, DMF, acetone, first
One kind in alcohol, ethanol, ethyl acetate or DMSO, adds equimolar taurine, and heating stirring obtains its taurate；Or will be each
One kind in the molten ether of kind of compound, DMF, acetone, methanol, ethanol, ethyl acetate or DMSO, in the concentrated sulfuric acid is added dropwise under ice-water bath
To pH=3, sulfate, etc. is made.
Such compound is effective for treatment human malignancies.Although the compound of the present invention can be without any
Prepare and be directly administered, but described various compounds are preferably used in the form of a pharmaceutical preparation, and method of administration can be non-bowel
Approach (such as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition of the compounds of this invention prepares as follows：Using standard and conventional technique, make the compounds of this invention
Combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily with acceptable adjuvant on galenic pharmacy and
Excipient combines and is prepared into particulate or microballoon.Solid dosage forms includes tablet, discrete particles, capsule, sustained release tablets, sustained release pellet etc.
Deng.Solid carrier can be at least one material, and it can serve as diluent, flavouring agent, solubilizer, lubricant, suspending agent, viscous
Mixture, disintegrant and coating agent.Inert solid carrier includes magnesium phosphate, magnesium stearate, smoothers sugar, lactose, pectin, the third two
Alcohol, polyoxyethylene sorbitan monoleate, dextrin, starch, gelatin, cellulose substances such as methylcellulose, microcrystalline cellulose, low melting point stone
Wax, polyethylene glycol, mannitol, cocoa butter etc..Liquid dosage form includes solvent, suspension such as injection, pulvis etc..
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can be according to patient
The state of an illness, the situation of diagnosis be specifically applied, the amount or concentration of compound used are in a wider scope
Regulation, generally, the amount scope of reactive compound are 0.5%~90% (weight) of composition.Another preferred scope is
0.5%-70%.
The compound with structure shown in formula I or its pharmaceutically acceptable salt of the present invention, has significantly to tumour in vitro
Inhibitory action.
Brief description of the drawings
The general structure of Fig. 1 compounds
Embodiment
With reference to embodiment, the present invention is described further, and embodiment is only explanatory, is in no way intended to it
The scope of the present invention is limited in any way.Described compound is carried out through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC)
Detection.Then can use such as infrared spectrum (IR), nuclear magnetic resoance spectrum (1H NMR,13C NMR), high resolution mass spectrum (HRMS)
Deng further confirming its structure.
Embodiment 1：4- ((3aR, 3a1S, 10aS) -2- tosyls ten dihydropyridine [3,2,1-ij] [1,6] naphthyridines -
1- yls) double (2- chloroethyls) butyl carbamates of butyl preparation
Step one：The preparation of the fixed acid of Chinese scholartree
Weigh 1.0g Sophoridines to be placed in 20mL5N potassium hydroxide aqueous solutions, be heated to reflux 12h, after reaction terminates, cooling
To room temperature, plus 5N hydrochloric acid solutions, control pH is less than 6, separates out a large amount of white solids, filters, and after filtrate concentration, residue adds methanol
Fully dissolving, is filtered to remove inorganic salts, obtains Sophoridine methanol solution, after being spin-dried for, and obtains Chinese scholartree and determines acid crude, again with methanol is recrystallized,
Separate out the fixed sour sterling of Chinese scholartree.13C NMR(101MHz,CDCl3)δ177.13,67.62,58.99,53.08,48.78,41.72,
35.94,34.64,33.47,28.38,26.46,26.37,24.50,23.33,23.13.HRMS：calcd for
C16H28N2O2:280.2151,found:280.2151.
Step 2：Chinese scholartree determines the preparation of acetoacetic ester
In the ethanol solution that the reaction solution of 5mL thionyl chlorides and 10mL absolute ethyl alcohols is added to the fixed acid of 1.0g Chinese scholartrees,
React a few hours, TLC display reactions are complete, filtering, after filtrate decompression concentration, obtain crude product, recrystallize, obtain sterling, be dried in vacuo
。13C NMR(101MHz,CDCl3)δ174.11,67.62,61.18,58.99,53.08,48.78,41.72,35.94,34.03,
33.47,28.38,26.46,26.37,24.72,23.33,23.13,14.70.HRMS：calcd for C18H32N2O2:
308.2464,found:308.2464.
Step 3：12-N- (4- Methyl benzenesulfonyls base) Chinese scholartree determines the preparation of ethyl butyrate
Product Chinese scholartree obtained by step 2 is determined into acetoacetic ester under the conditions of potassium carbonate acid binding agent, N- is carried out with paratoluensulfonyl chloride
Sulfonylation, TLC monitoring reaction process, post processing obtains 12-N- (4- Methyl benzenesulfonyls base) Chinese scholartree and determines ethyl butyrate crude product, crosses silicon
Glue post, is isolated and purified.1H NMR(400MHz,CDCl3) δ 7.67 (d, J=8.2Hz, 1H), 7.27 (d, J=8.2Hz, 1H),
4.13 (m, 2H), 3.64 (s, 2H), 3.48 (dd, J=13.5,4.4Hz, 0H), 2.92 (dd, J=12.3,6.7Hz, 2H),
(m, the 1H) of 2.47 (m, 1H), 2.41 (s, 2H), 2.24 (t, J=6.7Hz, 1H), 1.57 (m, 6H), 1.25 (m, 1H), 1.0513C
NMR(101MHz,CDCl3)δ174.11,141.84,138.78,130.04,128.59,66.82,61.18,60.86,53.08,
48.91,40.87,36.03,34.09,28.60,28.30,26.29,23.33,23.13,21.31,21.26,14.70.HRMS：
calcd for C24H36N2O4S:448.2396,found:448.2396.
Step 4：12-N- (4- Methyl benzenesulfonyls base) Chinese scholartree determines the preparation of butanol
Product obtained by step 3 is reduced with red aluminum solution, TLC monitoring reaction process, post processing obtains 12-N-
(4- Methyl benzenesulfonyls base) Chinese scholartree determines butanol crude product, crosses silicagel column, isolates and purifies.1H NMR(400MHz,CDCl3) δ 7.62 (d, J=
7.4Hz, 1H), 7.23 (d, J=7.5Hz, 1H), 3.75 (s, 1H), 3.52 (d, J=39.9Hz, 2H), 2.80 (m, 2H), 2.43
(t, J=12.3Hz, 1H), 2.37 (s, 2H), 2.02 (d, J=10.5Hz, 1H), 1.50 (dddd, J=93.5,67.4,37.7,
14.7Hz,9H),1.02(m,1H).13C NMR(101MHz,CDCl3)δ141.84,138.78,130.04,128.59,66.82,
62.44,60.86,53.08,48.91,40.87,36.03,33.43,31.39,28.30,26.29,24.01,23.33,
23.13,21.31.HRMS：calcd for C22H34N2O3S:406.2154,found:406.2154.
Step 5：4- ((3aR, 3a1S, 10aS) -2- tosyls ten dihydropyridine [3,2,1-ij] [1,6] naphthyridines -
1- yls) double (2- chloroethyls) butyl carbamates of butyl preparation
By the product obtained by step 4 under the conditions of potassium carbonate acid binding agent, reacted with mustargen sulfonic acid chloride, TLC monitorings are anti-
Process is answered, is post-processed, target compound crude product is obtained, silicagel column is crossed, isolates and purifies.13C NMR(101MHz,CDCl3)δ
159.28,141.84,138.78,130.04,128.59,66.82,66.08,60.86,53.08,48.91,47.01,41.63,
40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,23.13,21.31.HRMS：calcd for
C27H41Cl2N3O4S:573.2154,found:573.2154.
Synthetic method of the synthetic method of compound all referring to compound in embodiment 1 in following embodiments.With different knots
The paratoluensulfonyl chloride of step 3 in the sulfonic acid chloride substitution embodiment 1 of structure, other reaction conditions are similar.
Embodiment 2：4- ((3aR, 3a1S, 10aS) -2- ((3,4- 3,5-dimethylphenyls) sulfonyl) ten dihydropyridines [3,2,
1-ij] [1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,139.48,136.26,134.69,131.22,131.12,
125.91,66.82,66.08,60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,
28.30,26.29,24.09,23.33,23.13,20.55,19.62.HRMS：calcd for C28H43Cl2N3O4S:
587.2153,found:587.2153.
Embodiment 3：4- ((3aR, 3a1S, 10aS) -2- ((4- chlorphenyls) sulfonyl) ten dihydropyridines [3,2,1-ij]
[1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,140.36,139.69,130.44,129.52,66.82,66.08,
60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,
23.33,23.13.HRMS：calcd for C26H38Cl3N3O4S:593.3212,found:593.3212.
Embodiment 4：4- ((3aR, 3a1S, 10aS) -2- ((3,4- dichlorophenyls) sulfonyl) ten dihydropyridine [3,2,1-
Ij] [1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,141.66,137.97,132.51,128.70,128.28,
127.95,66.82,66.08,60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,
28.30,26.29,24.09,23.33,23.13.HRMS：calcd for C26H37Cl4N3O4S:627.1212,found:
627.1212.
Embodiment 5：4- ((3aR, 3a1S, 10aS) -2- ((4- bromophenyls) sulfonyl) ten dihydropyridines [3,2,1-ij]
[1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,139.26,132.29,130.38,130.23,66.82,66.08,
60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,
23.33,23.13.HRMS：calcd for C26H38BrCl2N3O4S:637.1212,found:637.1212.
Embodiment 6：4- ((3aR, 3a1S, 10aS) -2- ((4- nitrobenzophenones) sulfonyl) ten dihydropyridines [3,2,1-ij]
[1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,139.26,132.29,130.38,130.23,66.82,66.08,
60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,
23.33,23.13.HRMS：calcd for C26H38Cl2N4O6S:604.2325,found:604.2325.
Embodiment 7：4- ((3aR, 3a1S, 10aS) -2- ((4- fluorophenyls) sulfonyl) ten dihydropyridines [3,2,1-ij]
[1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ162.77,159.28,135.23,131.51,117.37,66.82,66.08,
60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,
23.33,23.13.
HRMS：calcd for C26H38Cl2FN3O4S:577.2131,found:577.2131.
Embodiment 8：4- ((3aR, 3a1S, 10aS) -2- ((4- (trifluoromethyl) phenyl) sulfonyl) ten dihydropyridines [3,
2,1-ij] [1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,145.48,135.59,129.01,125.97,124.37,66.82,
66.08,60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,
24.09,23.33,23.13.
HRMS：calcd for C27H38Cl2F3N3O4S:677.2310,found:677.2310.
Embodiment 9：4- ((3aR, 3a1S, 10aS) -2- ((4- methoxyphenyls) sulfonyl) ten dihydropyridine [3,2,1-
Ij] [1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ162.95,159.28,131.63,130.47,113.60,66.82,66.08,
60.86,56.04,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,
24.09,23.33,23.13.HRMS：calcd for C27H41Cl2N3O5S:589.2130,found:589.2130.
Embodiment 10：4- ((3aR, 3a1S, 10aS) -2- (thiophene -2- sulfonyls) ten dihydropyridines [3,2,1-ij] [1,
6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,131.78,127.83,117.71,66.82,66.08,60.49,
53.08,50.07,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,
23.13.HRMS：calcd for C24H37Cl2N3O4S2:565.2030,found:565.2030.
Embodiment 11：4- ((3aR, 3a1S, 10aS) -2- ((5- chlorothiophene -2- bases) sulfonyl) ten dihydropyridines [3,2,
1-ij] [1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,130.79,126.40,121.03,66.82,66.08,60.49,
53.08,50.07,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,
23.13.HRMS：calcd for C24H36Cl3N3O4S2:599.1213,found:599.1213.
Embodiment 12：4- ((3aR, 3a1S, 10aS) -2- ((5- bromothiophene -2- bases) sulfonyl) ten dihydropyridines [3,2,
1-ij] [1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,130.19,121.26,113.77,66.82,66.08,60.49,
53.08,50.07,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,
23.13.HRMS：calcd for C24H36BrCl2N3O4S2:643.0708,found:643.0708.
Embodiment 13：4- ((3aR, 3a1S, 10aS) -2- (naphthalene -1- sulfonyls) ten dihydropyridines [3,2,1-ij] [1,6]
Naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,134.44,134.12,134.06,133.28,131.43,
131.32,128.82,127.25,125.48,122.29,66.82,66.08,60.86,53.08,48.91,47.01,41.63,
40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,23.13.HRMS：calcd for
C30H41Cl2N3O4S:609.2195,found:609.2195.
Embodiment 14：4- ((3aR, 3a1S, 10aS) -2- ((5- (dimethylamino) naphthalene -1- bases) sulfonyl) ten dihydropyridines
[3,2,1-ij] [1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,144.80,138.37,133.15,133.05,129.08,
128.91,125.88,124.82,116.73,112.73,66.82,66.08,60.86,53.08,48.91,47.01,41.77,
41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,23.13.HRMS：calcd for
C32H46Cl2N4O4S:652.2617,found:652.2617.
Embodiment 15：4- ((3aR, 3a1S, 10aS) -2- (quinoline -8- sulfonyls) ten dihydropyridines [3,2,1-ij] [1,
6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,150.72,143.83,139.16,134.63,132.11,
131.52,130.85,127.97,125.58,66.82,66.08,60.86,53.08,48.91,47.01,41.63,40.87,
36.03,31.39,29.69,28.30,26.29,24.09,23.33,23.13.HRMS：calcd for C29H40Cl2N4O4S:
610.2147,found:610.2147.
Embodiment 16：4- ((3aR, 3a1S, 10aS) -2- (ethylsulfonyl) ten dihydropyridine [3,2,1-ij] [1,6] naphthalenes
Pyridine -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,66.82,66.08,60.24,53.08,50.21,48.37,
47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,23.13,10.16.HRMS：
calcd for C22H39Cl2N3O4S:511.2038,found:511.2038.
Embodiment 17：4- ((3aR, 3a1S, 10aS) -2- (N, N- dimethyl methyl acyl group) ten dihydropyridines [3,2,1-ij]
[1,6] naphthyridines -1- bases) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ159.28,66.82,66.08,60.42,53.08,49.98,47.01,
41.63,40.87,36.03,34.84,31.39,29.69,28.30,26.29,24.09,23.33,23.13.HRMS：calcd
for C22H40Cl2N4O4S:526.2147,found:526.2147.
Embodiment 18：4- ((3aR, 3a1S, 10aR) -2- benzoyls ten dihydropyridine [3,2,1-ij] [1,6] naphthyridines -
1- yls) double (2- chloroethyls) butyl carbamates of butyl preparation
13C NMR(101MHz,CDCl3)δ170.59,159.28,136.20,130.35,128.38,128.16,66.82,
66.08,60.28,53.08,47.49,47.01,41.63,40.66,36.71,32.48,29.69,28.30,26.29,
24.09,23.33,23.13.HRMS：calcd for C27H39Cl2N3O3:523.2368,found:523.2368.
Embodiment 19：4- ((3aR, 3a1S, 10aR) -2- benzoyls ten dihydropyridine [3,2,1-ij] [1,6] naphthyridines -
1- yls) double (2- chloroethyls) sulfamates of butyl preparation
Embodiment 20：4- ((3aR, 3a1S, 10aS) -2- (thiophene -2- sulfonyls) ten dihydropyridines [3,2,1-ij] [1,
6] naphthyridines -1- bases) double (2- chloroethyls) sulfamates of butyl preparation
13C NMR(101MHz,CDCl3)δ131.78,127.83,117.71,67.80,66.82,60.49,53.08,
51.66,50.07,41.68,40.87,36.03,31.39,29.07,28.30,26.29,24.09,23.33,23.13.HRMS：
calcd for C23H37Cl2N3O5S3:601.1272,found:601.1272.
Embodiment 21：4- ((3aR, 3a1S, 10aS) -2- (naphthalene -1- sulfonyls) ten dihydropyridines [3,2,1-ij] [1,6]
Naphthyridines -1- bases) double (2- chloroethyls) sulfamates of butyl preparation
13C NMR(101MHz,CDCl3)δ134.44,134.12,134.06,133.28,131.43,131.32,
128.82,127.25,125.48,122.29,67.80,66.82,60.86,53.08,51.66,48.91,41.68,40.87,
36.03,31.39,29.07,28.30,26.29,24.09,23.33,23.13.HRMS：calcd for C29H41Cl2N3O5S2:
645.1865,found:645.1865.
Embodiment 22：4- ((3aR, 3a1S, 10aS) -2- (quinoline -8- sulfonyls) ten dihydropyridines [3,2,1-ij] [1,
6] naphthyridines -1- bases) double (2- chloroethyls) sulfamates of butyl preparation
13C NMR(101MHz,CDCl3)δ150.72,143.83,139.16,134.63,132.11,131.52,
130.85,127.97,125.58,67.80,66.82,60.86,53.08,51.66,48.91,41.68,40.87,36.03,
31.39,29.07,28.30,26.29,24.09,23.33,23.13.HRMS：calcd for C28H40Cl2N4O5S2:
646.1817,found:646.1817.
Embodiment 23：4- ((3aR, 3a1S, 10aS) -2- (ethylsulfonyl) ten dihydropyridine [3,2,1-ij] [1,6] naphthalenes
Pyridine -1- bases) double (2- chloroethyls) sulfamates of butyl preparation
13C NMR(101MHz,CDCl3)δ67.80,66.82,60.24,53.08,51.66,50.21,48.37,41.68,
40.87,36.03,31.39,29.07,28.30,26.29,24.09,23.33,23.13,10.16.HRMS：calcd for
C21H39Cl2N3O5S2:547.1708,found:547.1708.
Embodiment 24：4- ((3aR, 3a1S, 10aR) -2- benzoyls ten dihydropyridine [3,2,1-ij] [1,6] naphthyridines -
1- yls) double (2- chloroethyls) sulfamates of butyl preparation
13CNMR(101MHz,CDCl3)δ170.59,136.20,130.35,128.38,128.16,67.80,66.82,
60.28,53.08,51.66,47.49,41.68,40.66,36.71,32.48,29.07,28.30,26.29,24.09,
23.33,23.13.HRMS：calcd for C26H39Cl2N3O4S:559.2038,found:559.2038.
Embodiment 25：
Compound SP-1 hydrochloric acid salt：Compound SP-1 white solid product 2.0g is taken, 8ml absolute ethyl alcohols are dissolved in.Frozen water
Bath is cooled to 5 DEG C, and it is 2 that 11.1% ethanol solution hydrochloride, which is added dropwise, to pH, continues at stir about 1h under ice-water bath.Filtering, vacuum is done
It is dry, obtain white solid powder.
Embodiment 26：
Compound SP-3 is into taurate：Compound SP-3 white solid product 2.5g are taken, 10ml absolute methanols are dissolved in.Plus
Heat adds equimolar taurine to after flowing back, and continues at stirred at reflux reaction about 1.5h.Reaction is finished, and is stood at room temperature
24h.Crystallization is separated out, is filtered, vacuum drying.
Embodiment 27：
Compound SP-4 is into sulfate：Compound SP-4 white solid product 2.0g are taken, 15ml acetone is dissolved in.Ice-water bath is cold
But to 0 DEG C, it is 3 that concentrated sulfuric acid solution, which is added dropwise, to pH, continues at stir about 1h under ice-water bath.Filtering, obtains white solid.
In order to which the pharmaceutical composition of the Sophoridine analog derivative containing mustargen of the invention is more fully explained, it is provided below down
Series preparation embodiment, the embodiment is merely to illustrate, rather than for limiting the scope of the present invention.The preparation can be used
Any reactive compound and its salt in the compounds of this invention.
Embodiment 28：
Hard gelatin capsule is prepared with following compositions：
Preparation technology：Supplementary material is pre-dried, 100 mesh sieves are crossed standby.After by recipe quantity, above-mentioned composition is mixed, filling
Enter in hard gelatin capsule.
Embodiment 29：
Tablet is prepared with following compositions：
Preparation technology：Supplementary material is pre-dried, 100 mesh sieves are crossed standby.The auxiliary material of recipe quantity is fully mixed.By raw material
Medicine is added in auxiliary material with incremental dilution method, and each added-time fully mixes 2-3 times, it is ensured that medicine is fully mixed with auxiliary material, crosses 20 mesh sieves,
2h is dried in 55 DEG C of ventilated drying ovens, dry particl crosses 16 mesh sieve whole grains, determines intermediates content, is well mixed, on tablet press machine
Tabletting.
Embodiment 30：
The preparation of parenteral solution：
Preparation method：Take active component to be added in the water for injection of solubilized solution polysorbate and propane diols, add medicinal
Alkali, which adjusts pH value, dissolves it to 4~8.Add activated carbon, stirring and adsorbing 30min, carbon removal, refined filtration, embedding, sterilizing.
Embodiment 31：
The preparation of injection freeze-dried powder：
Preparation method：Take active component to add water for injection, it is dissolved with medicinal basic regulation pH value to 4-8.Add
Mannitol, carries out autoclaving by the requirement of injection, adds activated carbon, using filtering with microporous membrane, filtrate is dispensed, and is adopted
With freeze-drying, loose block is made, sealing is produced.
Embodiment 32：
Extracorporeal anti-tumor function
(1) experiment material
Human liver cancer SMMC-7721, human colon carcinoma LoVo, human breast carcinoma MCF-7, human leukaemia K562, human cervical carcinoma Hela,
The cell line cellar cultures such as human lung cancer A549, human gastric cancer SGC-7901 and normal cell L929 are in 1640 containing 10% calf serum
In culture medium, 37 DEG C, cultivate under the conditions of 5%CO2 incubators and saturated humidity, 3-4d is passed on 1 time.By Tianjin, medical science is ground
Institute's Cytology Lab offer is provided.
MTT (Scientific research spescial companies)；RPMI1640 culture mediums (Hyclone companies)；Newly
Raw cow's serum (Hangzhou Sijiqing Biological Engineering Material Co., Ltd.)；Remaining reagent such as dimethyl sulfoxide (DMSO) (DMSO) is domestic point
Analysis is pure.
Positive control drug：Sophoridine, taxol
Testing sample：The compounds of this invention
Laboratory apparatus：Instrument CO2Incubator model (BB16/BB5060 makes every effort to achieve in Shanghai scientific instrument Co., Ltd), the U.S.；
Enzyme-linked immunosorbent assay instrument (model：Infinite M200 Tecan companies Swiss)；Inverted microscope (model：CK Olympus
The production of Japan of company) superclean bench (factory of Beijing semiconductor equipment one).
(2) experimental implementation
With compound processing human liver cancer SMMC-7721, human colon carcinoma LoVo, human breast carcinoma MCF-7, the white blood of people of the present invention
The cells such as sick K562, human cervical carcinoma Hela, human lung cancer A549, human gastric cancer SGC-7901 and normal cell L929, are determined with mtt assay
The antiproliferative activity of compound.
MTT experiment method is：The cell in good condition in exponential phase of growth is taken, every milliliter is made and contains 5 × 103It is individual thin
The suspension of born of the same parents.By cell suspension inoculation in 96 well culture plates, per the μ L of hole 100, point sample sets, control group (being not added with sample) and sky
White group (only culture medium), 4 multiple holes of every group of setting.It is placed in constant temperature CO224h is cultivated in incubator and changes liquid, respective concentration is added
Test-compound, culture 48h adds MTT, per the μ L of hole 10, and supernatant is sucked after reacting 4h in incubator, and 150 are added per hole
μ L DMSO, shake 5min on plate shaker, determine the trap in every hole, meter at wavelength 570nm with enzyme-linked immunosorbent assay instrument
IC is obtained by statistical software again after calculating cell inhibitory rate50Value.
(3) experimental result
The antitumor activity of the part of compounds of the present invention passes through IC50As a result as shown in table 1 value represents,.
The IC of the compound on tumor cell of table 150It is worth (μM)
(4) experiment conclusion
The Pharmacological experiment result shows that：It is administered simultaneously using Sophoridine and taxol as comparison medicine, with compound of the invention
In the case of, growth inhibition effect of the compound to selected tumour cell and normal cell is studied, by comparing their suppression
Rate processed and IC50Value is found：The antitumor activity of the compound of the present invention is far above Sophoridine；The compound on tumor of the present invention is thin
The growing multiplication inhibitory action of born of the same parents is less than to be suppressed to the growing multiplication of normal cell, illustrates that the selective suppression tumour of compound is thin
Born of the same parents；Inhibitory action to K562 and Hela cells is better than taxol, but is weaker than Japanese yew to the inhibitory action of SMMC-7721 cells
Alcohol.Such compound has the effect of significant anti-K562 and Hela cells, and relatively low to the toxicity of normal cell.
Claims (9)
1. compound or its pharmaceutically acceptable salt, stereoisomer with structure shown in formula I, it is characterised in that：
Wherein：
X is the hetero atoms such as O, S or N；
N is equal to 1 or 2；
R1For fatty carbonic acyl radical, fragrant carbonic acyl radical, fatty sulfonyl, fragrant sulfonyl, aromatic heterocycle sulfonyl, fatty phosphoryl,
Fragrant phosphoryl, benzyl or substituted benzyl, heteroaromatic benzyl or substitution heteroaromatic benzyl, olefin alkylation, alkynes alkyl；
Y is
Wherein R2For hydrogen, C1-4Straight or branched alkyl, cycloalkyl group, alkylene, olefin alkylation, alkynes base, alkynes alkyl,
Aromatic ring or substitution aromatic ring, heteroaromatic or substitution heteroaromatic, benzyl or substituted benzyl, heteroaromatic benzyl or substitution heteroaromatic benzyl.
2. the compound of right 1, its be with following formula (I a) compound, or its pharmaceutically acceptable salt,
Wherein：
R1, X, Y, n definition it is identical with the definition of the formula (I) of claim 1.
3. the compound of right 1, its be with following formula (I b) compound, or its pharmaceutically acceptable salt,
Wherein：
R1, X, Y, n definition it is identical with the definition of the formula (I) of claim 1.
4. the preparation method of the compound with structure shown in formula I as described in claim 1-3, it is characterised in that：12-N substitutions
Chinese scholartree determines acetoacetic ester (III), in dichloromethane, chloroform, acetonitrile, DMF, DMSO, ethyl acetate, acetone or THF equal solvents,
Reacted with reducing agent -10~100 DEG C, key intermediate II is made；Intermediate II again respectively with mustargen formyl chloride, mustargen sulphonyl
Chlorine, mustargen phosphoryl chloride phosphorus oxychloride in dichloromethane, chloroform, acetonitrile, DMF, DMSO, ethyl acetate, acetone or THF equal solvents,
In the presence of acid binding agent, the a-1 of target compound I, I a-2, wherein I a-3, R is made in -10~100 DEG C of reactions1, X, Y, n such as right will
Ask described in 1；
5. preparation method as claimed in claim 4, the reducing agent is selected from sodium borohydride, Lithium Aluminium Hydride, diisobutyl hydrogenation
Aluminium, palladium carbon or red aluminum solution.
6. preparation method as claimed in claim 4, the acid binding agent is selected from triethylamine, pyridine, potassium carbonate, sodium acid carbonate, carbon
Potassium hydrogen phthalate, sodium hydroxide or lithium hydroxide.
7. compound with structure shown in formula I and its pharmaceutically acceptable salt as described in claim 1-3, pharmaceutically acceptable
Salt refer to：Hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate,
Lactate, mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, richness
Horse hydrochlorate, taurate, gluconate, amino-acid salt.
8. a kind of pharmaceutical composition, it has structure shown in formula I comprising treatment effective dose as described in claim any one of 1-3
Compound or its pharmaceutically acceptable salt and one or more pharmaceutical carrier.
9. compound with structure shown in formula I or its pharmaceutically acceptable salt as described in claim any one of 1-3 for
Prepare the application in terms of antineoplastic.
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