CN105418487A - Carbazole sulfonamide derivative eutectic and preparation method thereof - Google Patents
Carbazole sulfonamide derivative eutectic and preparation method thereof Download PDFInfo
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- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
The present application discloses a novel carbazole sulfonamide derivative eutectic and a preparation method thereof. The carbazole sulfonamide derivative eutectic is formed by oxalic acid, maleic acid, malonic acid or glutaric acid, and a carbazole sulfonamide derivative, has an antimicrotubular effect, and significant tumor resistance, and has the advantages of simple synthesis, small side effects, and high dissolution rate and solubility.
Description
Technical field
The application relates to a kind of carbazole sulfonamide derivative eutectic, belongs to chemical field.
Background technology
Antitubulin is the effectively antitumor drug of a class, along with taxol widespread use clinically, with the deep understanding of the structure and fuction to microtubule, take tubulin as the concern that the research and development of the antitumor drug of target spot cause whole world drugmaker day by day.
At present, taxol and vinca Antitubulin have been successfully applied to all kinds of tumour of clinical treatment, but it is as the macromolecular natural product of one, its synthesis difficulty is large, bioavailability is low, toxic side effect, particularly, the appearance of multidrug resistant glycoprotein, makes its therapeutic receive serious challenge.Therefore, synthesizing new is necessary to all kinds of tumour effective small molecules Antitubulin.
Chinese patent (Authorization Notice No. CN1807413B) discloses a kind of carbazole sulfonamide derivative, it is the small molecules Antitubulin that a class is new, not only there is anti-microtubule effect, also there is significant anti-tumor activity, and it is little to have molecular weight, synthesis is simple, and the advantage that toxic side effect is little, has a good application prospect.
Carbazole sulfonamide derivative has significant anti-tumor activity, but this compound is difficult to water-soluble, and its dissolution rate does not reach States Pharmacopoeia specifications requirement far away.Making the medicament made have good dissolution rate, solubleness, is problem demanding prompt solution.
Summary of the invention
According to an aspect of the application, provide a kind of novel carbazole sulfone amide derivative eutectic, this carbazole sulfonamide derivative eutectic not only has anti-microtubule effect, can anti-tumor activity significantly, and have that molecular weight is little, synthesis is simple, toxic side effect is little, dissolution rate and the high advantage of solubleness.
Described carbazole sulfonamide derivative eutectic, is characterized in that, described carbazole sulfonamide derivative eutectic is the eutectic formed by oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid and carbazole sulfonamide derivative;
Described carbazole sulfonamide derivative is selected from least one in the compound with structural formula shown in formula I:
Wherein,
R
1represent hydrogen or R
1the alkoxyl group that the alkyl that representative is connected to one or more nitros of phenyl ring, amino, halogen, cyano group, ester group, amide group, hydroxyl, sulfydryl, carbonatoms are 1 ~ 6, carbonatoms are 1 ~ 6, aryloxy, carbonatoms are alkylthio, the artyl sulfo of 1 ~ 6;
R
2representative: hydrogen or carbonatoms are the alkyl of 1 ~ 6;
X represents: SO
2nR
3or NR
3sO
2, wherein R
3representative: the acyl group of the alkyl that hydrogen, carbonatoms are 1 ~ 6 or the replacement shown in formula II;
R in formula II
1representative: the alkyl that carbonatoms is 1 ~ 6 or the amine substituted alkyl shown in formula III;
In formula III, n=1 ~ 6; R
2, R
3represent identical or different following group respectively: hydrogen, carbonatoms are alkyl, hydroxyalkyl, the aminoalkyl of 1 ~ 6; Or R
2, R
35 ~ 7 yuan of cyclic amine groups be joined together to form by nitrogen;
Ar represents: the pyrimidyl of the phenyl of replacement, the pyridyl of replacement, pyrimidyl, replacement, thienyl, benzothienyl, benzothiazolyl, naphthyl or carbazyl;
Described substituted-phenyl be on phenyl at least one hydrogen atom be substituted base replace the group of formation; Described substituted pyridinyl be on pyridyl at least one hydrogen atom be substituted base replace the group of formation; Described substituted pyrimidyl be on pyrimidyl at least one hydrogen atom be substituted base replace the group of formation;
Described substituting group is selected from alkyl, the carbonatoms alkoxyl group that is 1 ~ 6, carbonatoms be 1 ~ 6 alkylthio, hydroxyl, sulfydryl, amino, amide group, ester group, nitro, cyano group or the halogen that carbonatoms is 1 ~ 6;
Described carbazole sulfonamide derivative does not comprise following compound:
9-ethyl-N-(4-p-methoxy-phenyl)-carbazole-3-sulphonamide;
N-(4-p-methoxy-phenyl)-9H-carbazole-3-sulphonamide;
9-ethyl-N-(4-chloro-phenyl-)-carbazole-3-sulphonamide;
N-(4-chloro-phenyl-)-9H-carbazole-3-sulphonamide;
N-(9-ethyl carbazole-3-replaces)-2,5-dichlorobenzene sulphonamide;
N-(9-methyl carbazole-3-replaces)-N-methyl-2,4 dichlorobenzene sulphonamide;
N-(9-ethyl carbazole-3-replaces)-2,5-dibromobenzene sulphonamide.
Preferably, described carbazole sulfonamide derivative is selected from:
9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 1);
9-methyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 2);
N-(2,4-Dimethoxyphenyl)-9-ethyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 3);
N-(2,5-Dimethoxyphenyl)-9-ethyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 4);
N-(3-chloro-4-methoxy phenyl)-9-ethyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 5);
N-(chloro-2, the 4-Dimethoxyphenyls of 5-)-9-ethyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 6);
N-(chloro-2, the 4-Dimethoxyphenyls of 5-)-9-methyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 7);
N-(chloro-2, the 5-Dimethoxyphenyls of 4-)-9-ethyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 8);
N-(chloro-2, the 5-Dimethoxyphenyls of 4-)-9-methyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 9);
9-methyl-N-(2,4,6-trimethoxyphenyl)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 10);
9-ethyl-6-nitro-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 11);
6-amino-9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 12);
9-ethyl-N-(2-methoxypyridine-5-replaces)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 13);
N-(2,6-dimethoxy-pyridine-3-replaces)-9-ethyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 14);
N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 15);
9-ethyl-N-(2-methoxypyridine-3-replaces)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 16);
N-[(dimethylin) ethanoyl]-9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide (hereinafter abbreviated as compound 17); Or
N-(2,6-dimethoxy-pyridine-3-replaces)-N-[(dimethylin) ethanoyl]-9-methyl carbazole-3-sulphonamide (hereinafter abbreviated as compound 18).
Further preferably, described carbazole sulfonamide derivative is N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulphonamide, has following structural formula:
According to the another aspect of the application, a kind of method preparing described carbazole sulfonamide derivative eutectic is provided, it is characterized in that, one in oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid and carbazole sulfonamide derivative are dissolved in organic solvent according to mol ratio 1:2 ~ 2:1, by evaporating solvent, obtain described carbazole sulfonamide derivative eutectic.Preferably, described organic solvent is ethanol and/or tetrahydrofuran (THF).
According to the another aspect of the application, a kind of method preparing described carbazole sulfonamide derivative eutectic is provided, it is characterized in that, grind after one in oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid is mixed according to mol ratio 1:2 ~ 2:1 with carbazole sulfonamide derivative, obtain described carbazole sulfonamide derivative eutectic.
According to the another aspect of the application, a kind of method preparing described carbazole sulfonamide derivative eutectic is provided, it is characterized in that, one in oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid is mixed according to mol ratio 1:2 ~ 2:1 with carbazole sulfonamide derivative, then grind after adding organic solvent, obtain described carbazole sulfonamide derivative eutectic;
The add-on of organic solvent described in process of lapping is: 0.5 ~ 10mL organic solvent/mmol carbazole sulfonamide derivative.
Preferably, described organic solvent is ethanol and/or tetrahydrofuran (THF).In process of lapping, the add-on of organic solvent is: every 1mmol carbazole sulfonamide derivative, adds the organic solvent of 0.5 ~ 10mL.
According to the another aspect of the application, provide a kind of pharmaceutical composition, it is characterized in that, described pharmaceutical composition comprises auxiliary material and carbazole sulfonamide derivative eutectic; At least one in the carbazole sulfonamide derivative eutectic that wherein said carbazole sulfonamide derivative eutectic is selected from above-mentioned arbitrary carbazole sulfonamide derivative eutectic, prepare according to above-mentioned either method.
Preferably, described auxiliary material comprises lactose and beta-cyclodextrin.Further preferably, in described pharmaceutical composition, the part by weight of carbazole sulfonamide derivative eutectic, lactose and beta-cyclodextrin is:
Carbazole sulfonamide derivative eutectic: lactose: beta-cyclodextrin=1:1 ~ 10:1 ~ 3.
According to the another aspect of the application, a kind of antitumour drug composition dispersible tablets is provided, it is characterized in that, containing above-mentioned arbitrary pharmaceutical composition, tackiness agent, disintegrating agent and lubricant.
Preferably, described binding agent is polyvinylpyrrolidone and/or hydroxypropylcellulose; Described disintegrating agent is selected from least one in crosslinked carboxymethyl fecula sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium; Described lubricant is Magnesium Stearate and/or micropowder silica gel.
Preferably, also correctives is contained in described antitumour drug composition dispersible tablets.Further preferably, described correctives be selected from Icing Sugar, stevioside, Abbas sweet at least one.
In the application, " alkyl ", refers to group alkane compound molecule losing any one hydrogen atom and formed, and described alkane compound comprises straight-chain paraffin, branched paraffin, naphthenic hydrocarbon, naphthenic hydrocarbon with side chain.
The beneficial effect that the application can produce comprises:
1) the carbazole sulfonamide derivative eutectic that provides of the application, has the advantage that solubleness is high.
2) preparation method that provides of the application is simple, environmental friendliness, is applicable to scale operation.
3) pharmaceutical composition that provides of the application, not only has anti-microtubule effect and significant anti-tumor activity, and the solubleness of active ingredient carbazole sulfonamide derivative eutectic in pharmaceutical composition is high.
4) dispersible tablet that provides of the application, good dispersity and there is higher stability.On the one hand, when the water soluble adjuvant in dispersible tablet dissolves, active ingredient has very high dissolution rate; On the other hand, dispersible tablet has high temperature, high light, high humidity environment and has higher tolerance, can stablize for a long time and deposit in high temperature, high light, high humidity environment.
Embodiment
Below in conjunction with embodiment in detail the application is described in detail, but the application is not limited to these embodiments.
Carbazole sulfonamide derivative in the embodiment of the present application is according to Authorization Notice No. method synthesis disclosed in the Chinese patent of CN1807413B.If no special instructions, other raw materials in the embodiment of the application are all bought by commercial sources.
The device information used in the embodiment of the application is as follows:
Mixing and ball milling machine is German Lay relaxation MM400 type.
13c-NMR characterizes the 600MHzDD2 type adopting Agilent company.
Embodiment 1 evaporating solvent legal system is for carbazole sulfonamide derivative eutectic
0.1mmol active pharmaceutical ingredient compound 1,0.1mmol enclosed molecule pentanedioic acid are joined in 10mL solvents tetrahydrofurane.Mix and blend is after 15 minutes, leave standstill 30 minutes, filter, filtrate is loaded 25mL test tube, prick hole with after preservative film sealing, naturally volatilize at being placed in 25 DEG C, the solidliquid mixture containing bulk crystals is obtained after 1 week, by the solidliquid mixture collecting by filtration bulk crystals of gained, and dry 12 hours in 60 DEG C, the crystal obtained is designated as sample 1-1
#.
Sample 1-2
#~ sample 1-21
#preparation manipulation and sample 1-1
#identical, unlike raw material type, consumption and volatilization temperature, sample 1-1
#~ sample 1-21
#each substance classes, consumption and solvent evaporates temperature be shown in Table 1.
Table 1
Embodiment 2 mixed grinding legal system is for carbazole sulfonamide derivative eutectic
0.1mmol active pharmaceutical ingredient compound 1,0.1mmol enclosed molecule pentanedioic acid, 0.1mL ethanol are joined in mixing and ball milling machine.At room temperature ball milling 30 minutes, after in 60 DEG C dry 12 hours.The solid sample obtained is designated as sample 2-1
#.
Sample 2-2
#~ sample 2-13
#preparation manipulation and sample 2-1
#identical, unlike raw material type, consumption and ball milling temperature.Sample 2-1
#~ sample 2-13
#each substance classes, consumption and ball milling temperature be shown in Table 2.
0.1mmol compound 10,0.1mmol pentanedioic acid are joined in mixing and ball milling machine.At room temperature ball milling 30 minutes, the solid sample obtained is designated as sample 2-14
#.
Sample 2-15
#~ sample 2-25
#preparation manipulation and sample 2-14
#identical, unlike raw material type, consumption and ball milling temperature.Sample 2-14
#~ sample 2-25
#each substance classes, consumption and ball milling temperature be shown in Table 2.
Table 2
Embodiment 3
13c-NMR crystal characterization
Get oxalic acid crystal, sodium oxalate crystal, propanedioic acid crystal, sodium malonate crystal, pentanedioic acid crystal, Sodium glutarate crystal, toxilic acid crystal, sodium maleate crystal respectively, pass through
13the C-NMR analysis organic acid-COOH wherein and-COO of organic acid salt
-chemical shift, as benchmark, the results are shown in Table shown in 3.
Table 3
| Organic acid | The chemical shift of-COOH | -COO -Chemical shift |
| Oxalic acid | 162ppm | 175ppm |
| Propanedioic acid | 169ppm | 178ppm |
| Pentanedioic acid | 178ppm | 184ppm |
| Toxilic acid | 167ppm | 172ppm |
To the sample 1-1 that embodiment 1 obtains
#~ sample 1-21
#with the sample 2-1 that embodiment 2 obtains
#~ sample 2-25
#carry out
13c-NMR analyzes, and the peak position near the chemical shift of wherein carboxyl-COOH is all consistent with the organic acid used in its respective sample, and namely above-mentioned sample all can detect carboxyl-COOH.Above-mentioned sample does not all detect carboxylic acid with-COO
-chemical shift peak.Interpret sample 1-1
#~ sample 1-21
#crystal and sample 2-1
#~ sample 2-25
#crystal in, organic acid and carbazole sulfonamide derivative do not form salt, and the carbazole sulfonamide derivative therefore in above-mentioned sample and organic acid exist with the form of eutectic.
Prepared by embodiment 4 tablet
tablet 1-1
#
preparation:
By 50g sample 1-1
#after mixing with 150g beta-cyclodextrin after grinding, add 350g lactose powder.Added croscarmellose sodium 22g, the aspartame 0.2g of 100 mesh sieves again, and mixed.Add 5% aqueous povidone solution to obtaining softwood, then granulate with 20 mesh sieves, in 80 DEG C of dryings, the whole grain of 18 mesh sieve.By the particle obtained, add micropowder silica gel 6g and mix, compressing tablet.Make 1000.
tablet 1-2
#
~ tablet 1-21
#
with tablet 2-1
#
~ tablet 2-25
#
preparation:
Prepare tablet 1-2
#~ tablet 1-21
#with tablet 2-1
#~ tablet 2-25
#operating process and tablet 1-1
#preparation process consistent, just respectively by sample 1-1
#change sample 1-2 into
#~ sample 1-21
#with sample 2-1
#~ sample 2-25
#.
Prepared by comparative example 1 tablet
tablet D1
#
preparation:
Prepare tablet D1
#operating process and tablet 1-1
#preparation process consistent, just by sample 1-1
#change compound 15 into.
Embodiment 5 result of extraction
To tablet 1-1
#~ tablet 1-21
#, tablet 2-1
#~ tablet 2-25
#with tablet D1
#carry out Comparative Study on Dissolution, the method specified according to China's coastal port, in simulated gastric fluid (0.1mol/L hydrochloric acid soln), test-results is in table 4 simultaneously:
Table 4
| Tablet | Dissolution rate | Tablet | Dissolution rate |
| Tablet 1-1 # | 96％ | Tablet 2-1 # | 95％ |
| Tablet 1-2 # | 96％ | Tablet 2-2 # | 97％ |
| Tablet 1-3 # | 97％ | Tablet 2-3 # | 96％ |
| Tablet 1-4 # | 96％ | Tablet 2-4 # | 96％ |
| Tablet 1-5 # | 96％ | Tablet 2-5 # | 97％ |
| Tablet 1-6 # | 96％ | Tablet 2-6 # | 96％ |
| Tablet 1-7 # | 97％ | Tablet 2-7 # | 96％ |
| Tablet 1-8 # | 96％ | Tablet 2-8 # | 97％ |
| Tablet 1-9 # | 96％ | Tablet 2-9 # | 96％ |
| Tablet 1-10 # | 97％ | Tablet 2-10 # | 98％ |
| Tablet 1-11 # | 96％ | Tablet 2-11 # | 98％ |
| Tablet 1-12 # | 96％ | Tablet 2-12 # | 98％ |
| Tablet 1-13 # | 96％ | Tablet 2-13 # | 98％ |
| Tablet 1-14 # | 96％ | Tablet 2-14 # | 96％ |
| Tablet 1-15 # | 97％ | Tablet 2-15 # | 96％ |
| Tablet 1-16 # | 96％ | Tablet 2-16 # | 97％ |
| Tablet 1-17 # | 97％ | Tablet 2-13 # | 96％ |
| Tablet 1-18 # | 96％ | Tablet 2-18 # | 96％ |
| Tablet 1-19 # | 98％ | Tablet 2-19 # | 98％ |
| Tablet 1-20 # | 98％ | Tablet 2-20 # | 98％ 8 --> |
| Tablet 1-21 # | 98％ | Tablet 2-21 # | 98％ |
| Tablet 2-22 # | 96％ | ||
| Tablet 2-23 # | 98％ | ||
| Tablet 2-24 # | 98％ | ||
| Tablet D1 # | 54％ | Tablet 2-25 # | 98％ |
Embodiment 6 stability
high temperature test
Get tablet 1-1
#, be placed in plate, be positioned in 60 DEG C of thermostatic drying chambers 10 days, respectively at the 0th day, the 5th day and sampling in the 10th day, detect stability project, the results are shown in Table 5, show tablet 1-1
#there is good high-temperature stability.
Table 5
| Time | 0th day | 5th day | 10th day |
| Outward appearance | White tablets | White tablets | White tablets |
| Active constituents of medicine content | 100.5％ | 100.3％ | 100.2％ |
| Dissolution rate | 96％ | 95％ | 95％ |
Same high temperature test method is adopted to detect tablet 1-2
#~ tablet 1-21
#with tablet 2-1
#~ tablet 2-25
#, test-results and tablet 1-1
#result similar, all show good high-temperature stability.
high humidity is tested
Get tablet 1-1
#, be placed in plate, be put in and fill KNO
3in the loft drier of saturated solution (25 DEG C, RH92.5%) 10 days, respectively at the 0th day, the 5th day and sampling in the 10th day, detect stability project, the results are shown in Table 6, show tablet 1-1
#there is good high humidity stability.
Table 6
| Time | 0th day | 5th day | 10th day |
| Outward appearance | White tablets | White tablets | White tablets |
| Active constituents of medicine content | 100.5％ | 100.3％ | 100.1％ |
| Dissolution rate | 96％ | 95％ | 95％ |
Same high humidity test method is adopted to detect tablet 1-2
#~ tablet 1-21
#with tablet 2-1
#~ tablet 2-25
#, test-results and tablet 1-1
#result similar, all show good high humidity stability.
strong illumination is tested
Get tablet 1-1
#, be placed in plate, under the condition of illumination 4500Lx, place 10 days, respectively at the 0th day, the 5th day and sampling in the 10th day, detect stability project, the results are shown in Table 7, show tablet 1-1
#there is good strong illumination stability.
Table 7
| Time | 0th day | 5th day | 10th day |
| Outward appearance | White tablets | White tablets | White tablets |
| Active constituents of medicine content | 100.5％ | 100.4％ | 100.3％ |
| Dissolution rate | 96％ | 96％ | 96％ |
Same high humidity test method is adopted to detect tablet 1-2
#~ tablet 1-21
#with tablet 2-1
#~ tablet 2-25
#, test-results and tablet 1-1
#result similar, all show good strong illumination stability.
The above, only several embodiments of the application, not any type of restriction is done to the application, although the application discloses as above with preferred embodiment, but and be not used to limit the application, any those skilled in the art, not departing from the scope of technical scheme, utilize the technology contents of above-mentioned announcement to make a little variation or modify and be all equal to equivalent case study on implementation, all belong within the scope of technical scheme.
Claims (10)
1. a carbazole sulfonamide derivative eutectic, is characterized in that, described carbazole sulfonamide derivative eutectic is the eutectic formed by oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid and carbazole sulfonamide derivative;
Described carbazole sulfonamide derivative is selected from least one in the compound with structural formula shown in formula I:
Wherein,
R
1represent hydrogen or R
1the alkoxyl group that the alkyl that representative is connected to one or more nitros of phenyl ring, amino, halogen, cyano group, ester group, amide group, hydroxyl, sulfydryl, carbonatoms are 1 ~ 6, carbonatoms are 1 ~ 6, aryloxy, carbonatoms are alkylthio, the artyl sulfo of 1 ~ 6;
R
2representative: hydrogen or carbonatoms are the alkyl of 1 ~ 6;
X represents: SO
2nR
3or NR
3sO
2, wherein R
3representative: the acyl group of the alkyl that hydrogen, carbonatoms are 1 ~ 6 or the replacement shown in formula II;
R in formula II
1representative: the alkyl that carbonatoms is 1 ~ 6 or the amine substituted alkyl shown in formula III;
In formula III, n=1 ~ 6; R
2, R
3represent identical or different following group respectively: hydrogen, carbonatoms are alkyl, hydroxyalkyl, the aminoalkyl of 1 ~ 6; Or R
2, R
35 ~ 7 yuan of cyclic amine groups be joined together to form by nitrogen;
Ar represents: the pyrimidyl of the phenyl of replacement, the pyridyl of replacement, pyrimidyl, replacement, thienyl, benzothienyl, benzothiazolyl, naphthyl or carbazyl;
Described substituted-phenyl be on phenyl at least one hydrogen atom be substituted base replace the group of formation; Described substituted pyridinyl be on pyridyl at least one hydrogen atom be substituted base replace the group of formation; Described substituted pyrimidyl be on pyrimidyl at least one hydrogen atom be substituted base replace the group of formation;
Described substituting group is selected from alkyl, the carbonatoms alkoxyl group that is 1 ~ 6, carbonatoms be 1 ~ 6 alkylthio, hydroxyl, sulfydryl, amino, amide group, ester group, nitro, cyano group or the halogen that carbonatoms is 1 ~ 6;
Described carbazole sulfonamide derivative does not comprise following compound:
9-ethyl-N-(4-p-methoxy-phenyl)-carbazole-3-sulphonamide;
N-(4-p-methoxy-phenyl)-9H-carbazole-3-sulphonamide;
9-ethyl-N-(4-chloro-phenyl-)-carbazole-3-sulphonamide;
N-(4-chloro-phenyl-)-9H-carbazole-3-sulphonamide;
N-(9-ethyl carbazole-3-replaces)-2,5-dichlorobenzene sulphonamide;
N-(9-methyl carbazole-3-replaces)-N-methyl-2,4 dichlorobenzene sulphonamide;
N-(9-ethyl carbazole-3-replaces)-2,5-dibromobenzene sulphonamide.
2. carbazole sulfonamide derivative eutectic according to claim 1, is characterized in that, described carbazole sulfonamide derivative is selected from:
9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide;
9-methyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide;
N-(2,4-Dimethoxyphenyl)-9-ethyl carbazole-3-sulphonamide;
N-(2,5-Dimethoxyphenyl)-9-ethyl carbazole-3-sulphonamide;
N-(3-chloro-4-methoxy phenyl)-9-ethyl carbazole-3-sulphonamide;
N-(chloro-2, the 4-Dimethoxyphenyls of 5-)-9-ethyl carbazole-3-sulphonamide;
N-(chloro-2, the 4-Dimethoxyphenyls of 5-)-9-methyl carbazole-3-sulphonamide;
N-(chloro-2, the 5-Dimethoxyphenyls of 4-)-9-ethyl carbazole-3-sulphonamide;
N-(chloro-2, the 5-Dimethoxyphenyls of 4-)-9-methyl carbazole-3-sulphonamide;
9-methyl-N-(2,4,6-trimethoxyphenyl)-carbazole-3-sulphonamide;
9-ethyl-6-nitro-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide;
6-amino-9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide;
9-ethyl-N-(2-methoxypyridine-5-replaces)-carbazole-3-sulphonamide;
N-(2,6-dimethoxy-pyridine-3-replaces)-9-ethyl carbazole-3-sulphonamide;
N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulphonamide;
9-ethyl-N-(2-methoxypyridine-3-replaces)-carbazole-3-sulphonamide;
N-[(dimethylin) ethanoyl]-9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulphonamide; Or
N-(2,6-dimethoxy-pyridine-3-replaces)-N-[(dimethylin) ethanoyl]-9-methyl carbazole-3-sulphonamide.
3. prepare the method for carbazole sulfonamide derivative eutectic described in claim 1 or 2, it is characterized in that, one in oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid and carbazole sulfonamide derivative are dissolved in organic solvent according to mol ratio 1:2 ~ 2:1, by evaporating solvent, obtain described carbazole sulfonamide derivative eutectic.
4. prepare the method for carbazole sulfonamide derivative eutectic described in claim 1 or 2, it is characterized in that, grind after one in oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid is mixed according to mol ratio 1:2 ~ 2:1 with carbazole sulfonamide derivative, obtain described carbazole sulfonamide derivative eutectic.
5. prepare the method for carbazole sulfonamide derivative eutectic described in claim 1 or 2, it is characterized in that, one in oxalic acid, toxilic acid, propanedioic acid or pentanedioic acid is mixed according to mol ratio 1:2 ~ 2:1 with carbazole sulfonamide derivative, then grind after adding organic solvent, obtain described carbazole sulfonamide derivative eutectic;
The add-on of organic solvent described in process of lapping is: 0.5 ~ 10mL organic solvent/mmol carbazole sulfonamide derivative.
6. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises auxiliary material and carbazole sulfonamide derivative eutectic; Wherein said carbazole sulfonamide derivative eutectic is selected from least one in carbazole sulfonamide derivative eutectic described in claim 1 or 2, method prepares according to any one of claim 3 to 5 carbazole sulfonamide derivative eutectic.
7. pharmaceutical composition according to claim 6, is characterized in that, described auxiliary material comprises lactose and beta-cyclodextrin.
8. pharmaceutical composition according to claim 7, is characterized in that, in described pharmaceutical composition, the part by weight of carbazole sulfonamide derivative eutectic, lactose and beta-cyclodextrin is:
Carbazole sulfonamide derivative eutectic: lactose: beta-cyclodextrin=1:1 ~ 10:1 ~ 3.
9. an antitumour drug composition dispersible tablets, is characterized in that, containing pharmaceutical composition, tackiness agent, disintegrating agent and lubricant described in any one of claim 6 to 8.
10. antitumour drug composition dispersible tablets according to claim 9, is characterized in that, described binding agent is polyvinylpyrrolidone and/or hydroxypropylcellulose; Described disintegrating agent is selected from least one in crosslinked carboxymethyl fecula sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium; Described lubricant is Magnesium Stearate and/or micropowder silica gel.
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Cited By (3)
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| CN105949174A (en) * | 2016-05-16 | 2016-09-21 | 中国医学科学院医药生物技术研究所 | Carbazole sulfonamide derivatives or pharmaceutical salts thereof as well as preparation method and application of carbazole sulfonamide derivatives or pharmaceutical salts thereof |
| CN110467598A (en) * | 2018-05-11 | 2019-11-19 | 中国医学科学院医药生物技术研究所 | A kind of carbazole sulfonamide derivative prodrug or its officinal salt and its preparation method and application |
| WO2021034192A1 (en) * | 2019-08-19 | 2021-02-25 | Seranovo Holding B.V. | Pharmaceutical eutectic salt formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1807413B (en) * | 2005-09-28 | 2010-05-05 | 中国医学科学院医药生物技术研究所 | Carbazole sulfonamide derivative and its preparation method |
| CN102068415A (en) * | 2010-12-28 | 2011-05-25 | 山西普德药业股份有限公司 | Carbazole sulfonamide anti-tumor medicine dispersible tablets and preparation method thereof |
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| CN1807413B (en) * | 2005-09-28 | 2010-05-05 | 中国医学科学院医药生物技术研究所 | Carbazole sulfonamide derivative and its preparation method |
| CN102068415A (en) * | 2010-12-28 | 2011-05-25 | 山西普德药业股份有限公司 | Carbazole sulfonamide anti-tumor medicine dispersible tablets and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949174A (en) * | 2016-05-16 | 2016-09-21 | 中国医学科学院医药生物技术研究所 | Carbazole sulfonamide derivatives or pharmaceutical salts thereof as well as preparation method and application of carbazole sulfonamide derivatives or pharmaceutical salts thereof |
| CN105949174B (en) * | 2016-05-16 | 2018-12-21 | 中国医学科学院医药生物技术研究所 | Carbazole sulfonamide derivative or its pharmaceutical salts and its preparation method and application |
| CN110467598A (en) * | 2018-05-11 | 2019-11-19 | 中国医学科学院医药生物技术研究所 | A kind of carbazole sulfonamide derivative prodrug or its officinal salt and its preparation method and application |
| CN110467598B (en) * | 2018-05-11 | 2021-04-13 | 中国医学科学院医药生物技术研究所 | Carbazole sulfonamide derivative prodrug or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
| WO2021034192A1 (en) * | 2019-08-19 | 2021-02-25 | Seranovo Holding B.V. | Pharmaceutical eutectic salt formulation |
| NL2023661B1 (en) * | 2019-08-19 | 2021-04-21 | Seranovo Holding B V | Pharmaceutical Eutectic Salt Formulation |
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