CN105418487B - Carbazole sulfonamide derivative eutectic and preparation method thereof - Google Patents
Carbazole sulfonamide derivative eutectic and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
This application discloses a kind of novel carbazole sulfamide derivative eutectics and preparation method thereof.The carbazole sulfonamide derivative eutectic is formed by oxalic acid, maleic acid, malonic acid or glutaric acid and carbazole sulfonamide derivative, with anti-micro-pipe effect, can significant antitumor activity, and have the advantages that synthesis is simple, toxic side effect is small, dissolution rate and solubility are high.
Description
Technical field
This application involves a kind of carbazole sulfonamide derivative eutectics, belong to chemical field.
Background technology
Antitubulin is a kind of effectively antitumor drug, with the extensive use of taxol clinically,
With the deep understanding of structure and function to micro-pipe, increasingly draw by the research and development of the antitumor drug of target spot of tubulin
The concern of whole world drugmaker is played.
Currently, taxol and vinca Antitubulin have been successfully applied to all kinds of tumours of clinical treatment, but its
As a kind of natural products of macromolecular, synthesis difficulty is big, and bioavilability is low, toxic side effect, in particular, multidrug resistant
Glycoprotein appearance, so that its therapeutic is received serious challenge.Therefore, synthesizing new, it is small point effective to all kinds of tumours
Sub- Antitubulin is necessary.
Chinese patent (Authorization Notice No. CN 1807413B) discloses a kind of carbazole sulfonamide derivative, is a new class of
Small molecule Antitubulin not only has anti-micro-pipe effect, also has significant antitumor activity, and have molecular weight
Small, synthesis is simple, and the small advantage of toxic side effect has a good application prospect.
Carbazole sulfonamide derivative has significant antitumor activity, but the compound is difficult to be dissolved in water, and dissolution rate is much
States Pharmacopoeia specifications requirement is not achieved.Medicament made of making has good dissolution rate, solubility, is a problem to be solved.
Invention content
According to the one side of the application, a kind of novel carbazole sulfamide derivative eutectic, the carbazole sulfonamide are provided
Derivative eutectic not only have anti-micro-pipe effect, can significant antitumor activity, and with molecular weight it is small, synthesis simply,
The advantage that toxic side effect is small, dissolution rate and solubility are high.
The carbazole sulfonamide derivative eutectic, which is characterized in that the carbazole sulfonamide derivative eutectic be by oxalic acid,
The eutectic that maleic acid, malonic acid or glutaric acid are formed with carbazole sulfonamide derivative；
The carbazole sulfonamide derivative is selected from least one of the compound with structural formula shown in Formulas I：
Wherein,
R1Represent hydrogen or R1Represent one or more nitros, amino, halogen, cyano, ester group, the amide for being connected to phenyl ring
Alkoxy that alkyl that base, hydroxyl, sulfydryl, carbon atom number are 1~6, carbon atom number are 1~6, aryloxy, carbon atom number 1
~6 alkylthio group, artyl sulfo；
R2It represents：The alkyl that hydrogen or carbon atom number are 1~6；
X is represented：SO2NR3Or NR3SO2, wherein R3It represents：It is taken shown in hydrogen, the alkyl that carbon atom number is 1~6 or Formula II
The acyl group in generation；
R in Formula II1It represents：Amine shown in the alkyl or formula III that carbon atom number is 1~6 replaces alkyl；
In formula III, n=1~6；R2、R3Respectively represent identical or different following group：Hydrogen, carbon atom number are 1~6
Alkyl, hydroxy alkyl, aminoalkyl；Or R2、R35~7 yuan of cyclic amine groups being joined together to form by nitrogen；
Ar is represented：Substituted phenyl, substituted pyridyl group, pyrimidine radicals, substituted pyrimidine radicals, thienyl, benzothienyl,
Benzothiazolyl, naphthalene or carbazyl；
The substituted-phenyl is the group that at least one hydrogen atom is substituted the replaced formation of base on phenyl；The substitution pyrrole
Piperidinyl is the group that at least one hydrogen atom is substituted the replaced formation of base on pyridyl group；The substituted pyrimidyl is on pyrimidine radicals
At least one hydrogen atom is substituted the group of the replaced formation of base；
The substituent group is selected from the alkyl that carbon atom number is 1~6, the alkoxy that carbon atom number is 1~6, carbon atom number 1
~6 alkylthio group, hydroxyl, sulfydryl, amino, amide groups, ester group, nitro, cyano or halogen；
The carbazole sulfonamide derivative does not include following compound：
9- ethyls-N- (4- methoxyphenyls)-carbazole -3- sulfonamide；
N- (4- methoxyphenyls) -9H- carbazole -3- sulfonamide；
9- ethyls-N- (4- chlorphenyls)-carbazole -3- sulfonamide；
N- (4- chlorphenyls) -9H- carbazole -3- sulfonamide；
N- (9- ethyl carbazoles -3- substitutions) -2,5- dichloro benzsulfamides；
- 2,4 dichloro benzsulfamide of N- (9- methyl carbazoles -3- substitutions)-N- methyl；
N- (9- ethyl carbazoles -3- substitutions) -2,5- dibromo benzsulfamides.
Preferably, the carbazole sulfonamide derivative is selected from：
9- ethyls-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide (hereinafter abbreviated as compound 1)；
9- methyl-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide (hereinafter abbreviated as compound 2)；
N- (2,4- Dimethoxyphenyls) -9- ethyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 3)；
N- (2,5- Dimethoxyphenyls) -9- ethyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 4)；
N- (3- chloro-4-methoxies phenyl) -9- ethyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 5)；
N- (the chloro- 2,4- Dimethoxyphenyls of 5-) -9- ethyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 6)；
N- (the chloro- 2,4- Dimethoxyphenyls of 5-) -9- methyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 7)；
N- (the chloro- 2,5- Dimethoxyphenyls of 4-) -9- ethyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 8)；
N- (the chloro- 2,5- Dimethoxyphenyls of 4-) -9- methyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 9)；
9- methyl-N- (2,4,6- trimethoxyphenyls)-carbazole -3- sulfonamide (hereinafter abbreviated as compound 10)；
9- ethyl -6- nitros-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide (hereinafter abbreviated as compounds
11)；
6- amino -9- ethyls-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide (hereinafter abbreviated as compounds
12)；
9- ethyls-N- (2- methoxypyridines -5- substitutions)-carbazole -3- sulfonamide (hereinafter abbreviated as compound 13)；
N- (2,6- dimethoxy-pyridines -3- substitutions) -9- ethyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 14)；
N- (2,6- dimethoxy-pyridines -3- substitutions) -9- methyl carbazole -3- sulfonamide (hereinafter abbreviated as compound 15)；
9- ethyls-N- (2- methoxypyridines -3- substitutions)-carbazole -3- sulfonamide (hereinafter abbreviated as compound 16)；
N- [(dimethylamino) acetyl group] -9- ethyls-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide is (following
It is abbreviated as compound 17)；Or
N- (2,6- dimethoxy-pyridines -3- substitutions)-N- [(dimethylamino) acetyl group] -9- methyl carbazole -3- sulfonamide
(hereinafter abbreviated as compound 18).
It is further preferred that the carbazole sulfonamide derivative is N- (2,6- dimethoxy-pyridine -3- substitutions) -9- methyl
Carbazole -3- sulfonamide, has the following structure formula：
According to the another aspect of the application, a kind of method preparing the carbazole sulfonamide derivative eutectic is provided, it is special
Sign is, by one kind in oxalic acid, maleic acid, malonic acid or glutaric acid with carbazole sulfonamide derivative according to molar ratio 1:2~
2:1 is dissolved in organic solvent, by evaporating solvent, obtains the carbazole sulfonamide derivative eutectic.Preferably, described organic
Solvent is ethyl alcohol and/or tetrahydrofuran.
According to the another aspect of the application, a kind of method preparing the carbazole sulfonamide derivative eutectic is provided, it is special
Sign is, by one kind in oxalic acid, maleic acid, malonic acid or glutaric acid with carbazole sulfonamide derivative according to molar ratio 1:2~
2:It is ground after 1 mixing, obtains the carbazole sulfonamide derivative eutectic.
According to the another aspect of the application, a kind of method preparing the carbazole sulfonamide derivative eutectic is provided, it is special
Sign is, by one kind in oxalic acid, maleic acid, malonic acid or glutaric acid with carbazole sulfonamide derivative according to molar ratio 1:2~
2:1 mixing, grinds after organic solvent then is added, obtains the carbazole sulfonamide derivative eutectic；
The addition of organic solvent described in process of lapping is：0.5~10mL organic solvents/mmol carbazole sulfonamides derive
Object.
Preferably, the organic solvent is ethyl alcohol and/or tetrahydrofuran.The addition of organic solvent is in process of lapping：
Per 1mmol carbazole sulfonamide derivatives, the organic solvent of 0.5~10mL is added.
According to the another aspect of the application, a kind of pharmaceutical composition is provided, which is characterized in that described pharmaceutical composition includes
Auxiliary material and carbazole sulfonamide derivative eutectic；The wherein described carbazole sulfonamide derivative eutectic is selected from any of the above-described carbazole sulfonamide
Derivative eutectic, at least one of the carbazole sulfonamide derivative eutectic being prepared according to any of the above-described method.
Preferably, the auxiliary material includes lactose and beta-cyclodextrin.It is further preferred that in described pharmaceutical composition, carbazole
The weight ratio of sulfamide 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 antineoplastic composition dispersible tablets are provided, which is characterized in that containing any of the above-described
Pharmaceutical composition, adhesive, disintegrant and lubricant.
Preferably, the binder is polyvinylpyrrolidone and/or hydroxypropyl cellulose；The disintegrant is selected from crosslinking
In sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium at least
It is a kind of；The lubricant is magnesium stearate and/or superfine silica gel powder.
Preferably, also contain corrigent in the antineoplastic composition dispersible tablets.It is further preferred that the corrigent is selected from
At least one of Icing Sugar, stevioside, Abbas's sweet tea.
In the application, " alkyl " refers to losing any one hydrogen atom on alkane compound molecule to be formed by group, institute
It includes linear paraffin, branched paraffin, cycloalkane, the cycloalkane with branch to state alkane compound.
The advantageous effect that the application can generate includes：
1) carbazole sulfonamide derivative eutectic provided herein, has the advantages that solubility is high.
2) preparation method provided herein is simple, environmental-friendly, is suitble to large-scale production.
3) pharmaceutical composition provided herein not only has anti-micro-pipe effect and significant antitumor activity, but also
The solubility of active component carbazole sulfonamide derivative eutectic in pharmaceutical composition is high.
4) dispersible tablet provided herein, good dispersion and have higher stability.On the one hand, when in dispersible tablet
When water soluble adjuvant dissolves, active component has very high dissolution rate；On the other hand, dispersible tablet is to high temperature, Qiang Guang, high humidity ring
Border has with higher tolerance, can stablize storage for a long time in high temperature, Qiang Guang, high humidity environment.
Specific implementation mode
The application is described in detail with reference to embodiment, but the application is not limited to these embodiments.
Carbazole sulfonamide derivative in the embodiment of the present application is according to the Chinese patent that Authorization Notice No. is CN 1807413B
Disclosed method synthesis.Unless otherwise instructed, other raw materials in embodiments herein are bought by commercial sources.
The device information used in embodiments herein is as follows：
Mixing and ball milling machine is German Lay relaxation MM400 types.
13C-NMR characterizations use the 600MHz DD2 types of Agilent companies.
Embodiment 1 evaporates solvent method and prepares carbazole sulfonamide derivative eutectic
0.1mmol active pharmaceutical ingredients compound 1,0.1mmol enclosed molecule glutaric acids are added to 10mL solvent tetrahydrochysene furans
In muttering.After being mixed 15 minutes, 30 minutes are stood, filtrate is packed into 25mL test tubes, hole is pricked after being sealed with preservative film by filtering,
It is placed at 25 DEG C and volatilizees naturally, the solidliquid mixture containing bulk crystals is obtained after 1 week, the solidliquid mixture of gained is filtered and is received
Collect bulk crystals, and dried 12 hours in 60 DEG C, obtained crystal is denoted as sample 1-1#。
Sample 1-2#~sample 1-21#Preparation manipulation and sample 1-1#It is identical, unlike raw material type, dosage and wave
Send out temperature, sample 1-1#~sample 1-21#Each substance classes, dosage and solvent volatilization temperature be shown in Table 1.
Table 1
2 mixed grinding method of embodiment prepares carbazole sulfonamide derivative eutectic
0.1mmol active pharmaceutical ingredients compound 1,0.1mmol enclosed molecules glutaric acid, 0.1mL ethyl alcohol are added to mixing
In ball mill.Ball milling 30 minutes at room temperature, after in 60 DEG C dry 12 hours.Obtained solid sample is denoted as sample 2-1#。
Sample 2-2#~sample 2-13#Preparation manipulation and sample 2-1#It is identical, the difference is that raw material type, dosage and ball
Grind temperature.Sample 2-1#~sample 2-13#Each substance classes, dosage and ball milling temperature be shown in Table 2.
0.1mmol compounds 10,0.1mmol glutaric acids are added in mixing and ball milling machine.Ball milling 30 minutes at room temperature,
Obtained solid sample is denoted as sample 2-14#。
Sample 2-15#~sample 2-25#Preparation manipulation and sample 2-14#It is identical, unlike raw material type, dosage and
Ball milling temperature.Sample 2-14#~sample 2-25#Each substance classes, dosage and ball milling temperature be shown in Table 2.
Table 2
Embodiment 313C-NMR crystal characterizations
Oxalic acid crystal, oxalic acid sodium crystal, malonic acid crystal, sodium malonate crystal, glutaric acid crystal, Sodium glutarate are taken respectively
Crystal, Malaysia acid crystal, sodium maleate crystal, pass through13C-NMR analyze organic acid therein-COOH and acylate-
COO-Chemical shift the results are shown in Table shown in 3 as benchmark.
Table 3
| Organic acid | The chemical shift of-COOH | -COO-Chemical shift |
| Oxalic acid | 162ppm | 175ppm |
| Malonic acid | 169ppm | 178ppm |
| Glutaric acid | 178ppm | 184ppm |
| Maleic acid | 167ppm | 172ppm |
The sample 1-1 that embodiment 1 is obtained#~sample 1-21#The sample 2-1 obtained with embodiment 2#~sample 2-25#Into
Row13C-NMR is analyzed, wherein the peak position near the chemical shift of carboxyl-COOH with the organic acid that is used in its respective sample
Unanimously, i.e., above-mentioned sample can detect carboxyl-COOH.Carboxylic acid is not detected with-COO in above-mentioned sample-Chemical shift peak.Explanation
Sample 1-1#~sample 1-21#Crystal and sample 2-1#~sample 2-25#Crystal in, organic acid and carbazole sulfonamide derive
Object not forming salt, therefore carbazole sulfonamide derivative in above-mentioned sample and organic acid are existed in the form of eutectic.
It is prepared by 4 tablet of embodiment
Tablet 1-1#Preparation：
By 50g samples 1-1#After being mixed with 150g beta-cyclodextrins after grinding, it is added 350g lactose powders.It added
Croscarmellose sodium 22g, the Aspartame 0.2g of 100 mesh sieve, and be uniformly mixed.5% polyvinylpyrrolidone is added
Softwood can be extremely made in aqueous solution, then is sieved and pelletized with 20 mesh, in 80 DEG C of dryings, 18 mesh sieves.The particle that will be obtained, adds micro mist
Silica gel 6g mixing, tabletting.It is made 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 is consistent, only respectively by sample 1-1#Change sample 1-2 into#~sample 1-21#With sample 2-1#~sample 2-25#。
It is prepared by 1 tablet of comparative example
Tablet D1#Preparation：
Prepare tablet D1#Operating process and tablet 1-1#Preparation process it is consistent, only by sample 1-1#Change compound into
15。
5 result of extraction of embodiment
To tablet 1-1#~tablet 1-21#, tablet 2-1#~tablet 2-25#With tablet D1#It is carried out at the same time dissolution rate and compares examination
It tests, according to method as defined in China's coastal port, in simulated gastric fluid (0.1mol/L hydrochloric acid solutions), test result is shown in Table
4：
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% |
| 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% |
6 stability of embodiment
Hot test
Take 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
It samples within 10th day, detects stability project, the results are shown in Table 5, show tablet 1-1#With good high-temperature stability.
Table 5
| Time | 0th day | 5th day | 10th day |
| Appearance | White tablets | White tablets | White tablets |
| Active constituents of medicine content | 100.5% | 100.3% | 100.2% |
| Dissolution rate | 96% | 95% | 95% |
Using same hot test method detection tablet 1-2#~tablet 1-21#With tablet 2-1#~tablet 2-25#, examination
Test result and tablet 1-1#Result it is similar, show good high-temperature stability.
High humility is tested
Take tablet 1-1#, it is placed in plate, is put in and fills KNO310 in the drying box of saturated solution (25 DEG C, RH 92.5%)
It, sampled respectively at the 0th day, the 5th day and the 10th day, detects stability project, the results are shown in Table 6, show tablet 1-1#With good
Good high humility stability.
Table 6
| Time | 0th day | 5th day | 10th day |
| Appearance | White tablets | White tablets | White tablets |
| Active constituents of medicine content | 100.5% | 100.3% | 100.1% |
| Dissolution rate | 96% | 95% | 95% |
Using same high humility test method detection tablet 1-2#~tablet 1-21#With tablet 2-1#~tablet 2-25#,
Test result and tablet 1-1#Result it is similar, show good high humility stability.
Strong illumination is tested
Take tablet 1-1#, be placed in plate, under conditions of illumination 4500Lx, place 10 days, respectively at the 0th day, the 5th day and
It samples within 10th day, detects stability project, the results are shown in Table 7, show tablet 1-1#With good strong illumination stability.
Table 7
| Time | 0th day | 5th day | 10th day |
| Appearance | White tablets | White tablets | White tablets |
| Active constituents of medicine content | 100.5% | 100.4% | 100.3% |
| Dissolution rate | 96% | 96% | 96% |
Using same high humility test method detection tablet 1-2#~tablet 1-21#With tablet 2-1#~tablet 2-25#,
Test result and tablet 1-1#Result it is similar, show good strong illumination stability.
The above is only several embodiments of the application, not does any type of limitation to the application, although this Shen
Please disclosed as above with preferred embodiment, however not to limit the application, any person skilled in the art is not taking off
In the range of technical scheme, makes a little variation using the technology contents of the disclosure above or modification is equal to
Case study on implementation is imitated, is belonged in technical proposal scope.
Claims (10)
1. a kind of carbazole sulfonamide derivative eutectic, which is characterized in that the carbazole sulfonamide derivative eutectic is by oxalic acid, horse
Carry out the eutectic that sour, malonic acid or glutaric acid are formed with carbazole sulfonamide derivative；Wherein, oxalic acid, maleic acid, malonic acid or penta 2
The molar ratio of acid and carbazole sulfonamide derivative is 1:2~2:1；
The carbazole sulfonamide derivative eutectic is used to prepare pharmaceutical composition；
The carbazole sulfonamide derivative is selected from least one of the compound with structural formula shown in Formulas I：
Wherein,
R1Represent hydrogen or R1Represent one or more nitros, amino, halogen, cyano, ester group, amide groups, the hydroxyl for being connected to phenyl ring
Alkoxy that alkyl that base, sulfydryl, carbon atom number are 1~6, carbon atom number are 1~6, aryloxy, carbon atom number are 1~6
Alkylthio group, artyl sulfo；
R2It represents：The alkyl that hydrogen or carbon atom number are 1~6；
X is represented：SO2NR3Or NR3SO2, wherein R3It represents：Replace shown in hydrogen, the alkyl that carbon atom number is 1~6 or Formula II
Acyl group；
R in Formula II1It represents：Amine shown in the alkyl or formula III that carbon atom number is 1~6 replaces alkyl；
In formula III, n=1~6；R2、R3Respectively represent identical or different following group：Hydrogen, carbon atom number be 1~6 alkyl,
Hydroxy alkyl, aminoalkyl；Or R2、R35~7 yuan of cyclic amine groups being joined together to form by nitrogen；
Ar is represented：Substituted phenyl, substituted pyridyl group, pyrimidine radicals, substituted pyrimidine radicals, thienyl, benzothienyl, benzo
Thiazolyl, naphthalene or carbazyl；
The substituted-phenyl is the group that at least one hydrogen atom is substituted the replaced formation of base on phenyl；The substituted pyridinyl
It is the group that at least one hydrogen atom is substituted the replaced formation of base on pyridyl group；The substituted pyrimidyl be on pyrimidine radicals at least
One hydrogen atom is substituted the group of the replaced formation of base；
It is 1~6 that the substituent group, which is selected from the alkyl that carbon atom number is 1~6, the alkoxy that carbon atom number is 1~6, carbon atom number,
Alkylthio group, hydroxyl, sulfydryl, amino, amide groups, ester group, nitro, cyano or halogen；
The carbazole sulfonamide derivative does not include following compound：
9- ethyls-N- (4- methoxyphenyls)-carbazole -3- sulfonamide；
N- (4- methoxyphenyls) -9H- carbazole -3- sulfonamide；
9- ethyls-N- (4- chlorphenyls)-carbazole -3- sulfonamide；
N- (4- chlorphenyls) -9H- carbazole -3- sulfonamide；
N- (9- ethyl carbazoles -3- substitutions) -2,5- dichloro benzsulfamides；
- 2,4 dichloro benzsulfamide of N- (9- methyl carbazoles -3- substitutions)-N- methyl；
N- (9- ethyl carbazoles -3- substitutions) -2,5- dibromo benzsulfamides.
2. carbazole sulfonamide derivative eutectic according to claim 1, which is characterized in that the carbazole sulfonamide derivative
It is selected from：
9- ethyls-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide；
9- methyl-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide；
N- (2,4- Dimethoxyphenyls) -9- ethyl carbazole -3- sulfonamide；
N- (2,5- Dimethoxyphenyls) -9- ethyl carbazole -3- sulfonamide；
N- (3- chloro-4-methoxies phenyl) -9- ethyl carbazole -3- sulfonamide；
N- (the chloro- 2,4- Dimethoxyphenyls of 5-) -9- ethyl carbazole -3- sulfonamide；
N- (the chloro- 2,4- Dimethoxyphenyls of 5-) -9- methyl carbazole -3- sulfonamide；
N- (the chloro- 2,5- Dimethoxyphenyls of 4-) -9- ethyl carbazole -3- sulfonamide；
N- (the chloro- 2,5- Dimethoxyphenyls of 4-) -9- methyl carbazole -3- sulfonamide；
9- methyl-N- (2,4,6- trimethoxyphenyls)-carbazole -3- sulfonamide；
9- ethyl -6- nitros-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide；
6- amino -9- ethyls-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide；
9- ethyls-N- (2- methoxypyridines -5- substitutions)-carbazole -3- sulfonamide；
N- (2,6- dimethoxy-pyridines -3- substitutions) -9- ethyl carbazole -3- sulfonamide；
N- (2,6- dimethoxy-pyridines -3- substitutions) -9- methyl carbazole -3- sulfonamide；
9- ethyls-N- (2- methoxypyridines -3- substitutions)-carbazole -3- sulfonamide；
N- [(dimethylamino) acetyl group] -9- ethyls-N- (3,4,5- trimethoxyphenyls)-carbazole -3- sulfonamide；Or
N- (2,6- dimethoxy-pyridines -3- substitutions)-N- [(dimethylamino) acetyl group] -9- methyl carbazole -3- sulfonamide.
3. the method for preparing carbazole sulfonamide derivative eutectic described in claims 1 or 2, which is characterized in that by oxalic acid, Malaysia
One kind in acid, malonic acid or glutaric acid is with carbazole sulfonamide derivative according to molar ratio 1:2~2:1 is dissolved in organic solvent
In, by evaporating solvent, obtain the carbazole sulfonamide derivative eutectic.
4. the method for preparing carbazole sulfonamide derivative eutectic described in claims 1 or 2, which is characterized in that by oxalic acid, Malaysia
One kind in acid, malonic acid or glutaric acid is with carbazole sulfonamide derivative according to molar ratio 1:2~2:It grinds, obtains after 1 mixing
The carbazole sulfonamide derivative eutectic.
5. the method for preparing carbazole sulfonamide derivative eutectic described in claims 1 or 2, which is characterized in that by oxalic acid, Malaysia
One kind in acid, malonic acid or glutaric acid is with carbazole sulfonamide derivative according to molar ratio 1:2~2:1 mixing, being then added has
It is ground after solvent, obtains the carbazole sulfonamide derivative eutectic；
The addition of organic solvent described in process of lapping is：0.5~10mL organic solvents/mmol carbazole sulfonamide derivatives.
6. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes auxiliary material and carbazole sulfonamide derivative eutectic；
The wherein described carbazole sulfonamide derivative eutectic in carbazole sulfonamide derivative eutectic as claimed in claim 1 or 2 extremely
Few one kind.
7. pharmaceutical composition according to claim 6, which is characterized in that the auxiliary material includes lactose and beta-cyclodextrin.
8. pharmaceutical composition according to claim 7, which is characterized in that in described pharmaceutical composition, carbazole sulfonamide spreads out
The weight ratio of biological eutectic, lactose and beta-cyclodextrin is：
Carbazole sulfonamide derivative eutectic：Lactose：Beta-cyclodextrin=1:1~10:1~3.
9. a kind of antineoplastic composition dispersible tablets, which is characterized in that containing claim 6 to 8 any one of them pharmaceutical composition,
Adhesive, disintegrant and lubricant.
10. antineoplastic composition dispersible tablets according to claim 9, which is characterized in that described adhesive is polyvinyl pyrrole
Alkanone and/or hydroxypropyl cellulose；The disintegrant is selected from crosslinked carboxymethyl fecula sodium, low-substituted hydroxypropyl cellulose, crosslinking
At least one of polyvinylpyrrolidone, croscarmellose sodium；The lubricant is magnesium stearate and/or micro mist silicon
Glue.
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| 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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| 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 |
Non-Patent Citations (1)
| Title |
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| "The role of cocrystals in pharmaceutical science";Ning Shan等;《Drug Discovery Today》;20080531;第13卷(第9-10期);第440-446页 * |
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