CN108030923A - The pharmaceutical composition and its application of * containing diaza and carbazole compound - Google Patents

The pharmaceutical composition and its application of * containing diaza and carbazole compound Download PDF

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Publication number
CN108030923A
CN108030923A CN201711490266.9A CN201711490266A CN108030923A CN 108030923 A CN108030923 A CN 108030923A CN 201711490266 A CN201711490266 A CN 201711490266A CN 108030923 A CN108030923 A CN 108030923A
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Prior art keywords
pharmaceutical composition
formula
compound
filler
copolyvidone
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CN201711490266.9A
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Chinese (zh)
Inventor
许乐
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Nanjing Zhonghui Network Technology Co Ltd
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Nanjing Zhonghui Network Technology Co Ltd
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Priority to CN201711490266.9A priority Critical patent/CN108030923A/en
Publication of CN108030923A publication Critical patent/CN108030923A/en
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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to field of pharmaceutical preparations, and in particular to one kind contains diaza

Description

The pharmaceutical composition and its application of * containing diaza and carbazole compound
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to one kind contains diazaAnd the drug regimen of carbazole compound Thing, and application of the pharmaceutical composition containing the compound in antitumor drug is prepared.
Background technology
Indole amine 2,3-dioxygenase (IDO) is the limit that unique catalysis tryptophan is metabolized along kynurenine pathway beyond liver Fast enzyme, has been found and a variety of close phases of mankind's major disease such as tumour, alzheimer disease, depression and cataract of old people Close, and IDO must be expressed or the exception of activity increases, and be a key factor for causing above-mentioned disease, therefore, screening is efficient IDO inhibitor can provide effective medicine for these diseases.
In recent years, research confirms IDO in a variety of solid tumors in such as lung cancer, liver cancer, breast cancer, colon cancer tumor tissues Expression is remarkably reinforced, and closely related with prognosis.Therefore, using IDO inhibitor be likely to become it is a kind of treat tumour have efficacious prescriptions Method.
Compound of formula I is the IDO kinase inhibitors that this seminar finds, there is high suppression to live colon cancer cell Property, show potential potential applicability in clinical practice.For most medicines, oral formulations low production cost, and administering mode letter Just, not coup injury skin or mucous membrane, receive use easy to patient.However, when studying the oral drug preparation of the compound, It was found that its bioavilability is not high, and after the oral formulations tablet prepared is stored 3 months, the moisture absorption is serious, occur on tablet spot, Loose phenomenon, therefore, it is necessary to develop the oral formulations that compound of formula I is stable, bioavilability is high,
The content of the invention
It is an object of the present invention to provide a kind of pharmaceutical composition for containing compound shown in formula (I), the medicine group Compound has the stability that high bioavilability is become reconciled,
It is another object of the present invention to provide the preparation method containing the pharmaceutical composition of compound shown in formula (I).
It is yet a further object of the present invention to provide the pharmaceutical composition containing compound shown in formula (I) to prepare for controlling Purposes in the medicine for the treatment of and/or pre- preventing tumor.
For above-mentioned purpose, the present invention provides following technical scheme：
In a first aspect, the present invention provides a kind of pharmaceutical composition, by weight, compound 10- shown in formula (I) is included 20%, copolyvidone 5-20%, hydroxypropyl-β-cyclodextrin 25-50%, filler 10-55%, disintegrant 10-35%, lubricant 0.5-1.5%,
According to the present invention, described pharmaceutical composition, by weight, includes compound 15-20% shown in formula (I), copolymerization dimension Ketone 5-15%, hydroxypropyl-β-cyclodextrin 25-40%, filler 15-45%, disintegrant 10-35%, lubricant 0.5-1.5%； Preferably, described pharmaceutical composition, by weight, includes compound 15-20%, copolyvidone 5-8%, hydroxypropyl shown in formula (I) Group-beta-cyclodextrin 25-40%, filler 15-30%, disintegrant 10-35%, lubricant 0.5-1.0%.
According to the present invention, the one kind or more of the filler in lactose, microcrystalline cellulose, glucose, dextrin, starch Kind；Preferably, the filler is lactose.
According to the present invention, the disintegrant is in crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose One or more；Preferably, the disintegrant is crospovidone.
According to the present invention, one or more of the lubricant in magnesium stearate, talcum powder, superfine silica gel powder；It is preferred that Ground, the lubricant are magnesium stearate.
According to the present invention, the copolyvidone is selected from copolyvidone S630 and copolyvidone VA64.
In some preferred embodiments, pharmaceutical composition of the invention, by weight, includes chemical combination shown in formula (I) Thing 15-20%, copolyvidone 5-8%, hydroxypropyl-β-cyclodextrin 30-40%, lactose 15-30%, crospovidone 20-35%, Magnesium stearate 0.5-1.0%.
According to the present invention, described pharmaceutical composition is tablet.
Second aspect, the preparation method of pharmaceutical composition of the present invention, comprises the following steps：
Step 1：The compound of formula I, copolyvidone and hydroxypropyl-β-cyclodextrin of formula ratio are dissolved in 80-90 DEG C of hot water In；
Step 2：The filler of half formula ratio and the disintegrant of 1/3rd formula ratios are added, passes through wet granulation Particle is prepared into, is dried at 45-50 DEG C to particle moisture content and is no more than 8%；
Step 3：Step 2 gained particle is crushed, crosses 80 mesh sieves, adds the filler and disintegrant of formula surplus, mixing Uniformly, wet granulation, is dried, and is crushed, and crosses 80 mesh sieves；
Step 4：The mix lubricant of step 3 gained particle and formula ratio is uniform, and tabletting to obtain the final product.
The third aspect, the present invention provide pharmaceutical composition of the present invention containing compound shown in formula (I) and are used to control in preparation Purposes in the medicine for the treatment of and/or pre- preventing tumor.Contain formula (I) using the present invention including easily sending out crowd or tumor patient to tumour The pharmaceutical composition of shown compound, effectively to reduce Tumor incidence, extend tumor patient life.
Embodiment
Representational embodiment is in order to which the present invention is better described, not for the protection model of the limitation present invention below Enclose.
1 1- of embodiment (2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5,6-def] carbazole -6 (1H) -one - 10- yls) -3- (4- carbethoxyl groups) phenylurea
The synthesis of the bromo- 3- of step 1 2- ((3- oxocyclohex -1- alkene -1- bases) amino) methyl benzoate
3.58g 3- amino -2- methyl-bromobenzoates, 1.68g hexamethylene -1,3- diketone are weighed in reaction bulb, adds second Sour 20ml dissolvings, 80 DEG C of reaction 8h, after reaction, remove solvent under reduced pressure, column chromatography purifies to obtain title compound.
LC-MS m/z:[M+H] +=325.
The synthesis of step 2 4- oxo -2,3,4,9- tetrahydrochysene -1H- carbazole -5- carboxylate methyl esters
1.62g steps 1 gains, 0.23g acid chlorides, (o-tolyl) phosphines of 1.22g tri- and 0.63g triethylamines are weighed in close In tube sealing, acetonitrile 15ml is added, when the lower 100 DEG C of sealings reaction 20 of nitrogen atmosphere is small, after reaction, cooling, adds water 15ml Dilution, dichloromethane extraction (50ml*3), anhydrous sodium sulfate drying, column chromatography purify to obtain title compound.
LC-MS m/z:[M+H] +=244.
Step 3 2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd the synthesis of [3,4,5,6-def] carbazole -6 (1H) -one
0.73g steps 2 gains, 1.5ml acetic acid and 8.6ml hydrazine hydrates are weighed in reaction bulb, adds methanol 40ml, is returned When stream reaction 8 is small, filter while hot, water, ethyl acetate and dichloromethane washing, obtain title compound.
LC-MS m/z:[M+H]+=226.
Step 4 10- (2- t-butoxycarbonyl aminos) ethyl -2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5, 6-def] carbazole -6 (1H) -one
10g N- t-butoxycarbonyl aminos ethanol and 23.96g TsCl are weighed in reaction bulb, adds pyridine 50ml dissolvings, Room temperature reaction overnight, after reaction, removes pyridine under reduced pressure, adds water 20ml, ethyl acetate extraction (50ml*3), anhydrous magnesium sulfate Dry, column chromatography purifies (1- (tertbutyloxycarbonyl) amino) ethanol-(4- toluenesulfonic acids) ester.
0.67g steps 3 gains and 0.3gNaH are weighed in reaction bulb, adds 10ml DMF dissolvings, 45 DEG C of reaction 2h Afterwards, 2.81g gained (1- (tertbutyloxycarbonyl) amino) ethanol-(4- toluenesulfonic acids) esters are added, 16h are stirred at room temperature, reaction terminates Afterwards, water 10ml is added, ethyl acetate extraction, anhydrous magnesium sulfate drying, is filtered, column chromatography purifies to obtain title compound.
LC-MS m/z:[M+H]+=369.
Step 5 10- aminoethyl -2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5,6-def] carbazole -6 (1H) - The synthesis of ketone
1.0g step 4 gains are weighed in reaction bulb, dichloromethane 15ml dissolvings is added, lower addition 10ml is stirred at room temperature Trifluoroacetic acid, reacts 5h, after reaction, solvent is removed under reduced pressure, with saturated sodium bicarbonate aqueous solution to pH to 8, ethyl acetate Extraction, anhydrous magnesium sulfate drying, filtration drying obtain title compound.LC-MS m/z:[M+H]+=269.
The preparation of step 6 4-aminobenzoic acid ethyl ester
Measurement 10ml ethanol is in reaction bulb, addition 0.4g 3- aminobenzoic acids, after stirring and dissolving, is slowly added dropwise at 0 DEG C Thionyl chloride, drop finish, and are warmed to room temperature stirring reaction 8h, after reaction, remove solvent under reduced pressure, saturated sodium bicarbonate solution is adjusted PH to 7-8, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, is concentrated to give title compound, for casting One step.
Step 7 1- (2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5,6-def] carbazole -6 (1H) -one -10- Base) -3- (4- carbethoxyl groups) phenylurea synthesis
0.40g step 6 gains are weighed in reaction bulb, it is 1 to add 30ml volume ratios:1 dichloromethane/unsaturated carbonate hydrogen The mixed solvent of sodium water solution, 0 DEG C, stirring is lower adds 0.22g Triphosgenes, the reaction was continued at 0 DEG C 30min, after reaction, Liquid separation, collected organic layer, after dry, after adding the dissolving of 10ml dichloromethane, add 0.15g step 5 gains, continues at 0 DEG C 10h is stirred, after reaction, column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):7.88-7.86(m,2H),7.80-7.77(m,3H),7.59-7.57(m, 1H),7.54-7.53(m,1H),7.38(m,1H),7.24-7.21(m,2H),4.69-4.67(m,2H),4.30-4.29(m, 2H),3.65-3.63(m,2H),2.78-2.76(m,2H),2.10-2.08(m,2H),1.89-1.87(m,2H),1.31-1.29 (m,3H)。
LC-MS m/z:[M+H]+=460.
2 1- of embodiment (2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5,6-def] carbazole -6 (1H) -one - 10- yls) -3- (4- carbethoxyl groups) phenylurea citrate synthesis
1 compound of 1.0g embodiments is weighed in reaction bulb, the dissolving of 20ml chloroforms is added, adds 0.42g citric acids, room temperature 3h is stirred, solvent is removed under reduced pressure, obtains title compound.
3 1- of embodiment (2,3,5,10- tetrahydrochysenes-[1,2] diazaAnd [3,4,5,6-def] carbazole -6 (1H) -one - 10- yls) -3- (4- carbethoxyl groups) phenylurea citrate synthesis
1 compound of 1.0g embodiments is weighed in reaction bulb, the dissolving of 20ml chloroforms is added, adds 0.21g citric acids, room temperature 3h is stirred, solvent is removed under reduced pressure, obtains title compound.
4 pharmaceutical composition stability study of embodiment
1st, it is formulated
2nd, preparation process
Step 1：The compound of formula I, copolyvidone and hydroxypropyl-β-cyclodextrin of formula ratio are dissolved in 80-90 DEG C of hot water In；
Step 2：The filler of half formula ratio and the disintegrant of 1/3rd formula ratios are added, passes through wet granulation Particle is prepared into, is dried at 45-50 DEG C to particle moisture content and is no more than 8%；
Step 3：Step 2 gained particle is crushed, crosses 80 mesh sieves, adds the filler and disintegrant of formula surplus, mixing Uniformly, wet granulation, is dried, and is crushed, and crosses 80 mesh sieves；
Step 4：The mix lubricant of step 3 gained particle and formula ratio is uniform, and tabletting to obtain the final product.
Preparation A-E to be placed 10 days under the conditions of RH70%60 DEG C, HPLC checked for impurities contents, the results are shown in Table 1,
Table 1
Experiment shows that the pharmaceutical composition stability for adding copolyvidone and hydroxypropyl-β-cyclodextrin significantly improves.
5 dissolution study of experimental example
Dissolution rate, paddle method 50r/min, with phosphate buffer are measured according to four general rules 0931 of Chinese Pharmacopoeia 2015 edition (pH6.8) 900mL is dissolution medium, and 30min samplings detect, detection method：Octadecylsilane chemically bonded silica is filler, high Liquid phase method measure is imitated, the results are shown in Table 2.
Table 2
Preparation Preparation A Preparation B Formulation C Preparation D Preparation E Preparation F Preparation G
Active constituent content (%) 80.2 53.7 68.4 70.3 85.6 92.7 95.8
6 compound of formula I pharmaceutical composition of experimental example
1st, it is formulated
2nd, preparation process
With the technique of embodiment 4, tabletting 100.
7 compound of formula I pharmaceutical composition of experimental example
1st, it is formulated
2nd, preparation process
With the technique of embodiment 4, tabletting 100.
1 vitro enzyme activity rating of experimental example
Establish IDO1/2 inhibition of enzyme activity molecule screening models, detection positive control drug Epacadostat (INCB024360) suppression IC on this model50Value, the results showed that ICs of the Epacadostat to IDO150It is worth for a 90nM left sides The right side, to the IC of IDO250It is worth for 3.0uM or so, it is close with document report, illustrate that screening model is built successfully.Under room temperature environment, The L-Trp of the IDO enzymes of 40nM and 900uM are mixed, and add reaction buffer (20mM ascorbate, 3.5uM methylene blue and0.2mg/mL catalase in 50mM potassium phosphate buffer pH 6.5), when room temperature reaction 3 is small, ultraviolet determination, Detection wavelength 321nm are then carried out in microplate reader.Enzymatic activity percentage (%)=(OD value dosing holes-OD is worth background)/(OD value control wells-OD is worth background) × 100%, then use Prism GraphPad sofeware software the Fitting Calculations IC50Value, the results are shown in Table 3.
Table 3
Compound IDO1(nM) IDO2(uM)
Epacadostat 90 3.0
2 compound of embodiment 80 0.8
The compound that can be seen that the present invention from above experimental result there is preferable suppression to live IDO1 and IDO2 kinases Property.
The cell in vitro activity rating of 2 the compounds of this invention of experimental example
Using Sulforhodamine B (SRB) colorimetric method, the HT29 human colon cancer cells of exponential phase are blown and beaten into unicellular Suspension, is inoculated in 96 well culture plates (5x103 cells/wells), 200 μ L of culture medium is added per hole, in 37 DEG C, 5%CO2In incubator Overnight incubation；After cell attachment, it is further cultured in the incubator after adding the test-compound and positive control drug of debita spissitudo 72 it is small when.Add 10% trichloroacetic acid after fixed at 4 DEG C 1 it is small when.Washed 5 times with distilled water, after dry, it is micro- that 70 are added per hole SRB solution (4mg/mL) is risen, room temperature dyes 20 minutes, and 1% acetic acid washs 5 times, dry.100 μ L10mM Tris- are added per hole Base solution dissolves SRB.Microplate reader detects each hole OD values, and record by following equation as a result, calculate inhibiting rate：Inhibiting rate (%) =(OD controls-OD administrations)/OD controls × 100%, and calculate IC50.It the results are shown in Table 4.
Table 4
Compound HT29 cells IC50Value
Epacadostat 50.1
2 compound of embodiment 15.4
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair On the premise of bright spirit and scope various modifications and change can be carried out to the present invention.The interest field of the present invention is not limited to The detailed description made above, and claims should be belonged to.

Claims (10)

1. a kind of pharmaceutical composition, by weight, includes compound 10-20%, copolyvidone 5-20%, hydroxypropyl shown in formula (I) Group-beta-cyclodextrin 25-50%, filler 10-55%, disintegrant 10-35%, lubricant 0.5-1.5%,
2. pharmaceutical composition as claimed in claim 1, it is characterised in that：By weight, comprising compound 15- shown in formula (I) 20%, copolyvidone 5-15%, hydroxypropyl-β-cyclodextrin 25-40%, filler 15-45%, disintegrant 10-35%, lubricant 0.5-1.5%.
3. pharmaceutical composition as claimed in claim 1, it is characterised in that：By weight, comprising compound 15- shown in formula (I) 20%, copolyvidone 5-8%, hydroxypropyl-β-cyclodextrin 25-40%, filler 15-30%, disintegrant 10-35%, lubricant 0.5-1.0%.
4. such as any one of them pharmaceutical composition of claim 1-3, it is characterised in that：The filler is selected from lactose, micro- One or more in crystalline cellulose, glucose, dextrin, starch；Preferably, the filler is lactose..
5. such as any one of them pharmaceutical composition of claim 1-3, it is characterised in that：The disintegrant is selected from the poly- dimension of crosslinking One or more in ketone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose；Preferably, the disintegrant is the poly- dimension of crosslinking Ketone.
6. such as any one of them pharmaceutical composition of claim 1-3, it is characterised in that：The lubricant is selected from stearic acid One or more in magnesium, talcum powder, superfine silica gel powder；Preferably, the lubricant is magnesium stearate.
7. such as any one of them pharmaceutical composition of claim 1-3, it is characterised in that：The copolyvidone is selected from copolymerization and ties up Ketone S630 and copolyvidone VA64.
8. such as any one of them pharmaceutical composition of claim 1-3, it is characterised in that：By weight, comprising formula (I) Suo Shi Compound 15-20%, copolyvidone 5-8%, hydroxypropyl-β-cyclodextrin 30-40%, lactose 15-30%, crospovidone 20- 35%, magnesium stearate 0.5-1.0%.
9. the preparation method of pharmaceutical composition of the present invention, comprises the following steps：
Step 1：The compound of formula I, copolyvidone and hydroxypropyl-β-cyclodextrin of formula ratio are dissolved in 80-90 DEG C of hot water；
Step 2：The filler of half formula ratio and the disintegrant of 1/3rd formula ratios are added, is prepared by wet granulation Into particle, dried at 45-50 DEG C to particle moisture content and be no more than 8%；
Step 3：Step 2 gained particle is crushed, crosses 80 mesh sieves, adds the filler and disintegrant of formula surplus, is uniformly mixed, Wet granulation, is dried, and is crushed, and crosses 80 mesh sieves；
Step 4：The mix lubricant of step 3 gained particle and formula ratio is uniform, and tabletting to obtain the final product.
10. claim 1-3 any one of them pharmaceutical composition is in preparing for the medicine for the treatment of and/or pre- preventing tumor Using.
CN201711490266.9A 2017-12-30 2017-12-30 The pharmaceutical composition and its application of * containing diaza and carbazole compound Withdrawn CN108030923A (en)

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CN201711490266.9A CN108030923A (en) 2017-12-30 2017-12-30 The pharmaceutical composition and its application of * containing diaza and carbazole compound

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CN108030923A true CN108030923A (en) 2018-05-15

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