WO2018153235A1 - 一种蓝萼甲素衍生物及其药学上可接受的盐或药物组合物及在制备治疗银屑病药物中的用途 - Google Patents
一种蓝萼甲素衍生物及其药学上可接受的盐或药物组合物及在制备治疗银屑病药物中的用途 Download PDFInfo
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- WO2018153235A1 WO2018153235A1 PCT/CN2018/075061 CN2018075061W WO2018153235A1 WO 2018153235 A1 WO2018153235 A1 WO 2018153235A1 CN 2018075061 W CN2018075061 W CN 2018075061W WO 2018153235 A1 WO2018153235 A1 WO 2018153235A1
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- derivative
- pharmaceutically acceptable
- pyridyl
- phenyl
- acceptable salt
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present application belongs to the field of chemical medicine, and relates to a scutellarin derivative and a pharmaceutically acceptable salt or pharmaceutical composition thereof and use thereof for preparing a medicament for treating psoriasis.
- Psoriasis is a common chronic, relapsing, inflammatory skin disease that seriously affects the quality of life of patients with psoriasis, cardiovascular disease, diabetes, hypertension, hyperlipidemia, obesity, intestinal infection, obstructive sleep
- diseases such as apnea, steatohepatitis and the mental agenda has increased.
- According to clinical manifestations can be divided into four types: psoriasis vulgaris, arthritic psoriasis, pustular psoriasis and erythrodermic psoriasis. More than 90% of patients are psoriasis vulgaris. The exact cause and pathogenesis of psoriasis remains unclear.
- Psoriasis affects 2-4% of the world's population, and clinical symptoms are thickened plaques that cause systemic pain, local dull pain, and itchy skin.
- the form of the rash can be a little bit like a drop, a coin, a map, a mixture, and the like.
- the quality of life of patients with psoriasis is lower than that of ordinary people, and their risk of concurrent multiple diseases will increase.
- psoriasis seriously harms the health of patients and it is very important to find effective drugs for treating psoriasis.
- drugs for treating psoriasis Due to the complexity of the mechanism of action, the long treatment period, and the course of the disease are often caused by environmental factors, most patients are difficult to adhere to drug treatment. Therefore, there is an urgent need to develop new therapeutic drugs with rapid curative effect, safe tolerance, small side effects, and strong patient compliance.
- CN104356090A discloses a thiazole derivative of scutellarin, a preparation method thereof and use thereof in anticancer action, but it is not disclosed as a medicament for treating psoriasis.
- CN104761460A and CN104887652A disclose a compound modified by a blue riminyl double bond, and also disclosed for its use in anti-tumor and anti-autoimmune diseases.
- CN1541643A discloses that scutellarin can treat autoimmune diseases, but scutellarin has poor water solubility and small polarity, and is not suitable for direct administration as a drug, and requires a large dose for a long time to produce a drug effect in the body; It has a short half-life and low bioavailability and cannot be used directly as a drug.
- CN104761460A and CN104887652A disclose a compound modified by a blue riminyl double bond.
- Studies have shown that although the problem of poor water solubility of scutellarin has been overcome to a certain extent, such scutellarin-derived compounds have poor general stability. It is easily hydrolyzed into alanine in aqueous solution and plasma to crystallize, which seriously affects its effectiveness and safety. It is also not suitable for direct use as an anti-psoriatic drug.
- the application provides a use of a scutellarin derivative, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for the preparation of a medicament for treating psoriasis, wherein the leucomycin derivative is represented by Formula I compound of:
- R 1 and R 2 are independently hydrogen, amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkene, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
- the scutellarin derivative described in the present application has enhanced water solubility and strong anti-psoriatic activity, avoiding the small polarity of the scutellarin and poor water solubility, and is not suitable for direct use.
- Drug administration, and scutellarin may require large doses in the body for a long time to produce a drug defect.
- R 1 and R 2 are independently hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-heptyl, n-octyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, n-hexyl, allyl, cyclohexyl, phenyl, benzyl, p-methoxyphenyl, methoxyphenyl, 4-chloro Phenyl, 3-chlorophenyl, o-chlorophenyl, N-3,4-dichlorophenyl, N-3,5-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4- Fluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl, 2-trifluoromethylphenyl,
- R 1 and R 2 are independently hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-heptyl, positive Octyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, n-hexyl, allyl, cyclohexyl, phenyl or benzyl.
- R 1 and R 2 are independently hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, allyl, cyclohexyl, phenyl Or benzyl.
- the scutellarin derivative is a combination having any one of the following formulas Ia to Ip or a combination of at least two:
- the pharmaceutically acceptable salt is an organic or inorganic acid salt of the cerulein derivative.
- the organic acid salt is selected from the group consisting of tartrate, stearate, oxalate, citrate, lactate, sorbate, fumarate, formate, acetate, benzoate Any one or at least two of a besylate, an ethanesulfonate, a resinate, a trifluoroacetate, a maleate, a methanesulfonate, a fumarate, an amino acid salt or a nicotinate Combination of species.
- the inorganic acid salt is selected from any one or at least two of iodate, phosphate, sulfate, hydroiodide, hydrobromide, nitrate, bromate or hydrochloride. combination.
- the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
- the pharmaceutical composition is in the form of an oral preparation, a parenteral preparation or an external preparation.
- the psoriasis is selected from psoriasis vulgaris, arthritic psoriasis, pustular psoriasis or erythrodermic psoriasis.
- the scutellarin derivative of the formula I can be easily obtained according to the existing preparation techniques, for example, according to the preparation method of the thiazolidine derivative of cyanidin disclosed in CN104356090A, by cyanosine. And the corresponding thiourea compound are prepared to obtain the scutellarin derivative of the formula I.
- the scutellarin derivative can be administered to a mammal, preferably a human, in need of treatment for psoriasis, administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or Pharmaceutical composition.
- alkyl refers to a hydrocarbon of the formula C n H 2n + 1, and the alkyl group may be linear or branched.
- C1-6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert Butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
- alkyl moiety i.e., alkyl
- an alkoxy group an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group
- alkyl i.e., alkyl
- alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom.
- alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl or 1,3-butadienyl, and the like.
- aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
- an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
- Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, and the like.
- treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
- pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
- a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
- the inorganic acid is selected from the group consisting of iodic acid, phosphoric acid, sulfuric acid, hydroiodic acid, hydrobromic acid, nitric acid, bromic acid or hydrochloric acid;
- the organic acid is selected from the group consisting of tartaric acid, stearic acid, oxalic acid, citric acid, lactic acid, and sorbitol.
- Acid fumaric acid, formic acid, acetic acid, benzoic acid, benzenesulfonic acid, ethanesulfonic acid, resinic acid, trifluoroacetic acid, maleic acid, methanesulfonic acid, fumaric acid, amino acid or nicotinic acid.
- pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
- the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
- pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
- compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
- suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
- Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
- the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
- the pharmaceutical composition is in the form of an oral formulation.
- the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
- Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
- compositions may also be in the form of a parenteral preparation such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
- the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
- the derivatives of the saponin and the pharmaceutically acceptable salts thereof and the pharmaceutical compositions of the present application have a strong activity of inhibiting the proliferation of human skin keratinocytes, i.e., have anti-psoriatic activity.
- the present application provides a scutellarin derivative, characterized in that the riminine derivative has the structure represented by the following formula I':
- R 1 and R 2 are independently amino, substituted or unsubstituted alkane, substituted or unsubstituted alkene, substituted or unsubstituted arene or substituted or unsubstituted heteroaryl.
- the scutellarin derivative or the scutellarin derivative of the present application has good water solubility after being salted, overcomes the problem of poorly water-soluble drug-forming property of scutellarin, and is found for the first time in the preparation of psoriasis for treatment.
- a scutellarin derivative obtained by di-substituting R 1 and R 2 on a nitrogen atom has superior psoriasis treatment than a mono- or unsubstituted sphingoid derivative on a nitrogen atom.
- the effect, pharmacological activity and safety are better.
- R 1 and R 2 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-heptyl, n-octyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, n-hexyl, allyl, cyclohexyl, phenyl or benzyl.
- the riminine derivative is any one of the following Formula If, Formula In, Formula Io, or Formula Ip:
- the present application provides a process for the preparation of a ruthenium derivative as described above, which is prepared by reacting 2-bromobluein with N,N-dialkylthiourea to obtain Formula I. 'Blue steroid derivative shown.
- reaction formula of the reaction is as follows:
- R 1 and R 2 are independently amino, substituted or unsubstituted alkane, substituted or unsubstituted alkene, substituted or unsubstituted arene or substituted or unsubstituted heteroaryl;
- said R 1 and R 2 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-heptyl, n-octyl, 2-pyridine Base, 3-pyridyl, 4-pyridyl, n-hexyl, allyl, cyclohexyl, phenyl or benzyl.
- R 1 and R 2 are independently methyl, ethyl, n-propyl or isopropyl.
- the rutin derivative and the pharmaceutically acceptable salt thereof and the pharmaceutical composition of the present invention can effectively inhibit the proliferation of keratinocytes, inhibit the keratinocyte inflammatory reaction caused by ⁇ -interferon, and can inhibit small The rat is acutely inflammatory and well tolerated.
- the derivatives of scutellarin and pharmaceutically acceptable salts thereof and pharmaceutical compositions of the present application are useful as anti-psoriatic drugs or prodrugs for the treatment of psoriasis.
- Figure 1 is a time-dose-dependent graph of the effect of the compound If hydrobromide (Compound 23) on the proliferation of human keratinocytes;
- FIG. 2 is a graph showing the inhibitory effect of the compound If hydrobromide (compound 23) on xylene-induced ear swelling in mice; wherein the abscissa represents a grouping, and the left-to-right group is a blank control group. , dexamethasone (30 mg/kg) group, compound 23 (10 mg/kg) group and compound 23 (50 mg/kg) group.
- N,N-Dimethylthiourea (12.66 mg, 0.12 mmol) was added to a solution of 2-bromo-blue succinone (50 mg, 0.12 mmol) in ethanol (4 ml). The reaction mixture was heated at reflux for 3 h. The temperature was slowly lowered, and a solid was precipitated, suction filtered, and dried to give a white solid powder 40.54 mg (Comp. 23), yield 67.91%. MS ESI-MS m/z 417 [H + ].
- N,N-Diethylthiourea (15.87 mg, 0.12 mmol) was added to a solution of 2-bromo-blue thiophene (50 mg, 0.12 mmol) in ethanol (4 ml). The reaction mixture was heated at reflux for 3 h. The temperature was slowly lowered, and a solid was precipitated, suction filtered, and dried to give a white solid powder, 38.23 mg, yield 60.62%. MS ESI-MS m/z 445 [H + ].
- N,N-Dipropylthiourea (19.23 mg, 0.12 mmol) was added to a solution of 2-bromo-blue sulphate (50 mg, 0.12 mmol) in ethanol (4 ml). The reaction mixture was heated at reflux for 3 h. The temperature was slowly lowered, and solid was precipitated, suction filtered, and dried to give a white solid powder (35.48 mg, yield 53.41%). MS ESI-MS m/z 473 [H + ].
- the effect of the scutellarin derivative of the present application or a pharmaceutically acceptable salt thereof on the proliferation of human keratinocytes was examined.
- the scutellarin derivative shown in Table 1 was used as a drug. The investigation was carried out as follows:
- the prepared cell suspension was taken, and the 96-well plate 3 plates were inoculated at 8000 cells/well and 150 ul/well, and cultured overnight at 37 ° C in a 5% CO 2 incubator. On the next day, 50 ul of different concentrations of the test solution were prepared for each well. Each concentration was set to 3 wells in parallel, and a vehicle control group (no drug), a cell control group (no drug, no solvent), and a blank medium control group (no cells, zero-hole) were set, and culture was continued for 48 hours. CCK-8 staining working solution was added, 110 ⁇ L/well, and incubation was continued for 1-4 h.
- the absorbance at 450 nm was measured on a Bio-Tek enzyme-linked immunosorbent assay. Results are the mean ⁇ standard deviation of parallel holes OD450nm Said.
- the original7.0 software was used for mapping and analysis. The OD value of each group of cells was plotted against the logarithmic concentration of the test drug to obtain a fitted curve, and the IC 50 value was obtained.
- IC 50 values in Table 1 that the scutellarin derivatives and their salts acted on human keratinocytes (HaCaT) for 48 h significantly affecting the growth and survival of cultured HaCaT keratinocytes within the tested concentration range. It is suggested that the scutellarin derivatives have a dose-dependent inhibitory effect on the proliferation of human epidermal keratinocytes.
- the IC 50 values of the compounds are shown in Table 1, and it can be seen that the leucomycin derivative (formula I) anti-psoriatic activity IC 50 were about 1 ⁇ 10 ⁇ M, less active dose.
- the structure of the compound 31 has a structure of
- CN1541643A discloses the king's date.
- the structure of the dimethylaminoblue hydrazone hydrochloride derivative (the compound disclosed in CN104761460A) in the compound 32 is
- the absorbance at 450 nm was measured on a Bio-Tek enzyme-linked immunosorbent assay. Results are the mean ⁇ standard deviation of parallel pores OD 450nm Said. Plot and analyze using Prism Graph software.
- the logarithmic concentration (LogC) of the test substance was plotted against the cell inhibition rate of each group to obtain a fitted curve, and the IC 50 value was obtained.
- Fig. 1 The results of the measurement of Compound 23 are shown in Fig. 1. The results showed that Compound 23 significantly affected the growth and survival of cultured HaCaT keratinocytes after treatment with human keratinocytes (HaCaT) for 24 h, 48 h and 72 h in the test concentration range. Compound 23 inhibited the proliferation of HaCaT cells in a dose-effect relationship and a time-effect relationship, suggesting that compound 23 has a dose-dependent inhibitory effect on the proliferation of human epidermal keratinocytes, and the inhibitory effect is prolonged with the drug action time. Enhanced. From Figure 1, it can be seen that the IC 50 values of Compound 23 for 24h, 48h and 72h are 1.935, 0.933 and 0.787 ⁇ M, respectively.
- mice were randomly divided into 4 groups, 5 in each group, which were blank control group, dexamethasone group 30 mg/kg group, compound 23 (10 mg/kg) group and compound 23 (50 mg/kg) group.
- Daily canned stomach administration of 0.25-0.3mL (according to body weight) the blank group was given the same volume of 5% glucose injection, continuous cans for 7 days, on the 8th day using xylene to mold the right ear of the mouse, each 15 ul xylene-induced inflammatory agents were applied to both sides of the right ear of the mouse. The left ear was not treated as a normal ear control. After 1 hour, the mice were sacrificed by cervical dislocation.
- the ears were cut along the baseline of the auricle, and the 8 mm diameter puncher was used in both ears.
- the ear pieces were taken out from the same part, and the weights of the left and right ears of each mouse were weighed on the electronic analysis scorpion.
- Fig. 2 is a graph showing the inhibition rate of compound 23 against xylene-induced ear swelling in mice. It can be seen from Fig. 2 that 10 mg/kg of compound 23 and 50 mg/kg of compound 23 are effective for inhibiting swelling of mouse ears. It is indicated that compound 23 has an acute anti-inflammatory effect. ‘
- the prepared 2 ⁇ 10 7 /mL cell suspension was added to a 5 ⁇ g/ ⁇ L ConA stock solution at a final concentration of 5 ⁇ g/mL, and a 96-well culture plate was inoculated at 0.1 mL/well. Add 0.1mL/well of different concentrations of test solution prepared. Each group was set up in parallel with 3 to 4 wells. At the same time, the vehicle control group (no drug), the stimulant control group (including ConA, no drug, no solvent), and the cell control group (excluding ConA, no drug and solvent) were set. , as well as a blank medium control group (no cells, zero holes). Set 37 °C, 5% CO 2 in culture 48h.
- the MTT solution was added at a concentration of 5 mg/mL, 20 ⁇ l/well, and culture was continued for 4 hours.
- the culture plate was taken out and centrifuged at 1000 rpm x 10 min.
- the supernatant of each well was aspirated, and 100 ⁇ L of SDS cell lysate was added to each well, and cultured overnight.
- the absorbance at 550 nm (OD 550 nm ) was measured on an enzyme-linked immunosorbent assay the next day.
- Results in the parallel hole OD 550nm mean ⁇ standard deviation Said.
- Statistical analysis of the mean was performed using SPSS 17.0 software, that is, the respective solvent groups were compared with the stimulant group, and each drug concentration test group was compared with the corresponding vehicle control group.
- the cell survival rate of each group was plotted against the concentration of the test drug, and the linear regression equation was obtained, and the statistical test of the correlation coefficient was performed to obtain the IC 50 value.
- Table 2 shows the results of the effect of compound 23 on the proliferation of mouse spleen lymphocytes induced by 5 ⁇ g/mL ConA after 48 h
- Table 3 shows the mouse spleen induced by 5 ⁇ g/mL ConA after 48 h of cyclosporin A treatment.
- Table 4 shows the results of the effect of triptolide on the proliferation of mouse spleen lymphocytes induced by 5 ⁇ g/mL ConA for 48 h, as can be seen from the data in Table 2-4:
- compound 23 had a significant effect on the proliferation of 5 ⁇ g/mL ConA-stimulated mouse spleen lymphocytes after 48h treatment, and its IC 50 value was about 9.41 ⁇ M.
- the reference drugs cyclosporine A and triptolide also showed varying degrees of inhibition at different concentrations tested.
- mice 40 BALB/c mice, half male and half female, were randomly divided into groups, and the weight of the individual should be within the range of ⁇ 20% of the average body weight. Animals should be acclimated to the environment for at least 5 days before the test, and healthy (female must be pregnant) mice were selected as test animals. The main inspection contents of the adaptation period: whether it is consistent with the quality indicators required at the time of ordering; general status check; whether the weight reaches the weight range required by the test. Unqualified abnormal animals are not included in this test. A single dose of the tail vein of the mice was injected at low, medium and high doses. According to the preliminary preparation of the blank preparation, the dose adjustment was 5 mg/kg, 10 mg/kg, 40 mg/kg, respectively. A control group was given, and an equal volume of vehicle was intravenously injected. .
- Observation methods include, but are not limited to, appearance signs, administration sites (with or without bleeding, redness, purpura, induration, suppuration, ulceration), coat, general behavior, mental state , glandular secretion, skin and mucous membrane color, respiratory state, fecal traits, genitals, death, etc. and other toxic symptoms; about 0 to 2 hours, 4 to 6 hours after each administration, each observation; if there are toxic symptoms Can increase the number of observations.
- mice showed no obvious side effects after a single intravenous injection of compound 23 (5 mg/kg, 10 mg/kg, 40 mg/kg), and no significant weight loss and decreased diet. After a single intravenous injection of Compound 24 (10 mg/kg), all animals died. It is indicated that compound 23 has better safety than compound 24.
- the present application illustrates the scutellarin derivative of the present application, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the use thereof in the preparation of a medicament for treating psoriasis, but the present application It is not limited to the above embodiments, that is, it does not mean that the present application must be implemented by relying on the above embodiments. It should be apparent to those skilled in the art that any modifications of the present application, equivalent substitution of the materials selected for the present application, and the addition of the auxiliary components, the selection of the specific manners, and the like, are all within the scope of the present application.
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Abstract
一种蓝萼甲素衍生物及其药学上可接受的盐或药物组合物及其在制备治疗银屑病的药物中的用途。
Description
本申请属于化学医药领域，涉及一种蓝萼甲素衍生物及其药学上可接受的盐或药物组合物及在制备治疗银屑病药物中的用途。
银屑病是一种常见的慢性、复发性、炎症性皮肤病，严重影响患者的生活质量，银屑病患者在心血管疾病、糖尿病、高血压、高血脂、肥胖、肠道感染、阻塞性睡眠呼吸暂停、脂肪性肝炎和精神议程等疾病的患病率增加。根据临床表现可以分为4种类型：寻常型银屑病、关节病型银屑病、脓疱型银屑病及红皮病型银屑病。其中90％以上患者为寻常型银屑病。银屑病的确切病因和发病机制尚不清楚。银屑病影响着世界2-4％的人口，临床症状表现为增厚性鳞屑斑，这些鳞屑斑会引起全身性疼痛、局部钝痛及皮肤瘙痒。皮疹形式可有点滴状、钱币状、地图状、混合状等多种类型。银屑病患者的生活质量要低于普通人，而且他们同时并发多种疾病的风险也会有所增加。
由此可见，银屑病严重危害患者的身体健康，寻找治疗银屑病的有效药物具有非常重要的意义。目前用于治疗银屑病的药物种类很多，由于其作用机制的复杂性，治疗周期长，病程常受环境因素诱发复发等因素，大部分患者难以坚持药物治疗。因此，迫切需要开发新的疗效快速、安全耐受、副作用小，病人依从性强的治疗药物。
CN104356090A公开了一种蓝萼甲素的噻唑衍生物及其制备方法和在抗癌作用中的用途，但未公开其可以作为治疗银屑病的药物。CN104761460A和CN104887652A公开了一种蓝萼甲素环外双键进行修饰的化合物，同时也公开了其在抗肿瘤和抗自身免疫疾病中的应用。CN1541643A公开了蓝萼甲素可以治疗自身免疫性疾病，但是蓝萼甲素水溶性差、极性小，不适合直接作为药物给药，在体内需要大剂量长时间才能产生药效；在体内消除快、半衰期短、生物利用度低，尚不能直接作为药物使用。
同时CN104761460A和CN104887652A公开的一种蓝萼甲素环外双键进行修饰的化合物，研究表明虽然一定程度克服了蓝萼甲素水溶性差的问题，但是此类蓝萼甲素衍生化合物，普遍稳定性差，在水溶液和血浆中极易水解成蓝萼甲素而结晶析出，严重影响其有效性和安全性，同样不适合直接作为抗银屑病药物使用。
发明内容
针对现有技术的不足，本申请的目的在于提供一种蓝萼甲素衍生物及其药学上可接受的 盐或药物组合物及在制备治疗银屑病药物中的用途。为达到此发明目的，本申请采用以下技术方案：
一方面，本申请提供一种蓝萼甲素衍生物或其药学上可接受的盐或药物组合物在制备治疗银屑病药物中的用途，所述蓝萼甲素衍生物为式I所示的化合物：
其中，R
1和R
2独立地为氢、氨基、取代或未取代的烷基、取代或未取代的烯烃基、取代或未取代的芳基或取代或未取代的杂芳基。
本申请所述的蓝萼甲素衍生物相对于蓝萼甲素，其水溶性增强，具有很强抗银屑病作用活性，避免了蓝萼甲素极性小，水溶性差，不适合直接作为药物给药，并且蓝萼甲素在体内可能需要大剂量、长时间才能产生药效的缺陷。在一些实施方案中，R
1和R
2独立地为氢、氨基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基、2-吡啶基、3-吡啶基、4-吡啶基、正己基、烯丙基、环己基、苯基、苄基、对甲氧基苯基、临甲氧基苯基、4-氯苯基、3-氯苯基、邻氯苯基、N-3，4-二氯苯基、N-3，5-二氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、2，4-二氟苯基、2，3，4-三氟苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-氯-5-三氟甲苯基、2-溴-5-三氟甲苯基、3，5-双(三氟甲基)苯基、2，4，6-三甲苯基、4-丙基苯基、N-对甲苯基、N-甲基-N-苯基、乙酰硫代氨基、N-乙酰基、1-萘基、2-苯乙基、3，5-二甲基1-吡唑基、2-异丙基苯基、3-氯-4-甲基苯基、2-氰基苯基、3-氰基苯基、4-氰基苯基、对异丙基苯基、2-甲氧基乙基、2-吗啉乙基、2-呋喃甲基、2，4，5-三苯基、2，4-二甲氧基苯基、3，4，5-三甲氧基苯基、吡啶-3-甲基、3-吗啉丙基、5-氟-2-甲基苯基、4-碘苯基、2-哌啶乙基、3-溴苯基、对甲氧基苄基、2，3-二氯苯基、4-三氟甲氧基苯基、对甲苄基、3-甲氧基苄基、4-苯氧基苯基、5-氯-2-甲基苯基、2-乙氧基苯基、4-羟基苯基、2，4-二甲氧基苯基、2-乙基苯基、4-乙基苯基、对-二甲氨基苯基、正癸基、2，6-二乙基苯基、4-溴苯基、2，4，6-三氯苯基、3-羟基苯基、3-甲氧基苯基、2，5-二氯苯基、2-溴苯基、2，6-二甲基苯基、5-氯-2-甲氧基苯基、2，6-二氯苯基、2，5-二甲氧基苯基、五氟苯基、4-乙氧基苯基、3-苯基丙基、2，5-二氟苯基、2-甲基-3-氯苯基、3，4-二甲基苯基、3-甲基苯基或2，5-二甲基苯基。
在一些优选实施方案中，R
1和R
2独立地为氢、氨基、甲基、乙基、正丙基、异丙基、正 丁基、叔丁基、异丁基、正庚基、正辛基、2-吡啶基、3-吡啶基、4-吡啶基、正己基、烯丙基、环己基、苯基或苄基。
在一些更优选实施方案中，R
1和R
2独立地为氢、氨基、甲基、乙基、正丙基、异丙基、正丁基、正己基、烯丙基、环己基、苯基或苄基。
作为本申请的优选实施方案，所述蓝萼甲素衍生物为具有如下式Ia～式Ip中的任意一种或至少两种的组合：
优选地，所述药学上可接受的盐为所述蓝萼甲素衍生物的有机酸盐或无机酸盐。
优选地，所述有机酸盐选自酒石酸盐、硬脂酸盐、草酸盐、枸橼酸盐、乳酸盐、山梨酸盐、延胡索酸盐、甲酸盐、乙酸盐、苯甲酸盐、苯磺酸盐、乙磺酸盐、树脂酸盐、三氟乙酸盐、马来酸盐、甲磺酸盐、富马酸盐、氨基酸盐或烟酸盐中的任意一种或至少两种的组合。
优选地，所述无机酸盐选自碘酸盐、磷酸盐、硫酸盐、氢碘酸盐、氢溴酸盐、硝酸盐、溴酸盐或盐酸盐中的任意一种或至少两种的组合。
优选地，所述药物组合物还包括药学上可接受的辅料。
优选地，所述药物组合物的剂型为口服制剂、肠胃外给药制剂或外用制剂。
在本申请中，所述银屑病选自寻常型银屑病、关节病型银屑病、脓疱型银屑病或红皮病型银屑病。在本申请中，式I所示蓝萼甲素衍生物可以根据现有的制备技术容易地获得，例如可以根据CN104356090A中公开的蓝萼甲素的噻唑衍生物的制备方法，通过蓝萼甲素和相应的硫脲类化合物制备得到式I所示蓝萼甲素衍生物。
在本申请中，所述蓝萼甲素衍生物可以施用于需要进行银屑病治疗的哺乳动物，优选人类，给予治疗有效量的式I所示的化合物或其药学上可接受的盐或其药物组合物。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“烷基”是指通式为C
nH
2n+1的烃基，该烷基可以是直链或支链的。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基或1，3-丁二烯基等。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1，2，3，4-四氢化萘等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等；所述无机酸选自碘酸、磷酸、硫酸、氢碘酸、氢溴酸、硝酸、溴酸或盐酸；所述有机酸选自酒石酸、硬脂酸、草酸、枸橼酸、乳酸、山梨酸、延胡索酸、甲酸、乙酸、苯甲酸、苯磺酸、乙磺酸、树脂酸、三氟乙酸、马来酸、甲磺酸、富马酸、氨基酸或烟酸。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服制剂形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可以为肠胃外给药制剂形式，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所 熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本申请所述蓝萼甲素的衍生物及其药学上可接受的盐以及药物组合物具有很强的抑制人皮肤角质形成细胞增殖的活性，即具有抗银屑病的活性。
另一方面，本申请提供一种蓝萼甲素衍生物，其特征在于，所述蓝萼甲素衍生物具有如下式I′所示结构：
其中R
1和R
2独立地为氨基、取代或未取代的烷烃基、取代或未取代的烯烃基、取代或未取代的芳烃基或取代或未取代的杂芳烃基。
本申请的蓝萼甲素衍生物或蓝萼甲素衍生物成盐后，水溶性好，克服了蓝萼甲素的水溶性差的成药性问题，并首次发现其在制备治疗银屑病中的良好作用；另一面，式I′所示蓝萼甲素衍生物，杂环侧链氮原子上双取代后，活性增强，安全性显著改善，克服了CN104356090A所报道化合物在本适应症(银屑病)用途中的不足，例如稳定性差，在水溶液和血浆中极易水解成蓝萼甲素而结晶析出，严重影响其有效性和安全性等问题。
在本申请中，在氮原子上进行了R
1和R
2双取代得到的蓝萼甲素衍生物具有比氮原子上单取代或未取代的蓝萼甲素衍生物更加优异的银屑病治疗效果，药理活性和安全性更佳。
在一些优选实施方案中，所述R
1和R
2独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基、2-吡啶基、3-吡啶基、4-吡啶基、正己基、烯丙基、环己基、苯基或苄基。
在一些优选实施方案中，所述蓝萼甲素衍生物为具有如下式If、式In、式Io或式Ip中的任意一种：
另一方面，本申请提供了如上所述的蓝萼甲素衍生物的制备方法，所述制备方法为：2-溴代蓝萼甲素与N，N-二烷基硫脲反应得到式I′所示蓝萼甲素衍生物。
在本申请中，所述反应的反应式如下：
其中R
1和R
2独立地为氨基、取代或未取代的烷烃基、取代或未取代的烯烃基、取代或未取代的芳烃基或取代或未取代的杂芳烃基；
优选地，所述R
1和R
2独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基、2-吡啶基、3-吡啶基、4-吡啶基、正己基、烯丙基、环己基、苯基或苄基。
更优选地，所述R
1和R
2独立地为甲基、乙基、正丙基或异丙基。
相对于现有技术，本申请具有以下有益效果：
本申请所述蓝萼甲素的衍生物及其药学上可接受的盐以及药物组合物可有效的抑制角质形成细胞的增生，抑制因γ-干扰素引起的角质形成细胞炎症反应，能够抑制小鼠急性炎症，并且安全耐受性良好。本申请的蓝萼甲素的衍生物及其药学上可接受的盐以及药物组合物可作为抗银屑病的药物或前药用于治疗银屑病。
本申请在氮原子上进行了R
1和R
2双取代得到的蓝萼甲素衍生物具有比氮原子上单取代或未取代的蓝萼甲素衍生物更加优异的银屑病治疗效果，药理活性和安全性更佳。
图1为式If化合物氢溴酸盐(化合物23)对人角质形成细胞增殖影响的时间剂量依赖曲线图；
图2为式If化合物氢溴酸盐(化合物23)对二甲苯所致的小鼠耳肿胀的抑制作用的结果图；其中，横坐标代表分组，从左至右的组别依次为空白对照组、地塞米松(30mg/kg)组、化合物23(10mg/kg)组和化合物23(50mg/kg)组。
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
实施例1(式If化合物氢溴酸盐的制备)
步骤1：2-溴代蓝萼甲素的制备
在室温下，向DMF(4ml)中的蓝萼甲素(100mg，0.30mmol)溶液中添加PyBr
3(96.22mg，0.30mmol)。将反应混合物在室温下搅拌5h，然后倾入水中，抽滤，干燥，得两种差向异构 体白色固体混合物106.33mg，收率86.1％。无须分离，直接投料下一步反应。MS ESI-MS m/z412[H
+]。
步骤2：式If化合物氢溴酸盐的制备
在室温下向乙醇(4ml)中的2-溴代蓝萼甲素(50mg，0.12mmol)溶液中加入N，N-二甲基硫脲(12.66mg，0.12mmol)。将反应混合物在回流下加热3h。缓慢降温，有固体析出，抽滤，干燥，得白色固体粉末40.54mg(化合物23)，收率67.91％。MS ESI-MS m/z417[H
+]。
实施例2(式In化合物氢溴酸盐的制备)
在室温下向乙醇(4ml)中的2-溴代蓝萼甲素(50mg，0.12mmol)溶液中加入N，N-二乙基硫脲(15.87mg，0.12mmol)。将反应混合物在回流下加热3h。缓慢降温，有固体析出，抽滤，干燥，得白色固体粉末38.23mg，收率60.62％。MS ESI-MS m/z445[H
+]。
实施例3(式Io化合物氢溴酸盐的制备)
在室温下向乙醇(4ml)中的2-溴代蓝萼甲素(50mg，0.12mmol)溶液中加入N，N-二丙基硫脲(19.23mg，0.12mmol)。将反应混合物在回流下加热3h。缓慢降温，有固体析出，抽滤，干燥，得白色固体粉末35.48mg，收率53.41％。MS ESI-MS m/z473[H
+]。
实施例4(式Ip化合物氢溴酸盐的制备)
在室温下向乙醇(4ml)中的2-溴代蓝萼甲素(50mg，0.12mmol)溶液中加入N，N-二异丙基硫脲(19.23mg，0.12mmol)。将反应混合物在回流下加热3h。缓慢降温，有固体析出，抽滤，干燥，得白色固体粉末30.17mg，收率45.41％。MS ESI-MS m/z473[H
+]。
实施例5
在本实施例中考察本申请的蓝萼甲素衍生物或其药学上可接受的盐对人角质形成细胞增殖的影响，本实施例中以表1所示的蓝萼甲素衍生物作为药物进行了考察，方法如下：
取预先制备好的细胞悬液，以8000个细胞/孔、150ul/孔接种96孔板3板，置37℃、5％CO
2培养箱中培养过夜。次日，每孔加配制好的不同浓度的受试药液50ul。各浓度设平行3孔，同时设溶媒对照组(无药)、细胞对照组(无药、无溶媒)、以及空白培养基对照组(无细胞，调零孔)，继续培养48h。加入CCK-8染色工作液，110μL/孔，继续培养1-4h。培养结束时在Bio-Tek酶联免疫检测仪上测定450nm处吸收值(OD450nm)。结果以平行孔OD450nm的均值±标准差
表示。采用origin7.0软件作图并分析。以各组细胞孔的OD值对受试药物对数浓度作图，得到拟合曲线，进而得出IC
50值。
由表1的IC
50值可以看出：在受试浓度范围内，蓝萼甲素衍生物及其盐类作用于人角质形成细胞(HaCaT)48h后明显影响培养的HaCaT角质形成细胞的生长存活，提示蓝萼甲素衍生物均对对人表皮角质形成细胞的增殖有明显的剂量依赖性抑制作用，在表1中示出了各化合物的IC
50值，可以看出蓝萼甲素衍生物(式I)的抗银屑病活性IC
50均在1～10μM左右，活性剂量较低。从表1数据可以看出，当式I中R
1和R
2均被取代后，化合物药理活性普遍增强(优于CN104356090A报道的氮原子上单取代或未取代的蓝萼甲素衍生物)，其中以化合物23的活性最佳。
表1
其中化合物31的蓝萼甲素的结构为
例如CN1541643A公开王枣子乙素。化合物32中二甲氨基蓝萼甲素盐酸盐衍生物(CN104761460A公开的)的结构为
实施例6
在本实施例中，考察蓝萼甲素的衍生物及其药学上可接受的盐对人角质形成细胞细胞增殖的抑制率与药物浓度的关系，以表1中化合物23作为示例性化合物，考察方法如下：
取预先制备好的细胞悬液，以8000个细胞/孔、150μl/孔接种96孔板3板，置37℃、5％CO
2培养箱中培养过夜。次日，每孔加配制好的不同浓度的受试药液50ul。各浓度设平行3孔，同时设溶媒对照组(无药)、细胞对照组(无药、无溶媒)、以及空白培养基对照组(无细胞，调零孔)，继续培养24h、48h和72小时。加入CCK-8染色工作液，110μL/孔，继续培养1-4h。培养结束时在Bio-Tek酶联免疫检测仪上测定450nm处吸收值(OD
450nm)。结果以平行孔OD
450nm的均值±标准差
表示。采用Prism Graph软件作图并分析。同时根据各药物浓度处理组的均值和溶媒对照组的均值求各组细胞抑制率，即细胞抑制率(％)＝[1-(药物处理组均值-空白对照组)/(溶媒对照组均值-空白对照组)]×100％。以各组细胞抑制率对受试物对数浓度(LogC)作图，得到拟合曲线，得出IC
50值。
化合物23的测定结果如图1所示，结果显示：在受试浓度范围内，化合物23作用人角质形成细胞(HaCaT)24h、48h和72h后明显影响培养的HaCaT角质形成细胞的生长存活。化 合物23对HaCaT细胞增殖的抑制具有量-效关系和时-效关系，提示化合物23对人表皮角质形成细胞的增殖有明显的剂量依赖性抑制作用，并且抑制作用随着药物作用时间的延长而增强。由图1可以得出化合物23作用24h、48h和72h的IC
50值分别为1.935、0.933和0.787μM。
实施例7
在本实施例中，考察蓝萼甲素的衍生物及其药学上可接受的盐对二甲苯所致的小鼠耳肿胀的抑制作用，以化合物23作为示例性药物，考察方法如下：
取20只小鼠，随机分组为4组，每组5只，分别为空白对照组、地塞米松组30mg/kg组、化合物23(10mg/kg)组和化合物23(50mg/kg)组。每日罐胃给药0.25-0.3mL(根据体重换算)，空白组给予同体积的5％葡萄糖注射液，连续罐胃7天，第8日采用二甲苯对小鼠右耳进行造模，各鼠右耳两面各涂15ul二甲苯致炎剂，左耳不作处理为正常耳对照，1小时后颈椎脱口处死小鼠，沿耳郭基线剪下两耳，用直径8mm打孔器分别在两耳的同一部位取下耳片，于电子分析天枰上分别称取各小鼠的左右耳重量。按以下公式计算耳廓肿胀率及耳廓肿胀抑制率。肿胀率(％)＝(致炎侧耳片重量一非致炎侧耳片重量)/非致炎侧耳片重量×100％；肿胀抑制率(％)＝(模型组平均肿胀度-给药组平均肿胀度)/模型组平均肿胀度×100％。
图2示出了化合物23对二甲苯所致的小鼠耳肿胀的抑制率结果，由图2可知，10mg/kg的化合物23和50mg/kg的化合物23均能有效的抑制小鼠耳肿胀，说明化合物23具有急性抗炎作用。′
实施例8
在本实施例中，考察蓝萼甲素的衍生物及其药学上可接受的盐对ConA诱导的小鼠脾淋巴细胞增殖的影响，以化合物23分别作为示例性药物，考察方法如下：
取制备好的2×10
7/mL细胞悬液，按终浓度为5μg/mL加入5μg/μL的ConA储存液，以0.1mL/孔接种96孔培养板。再加配制好的不同浓度的受试药液0.1mL/孔。各组设平行3～4孔，同时设溶媒对照组(无药)、刺激剂对照组(含ConA，不含药，不含溶媒)、细胞对照组(不含ConA，不含药物和溶媒)，以及空白培养基对照组(无细胞，调零孔)。置37℃，5％CO
2中培养48h。加浓度为5mg/mL的MTT液，20μl/孔，继续培养4h。培养板取出后离心，1000rpm×10min。吸除各孔上清，每孔加SDS细胞裂解液100μL，培养过夜。次日在酶联免疫检测仪上测定550nm处吸收值(OD
550nm)。结果以平行孔OD
550nm的均值±标准差
表示。用SPSS17.0软件作均数的统计学检验，即分别将各自溶媒组与刺激剂组比较，以及各药物浓度试验组与相应溶媒对照组比较。再根据药物处理组的均值与溶媒对照组的均值求各组细胞存活率，即细胞存活率(％)＝药物处理组均值/溶媒对照组均值×100％。以各组细胞存活率 对受试药物浓度作图，求直线回归方程，并做相关系数的统计学检验，求IC
50值。
表2示出了化合物23作用48h后对5μg/mL ConA诱导的小鼠脾淋巴细胞增殖的影响结果数据，表3示出了环孢素A作用48h后对5μg/mL ConA诱导的小鼠脾淋巴细胞增殖的影响结果数据，表4示出了雷公藤内酯醇作用48h后对5μg/mL ConA诱导的小鼠脾淋巴细胞增殖的影响结果数据，由表2-4的数据可以看出：在受试浓度范围内，化合物23作用48h后对5μg/mL ConA刺激的小鼠脾淋巴细胞增殖有明显影响，其IC
50值约为9.41μM。对照药环孢霉素A和雷公藤内酯醇在不同的受试浓度下也表现出不同程度的抑制作用。
表2
注：(1)与刺激剂对照组比较，
*：＜0.05；
**：＜0.01
(2)与溶媒组比较，
#：＜0.05；
##：＜0.01
表3
注：(1)与刺激剂对照组比较，
*：＜0.05；
**：＜0.01
(2)与溶媒组比较，
#：＜0.05；
##：＜0.01
表4
注：(1)与刺激剂对照组比较，
*：＜0.05；
**：＜0.01
(2)与溶媒组比较，
#：＜0.05；
##：＜0.01
实施例9
在本实施例中，对化合物23和化合物24的急性毒性进行考察，方法如下：
试验方法：
实验方法：采用BALB/c小鼠40只，雌雄各半，动物称重后随机分组，个体体重应在平均体重±20％范围内。试验前动物需先适应环境至少5天，选择健康(雌性须未孕)小鼠作为受试动物。适应期的主要检查内容：是否与订购时要求的质量指标一致；一般状态检查；体重是否达到试验要求的体重范围。不合格的异常动物不纳入本试验。小鼠尾静脉单次给药，注射低、中、高剂量，根据空白制剂预实验，剂量调整分别为5mg/kg、10mg/kg、40mg/kg，另设对照组，静脉注射等体积的溶媒。
观察方法：(1)一般状态观察：观察动物包括但不限于小鼠外观体征、给药部位(有无出血、红肿、瘀紫、硬结、化脓、溃烂)、被毛、一般行为活动、精神状态、腺体分泌、皮肤和粘膜颜色、呼吸状态、粪便性状、生殖器、死亡等情况及其它毒性症状；每次给药后约0～2小时、4～6小时各观察1次；若有毒性症状可增加观察次数。(2)大体解剖观察：于试验第8天将各组所有存活小鼠解刨观察，并对给药部位及大体解剖观察发现可能与供试品相关的异常脏器组织进行拍照记录。(3)濒死动物的处置：记录小鼠状态及观察时间，测定体重。(4)死亡动物的处置：记录小鼠死亡时间或发现死亡时间，测定体重后迅速解剖进行大体观察，并推测其死因。
实验结果：BALB/c小鼠单次静脉注射化合物23(5mg/kg、10mg/kg、40mg/kg)后未出现明显毒副作用，未见明显体重下降和饮食量下降趋势。单次静脉注射化合物24(10mg/kg)后，动物全部死亡。说明化合物23比化合物24具有更好的安全性。
申请人声明，本申请通过上述实施例来说明本申请的蓝萼甲素衍生物或其药学上可接受 的盐或药物组合物，以及它们在制备治疗银屑病药物中的用途，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请所选用原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。
Claims (15)
- 一种蓝萼甲素衍生物或其药学上可接受的盐或包含其或其药学上可接受的盐的药物组合物在制备治疗银屑病药物中的用途，其中，所述蓝萼甲素衍生物为式I所示的化合物：其中，R 1和R 2独立地为氢、氨基、取代或未取代的烷烃基、取代或未取代的烯烃基、取代或未取代的芳烃基或取代或未取代的杂芳烃基。
- 根据权利要求1所述的用途，其中，R 1和R 2独立地为氢、氨基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基、2-吡啶基、3-吡啶基、4-吡啶基、正己基、烯丙基、环己基、苯基、苄基、对甲氧基苯基、临甲氧基苯基、4-氯苯基、3-氯苯基、邻氯苯基、N-3，4-二氯苯基、N-3，5-二氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、2，4-二氟苯基、2，3，4-三氟苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-氯-5-三氟甲苯基、2-溴-5-三氟甲苯基、3，5-双(三氟甲基)苯基、2，4，6-三甲苯基、4-丙基苯基、N-对甲苯基、N-甲基-N-苯基、乙酰硫代氨基、N-乙酰基、1-萘基、2-苯乙基、3，5-二甲基1-吡唑基、2-异丙基苯基、3-氯-4-甲基苯基、2-氰基苯基、3-氰基苯基、4-氰基苯基、对异丙基苯基、2-甲氧基乙基、2-吗啉乙基、2-呋喃甲基、2，4，5-三苯基、2，4-二甲氧基苯基、3，4，5-三甲氧基苯基、吡啶-3-甲基、3-吗啉丙基、5-氟-2-甲基苯基、4-碘苯基、2-哌啶乙基、3-溴苯基、对甲氧基苄基、2，3-二氯苯基、4-三氟甲氧基苯基、对甲苄基、3-甲氧基苄基、4-苯氧基苯基、5-氯-2-甲基苯基、2-乙氧基苯基、4-羟基苯基、2，4-二甲氧基苯基、2-乙基苯基、4-乙基苯基、对-二甲氨基苯基、正癸基、2，6-二乙基苯基、4-溴苯基、2，4，6-三氯苯基、3-羟基苯基、3-甲氧基苯基、2，5-二氯苯基、2-溴苯基、2，6-二甲基苯基、5-氯-2-甲氧基苯基、2，6-二氯苯基、2，5-二甲氧基苯基、五氟苯基、4-乙氧基苯基、3-苯基丙基、2，5-二氟苯基、2-甲基-3-氯苯基、3，4-二甲基苯基、3-甲基苯基或2，5-二甲基苯基。
- 根据权利要求1所述的用途，其中，R 1和R 2独立地为氢、氨基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基、2-吡啶基、3-吡啶基、4-吡啶基、正己基、烯丙基、环己基、苯基或苄基。
- 根据权利要求1所述的用途，其中，R 1和R 2独立地为氢、氨基、甲基、乙基、正丙 基、异丙基、正丁基、正己基、烯丙基、环己基、苯基或苄基。
- 根据权利要求1-4任一项所述的用途，其中，所述蓝萼甲素衍生物为具有如下式Ia～式Ip中的任意一种或至少两种的组合：
- 根据权利要求1-5中任一项所述的用途，其中，所述药学上可接受的盐为所述蓝萼甲素衍生物的有机酸盐或无机酸盐；优选地，所述有机酸盐选自酒石酸盐、硬脂酸盐、草酸盐、枸橼酸盐、乳酸盐、山梨酸盐、延胡索酸盐、甲酸盐、乙酸盐、苯甲酸盐、苯磺酸盐、乙磺酸盐、树脂酸盐、三氟乙酸盐、马来酸盐、甲磺酸盐、富马酸盐、氨基酸盐或烟酸盐中的任意一种或至少两种的组合；优选地，所述无机酸盐选自碘酸盐、磷酸盐、硫酸盐、氢碘酸盐、氢溴酸盐、硝酸盐、 溴酸盐或盐酸盐中的任意一种或至少两种的组合。
- 根据权利要求1-6中任一项所述的用途，其中，所述药物组合物还包括药学上可接受的辅料；优选地，所述药物组合物的剂型为口服制剂、肠胃外给药制剂或外用制剂。
- 根据权利要求1-7中任一项所述的用途，其中，所述银屑病选自寻常型银屑病、关节病型银屑病、脓疱型银屑病或红皮病型银屑病。
- 一种蓝萼甲素衍生物，其具有如下式I′所示结构：其中R 1和R 2独立地为氨基、取代或未取代的烷烃基、取代或未取代的烯烃基、取代或未取代的芳烃基或取代或未取代的杂芳烃基。
- 根据权利要求9所述的蓝萼甲素衍生物，其中，所述R 1和R 2独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、正庚基、正辛基、2-吡啶基、3-吡啶基、4-吡啶基、正己基、烯丙基、环己基、苯基或苄基。
- 根据权利要求9所述的蓝萼甲素衍生物，其具有如下式If、式In、式Io或式Ip中的任意一种：
- 根据权利要求9-11任一项所述的蓝萼甲素衍生物的药学上可接受的盐，其特征在于，所述药学上可接受的盐为所述蓝萼甲素衍生物的有机酸盐或无机酸盐。
- 根据权利要求12所述的蓝萼甲素衍生物的药学上可接受的盐，其中，所述有机酸盐选自酒石酸盐、硬脂酸盐、草酸盐、枸橼酸盐、乳酸盐、山梨酸盐、延胡索酸盐、甲酸盐、乙酸盐、苯甲酸盐、苯磺酸盐、乙磺酸盐、树脂酸盐、三氟乙酸盐、马来酸盐、甲磺酸盐、富马酸盐、氨基酸盐或烟酸盐中的任意一种。
- 根据权利要求12所述的蓝萼甲素衍生物的药学上可接受的盐，其中，所述无机酸盐选自碘酸盐、磷酸盐、硫酸盐、氢碘酸盐、氢溴酸盐、硝酸盐、溴酸盐或盐酸盐中的任意一种。
- 根据权利要求9-11任一项所述的蓝萼甲素衍生物的制备方法，其包括：使2-溴代蓝萼甲素与N，N-二烷基硫脲反应，得到式I′所示蓝萼甲素衍生物。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP18758035.2A EP3586843B1 (en) | 2017-02-23 | 2018-02-02 | Glaucocalyxin a derivative, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof and uses thereof in treating psoriasis |
| CN201880009428.9A CN110248656B (zh) | 2017-02-23 | 2018-02-02 | 一种蓝萼甲素衍生物及其药学上可接受的盐或药物组合物及在制备治疗银屑病药物中的用途 |
| JP2019537224A JP6860677B2 (ja) | 2017-02-23 | 2018-02-02 | グローコカリキシンａ誘導体、その医薬的に許容できる塩または医薬組成物、およびこれらの乾癬治療用医薬の調製における使用 |
| US16/488,048 US11406622B2 (en) | 2017-02-23 | 2018-02-02 | Glaucocalyxin a derivative, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof and uses thereof in preparation of drugs for treating psoriasis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNPCT/CN2017/074538 | 2017-02-23 | ||
| CN2017074538 | 2017-02-23 |
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| WO2018153235A1 true WO2018153235A1 (zh) | 2018-08-30 |
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| PCT/CN2018/075061 WO2018153235A1 (zh) | 2017-02-23 | 2018-02-02 | 一种蓝萼甲素衍生物及其药学上可接受的盐或药物组合物及在制备治疗银屑病药物中的用途 |
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| Country | Link |
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| US (1) | US11406622B2 (zh) |
| EP (1) | EP3586843B1 (zh) |
| JP (1) | JP6860677B2 (zh) |
| CN (1) | CN110248656B (zh) |
| WO (1) | WO2018153235A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023202439A1 (zh) | 2022-04-22 | 2023-10-26 | 苏州沪云新药研发股份有限公司 | 二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113018250A (zh) * | 2021-02-25 | 2021-06-25 | 杭州泽宇生物技术有限公司 | 一种天然药物的外用制剂、制备方法及其应用 |
| CN115317477B (zh) * | 2022-04-26 | 2023-09-19 | 新乡医学院 | 研究蓝萼庚素对非酒精性脂肪肝的治疗作用和机制的方法 |
Citations (4)
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| CN1541643A (zh) | 2003-04-29 | 2004-11-03 | 宿州绿源中医药科技有限公司 | 王枣子乙素作为免疫抑制剂的应用 |
| CN104356090A (zh) | 2014-10-30 | 2015-02-18 | 新乡医学院 | 一种蓝萼甲素的噻唑衍生物及其制备方法和应用 |
| CN104761460A (zh) | 2015-03-26 | 2015-07-08 | 苏州沪云肿瘤研究中心股份有限公司 | 蓝萼甲素衍生物及其制备方法和应用 |
| CN104887652A (zh) | 2015-05-13 | 2015-09-09 | 苏州沪云肿瘤研究中心股份有限公司 | 蓝萼甲素衍生物及其药学上可接受的盐的剂型 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE337003T1 (de) | 2003-04-28 | 2006-09-15 | Biofrontera Bioscience Gmbh | Verwendung von riluzole kombiniert mit geeigneten hilfs-und zusatzstoffen zur behandlung von krankheiten, die durch eine hyperproliferation von keratinozyten gekennzeichnet sind, insbesondere neurodermitis und psoriasis |
| CN104817464B (zh) * | 2015-03-26 | 2017-12-15 | 苏州沪云肿瘤研究中心股份有限公司 | 二甲氨基蓝萼甲素盐酸盐晶型 |
| US10196344B2 (en) | 2015-03-26 | 2019-02-05 | Suzhou Pharmavan Cancer Research Center Co., Ltd. | Glaucocalyxin a derivative and preparation method and application thereof |
-
2018
- 2018-02-02 EP EP18758035.2A patent/EP3586843B1/en active Active
- 2018-02-02 JP JP2019537224A patent/JP6860677B2/ja active Active
- 2018-02-02 US US16/488,048 patent/US11406622B2/en active Active
- 2018-02-02 WO PCT/CN2018/075061 patent/WO2018153235A1/zh unknown
- 2018-02-02 CN CN201880009428.9A patent/CN110248656B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1541643A (zh) | 2003-04-29 | 2004-11-03 | 宿州绿源中医药科技有限公司 | 王枣子乙素作为免疫抑制剂的应用 |
| CN104356090A (zh) | 2014-10-30 | 2015-02-18 | 新乡医学院 | 一种蓝萼甲素的噻唑衍生物及其制备方法和应用 |
| CN104761460A (zh) | 2015-03-26 | 2015-07-08 | 苏州沪云肿瘤研究中心股份有限公司 | 蓝萼甲素衍生物及其制备方法和应用 |
| CN104887652A (zh) | 2015-05-13 | 2015-09-09 | 苏州沪云肿瘤研究中心股份有限公司 | 蓝萼甲素衍生物及其药学上可接受的盐的剂型 |
Non-Patent Citations (1)
| Title |
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| See also references of EP3586843A4 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023202439A1 (zh) | 2022-04-22 | 2023-10-26 | 苏州沪云新药研发股份有限公司 | 二萜化合物衍生物或其盐在制备防治特应性皮炎的药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3586843A1 (en) | 2020-01-01 |
| CN110248656A (zh) | 2019-09-17 |
| EP3586843B1 (en) | 2022-11-16 |
| EP3586843A4 (en) | 2020-08-26 |
| US11406622B2 (en) | 2022-08-09 |
| US20200061029A1 (en) | 2020-02-27 |
| JP2020503366A (ja) | 2020-01-30 |
| JP6860677B2 (ja) | 2021-04-21 |
| CN110248656B (zh) | 2022-05-24 |
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