CN117164588A - Quinoline alkaloid, pharmaceutical composition thereof, preparation method and application thereof - Google Patents
Quinoline alkaloid, pharmaceutical composition thereof, preparation method and application thereof Download PDFInfo
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- CN117164588A CN117164588A CN202311130085.0A CN202311130085A CN117164588A CN 117164588 A CN117164588 A CN 117164588A CN 202311130085 A CN202311130085 A CN 202311130085A CN 117164588 A CN117164588 A CN 117164588A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 title claims description 23
- 206010003658 Atrial Fibrillation Diseases 0.000 claims abstract description 27
- 102000004257 Potassium Channel Human genes 0.000 claims abstract description 22
- 108020001213 potassium channel Proteins 0.000 claims abstract description 22
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides 2 quinoline alkaloids 1-2 with novel framework types of 6/6/11/6 ring systems, a pharmaceutical composition and a preparation method thereofMethods and applications, which belong to the technical fields of phytochemistry and pharmacy. The compound 1-2 provided by the invention is K with remarkable activity v 1.5 Potassium ion channel inhibitors useful in the preparation of Potassium ion channel K v 1.5 inhibitors for the preparation of a medicament for the treatment or prophylaxis of cardiovascular, central nervous system or tumor diseases such as atrial fibrillation, cardiac arrhythmias, pulmonary hypertension, parkinson's disease, tumors, epilepsy, etc.
Description
Technical field:
the invention belongs to the technical field of phytochemistry and pharmacy, and particularly relates to quinoline alkaloid 1-2 with a novel framework type, pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and a preparation method of the compound and the pharmaceutical composition thereof V The application of the potassium ion channel inhibitor of type 1.5 in preparing medicaments for treating or preventing cardiovascular diseases, central nervous system diseases or tumor diseases such as atrial fibrillation, arrhythmia, pulmonary hypertension, parkinsonism, tumors, epilepsy and the like.
The background technology is as follows:
atrial fibrillation is one of the most common cardiac arrhythmias in clinic, the prevalence rate of atrial fibrillation in China is about 0.7%, the higher the age is, the higher the prevalence rate of people over 65 years old is increased to 4%, the prevalence rate of people over 20% in all senile cerebral apoplexy patients is the main cause of cardiac cerebral apoplexy, patients and cardiovascular and cerebrovascular doctors are always plagued, the clinical serious medical requirements are not satisfied, and the related medicine development still has a large space. An important mechanism for the development of atrial fibrillation is atrial electrical remodeling characterized by a significant reduction in atrial Effective Refractory Period (ERP) and action potential time course (APD), accompanied by an increase in atrial conduction. Drugs with atrial selectivity are ideal drugs for the treatment of atrial fibrillation.
K v 1.5 potassium ion channel, a subtype of voltage-gated potassium ion channel, is abundantly expressed in the atria, mediates delayed rectifier (IKur) current in ultrafast human cells of the heart, whereas IKur has been shown to be selectively involved in atrial repolarization in cardiac tissue, so kv1.5 potassium ion channel is a very promising target for the treatment of atrial fibrillation (Atrial Fibrillation, AF). Inhibition of the kv1.5 potassium ion channel results in an increase in atrial action potential duration, thereby increasing the refractory period of atrial fibrillation. Although Kv1.5 ionChannels are expressed in various tissues of the human body, but their functional expression in atrial rather than ventricular muscles of the heart makes them a promising and safe target for the treatment of atrial fibrillation.
Currently, commonly used therapeutic agents for atrial fibrillation are class I antiarrhythmic agents, such as propafenone, flecainide, and class III antiarrhythmic agents, such as amiodarone. These drugs can also affect ventricular excitation and repolarization while prolonging action potential and atrial repolarization. Research shows that K v 1.5 channel protein is specifically expressed in human atrial myocytes, which is an atrial myocyte overspeed delay rectifier potassium current (ultra-rapid delayed rectifier potassium current, I) Kur ) The current participates in the repolarization process of action potential without being found to play a role in the ventricular muscle repolarization process. K (K) v The specific expression of the 1.5 channel protein in the atrial muscle makes it a hotspot for the study of new atrial fibrillation therapeutics. K when atrial fibrillation occurs v 1.5 expression of the channel protein is significantly compensatory down-regulated, thus inhibiting K v The 1.5 channel can effectively prolong the effective refractory period and action potential duration of heart tissue, thereby relieving and treating atrial fibrillation, and the inhibitor can be used as an alternative novel medicament for treating atrial fibrillation.
In addition to atrial fibrillation, K v Mutations in the 1.5 channel gene can also lead to various diseases such as pulmonary hypertension. In astrocyte K v 1.5 is closely related to the Src family of protein tyrosine kinases responsible for astrocyte proliferation and K in bladder, skin, ovarian and lymph node cancers v 1.5 are highly expressed in these tumor cells. In addition, the voltage-gated potassium channel Kv1.5 is widely distributed in tissues and organs such as heart, brain, liver, kidney and the like, and has close connection with cardiovascular and central nervous system or tumor diseases such as atrial fibrillation, arrhythmia, pulmonary hypertension, parkinsonism, tumors, epilepsy and the like.
To date, the structure of quinoline alkaloid 1-2 with a novel framework of 6/6/11/6 of the invention is not reported in the prior art, and pharmacological effects thereof are not reported.
The invention comprises the following steps:
the invention aims at: provides 2 quinoline alkaloids 1-2 with novel frameworks of 6/6/11/6 spiro systems, pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and a preparation method of the compounds and the pharmaceutical composition thereof V The application of the calcium ion channel inhibitor of type 1.5 in preparing medicaments for treating or preventing cardiovascular diseases, central nervous system diseases or tumor diseases such as atrial fibrillation, arrhythmia, pulmonary hypertension, parkinsonism, tumors, epilepsy and the like.
The above object of the present invention is achieved by the following technical solutions:
quinoline alkaloid 1-2 with 6/6/11/6 skeleton shown in the following structural formula and medicinal salt thereof,
the pharmaceutically acceptable salts of the compounds 1-2 refer to pharmaceutically acceptable salts, and include salts formed with organic acids or inorganic acids, wherein the organic acids are tartaric acid, maleic acid, succinic acid, citric acid and the like, and the inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like.
The invention also provides application of the quinoline alkaloid compound and analogues or pharmaceutically acceptable salts thereof in preparing medicaments for treating or preventing cardiovascular, central nervous system or tumor diseases such as atrial fibrillation, arrhythmia, parkinsonism, tumors, epilepsy and the like, and preparing potassium ion channel K v 1.5 use of inhibitors.
The invention provides a method for preparing quinoline alkaloid compounds, which comprises the steps of taking 100 kg of dry uncaria stems and branches with hooks, crushing, extracting with 50% industrial ethanol/water under reflux for three times, merging the extracting solutions, concentrating under reduced pressure to obtain a total extract, suspending the total extract with sulfuric acid solution with pH value of 1-3, extracting with ethyl acetate for three times, removing most of non-alkali components, regulating the pH value of the acid aqueous solution left after extraction to 9-10 with 5% NaOH solution, and then extracting with chloroform for three times to obtain 80 g of total alkaloid extractMixing the total alkaloid extract with C18CE filler, and separating by reversed phase C18CE column chromatography (50% methanol water-100% methanol water) to obtain 1.1-1.8. Wherein the 65% methanol water eluted component 1.6 is eluted by petroleum ether-ethyl acetate system, and petroleum ether is used for: ethyl acetate = 2: eluting with 1 to obtain component 1.6.7, subjecting component 1.6.7 to high performance liquid chromatography (Waters C18-X-bridge column, 3mL/min,35% acetonitrile/water) to obtain compound 1 (t) R =16.2 min) and compound 2 (t R ＝18.6min)。
The invention also provides a pharmaceutical composition comprising any one or any combination of quinoline alkaloid compounds 1-2 of the 6/6/11/6 ring system, and at least one pharmaceutically acceptable carrier.
The invention further provides application of the pharmaceutical composition in preparing medicines for treating or preventing atrial fibrillation and arrhythmia or medicines for reducing pulmonary arterial hypertension. And application of the pharmaceutical composition in preparing medicines for treating epilepsy and preparing potassium ion channel K v 1.5 use of inhibitors.
The invention also provides a preparation method of the pharmaceutical composition, wherein the compound 1-2 is prepared by the method for preparing the compound 1-2, and then a pharmaceutically acceptable carrier is added.
Quinoline alkaloids are derived from the biogenic pathway either from the anthranilic acid pathway or from the rearrangement of tryptophan or indole alkaloids. The invention carries out systematic research on quinoline alkaloid components in uncaria of Rubiaceae, and obtains two novel quinoline alkaloids with 6/6/11/6 ring systems by utilizing various separation and purification means including methods such as normal phase silica gel column chromatography, reverse phase medium pressure or high pressure liquid chromatography and the like. The alkaloid obtained by separation is subjected to ion channel inhibition activity screening, and the compounds 1-2 are found to be in potassium ion channel K v 1.5 has very good inhibitory activity and very good selectivity, is a potassium channel-inhibiting compound of vegetable origin, and can be used for preparing K v Type 1.5 potassium ion channel inhibitors.
The quinoline alkaloid compounds of the 6/6/11/6 ring system of the present invention and pharmaceutical compositions thereof may be in any suitable form, such as solid, semi-solid, liquid or aerosol forms. In general, the medicament contains a compound or extract of the invention as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral administration. The active ingredients may be compounded, for example, with conventional nontoxic pharmaceutically acceptable carriers and/or excipients, into tablets, pills, capsules and the like, and other suitable forms of use. Pharmaceutically acceptable carriers for use in the compositions include, for example, water, dextrose, lactose, acacia, and the like, and other carriers suitable for use in preparing solid, semi-solid, liquid, or aerosol forms of formulations. The composition may additionally contain stabilizers, thickeners, and/or colorants and fragrances.
The quinoline alkaloid compounds of the 6/6/11/6 ring system and pharmaceutically acceptable salts or other forms thereof can be orally or not administered, the dosage varies according to the medicines, and 1-100mg per day is suitable for adults.
For oral administration, the compound is first mixed with conventional pharmaceutically acceptable adjuvants such as excipients, disintegrants, binders, lubricants, antioxidants, coating agents, colorants, fragrances, surfactants, etc., and administered in the form of granules, capsules, tablets, etc.: the parenteral administration may be in the form of an injection, an infusion or a suppository. In preparing the above formulations, conventional formulation techniques may be used.
Compared with the prior art, the invention has the following advantages:
1. the invention provides a new quinoline alkaloid compound 1-2 with a 6/6/11/6 ring system, which has very strong innovation in the brand new chemical structure type and fills the blank of the prior art.
2. Compound 1-2 of the invention and a positive control drug DPO-1 are directed against K v 1.5 comparison of inhibition Activity of Potassium ion channel experiments while Compound 1-2 acts on a portion of the ion channel of myocardial expression at 25. Mu.M, the results show that Compound 1-2 selectively inhibits K v 1.5 potassium ion channels. Further studies showed that compounds 1-2 inhibited K in a concentration dependent manner v 1.5 IC thereof 50 The values and Hill coefficient were 13.85.+ -. 0.67. Mu.M and 8.87.+ -. 1.06. Mu.M, respectively. The inhibition of compounds 1 and 2 was more clearly reflected by the current-voltage relationship of the channel made by whole cell recordings. Thus, compounds 1 and 2 act as K v 1.5 and has a certain selectivity for part of the ion channels of the myocardial expression, can become a therapeutic K v 1.5 lead compounds for related diseases such as atrial fibrillation.
3. The invention also provides the application of the novel quinoline alkaloid 1-2 of the 6/6/11/6 ring system or the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparing medicaments for treating or preventing atrial fibrillation, arrhythmia, pulmonary hypertension, parkinsonism, tumors and epilepsy, and preparing potassium ion channel K v 1.5 use of inhibitors.
Description of the drawings:
FIG. 1 is a schematic structural diagram of quinoline alkaloid compounds 1-2 of the present invention;
FIG. 2 is a schematic diagram of the single crystal X-ray diffraction structure of quinoline alkaloid compound 1 of the present invention;
FIG. 3 is a flow chart of the extraction and separation of the present invention;
FIG. 4 shows the electrophysiological effects of compounds 1 and 2 on the Kv1.5 channel. (A) Compounds 1 and 2 vs K v Dose-response curve for inhibition of peak current of 1.5. The data were fitted using Hill equation and the points represent the mean ± SD (n=4-6). (B) Representative whole cell K triggered by depolarization of 1.25s by +50mV in the absence (control) and in the presence of different concentrations of Compounds 1 and 2 and DPO-1 (positive control) v 1.5 current. Steady state activation and deactivation curves for (C, E) control (black) and 15 μm compound 1 or 12.5 μm compound 2 (red) and flush (blue). The data is fitted to the boltzmann equation. Data are expressed as mean ± standard deviation (n=4-6). (D, F) scatter plots show steady-state inactivation of V of the Kv1.5 channel under control (black), 15. Mu.M Compound 1 or 12.5. Mu.M Compound 2 (red) and rinse (blue) conditions 1/2 Deactivation.
The specific embodiment is as follows:
the following describes the embodiments of the present invention with reference to the drawings, but is not limited thereto. Modifications of the invention in accordance with the essence of the invention are within the scope of the invention.
Example 1:
preparation and structural identification of quinoline alkaloid compounds 1-2:
the separation flow is as follows: taking 100 kg of dry uncaria stems and branches, carrying out reflux extraction on the crushed dry uncaria stems and branches with 50% industrial ethanol/water for three times, combining the extracting solutions, concentrating under reduced pressure to obtain a total extract, suspending the total extract with sulfuric acid solution with pH=1-3, extracting for three times with ethyl acetate, removing most of non-alkali components, regulating the pH of the residual acid aqueous solution after extraction to 9-10 with 5% NaOH solution, fully extracting for three times with chloroform to obtain 80 g of total alkaloid extract, stirring the total alkaloid extract with C18CE filler, and carrying out segmentation by using reversed-phase C18CE column chromatography (50% methanol water-100% methanol water) to obtain 1.1-1.8. Eluting 65% methanol water eluted component 1.6 with petroleum ether-ethyl acetate system, eluting with petroleum ether:ethyl acetate=2:1 to obtain component 1.6.7, subjecting component 1.6.7 to high performance liquid chromatography (Waters C18-X-bridge column, 3mL/min,35% acetonitrile/water) to obtain compound 1 (t) R =16.2 min) and compound 2 (t R ＝18.6min)。
The structure of compound 1-2 was determined by nuclear magnetic data (Table-1), high resolution mass spectrometry (HRESIMS), calculation of circular dichroism (ECD), ultraviolet (UV) spectra, and other spectroscopic data. Finally, the absolute configuration of compound 1 was verified by single crystal X-ray diffraction analysis (fig. 2).
And (3) structural identification: the molecular structural formulas (1) to (2) of the compounds correspond to the compounds 1 to 2 respectively:
compound 1, white needle-like crystals; mp 258-260 ℃;MeOH)；UV(MeOH)λ max (logε):207(2.81),252(2.18),283(1.58)nm；ECD(MeOH)λ(Δε):213(–16.33),239(+4.48),261(–2.51),288(+1.49)nm；IR(KBr)ν max 3384,3226,2931,2870,2798,1713,1620,1471,1383,1326,1174,749cm -1 ； 1 H and 13 c NMR data, see Table 1; positive HRESIMS m/z 354.2174[ M+H ]] + (calcd for C 21 H 28 O 2 N 3 ,354.2182).
Compound 2, colorless oily compound:UV(MeOH)λ max (logε):207(2.68),251(2.07),284(1.44)nm；ECD(MeOH)λ(Δε):212(+1.91),233(+10.04),257(–7.37),285(–3.23)nm；IR(KBr)ν max 3250,2925,2873,2812,1714,1676,1619,1471,1339,1214,1183,759,680,628cm -1 ； 1 H and 13 c NMR data, see Table 1; positive HRESIMS m/z 354.2170[ M+H ]] + (calcd for C 21 H 28 O 2 N 3 ,354.2182).
TABLE 1 Nuclear magnetic data of Compounds 1-2 in deuterated chloroform
The frequency of the recording nuclear magnetism is: hydrogen spectrum 600 mhz and carbon spectrum 150 mhz.
"m" means multiple peaks or overlapping peak shapes.
Example 2:
quinoline alkaloid compounds 1-2 pairs of K V The experimental method and the results of the inhibition activity of the type 1.5 potassium ion channel are as follows:
1. cell preparation and expression.
Human Embryonic Kidney (HEK) 293T cells were cultured in DMEM (Gbico) medium supplemented with 10% calf serum (VivaCell) and 1% penicillin-streptomycin diab (VivaCell). Cultured HEK293T cells were treated with Lipofectamine 3000 (Invitrogen) transfection reagent (Amersham pharmacia Biotech) pCDNA3.1-K v 1.5 and pCDNA3.1-EGFP plasmids were transiently transfected. Success ofTransfected Human Embryonic Kidney (HEK) 293T cells were used within 48 hours.
2. Electrophysiology experiments.
All electrophysiological recording experiments were performed at room temperature (about 24 ℃). The borosilicate glass is used for preparing a microelectrode (Sutter Instruments), a microelectrode drawing instrument (P-1000,Sutter Instrument) is used for drawing, the microelectrode with impedance of 2-4 MΩ is prepared through heating and polishing, and a patch clamp amplifier is used for whole-cell current recording. During a time interval of 7 seconds, a clamp potential (HP) of-80 mV depolarizes by 1.25s+50mV, and the current in the process is recorded. The current is amplified and data converted by an amplifier (SUTTER IPA-2, USA). The current was passed through a low energy filter at 5kHz and then sampled at 50 kHz. Data acquisition and analysis was done with the SutterPatch software. Extracellular solution component (in mM): 140NaCl,5KCl,1MgCl 2 ,2CaCl 2 10Glucose and 10HEPES (ph=7.4, adjusted with NaOH). Intra-electrode solution composition (in mM): 130KCl,1MgCl 2 ,5Na 2 ATP,10HEPES and 5EGTA (ph=7.4, adjusted with KOH).
3. Data analysis and statistics
Both data collection and statistical analysis were done using Graphpad 8.0. IC (integrated circuit) 50 The values and the hill coefficients are according to the hill equation y=i Min +(I Max -I Min )/[1+10(LogIC 50 -C)×Hillslope]Calculated from the collected data. Here IC 50 Is the concentration at half maximum current inhibition, C is the concentration of the compound, I Min Is the minimum inhibition rate, I Max Is the maximum inhibition rate and Hillslope is the hill coefficient. All data are mean ± standard error. Both data collection and statistical analysis were done using Graphpad 8.0. IC (integrated circuit) 50 The values and the hill coefficients are according to the hill equation y=i Min +(I Max I Min )/[1+10(LogIC 50 -C)×Hillslope]Calculated from the collected data. Here IC 50 Is the concentration at half maximum current inhibition, C is the concentration of the compound, I Min Is the minimum inhibition rate, I Max Is the maximum inhibition rate and Hillslope is the hill coefficient. All data are mean ± standard error.
4. Compound 1-2 and positive control DPO-1 are directed against K v 1.5 comparison of inhibition Activity of Potassium ion channel (Table 2), while Compounds 1-2 act on a portion of the ion channel expressed by the myocardium at 25. Mu.M, the results show that both Compounds 1 and 2 can selectively inhibit K v 1.5 potassium ion channels (FIG. 4). Further studies showed that compound 1 inhibited K in a concentration dependent manner v 1.5 IC thereof 50 IC with a value of 13.85+ -0.67 μM, compound 2 50 The value was 8.87.+ -. 1.06. Mu.M. The inhibition of compound 1 was more clearly reflected by the current-voltage relationship of the channel made by whole cell recordings (fig. 4).
5、K v 1.5 Potassium ion channel is an ultrafast delay rectifier Potassium Current I kur Is specifically expressed in atrial myocytes but hardly expressed in ventricular myocytes, and plays a key role in atrial fibrillation electrokinetic reconstruction. K when atrial fibrillation occurs v 1.5 significant compensatory downregulation of channel protein expression, inhibition of K v The 1.5 channel enables an atrial Effective Refractory Period (ERP) and an action potential time course (APD) to be effectively prolonged, thereby alleviating and treating atrial fibrillation. Thus, compounds 1 and 2 act as K v 1.5 and has a certain selectivity for part of ion channels of myocardial expression, is expected to become a therapeutic K v 1.5 lead compounds for related diseases such as atrial fibrillation.
TABLE 2 Compounds 1-2 and DPO-1 vs. K v 1.5 dose-Effect data
Compound 1-2 and positive control DPO-1 act on K at different concentrations v 1.5, the effect of compound on its peak current was recorded, compound 1, compound 2 and the positive control all showed different degrees of inhibition. Wherein, the IC of DPO-1 50 IC for Compound 1 with a value of 203.3+ -7.67 nM 50 IC with a value of 13.85.+ -. 0.67. Mu.M for Compound 2 50 The value was 8.87.+ -. 1.06. Mu.M.
Formulation examples
In the following formulation examples, conventional reagents are selected and formulation preparation is performed according to the conventional methods, and this application example only embodies that at least one of the compounds 1 to 2 of the present invention can be prepared into different formulations, and specific reagents and operations are not specifically limited:
1. one or a combination of the compounds 1-2 or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) is dissolved by a small amount of DMSO, and then water for injection is added according to the conventional method, fine filtration, encapsulation and sterilization are carried out to prepare injection, and the concentration of the injection is 0.5-10 mg/mL.
2. Dissolving one or a combination of the compounds 1-2 or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) in a small amount of DMSO, dissolving in sterile water for injection, stirring to dissolve, filtering by using a sterile suction filter funnel, performing sterile fine filtration, subpackaging in an ampoule, and performing sterile sealing after low-temperature freeze drying to obtain the powder injection.
3. One or a combination of the compounds 1-2 or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) is added with excipient according to the weight ratio of the excipient to the excipient of 9:1 to prepare powder.
4. One or a combination of the compounds 1-2 or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) is added with excipient according to the weight ratio of 5:1, and the mixture is granulated and tabletted.
5. One or a combination of the compounds 1-2 or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) is prepared into oral liquid according to the conventional oral liquid preparation method.
6. One or a combination of the compounds 1-2, or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like), is added with excipient according to the weight ratio of 5:1, and is prepared into capsules.
7. One or a combination of the compounds 1-2 or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) is added with excipient according to the weight ratio of 5:1 to prepare the granule.
8. Taking any one of the compounds 1-2, or a combination thereof, or preparing salt by using organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like), adding water for injection according to the conventional method, finely filtering, filling and sterilizing to prepare injection.
9. Taking any one of the compounds 1-2, or a combination thereof, or a salt prepared by utilizing organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like), dissolving the salt in sterile water for injection, stirring to dissolve the salt, filtering the solution by using a sterile suction filter funnel, performing sterile fine filtration, sub-packaging the solution in ampoule bottles, and performing sterile fusion sealing after low-temperature freeze drying to obtain the powder injection.
10. Taking compound 1-2 or any one of them, or preparing salt with organic acid (tartaric acid, maleic acid, succinic acid, citric acid, etc.) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), adding excipient at a weight ratio of 9:1, and making into powder.
11. Taking any one of the compounds 1-2 or the combination thereof, or preparing salt by using organic acid (tartaric acid, maleic acid, succinic acid, citric acid and the like) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like), adding excipient according to the weight ratio of the excipient to the excipient of 1:5-1:10, granulating and tabletting.
12. Taking any one of the compounds 1-2, or their combination, or using salt prepared from organic acid (tartaric acid, maleic acid, succinic acid, citric acid, etc.) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), and making into oral liquid according to conventional oral liquid preparation method.
13. Taking any one of the compounds 1-2, or their combination, or preparing into salt with organic acid (tartaric acid, maleic acid, succinic acid, citric acid, etc.) or inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), adding excipient at a weight ratio of 5:1, and making into capsule, granule or granule.
The above examples of formulation are only for illustrating possible embodiments of the present invention, and not for limiting the use of the present invention, and various changes and modifications can be made by one skilled in the relevant art without departing from the spirit and scope of the present invention, so that all equivalent technical solutions are also within the scope of the present invention, and the scope of the present invention should not be limited to the description of the text.
Claims (10)
1. Quinoline alkaloid 1-2 with novel 6/6/11/6 ring system skeleton shown in the following structural formula or pharmaceutically acceptable salt thereof,
2. the quinoline alkaloid 1-2 with the 6/6/11/6 skeleton or the pharmaceutically-acceptable salt thereof according to claim 1, wherein the pharmaceutically-acceptable salt is pharmaceutically-acceptable salt, and comprises salt formed by quinoline alkaloid 1-2 with the 6/6/11/6 skeleton and organic acid or inorganic acid, wherein the organic acid is tartaric acid, maleic acid, succinic acid and citric acid, and the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
3. Use of quinoline alkaloid 1-2 of 6/6/11/6 skeleton or its pharmaceutically acceptable salt in the manufacture of a medicament for the treatment or prophylaxis of atrial fibrillation, cardiac arrhythmia, pulmonary hypertension, parkinson's disease, tumour, epilepsy.
4. Preparation of the quinoline alkaloid 1-2 of 6/6/11/6 skeleton or its pharmaceutically-acceptable salt in the preparation of potassium ion channel K v 1.5 use of inhibitors.
5. The preparation method of quinoline alkaloid 1-2 with 6/6/11/6 skeleton as defined in claim 1, wherein the method comprises the following steps: pulverizing ramulus Uncariae cum Uncis with ramulus Uncariae cum Uncis, reflux-extracting with 50% industrial ethanol/water for three times, mixing extractive solutions, concentrating under reduced pressure to obtain total extract, suspending the total extract with sulfuric acid solution with pH=1-3, extracting with ethyl acetate for three times, removing most of non-alkali components, regulating pH of the rest acid aqueous solution after extraction with 5% NaOH solution to 9-10, extracting with chloroform for three times to obtain total alkaloid extract, mixing the total alkaloid extract with C18CE filler, separating with reversed phase C18CE column chromatography and 50% methanol water-100% methanol water to obtain 1.1-1.8; eluting 65% methanol water eluted component 1.6 with petroleum ether-ethyl acetate system, eluting with petroleum ether:ethyl acetate=2:1 to obtain component 1.6.7, subjecting component 1.6.7 to high performance liquid chromatography, waters C18-X-bridge column, 3mL/min, and 35% acetonitrile/water to obtain compound 1 and compound 2.
6. Potassium ion channel K v 1.5 inhibitors comprising quinoline alkaloid 1-2 of the 6/6/11/6 backbone of claim 1 or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising one or a combination of quinoline alkaloids 1-2 of the 6/6/11/6 backbone of claim 1, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.
8. The use of the pharmaceutical composition of claim 7 for the preparation of a medicament for the treatment or prevention of atrial fibrillation, cardiac arrhythmia, pulmonary hypertension, parkinson's disease, tumor, epilepsy.
9. The pharmaceutical composition of claim 7 for preparing potassium channel K v 1.5 use of inhibitors.
10. A process for the preparation of a pharmaceutical composition according to claim 7, characterized in that it comprises the following steps: pulverizing ramulus Uncariae cum Uncis with ramulus Uncariae cum Uncis, reflux-extracting with 50% industrial ethanol/water for three times, mixing extractive solutions, concentrating under reduced pressure to obtain total extract, suspending the total extract with sulfuric acid solution with pH=1-3, extracting with ethyl acetate for three times, removing most of non-alkali components, regulating pH of the rest acid aqueous solution after extraction with 5% NaOH solution to 9-10, extracting with chloroform for three times to obtain total alkaloid extract, mixing the total alkaloid extract with C18CE filler, separating with reversed phase C18CE column chromatography and 50% methanol water-100% methanol water to obtain 1.1-1.8; eluting 65% methanol water eluted component 1.6 with petroleum ether-ethyl acetate system, eluting with petroleum ether:ethyl acetate=2:1 to obtain component 1.6.7, subjecting component 1.6.7 to high performance liquid chromatography, waters C18-X-bridge column, 3mL/min, and 35% acetonitrile/water to obtain compound 1 and compound 2; and (3) taking the compound 1 or/and the compound 2, and adding a pharmaceutically acceptable carrier.
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| Title |
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| YANG-ZENG, HUANG, ET AL.: "Establishment of HPLC fingerprints of alkaloids in Ramulus Uncariae Cum Uncis and identification of different sources of medicinal materials", 《ZHONGYAOCAI》, vol. 37, no. 2, 31 December 2014 (2014-12-31), pages 233 - 236 * |
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