CN101775019B - Melotenine and pharmaceutical composition as well as preparation method and application thereof - Google Patents
Melotenine and pharmaceutical composition as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an active ingredient of melotenine analogue shown in the formula (I) for resisting tumour as well as a preparation method and a medical application thereof.
Description
Technical field: the invention belongs to technical field of pharmaceuticals, particularly, the monoterpene indole alkaloid compounds slender lobule mountain orange plain first (melotenineA) and the organic and inorganic acid salt thereof that relate to novel skeleton, with it is the pharmaceutical composition of effective ingredient, its preparation method and their application in preparation treatment or preventing cancer medicine.
Background technology: tumour is a world-famous puzzle.At annual newly-increased 1,600,000 tumor patients in heilongjiang of China, 1,300,000 tumor patients in heilongjiang death there is every year.Though the chemotherapeutics that uses clinically has certain curative effect at present, brings huge human body misery and stress to patient greatly because of its toxicity, the discovery of the antitumor drug that new determined curative effect and toxic side effect are less relatively is extremely urgent.The slender lobule mountain plain first of orange (melotenine A) is the new compound that comes from the natural phant.Do not report before this about the structure and the medical active of this compound.
Summary of the invention: the objective of the invention is to: monoterpene indole alkaloid compounds slender lobule mountain orange plain first (melotenine A) and analogue thereof are provided, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.); Its preparation method; The pharmaceutical composition that it is formed as effective constituent and pharmaceutically acceptable carrier or vehicle; And compound slender lobule mountain orange plain first (melotenine A) analogue and the purposes of pharmaceutical salts in preparation prevention or treatment liver cancer, leukemia, carcinoma of the pancreas, mammary cancer and lung cancer drugs thereof.
Above-mentioned purpose of the present invention is achieved by the following technical solutions:
Monoterpene Benzazole compounds slender lobule mountain orange plain first (melotenine A) analogue or its pharmaceutical salts shown in the formula (I)
Wherein:
R
1Be selected from C
1-10Alkyl, C
2-10Thiazolinyl or C
2-10Alkynyl, preferred R
1Be C
1-6Alkyl, preferred R
1Be methyl;
R
2Be selected from hydrogen or COOR
3, R wherein
3Be selected from C
1-10Alkyl, C
2-10Thiazolinyl or C
2-10Alkynyl, preferred R
2Be COOCH
3
The Y representative is optional by 1-5 R
4The C that replaces
2-10Alkylidene group, C
2-10Alkylidene, C
2-10Alkenylene, C
2-10Inferior thiazolinyl, C
2-10Alkynylene or C
2-10Inferior alkynyl; Preferred Y representative is optional by C
1-6The C that alkyl replaces
2-6Alkylidene group, C
2-6Alkylidene, C
2-6Alkenylene or C
2-6Inferior thiazolinyl, preferred Y representative is optional by C
1-6The C that alkyl replaces
2-4Alkylidene group, C
2-4Alkylidene, C
2-4Alkenylene or C
2-4Inferior thiazolinyl, most preferred Y representative
R
4Be selected from hydrogen, C
1-10Alkyl, C
2-10Thiazolinyl or C
2-10Alkynyl.
Most preferred formula (I) monoterpene Benzazole compounds is the plain first of slender lobule mountain orange:
Described pharmaceutical salts is meant pharmacy acceptable salt, includes but not limited to and organic acid, or the salt of mineral acid formation.Described organic acid includes but not limited to tartrate or citric acid or formic acid or oxalic acid, and mineral acid includes but not limited to hydrochloric acid or sulfuric acid or phosphoric acid.
Another aspect of the present invention provides the preparation method suc as formula the monoterpene Benzazole compounds shown in (I), may further comprise the steps:
(1) formula (II) compound and PhSeCH
2The CHO reaction obtains formula (III) compound:
R wherein
1, R
2Implication identical with claim 1;
(2) reaction of formula (III) compound and formula (IV) compound obtains the formula V compound:
Wherein L is a leavings group, and Y is identical with the implication of claim 1;
(3) cyclization of formula V compound obtains formula (I) compound:
In this method, the structure optimization of formula (IV) compound is:
Wherein the X representative is optional by 1-5 R
4The C that replaces
1-4Alkylidene group, C
2-4Alkenylene or C
2-4Alkynylene, L are leavings group, R
4Identical with the implication of claim 1;
In a preferred method, formula (III) compound and formula (IV-1) or formula (IV-2) reaction obtain formula (V-1) or formula (V-2), and cyclization obtains formula (I-1) or formula (I-2) compound again:
The most preferred compound slender lobule of the present invention mountain plain first of orange (melotenine A) also can prepare as follows: get plant slender lobule mountain orange, water or organic solvent extraction, extract obtainedly remove abiotic bases material, the monoterpene indole alkaloid slender lobule mountain orange plain first of utilizing silica gel column chromatography to separate to obtain shown in the formula (I) (melotenine A) by acid-alkali treatment.Described extraction is to carry out under the temperature that refluxes, described organic solvent is selected from alcoholic solvent, ketones solvent, esters solvent or ether solvent, wherein said alcoholic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, Pentyl alcohol, described ketones solvent is selected from acetone, butanone, methyl iso-butyl ketone (MIBK), and described esters solvent is selected from ethyl acetate.Described acid-alkali treatment can be: in extract, add acid for example hydrochloric acid or sulphur acid for adjusting pH value to 1.0-3.0, with organic solvent ethyl acetate extraction 1-4 time for example, water layer with alkali for example adjusting such as ammoniacal liquor or sodium hydroxide or yellow soda ash pH value to 8.0-10.0, use ethyl acetate extraction 1-4 time again, merge concentrated acetic acid ethyl ester extract.
Concrete method is: get plant slender lobule mountain orange complete stool, after drying, the pulverizing, with ethanol-extracted 1-4 time, each 1-4 hour, get pure medicinal extract, pass through acid-alkali treatment then, remove abiotic bases material, under alkaline condition, use organic solvent extraction, concentrate the organic solvent extraction layer, medicinal extract utilizes silica gel column chromatography, separates the compound slender lobule mountain orange plain first (melotenine A) that obtains shown in the formula (I) as elution system with sherwood oil/acetone.
Method is more specifically: get the slender lobule mountain orange plant complete stool after air-dry, with 70 ℃ of heating of 90% ethanol, refluxing extraction 3 times reclaims solvent, is concentrated to small volume, add 5%HCl and regulate pH value to 2, with ethyl acetate extraction 3 times, water layer is regulated pH value to 9 with 10% ammoniacal liquor, uses ethyl acetate extraction again 3 times, concentrate ethyl acetate layer, the ethyl acetate part is carried out 200-300 order silica gel column chromatography with behind the silica gel mixed sample, is divided into 7 sections Frs 1-7, with sherwood oil/acetone gradient elution segmentation, allocation proportion is chloroform/methanol 1: 0,15: 1, and 10: 1,6: 1,3: 1,1: 1,0: 1, Fr1 is an eluent with sherwood oil/acetone=12/1, and silica gel 100g column chromatography for separation gets slender lobule mountain orange plain first (melotenineA).
Slender lobule of the present invention mountain orange extract contains slender lobule mountain orange plain first (melotenine A) or its pharmaceutical salts 10-95% (weight) shown in the formula (I) and can prepare as follows: get plant slender lobule mountain orange, use organic solvent extraction, extract obtainedly remove abiotic bases material, utilize the further separation and purification of silica gel column chromatography by acid-alkali treatment.Described extraction is to carry out under the temperature that refluxes, organic solvent is selected from alcoholic solvent, ketones solvent, esters solvent or ether solvent, wherein alcoholic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, Pentyl alcohol, ketones solvent is selected from acetone, butanone, methyl iso-butyl ketone (MIBK), and esters solvent is selected from ethyl acetate.Acid-alkali treatment is meant: in extract, add acid for example hydrochloric acid or sulphur acid for adjusting pH value to 1.0-3.0, with organic solvent ethyl acetate extraction 1-4 time for example, water layer with alkali for example adjusting such as ammoniacal liquor or sodium hydroxide or yellow soda ash pH value to 8.0-10.0, use ethyl acetate extraction 1-4 time again, merge concentrated acetic acid ethyl ester extract.
Pharmaceutical composition, formula (I) compound or pharmaceutically acceptable salt thereof that wherein contains claim 1 be as effective constituent, and contain conventional pharmaceutical carrier.
The application of formula (I) compound or pharmaceutically acceptable salt thereof in treatment or preventing cancer medicine.
The application of formula (I) compound or pharmaceutically acceptable salt thereof in preparation treatment liver cancer, leukemia, carcinoma of the pancreas, mammary cancer and lung cancer drugs.
Compound slender lobule of the present invention mountain orange plain first (melotenine A) but analogue or its salt per os or without the mouth administration, dosage is had nothing in common with each other because of medicine is different, concerning the adult, every day, 1-1000mg was proper.
In this specification sheets, " alkyl " is meant the aliphatic hydrocarbyl of saturated straight or branched, preferably has 1-10 carbon atom, more preferably have 1-6 carbon atom, more preferably have 1-4 carbon term.Representational example comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl etc.
Term " thiazolinyl " is meant to have at least one carbon-carbon double bond, and the aliphatic hydrocarbyl of straight or branched preferably has 2-10 carbon atom, more preferably has 2-6 carbon atom, more preferably has 2-4 carbon.Representational example comprises vinyl, propenyl, allyl group, butenyl, pentadienyl etc.
Term " alkynyl " is meant to have at least one carbon carbon triple bond, and the aliphatic hydrocarbyl of straight or branched preferably has 2-10 carbon atom, more preferably has 2-6 carbon atom, more preferably has 2-4 carbon.Representational example comprises ethynyl, proyl, butynyl etc.
In this specification sheets, subunit is meant that corresponding group links to each other by two singly linked modes with other structure, and for example ethylidene is-CH
2CH
2-, vinylidene is-CH=CH-; Inferior base is meant that corresponding group links to each other with a doubly linked mode by a singly-bound with other structure, and for example methyne is-CH=.
During the oral administration administration, compound and conventional medicinal adjuvant such as vehicle, disintegrating agent, tamanori, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc. are mixed, be made into form administrations such as granule, capsule, tablet; Can injection liquid during non-oral administration, form administration such as infusion solution or suppository.When preparing above-mentioned preparation, can use conventional preparation technique.
Embodiment:
Following experimental example, embodiment and example of formulations can illustrate in greater detail the present invention, but do not limit the present invention in any form.
Experimental example 1:
The The compounds of this invention slender lobule mountain plain first of orange (melotenine A) has tangible anti-tumor activity, and experimental technique and result are as follows:
One, materials and methods:
1. sample and preparation:
It is colourless that sample is, and the stock solution that dimethyl sulfoxide (DMSO) (DMSO) dissolving is formulated as 10mg/ml concentration keeps in Dark Place standby.
2. cell strain:
SK-BR-3, the human breast cancer cell strain
SMMC7721, human hepatoma cell strain
HL-60, human leukemia cell line
PANC-1, human pancreas cancer cell strain
A549, human lung carcinoma cell line
3. experimental technique:
(1) inoculating cell: be made into the individual cells suspension with the nutrient solution (DMEM or RMPI1640) that contains 10% foetal calf serum, with every hole 10000-20000 cell inoculation to 96 orifice plates, every pore volume 100ul, attached cell shifts to an earlier date 12 hours inoculation culture.
(2) add testing compound solution (compound monomer fixed concentration 40uM primary dcreening operation, crude extract 100ug/ml primary dcreening operation, in this concentration growth of tumour cell being suppressed near 50% compound establishes 5 concentration and enters gradient and sieve again), every hole final volume 200ul, 3 multiple holes are all established in every kind of processing.
(3) colour developing: cultivate after 48 hours for 37 degrees centigrade, every hole adds MTT solution 20ul.Continued to hatch 4 hours, and stop to cultivate, the careful suction abandons that culture supernatant 100ul is to avoid cell loss in the hole, and every hole adds 20% SDS100ul, and night incubation (37 ℃ of temperature) is fully melted crystallisate.
(4) colorimetric: select the 595nm wavelength, enzyme-linked immunosorbent assay instrument (Bio-Rad 680) reads each hole absorbance value, and the record result is an X-coordinate with concentration, cell survival rate is that ordinate zou is drawn cell growth curve, uses the IC50 value of two-point method (Reed and Muench method) computerized compound.
(5) positive control: cis-platinum
Two, result:
The table 1. slender lobule mountain plain first of orange (melotenine A) is to the half-inhibition concentration (IC of human tumor cell line growth
50, μ M)
Three, conclusion:
Under this experiment condition, the plain first of compound slender lobule mountain orange (melotenine A) comprises human breast cancer cell strain (SK-BR-3) to above, human hepatoma cell strain (SMMC7721), human leukemia cell line (HL-60), human pancreas cancer cell strain (PANC-1), the half-inhibition concentration (IC50) of human lung carcinoma cell line (A549) growth is between 0.9-10.7 μ M, Compound D, G to the half-inhibition concentration (IC50) of the growth of above tumor line between 1.7-25.9 μ M, according to Chinese Journal of Pharmaceuticals 1993,24:455-457, the active improvement mtt assay of the evaluation antitumorigenic substance of propositions such as Zhou Jianjun is reached a conclusion: above-mentioned data presentation the effect of obvious suppression cancer.
Embodiment 1:
14kg plant complete stool slender lobule mountain orange (Melodinus henryi Craib) after air-dry heats (70 ℃) refluxing extraction 3 times with 90% ethanol, reclaim solvent, be concentrated to small volume, add 5%HCl and regulate pH value to 2, with ethyl acetate extraction 3 times, water layer is regulated pH value to 9 with 10% ammoniacal liquor, uses ethyl acetate extraction again 3 times, weigh behind the concentrated ethyl acetate layer 17g.After the ethyl acetate part is mixed sample with proper silica gel, carry out silica gel column chromatography (400g, 200-300 order, Haiyang Chemical Plant, Qingdao) and be divided into 7 sections (Frs 1-6), with sherwood oil/acetone gradient elution segmentation (allocation proportion: 1: 0,15: 1,10: 1,6: 1,3: 1,1: 1,0: 1).Fr1 (1.8g) is an eluent with sherwood oil/acetone=12/1, and silica gel 100g column chromatography for separation gets slender lobule mountain orange plain first (melotenine A).
The chemical structural formula of the slender lobule mountain plain first of orange (melotenine A) is:
Molecular weight 334, molecular formula C
21H
22N
2O
2Optically-active: [α]
25 D=-136.5 ° (c 0.20, CHCl
3).Clear crystal.Be soluble in chloroform, acetone, organic solvents such as methyl alcohol.
UV spectrum, infrared spectra, mass spectrum and the nuclear magnetic resonance spectrum that the structure of the plain first of slender lobule mountain orange (melotenine A) is based on it be two dimensional NMR spectrum and determining particularly.
Ultraviolet spectrum data: UV λ (max) is (MeOH): 328 (3.92), 298 (3.82), 265 (4.21), 221 (4.64) nm
Ir data: IR v (max) is (KBr): 3440,2948,1680,1610,1436,1244
Mass-spectrometric data: HR-ESI-MS (m/z): 335.1772[M+H]
+
1H NMR and
13C NMR data see Table 2.
It is shown in the formula (II) that above data are analyzed the chemical structure that has confirmed the slender lobule mountain plain first of orange (melotenine A) in conjunction with 2D NMR.
The table 2. slender lobule mountain plain first of orange (melotenine A)
1H NMR and
13C NMR data (CDCl
3)
Embodiment 2
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A) earlier, adds 4% ethanol solution of sulfuric acid,
Filter, drying is made sulfuric acid slender lobule mountain orange plain first (melotenine A).
Embodiment 3:
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A), adds 4% hydrochloric acid acid solution,
Filter, drying is made hydrochloric acid slender lobule mountain orange plain first (melotenineA).
Embodiment 4:
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A), adds 4% phosphoric acid acid solution,
Filter, drying is made phosphoric acid slender lobule mountain orange plain first (melotenineA).
Embodiment 5:
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A)), the tartaric acid solution of adding 4%,
Filter, drying is made slender lobule mountain orange plain first (melotenineA).
Embodiment 6:
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A), adds 4% citric acid solution,
Filter, drying is made citric acid slender lobule mountain orange plain first (melotenine A).
Embodiment 7:
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A), adds 4% formic acid solution,
Filter, drying is made formic acid slender lobule mountain orange plain first (melotenineA).
Embodiment 8:
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A), adds 4% oxalic acid solution,
Filter, drying is made oxalic acid slender lobule mountain orange plain first (melotenine A).
Embodiment 9
The preparation of the plain first analogue of slender lobule mountain orange
Embodiment 10
The preparation of the plain first analogue of slender lobule mountain orange
Example of formulations 1:
Method by embodiment 1-10 makes slender lobule mountain orange plain first (melotenine A) earlier, and utilizes organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), add the injection water routinely, smart filter, injection liquid is made in the embedding sterilization.
Example of formulations 2:
Press embodiment 1
-10Method make slender lobule mountain orange plain first (melotenine A) earlier, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), it is dissolved in the sterile water for injection, stirring makes molten, filters with aseptic suction funnel, aseptic more smart filter, be sub-packed in 2 ampoules, aseptic sealing by fusing gets powder injection behind the frozen drying.
Example of formulations 3:
Institute's separation is obtained slender lobule mountain orange plain first (melotenine A), and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) salt of making, with the vehicle weight ratio be that 9: 1 ratio adds vehicle, make pulvis.
Example of formulations 4:
Press embodiment 1
-10Method make slender lobule mountain orange plain first (melotenine A) earlier, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) salt of making is 1 in itself and vehicle weight ratio: 5-1: 10 ratio adds vehicle, pelletizing press sheet.
Example of formulations 5:
Press embodiment 1
-10Method make slender lobule mountain orange plain first (melotenine A) earlier, and the salt that utilizes organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) to make, the oral liquid method for making is made oral liquid routinely.
Example of formulations 6:
Method by embodiment 1 makes slender lobule mountain orange plain first (melotenine A) earlier, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), in itself and vehicle weight ratio is that 5: 1 ratio adds vehicle, makes capsule or granule or electuary.
Example of formulations 7:
Press embodiment 1
-10Method make slender lobule mountain orange plain first (melotenine A) earlier, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), in itself and vehicle weight ratio is that 3: 1 ratio adds vehicle, makes capsule or granule or electuary.
Claims (15)
1. the monoterpene indole alkaloid shown in the formula (I) or its pharmaceutical salts,
R wherein
1Be selected from C
1-10Alkyl, C
2-10Thiazolinyl or C
2-10Alkynyl;
R
2Be selected from hydrogen or COOR
3, R wherein
3Be selected from C
1-10Alkyl, C
2-10Thiazolinyl or C
2-10Alkynyl;
The Y representative is optional by 1-5 R
4The C that replaces
2-10Alkylidene group, C
2-10Alkenylene,, C
2-10Alkynylene or C
2-10Inferior alkynyl; R
4Be selected from hydrogen, C
1-10Alkyl, C
2-10Thiazolinyl or C
2-10Alkynyl.
2. monoterpene indole alkaloid as claimed in claim 1 or its pharmaceutical salts, wherein Y represents C
2-4Alkylidene group, C
2-4Alkenylene, R
4Be selected from hydrogen or C
1-4Alkyl.
3. monoterpene indole alkaloid as claimed in claim 2 or its pharmaceutical salts, wherein Y represents C
4Alkenylene, R
3Be selected from hydrogen or methyl.
4. monoterpene indole alkaloid as claimed in claim 3 or its pharmaceutical salts, wherein Y representative:
5. monoterpene indole alkaloid as claimed in claim 4 or its pharmaceutical salts, it is the plain first of slender lobule mountain orange:
6. as the described pharmaceutical salts of claim 1-5, be meant pharmacy acceptable salt.
7. as the described pharmaceutical salts of claim 1-5, be the salt that forms with organic acid or mineral acid.
8. as the described pharmaceutical salts of claim 1-5, be salt with tartrate or citric acid or formic acid or oxalic acid or hydrochloric acid or sulfuric acid or phosphoric acid formation.
9. the preparation method of the monoterpene Benzazole compounds shown in claim 1 formula (I) may further comprise the steps:
(1) formula (II) compound and PhSeCH
2The CHO reaction obtains formula (III) compound:
R wherein
1, R
2Implication identical with claim 1;
(2) reaction of formula (III) compound and formula (IV) compound obtains the formula V compound:
Wherein L is a leavings group, and Y is identical with the implication of claim 1;
(3) cyclization of formula V compound obtains formula (I) compound:
10. preparation method as claimed in claim 9, the structure of its Chinese style (IV) compound is:
Wherein the X representative is optional by 1-5 R
4The C that replaces
1-4Alkylidene group, C
2-4Alkenylene or C
2-4Alkynylene, L are leavings group, R
4Identical with the implication of claim 1.
11. method for preparing the plain first of slender lobule mountain orange, may further comprise the steps: get plant slender lobule mountain orange, water or organic solvent extraction, extract obtainedly remove abiotic bases material by acid-alkali treatment, use 400g, 200-300 order silica gel carries out column chromatography, is divided into 7 sections Frs 1-7, with sherwood oil/acetone gradient elution segmentation, allocation proportion is: 1: 0, and 15: 1,10: 1,6: 1,3: 1,1: 1,0: 1, Fr1 is an eluent with sherwood oil/acetone=12/1, separates the plain first of monoterpene indole alkaloid slender lobule mountain orange that obtains shown in the formula (I).
12. preparation method as claim 11, described extraction is to carry out under the temperature that refluxes, described organic solvent is selected from alcoholic solvent, ketones solvent, esters solvent or ether solvent, wherein said alcoholic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, Pentyl alcohol, described ketones solvent is selected from acetone, butanone, methyl iso-butyl ketone (MIBK), and described esters solvent is selected from ethyl acetate.
13. pharmaceutical composition, formula (I) compound or pharmaceutically acceptable salt thereof that wherein contains claim 1-6 be as effective constituent, and contain at least a pharmaceutically acceptable carrier.
14. the application of the formula of claim 1-6 (I) compound or pharmaceutically acceptable salt thereof in preparation treatment or preventing cancer medicine.
15. the application of the formula of claim 1-6 (I) compound or pharmaceutically acceptable salt thereof in preparation treatment or prevention liver cancer, leukemia, carcinoma of the pancreas, mammary cancer and lung cancer drugs.
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