CN104961790B - Asiatic acid derivative, preparation method and its application in preparation antidepressant - Google Patents
Asiatic acid derivative, preparation method and its application in preparation antidepressant Download PDFInfo
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Abstract
The present invention provides a kind of asiatic acid derivative compound for meeting logical formula (I) or its pharmaceutically acceptable salt or ester or its any optical isomer or any tautomer:
Description
Technical field
The invention belongs to field of natural medicinal chemistry, are related to a kind of compound more particularly to a kind of asiatic acid derivative
And preparation method thereof and its preparation antidepressant in application.
Background technique
Asiatic acid also known as asiatic acid are from medicinal umbelliferae centella (Centella asiatica (L.)
Urban the Ursane pentacyclic triterpenoid extracted in), structural formula are as follows:
Since asiatic acid has extensive biological activity, it is therefore widely used in field of natural medicinal chemistry, it is right
Antitumor, improvement cognition, anti-diabetic, anti-inflammatory, antibacterial, promotion wound healing etc. have good effect.
Depression is a kind of common and easy ignored mental disease, low for Major Clinical with significant and lasting mental state
Feature is the main Types of mood disorder.Clinical visible mental state is low unbecoming with its situation, and the downhearted of mood can be from bored
Do not find pleasure in extremely grieved, depression of feeling oneself inferior or even pessimistic and worldweary can have conamen or behavior；Even occur numb；Some cases
There are apparent anxiety and sports type intense；Serious person may occur in which the psychotic symptoms such as illusion, vain hope.Breaking-out continues at least every time
2 weeks or more, elder or even several years, majority of cases have the tendency that recurrent exerbation, and breaking-out is most of every time to alleviate, and can partially have
Residual symptoms switch to chronic.It is announced according to the World Health Organization, various depression illness account for population in the world 3%-5%.It expects
The year two thousand twenty, depression will become the second largest common disease in the whole world.Therefore, there is an urgent need to safe and efficient, cheap antidepressions
Medicine.
Clinically the antidepressants of a line mainly include that (SSRI is represented selective serotonin reuptake inhibitor at present
Agents fluoxetine, Paxil, Sertraline, Fluvoxamine, Citalopram and escitalopram), serotonin and remove first kidney
Upper parathyrine reuptaking inhibitor (SNRI represents drug Venlafaxine and Duloxetine), norepinephrine and specificity 5- hydroxyl
Tryptamines energy antidepressants (NaSSA represents drug Mirtazapine) etc..Traditional tricyclic antidepressants, tetracyclic antidepressants and monoamine oxidation
Enzyme inhibitor is since adverse reaction is larger, using being restricted.
Inventor is after years of research and found that asiatic acid is detailed with preferable antidepressant effect, such as in CN1256090C
The antidepressant effect of asiatic acid carefully is provided, but its bioavilability is poor, it is therefore desirable to find a kind of antidepressant activity
Good, bioavilability more preferably asiatic acid derivative.
Summary of the invention
The present invention is to solve the above problem in the prior art to propose.
The present invention provides a new class of asiatic acid derivative compounds.
The present invention also provides a kind of preparation method of above-mentioned asiatic acid derivative compound and its preparing antidepressants
Application in object.
To achieve the above object, the invention adopts the following technical scheme:
The first aspect of the invention be to provide a kind of asiatic acid derivative compound for meeting logical formula (I) or its pharmaceutically
Acceptable salt or ester or its any optical isomer or any tautomer:
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11It can independently identical or differently be hydrogen, hydroxyl, carboxylic
Base, carbonyl, C1-6Alkane hydroxyl, C1-6Alkane carboxyl, C1-6Alkoxy, it is unsubstituted or by C1-6Alkyl, halogen, hydroxyl or C1-6Alkoxy
One substitution or polysubstituted C3-6Naphthenic base is unsubstituted or replaced by halogen one or polysubstituted C1-6Alkyl, C2-6Alkenyl or
C2-6Alkynyl group.
In above compound, it is preferable that wherein R6For first hydroxyl, R9For-COOM, R10It is formula (II) compound for hydroxyl:
Wherein,
R1、R2、R3、R4、R5、R7、R8、R11It can independently identical or differently be hydrogen, hydroxyl, carboxyl, carbonyl, C1-6Alkane hydroxyl
Base, C1-6Alkane carboxyl, C1-6Alkoxy, it is unsubstituted or by C1-6Alkyl, halogen, hydroxyl or C1-6The substitution or polysubstituted of alkoxy one
C3-6Naphthenic base is unsubstituted or replaced by halogen one or polysubstituted C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group；
M is hydrogen or alkali metal.
In above compound, it is highly preferred that wherein R1For carbonyl, R2For hydrogen, R3 is hydroxyl.
In above compound, it is highly preferred that wherein R1For hydroxyl, R2For hydroxyl, R3For hydrogen.
The second aspect of the invention is to provide a kind of preparation method of any of the above-described asiatic acid derivative compound,
What structural modification obtained is carried out to asiatic acid by microorganism.
In above-mentioned preparation method, it is preferable that the microorganism is that Gliocladium roseum and/or cunninghamella echinulata original become
Kind.
In above-mentioned preparation method, it is preferable that the preparation method specifically includes:
Step 1: the microorganism conversion reaction of asiatic acid: asiatic acid being dissolved in organic solvent, being made into concentration is
The substrate solution of 5-25g/l is added to progress microorganism conversion reaction in the microorganism fungus kind through cultivating；
Step 2: the extraction separation and purification of product: extracting the product that step 1 obtains with organic extractant, then dense
It contracts, isolate and purify to obtain compound described in claim 1.
In above-mentioned preferred preparation method, it is highly preferred that converting reaction temperature in the step 1 is 20-30 DEG C, more preferably
25-28 DEG C, the reaction time is at least 5 days, more preferably 7-10 days.
The third aspect of the invention is to provide a kind of asiatic acid derivative compound as described in any of the above-described or by above-mentioned
The asiatic acid derivative compound of any preparation method preparation is used to prepare the application of antidepressant.
The fourth aspect of the invention is to provide a kind of medicine composition for treating depression, and described pharmaceutical composition includes having to resist
Any of the above-described asiatic acid derivative compound of depression effect is spread out by asiatic acid prepared by any of the above-described the method
Raw compounds or their pharmaceutically acceptable salt or ester or its any optical isomer or any tautomer, and
One or more pharmaceutical acceptable carrier or excipient.
The present invention by adopting the above technical scheme, compared with prior art, has the following technical effect that
By mouse forced swimming test and Tail suspension test research shows that asiatic acid derivative compound of the invention
Antidepressant activity with higher.
Specific embodiment
The present invention provide a kind of asiatic acid derivative compound for meeting logical formula (I) or its pharmaceutically acceptable salt or
Ester or its any optical isomer or any tautomer:
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11It can independently identical or differently be hydrogen, hydroxyl, carboxylic
Base, carbonyl, C1-6Alkane hydroxyl, C1-6Alkane carboxyl, C1-6Alkoxy, it is unsubstituted or by C1-6Alkyl, halogen, hydroxyl or C1-6Alkoxy
One substitution or polysubstituted C3-6Naphthenic base is unsubstituted or replaced by halogen one or polysubstituted C1-6Alkyl, C2-6Alkenyl or
C2-6Alkynyl group.
In above compound, it is preferable that wherein R6For first hydroxyl, R9For-COOM, R10It is formula (II) compound for hydroxyl:
Wherein,
R1、R2、R3、R4、R5、R7、R8、R11It can independently identical or differently be hydrogen, hydroxyl, carboxyl, carbonyl, C1-6Alkane hydroxyl
Base, C1-6Alkane carboxyl, C1-6Alkoxy, it is unsubstituted or by C1-6Alkyl, halogen, hydroxyl or C1-6The substitution or polysubstituted of alkoxy one
C3-6Naphthenic base is unsubstituted or replaced by halogen one or polysubstituted C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group；
M is hydrogen or alkali metal.
In above compound, it is highly preferred that wherein R1For carbonyl, R2For hydrogen, R3 is hydroxyl, and structural formula is preferred are as follows:
Chemical name are as follows: 2- oxo -3 β, 21 β, 23- trihydroxy -12- alkene -28- ursolic acid.
In above compound, it is highly preferred that wherein R1For hydroxyl, R2For hydroxyl, R3For hydrogen, structural formula is preferred are as follows:
Chemical name are as follows: 2 α, 3 β, 7 β, 23- tetrahydroxy -12- alkene -28- ursolic acid.
The present invention is described in more detail below by specific embodiment, for a better understanding of the present invention,
But following embodiments are not intended to limit the scope of the invention.
Embodiment 1
The preparation and extraction separation of compound 1:
Gliocladium roseum is accessed with 2% inoculum concentration in the triangular flask of 10 bottles of 1000ml (every bottle of 400ml culture medium)
3.3657 strain of Gliocladium roseum CGMCC, sets in constant temperature oscillator, 180rpm, 27 DEG C culture 72 hours after plus
Enter 300mg substrate asiatic acid (being dissolved in 20ml ethyl alcohol, every bottle of addition 2ml), continues culture 10 days.After fermentation, it filters
Mycelium, filtrate are extracted 3 times with isometric ethyl acetate, mycelium with 500ml ethyl acetate ultrasonic extraction three times, every time
Acetic acid ethyl acetate extract is set and is concentrated into small size on Rotary Evaporators by 30min, combining extraction liquid and extracting solution, dry, respectively
It obtains conversion reaction extract (1.8g).
The a small amount of ethyl alcohol of conversion reaction extract is dissolved, in treble silica gel mixed sample, the separation of 25g silica gel, chloroform/methanol
Gradient elution (from 97:3 to 90:10, total 3000ml), is collected into 3 flow points: A (537.7mg), B (48.6mg), C
(268.9mg).Flow point A is prepared with semipreparative high performance liquid chromatography instrument, mobile phase: methanol/water/formic acid (60:40:0.05, V/
V/V), flow velocity 3ml/min, Detection wavelength: 210nm obtains a compound 1 (117.4mg), retention time 11.72min.
The preparation and extraction separation of compound 2:
With 2% inoculum concentration access thorn small gram of Mildy Way of spore in the triangular flask of 15 bottles of 1000ml (every bottle of 400ml culture medium)
Mould 3.2000 strain of original mutation Cunninghamella echinulata CGMCC, sets in constant temperature oscillator, 180rpm, 27 DEG C
500mg substrate asiatic acid (being dissolved in 30ml ethyl alcohol, every bottle of addition 2ml) is added after culture 72 hours, continues culture 10 days.Hair
After the completion of ferment, mycelium is filtered, three times with isometric ethyl acetate extraction, mycelium is ultrasonic with 500ml ethyl acetate for filtrate
It extracts three times, each 30min, combined ethyl acetate extract liquor and extracting solution are set and are concentrated into small size on Rotary Evaporators, do
It is dry, obtain conversion reaction extract 3.5g.
The a small amount of ethyl alcohol of conversion reaction extract is dissolved, in twice heavy silica gel mixed sample, the separation of 40g silica gel, chloroform/methanol
Gradient elution (from 99:1 to 92:8, total 5450ml), is collected into 9 flow points: A (1673.1mg), B (189.6mg), C
(65.0mg), D (228.2mg), E (85.6mg), F (23.7mg), G (212.7mg), H (34.0mg), I (200.4mg).Wherein
Flow point G is prepared with semipreparative high performance liquid chromatography instrument, mobile phase: methanol/water/formic acid (69:31:0.05, V/V/V), flow velocity
3ml/min, Detection wavelength: 210nm obtains a compound 2 (115.3mg), retention time 12.63min.
Embodiment 2
The Structural Identification of compound 1:
Compound 1 is white solid, and HR-ESI-MS provides 501.3243 ([M-H] -), pushes away in conjunction with 1H-NMR and 13C-NMR
It is disconnected to determine that molecular formula is C30H46O6.In 1H-NMR (600MHz, pyridine-d5), show that the compound there are six groups of methyl hydrogens
Signal δ 1.39 (3H, o), δ 1.17 (3H, s), δ 1.08 (3H, d, 6.6), δ 1.03 (3H, s), δ 0.95 (3H, s), δ 0.83 (3H,
s)；There is an active hydrogen signal: δ 5.50 (t, 3.6), thus it is speculated that may be the hydrogen in double bond at low field.In 13C-NMR show two not
Saturated carbon atom δ 125.9 and δ 139.8, a carboxyl carbon atom δ 179.5.In summary information may infer that the compound is
Ursane pentacyclic triterpene acids compound.
The hydrocarbon of compound 1 can further be belonged to according to HSQC, HMBC spectrum.
Compared with asiatic acid, in 1H-NMR spectrum, compound 1 occurs one at 3.82ppm (1H, dt, J=4.8,9.6Hz)
A hydrogen signal；In 13C-NMR spectrum, occur company's oxygen carbon signal at 70.9ppm, it is related both in hsqc spectrum；In HMBC
In spectrum, it can be observed that δ 70.9 and Ha-22 (δ 2.64, dd, J=4.2,12.6Hz), He-22 (δ 2.24, t, J=12.0Hz),
The coherent signal of H-30 (δ 1.39, o), prompts new hydroxyl signal to be located at C-21., while C-20 and C-22 are respectively to low field
It is displaced 8.8ppm and 9.8ppm, above data illustrates that C-21 are connected with hydroxyl, in NOESY spectrum, it can be observed that H-21 (δ
3.82, dt, J=4.8,9.6Hz) with Ha-22 (δ 2.64, dd, J=4.2,12.6Hz) between NOE synergy, it is thus determined that 21-
OH is beta comfiguration.Meanwhile the coupling constant of H-21 (δ 3.82, dt, J (22a, 21a)=9.6Hz, J (22e, 21a)=4.8Hz)
Show that H-21 is located at axial bond, further demonstrates that the hydroxyl is beta comfiguration.Meanwhile there is a carbonyl in δ 213.1 in 13C-NMR spectrum
Base carbon signal, the carbonyl carbon and H-1 (δ 2.55, d, 12.0), H-3 (δ 5.06, s) are long-range related, and C-1, C-4 are respectively to low field
It is displaced 6.2ppm and 6.7ppm, above data illustrates that C-2 hydroxyls are oxidized to carbonyl.To sum up, the structure of compound 1 is determined
Are as follows: 2- oxo -3 β, 21 β, 23- trihydroxy -12- alkene -28- ursolic acid is a noval chemical compound, 1H-NMR spectrum, 13C-NMR spectrum
Signals assignment is shown in Table 1.
1H NMR and the 13C NMR data of 1. compound 1 of table
Embodiment 3
The Structural Identification of compound 2:
Compound 2 is white solid, and HR-ESI-MS provides 503.3401 ([M-H] -), pushes away in conjunction with 1H-NMR and 13C-NMR
It is disconnected to determine that molecular formula is C30H48O6.In 1H-NMR (600MHz, pyridine-d5), show that the compound has 6 methyl hydrogens
Atom signals δ 1.37 (6H, s), δ 1.14 (3H, s), δ 1.07 (3H, s), δ 1.00 (3H, d, 6.6), δ 0.92 (3H, d, 6.6)；
There is an active hydrogen signal δ 5.61 (o) at low field, thus it is speculated that may be the hydrogen in double bond.Two unsaturated carbon originals are shown in 13C-NMR
Sub- δ 126.4 and δ 139.5, a carboxyl carbon atom δ 180.5.In summary information may infer that the compound is Ursane
Pentacyclic triterpene acids compound.
The hydrocarbon of compound 2 can further be belonged to according to HSQC, HMBC spectrum.
Compared with asiatic acid, in 1H-NMR (600MHz, pyridine-d5), compound 2 is in 4.45ppm (1H, dd, J
=4.2,10.8Hz) there is a hydrogen signal；In 13C-NMR spectrum, occurs company's oxygen carbon signal at 73.4ppm, in HSQC
It is related both in spectrum；In HMBC spectrum, it can be observed that δ 73.4 and H-5 (δ 2.04, m), H-9 (δ 1.84, m), H-26 (δ
1.37, s) coherent signal prompts new hydroxyl signal to be located at C-7.C-6 and C-8 is respectively to low field displacement 4.4ppm simultaneously
And 6.4ppm, equally also illustrate C-7 and is connected with hydroxyl.
In NOESY spectrum, it can be observed that H-7 (4.45ppm, dd, J=4.2,10.8Hz) and Ha-6 (δ 2.17, o) it
Between NOE synergy, it is thus determined that 7-OH be beta comfiguration.Meanwhile H-7 (δ 4.45, dd, J (6a, 7a)=10.8Hz, J (6e, 7a)=
Coupling constant 4.2Hz) also indicates that H-7 is located at axial bond, further demonstrates that the hydroxyl is beta comfiguration.To sum up, compound 2 is determined
Structure are as follows: 2 α, 3 β, 7 β, 23- tetrahydroxy -12- alkene -28- ursolic acid, be a noval chemical compound, 1H-NMR spectrum, 13C-NMR spectrum
Signals assignment is shown in Table 2.
1H NMR and the 13C NMR data of 2. compound 2 of table
Embodiment 4
The research of the antidepressant activity of compound 1 and compound 2:
Whether mouse shows the effect of antidepression sample in mouse forced swimming test and Tail suspension test, is antidepressant
Basic screening test.
Mouse forced swimming test:
Mouse is divided into 3 groups using random digits table, every group 12, i.e. blank control group, 1 (10mg/ of noval chemical compound
Kg) group, noval chemical compound 2 (10mg/kg) group, the daily stomach-filling of groups of animals 1 time, each 0.2ml/10g, successive administration 7 days.Even
Continuous administration carried out mouse forced swimming test dead time record after 7 days respectively.
Mouse is individually placed in diameter 12cm, depth of water 15cm in 25 DEG C of water temperature of circular glass container, is put between glass jar
One opaque partition, sees each other to prevent mouse, observes the accumulative dead time in 6min.Determine motionless standard: mouse exists
Stop struggling in water, or be in floating state, only tiny limb motion is to keep head to keep afloat.
The mouse for giving compound 1 and compound 2 significantly shortens non-swimming time, shows compound 1 and chemical combination
Object 2 has effects that antidepression (being shown in Table 3).
Table 3. influences each group mouse dead time after being administered
Note: P < 0.05 *, compared with blank control group.
Tail suspension test:
It is grouped and is administered same mouse forced swimming test.Mouse tail (at away from tail point 1cm) is sticked to adhesive plaster and is higher by table
On the batten of face 5cm, make it in handstand state, mouse sight is isolated with plate in surrounding.Mouse is earned to overcome abnormal position
Bundle activity, but occur motionless, the disappointed state of display after movable a period of time.When the dead time for recording mouse in 6min is disappointment
Between.
The mouse for giving compound 1 and compound 2 significantly shortens the aerial dead time, shows compound 1 and chemical combination
Object 2 has effects that antidepression (being shown in Table 4).
Table 4. influences each group mouse dead time after being administered
Note: P < 0.001 * * P < 0.01, * * *, compared with blank control group.
Specific embodiments of the present invention are described in detail above, but it is merely an example, the present invention is simultaneously unlimited
It is formed on particular embodiments described above.To those skilled in the art, any couple of present invention carries out equivalent modifications and
Substitution is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and
Modification, all should be contained within the scope of the invention.
Claims (2)
- Application of 1.2- oxo -3 β, 21 β, the 23- trihydroxy -12- alkene -28- ursolic acid in preparation antidepressant, wherein 2- The structural formula of oxo -3 β, 21 β, 23- trihydroxy -12- alkene -28- ursolic acid is as shown in compound 1:
- 2. a kind of medicine composition for treating depression, which is characterized in that described pharmaceutical composition includes -3 β of 2- oxo, tri- hydroxyl of 21 β, 23- Base -12- alkene -28- ursolic acid, wherein the structural formula such as chemical combination of 2- oxo -3 β, 21 β, 23- trihydroxy -12- alkene -28- ursolic acid Shown in object 1:
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| CN104961790A (en) | 2015-10-07 |
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