CN103739637A - 2-O-beta-D-glucose-4-methoxy-6,4'-dihydroxy diphenyl ketone, and preparation method and application thereof - Google Patents

Abstract

The invention relates to the field of biological medicines, and particularly relates to 2-O-beta-D-glucose-4-methoxy-6,4'-dihydroxy diphenyl ketone (I) shown in the specification. The invention also discloses a preparation method of 2-O-beta-D-glucose-4-methoxy-6,4'-dihydroxy diphenyl ketone. 2-O-beta-D-glucose-4-methoxy-6,4'-dihydroxy diphenyl ketone is obtained by performing biotransformation on 2,6,4'-trihydroxy-4-methyoxy diphenyl ketone by using a strain with a collection number of NRRL1086 (Northern Regional Research Laboratory). The invention further discloses application of 2-O-beta-D-glucose-4-methoxy-6,4'-dihydroxy diphenyl ketone to antianaphylaxis.

Description

2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel, Its Preparation Method And Use

Technical field

The present invention relates to bio-pharmaceutical field, be specifically related to 2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel and preparation method thereof, the invention also discloses its antianaphylactic purposes.

Background technology

The anaphylactic diseases such as allergic rhinitis, asthma, idiopathic dermatitis, colitis, food anaphylaxis, drug allergy are class common diseases, along with the control of infectious diseases and the raising of industrialization degree, the sickness rate of anaphylactic disease is and increases year by year trend in worldwide, has become the Global Health problem that national governments show great attention to.Doctor trained in Western medicine is known this cause of disease at present not yet completely, Chinese materia medica has its advantage characteristic preventing and treating aspect anaphylactic disease, especially at mitigate the disease, prevent recurrence, maintain the aspects such as the state of an illness is long-term, stable, the life quality that improves patient and have good result, but still insufficient to the science explaination of its validity.Therefore, from resourceful Chinese medicine, find novel Claritin, for the control of anaphylactic disease, there are realistic meaning and bright prospects.In the early-stage Study of China Medicine University's Chinese medicine compound prescription laboratory, find, 2-O-α-L-rhamnosyl-4,6,4 '-trihydroxybenzophenone has obvious anti-allergic effects.But natural origin and the kind of benzophenone glucosides are limited, and cost is high, utilize the glycosylation modified rare report of microorganism of benzophenone aglycon.

Microbial transformation is to utilize the specific enzymes exogenous compound of microorganisms to carry out the specific biochemical reaction of structural modification.Microbial transformation has the three-dimensional arrangement selectivity of height, can the catalysis of single-minded ground specifically react, without loaded down with trivial details protection and deprotection, operate, and has advantages of efficient, environmental protection, is a kind of effective ways that natural radioactivity compound carries out structural modification.If introduce glycosyl in the benzophenone compound that contains multiple hydroxyls, can increase the kind of benzophenone glucosides, and then filter out the active even active higher compounds that have more.

Summary of the invention

The invention discloses the compound of structural formula I:

Called after 2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel.The present invention also comprises the solvate of the compound of structural formula I simultaneously.

It ¹³c-NMR data are C (1) 111.8, C (2) 158.4, C (3) 95.0, C (4) 164.3, C (5) 96.9, C (6) 159.1, C (7) 197.0, C (1 ') 138.5, C (2 ') 133.5, C (3 ') 116.0, C (4 ') 164.0, C (5 ') 116.0, C (6 ') 133.5, with 2,6,4 '-trihydroxy--4-methoxy benzophenone ¹³c-NMR data are compared, and can determine that its parent nucleus is 2,6,4 '-trihydroxy--4-methoxy benzophenone, can determine that by the variation in chemical shift sugar is to be connected in C ₂on position.Also have in addition 6 Glucose Carbon signals, be respectively GLC (1) 102.6, GLC (2) 74.8, GLC (3) 77.9, GLC (4) 71.3, GLC (5) 78.3, GLC (6) 62.6.It also has separately a methoxyl group carbon signal to be: C _4-OMe55.9.

Pharmacological testing proves, formula I compound of the present invention has excellent antiallergic effect.

Formula I compound of the present invention preferably uses bioconversion method with 2,6, and 4 '-trihydroxy--4-methoxy benzophenone is that substrate transforms preparation, and method is as follows:

In order to find suitable conversion 2,6,4 '-trihydroxy--4-methoxy benzophenone becomes 2-O-β-D-Glucose-4-methoxyl group-6, the bacterial classification of 4 '-dihydroxy benaophenonel, the present invention has screened multiple bacterial classifications altogether, found that, preserving number is that NRRL1086 bacterial classification is to 2,6,4 '-trihydroxy--4-methoxy benzophenone has stronger conversion capability (in Table 2).

Screen liquid nutrient medium used (PDA): 200 grams of fresh peeling potatos add after boiling water 500ml boils 15min filters, and filtrate adds glucose 20g, KH ₂pO ₄3.0g, MgSO ₄0.75g, Vb ₁10.0mg, adding distil water is settled to 1.0L, adds NaOH or HCl adjust pH to 6.0, every bottle of packing 30ml liquid nutrient medium of 150ml Erlenmeyer flask, 121 ℃, 0.15MPa sterilizing 20min.

During strain screening, preserve bacterial classification slant medium used and be the agar that adds 1.5% at aforesaid liquid substratum, the every pipe 5ml of 15ml tool plug test tube, makes after 121 ℃, 0.15MPa sterilizing 20min are cooling.

The preservation of bacterial classification and activation: actication of culture adopts two step activation methods, referring to: Nair, M.S.R., and Basile, D.V.Bioconversion of artenium B to artmisinn. natural product magazine (Jounal of Natural Products) 1993,56 (9): 1559.First bacterial classification is inoculated in to liquid nutrient medium, after 28 ℃ of 180r/min rotating and culturing 24-48h, transfers in another liquid nutrient medium, inoculum size 1-5%(V/V), with application of sample after condition cultivation 24h.

The preparation of sample and application of sample: 2,6,4 '-trihydroxy--4-methoxy benzophenone is dissolved in ethanol, is made into 10mg/ml solution for standby; Every bottle of bacterium liquid (30ml) through two step activation adds 0.5ml sample solution, makes every bottle of bacterium liquid containing 2,6,4 '-trihydroxy--4-methoxy benzophenone 5mg.With condition, cultivate after 120h, stopped reaction, filters thalline, and fermented liquid extracts 3～5 times by the ethyl acetate of equivalent, combining extraction liquid, recovery ethyl acetate; Be extracted medicinal extract, extraction using alcohol 3 times for thalline, united extraction liquid, reclaims ethanol, obtains extracting medicinal extract, by two kinds of medicinal extract and also, adds a little acetic acid ethyl dissolution standby thin layer and identifies use.

Blank: blank is established positive control (substrate+substratum), negative control (substratum+bacterium), solvent control (substratum+bacterium+ethanol), cultivation and extraction conditions are the same.

The thin layer of converted product is identified:

Thin layer condition:

Thin layer plate: the silica gel G plate that 0.7% CMC-Na makes.

Developping agent: chloroform: methyl alcohol: water (85: 15: 0.15).

Developer: 10% sulfuric acid ethanol.

Operation:

Transform extract and blank extract and put in thin layer plate respectively, ascending method is fully launched rear taking-up and is naturally dried, and spray is with 10% sulfuric acid ethanol, and heating develops the color.Conversion results is in Table 2.

Table 2 microbial transformation 2,6,4 '-trihydroxy--4-methoxy benzophenone the selection result

Bacterial classification	The selection result
		Mucor sp.	—
Streptomyces sp.	—
		Beauveria sp.	—
Rhizopus sp.	—
		Gibberella sp.	—
NRRL-5646	+++
		SC-2831	—
SC-2831-DD	—
		U1315-BN	—
Alternaria sp.	—
		Alternaria sp.	—
Fusarium sp.	—
		Phomopsis sp.	—
Phomopsis sp.	—
		G.deliquescens. NRRL-1086	+++

From the selection result, there are 2 kinds of bacterium to transform, NRRL 1086, through measuring and calculating, transformation efficiency can reach 65%.And NRRL 5646 is not glycosylation conversion.Therefore, the present invention selects bacterial strain NRRL 1086, and with 2,6,4 '-trihydroxy--4-methoxy benzophenone is that raw material is prepared 2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel.

The invention discloses a kind of preparation method of preparation I compound, with preserving number be NRRL 1086 bacterial strains to 2,6,4 '-trihydroxy--4-methoxy benzophenone carries out bio-transformation acquisition.

Preferred method is: with 2,6,4 '-trihydroxy--4-methoxy benzophenone is substrate, utilize the bacterial strain of preserving number for NRRL 1086, substrate and this bacterial strain are cultivated altogether 3～8 days in substratum, and termination reaction, with organic solvent extraction, concentrated extract, is separated and be get final product by silica gel column chromatography.

Wherein organic solvent is selected from one or more in ethyl acetate, chloroform, methylene dichloride, ethyl formate, butylacetate, toluene, normal hexane, propyl carbinol.More preferably ethyl acetate.

Silica gel column chromatography separation is carried out gradient elution with chloroform and methyl alcohol.

Substratum contains 10 ~ 30% potato decoction liquor, KH ₂pO ₄, MgSO ₄, VITMAIN B1 and be selected from Portugal

One or more carbon sources in grape sugar, sucrose, bud sugar, starch, medium pH=5.0 ~ 7.0.Be weight percentage.

Wherein, by 100 milliliters of 20% potato decoction liquor, in substratum, the preferred content of each component is KH ₂pO ₄containing 0.1 ~ 0.5 gram; MgSO ₄containing 0.05 ~ 0.5 gram; Glucose or sucrose 0.5-2.5 gram.

Highly preferred preparation method is: by preserving number be the bacterial strain of NRRL 1086 by inclined plane inoculating in liquid nutrient medium, put 28 ℃, rotating speed is to cultivate and within 24 hours, become seed liquor in the shaking table of 180r/m, and seed liquor continues to cultivate 24 hours after being forwarded to fermented liquid, adds conversion of substrate; Continuation is cultivated after 144 hours and is stopped catalyzed reaction, filters thalline, and fermented liquid extracts 5 times by the ethyl acetate of equivalent, and combining extraction liquid, recovery ethyl acetate, be extracted medicinal extract, and medicinal extract is column chromatography for separation after silica gel mixed sample; Take chloroform-methanol as elution system.Converted product, through recrystallizing methanol, obtains yellow unformed Powdered converted product.

Pharmacological testing proves, structural formula I compound of the present invention has significant anti-allergic effects, is below test method and result:

2-O-β-D-Glucose-4-methoxyl group-6, the research of 4 '-dihydroxy benaophenonel antiallergic activity

1, mouse skin passive anaphylaxis (PCA)

Hair is shaved at male ICR mouse back, and places magnetic tubule in left and right foot sole of the foot central authorities.Every group of 8-10 only, after etherization, back intradermal injection anti-DNP IgE monoclonal antibody (Sigma) (2 times of dilutions) 20 μ L, after 23 hours, random gavage gives each group of medicine, wherein positive control drug is Vena (DPH), after 1 hour, tail vein injection is containing AZO-blue (0.5%NS preparation) 0.25ml of dinitrophenol(DNP)-bovine serum albumin (DNP-BSA), computer real-time acquisition records mouse itch number of times and Assay of spontaneous activity in 1 hour, and carries out data analysis with MA201 software.De-cervical vertebra is put to death mouse, gets back locus coeruleus, with 37 ℃ of soaked overnight of 0.7mL 1M potassium hydroxide solution, adds acetone/phosphoric acid solution next day, mixes rear filtration, clear liquid colorimetric estimation 620nm place absorbancy, and conversion is dyestuff seepage discharge.

The results are shown in following table:

The impact that the table 1-1 medicine vascular permeability that passive anaphylaxis causes on mouse skin raises

Group	Dosage (mg/kg)	(μ g) for dyestuff seepage discharge	Inhibiting rate (%)
				Negative control	-	2.06±0.41	-
Model	-	7.13±1.30 ##	-
				Low dosage	5	5.11±0.33	39.84
High dosage	20	3.99±0.46 *	61.53
				DPH	20	3.11±0.18 *	79.30

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05

The impact of the table 1-2 medicine itch behavior that passive anaphylaxis causes on mouse skin

Group	Dosage (mg/kg)	Itch number of times	Inhibiting rate (%)	The itch time (S)	Inhibiting rate (%)
						Negative control	-	24.0±2.8	-	18.7±3.1	-
Model	-	57.5±9.9 ##	-	50.0±6.3 ##	-
						Low dosage	5	45.2±5.2	36.70	38.1±4.3	38.02
High dosage	20	35.1±5.4 *	66.87	27.3±3.8 *	72.52
						DPH	20	26.8±3.6 *	91.64	18.6±3.0 **	100.32

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05, ^*p < 0.01

The impact of the table 1-3 medicine spontaneous activity that passive anaphylaxis causes on mouse skin

Group	Dosage (mg/kg)	Assay of spontaneous activity	Inhibiting rate (%)
				Negative control	-	294.7±70.6	-
Model	-	548.5±80.9 #	-
				Low dosage	5	415.5±73.4	52.40
High dosage	20	360.3±57.1 *	74.15
				DPH	20	230.8±36.3 **	125.17

Compared with negative control group ^#p < 0.05, compared with model group ^*p < 0.05, ^*p < 0.01

From above result, model group mouse skin dyestuff seepage discharge, itch number of times and time and Assay of spontaneous activity all obviously increase, by statistics, and with negative control group comparison, have remarkable or highly significant difference, prompting PCA reaction can cause mouse skin oedema itch and similar irritated state; Ig administration in advance 5,20mg/kg once, obviously inhibition group hydroderma, itch behavior and spontaneous activity, by statistics, all there were significant differences with model group for high dose group and DPH group.Show 2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel has obvious inhibition mouse passive anaphylaxis effect.

2, the mouse skin allergy reaction that histamine brings out

Hair is shaved at male ICR mouse back, and places magnetic tubule in sole central authorities.Every group of 8-10 only, after mark, random gavage gives each group of medicine, after 1 hour, etherization, back intradermal injection histamine 1 00nmol/20 μ l/, the capacity physiological saline such as negative control group injection, tail vein injection 0.5% AZO-blue 0.25ml immediately, computer real-time acquisition records mouse itch number of times and Assay of spontaneous activity in 1 hour, and carries out data analysis with MA201 software.De-cervical vertebra is put to death mouse, gets back locus coeruleus, and the same mensuration absorbancy, the results are shown in following table:

The impact that the table 2-1 medicine vascular permeability that passive anaphylaxis causes on mouse skin raises

Group	Dosage (mg/kg)	(μ g) for dyestuff seepage discharge	Inhibiting rate (%)
				Negative control	-	2.40±0.31	-
Model	-	39.88±3.24 ##	-
				Low dosage	5	35.31±6.32	12.19
High dosage	20	30.51±3.36 *	25.00
				DPH	20	9.73±1.44 **	80.44

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.01, ^*p < 0.05

The impact of the table 2-2 medicine itch behavior that passive anaphylaxis causes on mouse skin

Group	Dosage (mg/kg)	Itch number of times	Inhibiting rate (%)	The itch time (S)	Inhibiting rate (%)
						Negative control	-	20.8±6.4	-	14.9±4.6	-
Model	-	77.0±9.9 ##	-	50.4±6.3 #	-
						Low dosage	5	50.3±6.2	47.51	35.2±4.1	42.81
High dosage	20	49.2±12.3	49.47	30.3±3.5	56.62
						DPH	20	28.6±6.5 *	86.12	20.3±3.7 *	84.79

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05, ^*p < 0.01

The impact of the table 2-3 medicine spontaneous activity that passive anaphylaxis causes on mouse skin

Group	Dosage (mg/kg)	Assay of spontaneous activity	Inhibiting rate (%)
				Negative control	-	174.5±51.1	-
Model	-	607.5±139.8 #	-
				Low dosage	5	400.1±73.1	47.90
High dosage	20	410.6±92.9	45.47
				DPH	20	246.9±47.1 *	83.28

Compared with negative control group ^#p < 0.05, compared with model group ^*p < 0.05

From above result, model group mouse skin dyestuff seepage discharge, itch number of times and time and Assay of spontaneous activity all obviously increase, by statistics, with negative control group comparison, have significantly or highly significant difference, prompting histamine can cause mouse skin oedema itch and similar irritated state; The 20mg/kg of ig administration in advance once, obviously inhibition group hydroderma, all there were significant differences for model group, the itch behavior of simultaneously histamine being brought out and spontaneous activity strengthen, and also have certain inhibition trend.Show 2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel has the mouse anaphylaxis effect that obvious inhibition histamine causes.

3, the dependent mouse three-phase of IgE anaphylaxis (Triphasic model)

Female mouse BALB/C mice tail vein injection 1ml IgE monoclonal antibody, after 24h, in two ears of about mouse, outside is coated with respectively 0.15% 2, 4-dinitrofluorobenzene (DNFB) 25 μ l, negative control group tail vein injection NS, two ears be coated with control solvent (acetone: sweet oil 3: 1) in advance 1h give each group of medicine or in advance 2h give positive control drug hydrocortisone (being abbreviated as Pred) 5mg/kg, measure respectively 1h before administration and after attacking, 2h, 4h, 8h, 12h, 24h, d2-d15 mouse left and right ear thickness, calculated thickness is poor, and calculate respectively 0-4h with reference to formula, 4-48h, area under curve AUC in the d2-d15 timed interval, with this, reflect Acute Phase, tardy phase and extremely tardy equal three-phase anaphylaxis intensity.Result is as follows:

The impact of table 3-1 medicine on the dependent mouse skin three-phase of IgE anaphylaxis Acute Phase

Group	Dosage (mg/kg)	Ear swelling AUC (0-4h, h *10 -2mm)	Inhibiting rate (%)
				Negative control	-	-0.54±0.24	-
Model	-	1.87±0.49 ##	-
				Low dosage	5	1.60±0.25 **	11.20
High dosage	20	0.25±0.44 *	67.22
				Pred	5	-1.36±0.80 **	134.02

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05, ^*p < 0.01

The impact of table 3-2 medicine on the tardy phase of IgE dependent mouse skin three-phase anaphylaxis

Group	Dosage (mg/kg)	Ear swelling AUC (4-8h, h *10 -2mm)	Inhibiting rate (%)
				Negative control	-	-3.4±3.1	-
Model	-	32.4±7.4 ##	-
				Low dosage	5	17.4±2.6 *	41.90
High dosage	20	7.1±1.6 **	70.67
				Pred	5	8.6±12.1 **	66.48

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05, ^*p < 0.01

The impact of table 3-3 medicine on the extremely tardy phase of the dependent mouse skin three-phase of IgE anaphylaxis

Group	Dosage (mg/kg)	Ear swelling AUC (4-8h, h *10 -2mm)	Inhibiting rate (%)
				Negative control	-	38.6±18.3	-
Model	-	424.1±45.9 ##	-
				Low dosage	5	250.6±54.2 *	45.01
High dosage	20	159.5±56.8 **	68.64
				Pred	5	157.0±69.2 **	69.38

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05, ^*p < 0.01

As can be seen here, mouse is giving after IgE sensitization, then is coated with DNFB, can cause ear's anaphylaxis, and ear swelling is 1h after attack respectively, 24h and the 6th day appearance 3 peaks, i.e. Acute Phase, tardy phase and extremely tardy phase; Ig gives medicine 20mg/kg 1 time in advance, obviously inhibition group three-phase anaphylaxis, and especially to rear 2 phase reactions, inhibition degree is suitable with positive drug effect.Show 2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel has the three-phase anaphylaxis effect of obvious inhibition IgE mediation.

4, DNFB is coated with the mouse chronic skin anaphylaxis causing repeatedly

Male BALB/C mice ip 10 μ g dinitrophenol(DNP)-ascaris suum extracts (DNP-Asc) and 1mg alumina gel (alum), in d14, d16, d18, d20, d22 subsequently, in two ears of mouse left and right, outside is coated with respectively 0.15%DNFB acetone soln 25 μ l, d27 plays beginning ig and gives each group of medicine, and continuous 10 days, d35, mouse anesthesia, eye socket is got blood, and separation of serum carries out IgE mensuration.D36 is coated with 0.15%DNFB acetone soln 25 μ l again, and measure and attack itch situation in rear 2h, and ear's swelling situation of 6h and 24h; After measuring, put to death mouse, win thymus gland spleen, weigh, and calculate organ index.

Result is as follows:

Table 4-1 medicine is coated with the impact of the mouse swelling causing repeatedly on DNBP

Group	Dosage (mg/kg)	Ear swelling (6h *10 -2)	Inhibiting rate (%)	Ear swelling (24h *10 -3)	Inhibiting rate (%)
						Negative control	-	0.21±0.07	-	1.33±0.26	-
Model	-	7.79±0.92 ##	-	28.05±1.33 # #	-
						Low dosage	5	4.31±1.13 *	45.91	21.01±3.10 *	26.34
High dosage	20	5.13±0.44 *	35.09	22.13±1.31 *	22.16
						FK506	10	1.99±0.51 **	76.52	24.77±0.27	12.28

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05, ^*p < 0.01

Table 4-2 medicine is coated with the impact of the mouse itch behavior causing repeatedly on DNBP

Group	Dosage (mg/kg)	Itch number of times	Inhibiting rate (%)	The itch time (s)	Inhibiting rate (%)
						Negative control	-	202.0±85.4	-	90.7±41.6	-
Model	-	1239.4±55.9 ##	-	482.7±20.3 # #	-
						Low dosage	5	960.1±91.1 *	26.92	430.0±25.1	13.44
High dosage	20	949.1±54.3 *	27.98	432.3±34.4	12.86
						FK506	10	602.5±63.5 **	61.39	244.2±28.7 **	60.84

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.05, ^*p < 0.01

Table 4-3 medicine is coated with the impact of mouse model thymus gland index and spleen index repeatedly on DNBP

Group	Dosage (mg/kg)	Thymus index (mg/10g)	Index and spleen index (mg/10g)
				Negative control	-	2.91±0.31	23.88±0.31
Model	-	2.34±0.29	29.85±1.65 #
				Low dosage	5	2.63±1.02	27.82±1.32
High dosage	20	3.21±1.81	25.23±0.66
				FK506	10	1.11±0.13 *	26.69±1.36

Compared with negative control group ^#p < 0.05, compared with model group ^*p < 0.05

Table 4-4 medicine is coated with the impact of mouse model SERUM IgE repeatedly on DNBP

Group	Dosage (mg/kg)	SERUM IgE (ng/ml)
			Negative control	-	692.1±148.6
Model	-	2067.7±245.9 # #
			Low dosage	5	1899.6±354.2
High dosage	20	1353.5±156.8
			FK506	10	3053.1±169.2 **

Compared with negative control group ^##p < 0.01, compared with model group ^*p < 0.01

As can be seen here, DNFB is repeatedly coated with and can causes the anaphylaxis of mouse chronic skin, and show as SERUM IgE highly significant and raise, 6h after attacking, there is serious itch in mouse, in observation 2h, itch number of times and time and negative control group comparison, all highly significant increases; 6h and 24h, all there is serious swelling in ear, to the inhibiting rate of 24h ear swelling higher than positive control drug FK506(20% powder) (Fujisawa Pharmaceutical co.L.td.Osaka, Japan), not the latter does not suppress the side effect of thymus gland and rising SERUM IgE; Low dose group itch number of times significantly reduces, and shows 2-O-β-D-Glucose-4-methoxyl group-6, and 4 '-dihydroxy benaophenonel has the reactivity of obvious inhibition chronic allergic.

2-O-β-D-Glucose-4-of the present invention methoxyl group-6,4 '-dihydroxy benaophenonel can mix with pharmaceutically acceptable carrier, for the preparation of medicine for treatment compositions.Can be prepared into formulation general in pharmaceutics, as parenteral dosage forms such as the gastrointestinal administration formulations such as capsule, tablet, pill, oral liquid, granule, tincture, sustained release dosage and injection, transdermal patch, external preparations.

Embodiment

Embodiment 1

2-O-β-D-Glucose-4-methoxyl group-6, the preparation of 4 '-dihydroxy benaophenonel:

Substrate 2,6,4 '-trihydroxy--4-methoxy benzophenone 200mg is dissolved in 20mL ethanol; The glucose solution 100mL of preparation 0.5g/ml, sterilizing (the same PDA of condition); Bacterial classification NRRL1086 by the solid inclined plane inoculating of 4 ℃ to liquid PDA substratum (substratum by 100 milliliter of 20% potato decoction liquor containing KH ₂pO ₄0.3 gram; MgSO ₄0.75 gram; 10 grams of glucose; 0.01 gram of preparation of VITMAIN B1, liquid nutrient medium divides the triangular flask that is filled to 150mL, every bottled liquid 30mL), to shaking table, cultivate 24 hours (28 ℃, 180r/m), be seed liquor; Seed liquor is transferred under aseptic condition in liquid PDA substratum (substratum composition is the same), in shaking table, continues to cultivate 24 hours.Every bottle adds 1mL 2,6,4 '-trihydroxy--4-methoxy benzophenone solution and 3mL sucrose solution, cultivate termination reaction after 144 hours.Fermented liquid extracts 6 times by the ethyl acetate of equivalent, combining extraction liquid, recovery ethyl acetate; Be extracted medicinal extract 289mg, take 100-200 order silica gel 0.8g and residue and evenly mix sample, column chromatography 200～300 order 20g dry column-packings, chloroform-methanol gradient elution, in chloroform-methanol=90: in 10 eluting fraction, can obtain target converted product 2-O-β-D-Glucose-4-methoxyl group-6,4 '-dihydroxy benaophenonel, through recrystallizing methanol, obtain yellow unformed powder 113mg.

Its carbon spectrum as above-mentioned.

Embodiment 2

Tablet

Get 2-O-β-D-Glucose-4-methoxyl group-6 that embodiment 1 makes, 4 '-dihydroxy benaophenonel 100g and starch 50g, dextrin 50g mixes, with appropriate 30% ethanol, make wetting agent, make softwood, ordinary method is granulated, add appropriate Magnesium Stearate to mix, make tablet.

Claims (9)

1. the compound of structural formula I or its pharmaceutically acceptable solvate:

。

2. the compound of claim 1 or the preparation method of its pharmaceutically acceptable solvate, is characterized in that: with preserving number be NRRL1086 bacterial strain to 2,6,4 '-trihydroxy--4-methoxy benzophenone carries out bio-transformation acquisition.

3. the preparation method of claim 2, wherein bioconversion method is as follows: with 2,6,4 '-trihydroxy--4-methoxy benzophenone is substrate, utilizes the bacterial strain that preserving number is NRRL1086, substrate and this bacterial strain are cultivated altogether 4 ~ 7 days in substratum, termination reaction, fermented liquid organic solvent extraction, concentrated extract, obtain medicinal extract, by silica gel column chromatography, separate and obtain target compound.

4. the preparation method of claim 3, wherein organic solvent comprises: ethyl acetate, chloroform, methylene dichloride, ethyl formate, butylacetate, toluene, hexane, propyl carbinol etc.

5. the preparation method of claim 3, substratum contains 10 ~ 30% potato decoction liquor, KH ₂pO ₄, MgSO ₄, VITMAIN B1 and be selected from glucose, sucrose, bud sugar, starch one or more carbon source, medium pH=5.0 ~ 7.0.

6. the preparation method of claim 3, wherein by 100 milliliters of 20% potato decoction liquor, KH ₂pO ₄0.1 ~ 0.5 gram; MgSO ₄0.05 ~ 0.5 gram; Glucose 0.5-2.5 gram (or sucrose 0.5-2.5 gram).

7. the preparation method of claim 2, wherein bacterial classification first activates before cultivation, soak time 20～30h.

8. a pharmaceutical composition, wherein contains compound or its pharmaceutically acceptable solvate and the pharmaceutically acceptable carrier of claim 1.

9. the compound of claim 1 or its pharmaceutically acceptable solvate are for the preparation of the purposes of Claritin.