CN103159710A - Antiviral decalin derivate - Google Patents

Abstract

The invention relates to an antiviral decalin derivate, and in particular relates to a raw material medicine. The antiviral decalin derivate comprises a compound shown in formula I, which is taken as an active component, wherein R1 and R2 are respectively independently selected from hydrogen, potassium or sodium. The invention also relates to a medicine composition prepared from the raw material medicine, a method for preparing the raw material medicine, and pharmaceutical application of the raw material medicine. The raw material medicine provided by the invention has good pharmaceutical property.

Description

For antiviral Decahydronaphthalenederivative derivative

Technical field

The invention belongs to medical technical field, relate to a kind of can be used for for antiviral Decahydronaphthalenederivative derivative.

Background technology

The dry aerial parts that Herba Andrographis is acanthaceous plant Herba Andrographis (Andrographispaniculata (Burm.F.) Nees), tap when at the beginning of the autumn, cauline leaf is luxuriant, dries.Herba Andrographis has another name called Chun Lianqiuliu, Herba Andrographitis, Lan Helian, Radix Gentianae, golden vanilla, golden tack, India's grass, eel grass etc.Clearing heat and detoxicating, anti-inflammatory, swelling and pain relieving effect are arranged.Cure mainly bacillary dysentery, urinary tract infections, acute tonsillitis, enteritis, pharyngolaryngitis, pneumonia and influenza etc., external application can be treated sore furuncle poison, trauma infection contamination etc.Main product is in provinces such as Guangdong, Fujian, and also introduce a fine variety on the ground such as Central China, North China, northwest.Oneself records this kind in one one of 2010 editions pharmacopeia of the People's Republic of China (PRC).

Comprise following chemical constitution in known Herba Andrographis: the rographolide with typical perhydronaphthalene structure (has another name called andrographolide, Andrographolide), desoxyandrographolide (has another name called dexyandrographolide, deoxyandrographolide), Neoandrographolide (has another name called Neoandrographolide, Neoandrographolide), deoxydidehydrorographolide (has another name called 14-Deoxy-11,12-didehydro-andrographolide, deoxydidehydroandrographolide).People also are prepared into these compounds their derivative through structure of modification in addition, for example:

Rographolide-(deshydroxy, dehydrogenation)-> deoxydidehydrorographolide-(two succinic acid esterification)-dehydroandrograpolide succinate-(further forming an alkali metal salt)-potassium dehydroandrographolide succinate (half K salt) or potassium sodium dehydroandroan drographolide succinate (K-Na salt) etc., their chemical structure difference is as follows:

There is the functions such as clearing heat and detoxicating, cool blood detumescence such as potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate for representing medicine with rographolide (Andrographolide) and derivative thereof.The main effective constituent of the creat formulations commonly used such as treatment upper respiratory tract infection, acute bacillary dysentery, viral cold.Early 1970s, the domestic beginning, by after the cauline leaf of Herba Andrographis or herb extraction, made the common oral preparation such as andrographis tablet.Although ordinary preparation has certain restraining effect to bacterium, virus county, because of the water insoluble power deficiency of its main effective constituent.

Because rographolide is the effective constituent of extracting from Herba Andrographis, monomer purity is high, and quality product and pharmacological action have more advantage than Herba Andrographis.The oral dosage forms such as rographolide tablet, capsule, soft capsule, dripping pill are produced in the own approval of SFDA at present.Its shortcoming is that rographolide is the diterpenes diterpenoids lactones compound, is insoluble in water, usually only can oral administration.For the demand of virus infection acute disease clinically, by introducing different hydrophilic radicals in its structure, strengthen its water-soluble injection that is prepared into, improve curative effect.In China, from the seventies, start the rographolide soluble derivative is studied, developed a series of injections, wherein main product is potassium dehydroandrographolide succinate and potassium sodium dehydroandroan drographolide succinate.

Potassium dehydroandrographolide succinate is rographolide through esterification, dehydration, salify and the POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE of making; Potassium sodium dehydroandroan drographolide succinate be by potassium dehydroandrographolide succinate and sodium hydroxide or carbonic acid (hydrogen) reacting of sodium and the dehydroandrograpolide succinate natrium potassium salt, or jointly react and obtain with carbonic acid (hydrogen) potassium and carbonic acid (hydrogen) sodium by dehydroandrograpolide succinate; Be widely used in clinically the virus diseases such as the high heat for the treatment of, respiratory tract infection, children's rotavirus enteritis, mumps, be one of indispensable pure Chinese medicinal preparation of Emergency department in hospital of TCM (chamber), broken traditional saying that Chinese medicine can only be used for treating chronic disease.

It is clinical that oneself is widely used in current potassium sodium dehydroandroan drographolide succinate, and meanwhile its untoward reaction happens occasionally.According to national drug adverse reaction monitoring center, circulated a notice of in recent years, about the main adverse reaction of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate injection is anaphylaxis and thrombopenia.The main reason that the concrete analysis untoward reaction produces has (1) individual difference (allergic constitution) to cause; (2) oxidation of hydrolysis, open loop, isomerization and the unsaturated link(age) of lactone, easily occur in rographolide poor stability.(3) purity of initial feed (rographolide) is not high, major impurity is macromolecule plant albumen, rographolide hydrolysis, oxidation products and pigment etc., activated carbon decolorizing for bibliographical information, with the ultra-filtration membrane of molecular interception amount 5000, carries out after ultrafiltration the LD50 of mouse single dose intravenous administration to be brought up to 910mg/kg from 757mg/kg; (4) rographolide causes unstable product quality in the process of esterification, dehydration because production technique is unstable.In sum, although this characteristic of traditional Chinese medicine has determined the kind untoward reactions more or less such as potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate, be inevitable, it is also a undisputable fact that the purity of improving the quality of products can increase substantially the product clinical safety.

Therefore, those skilled in the art expect to have new method for clinical andrographolidume derivative such as the potassium dehydroandrographolide succinate that the typical perhydronaphthalene structure of having of superperformance is provided, potassium sodium dehydroandroan drographolide succinate etc.

Summary of the invention

The purpose of this invention is to provide a kind of new andrographolidume derivative with typical perhydronaphthalene structure such as potassium dehydroandrographolide succinate, potassium sodium dehydroandroan drographolide succinate etc., its material medicine that particularly can be used as the compounding pharmaceutical preparation is used.The present invention is achieved in the following ways.

First aspect present invention provides a kind of material medicine, comprising as activeconstituents with the following formula I compound:

Wherein R1 and R2 are selected from hydrogen, potassium or sodium independently of one another.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, wherein said formula I compound is selected from the compound of following formula Ia to formula If:

According to the described material medicine of the arbitrary embodiment of first aspect present invention, it measures in the need testing solution color atlas obtained according to following [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, be about 0.83～0.93 place in relative retention time and show an impurity peaks (in the present invention, this impurity is called RRT0.88 impurity);

[HPLC method A]:

According to two appendix VD high effective liquid chromatography for measuring of Chinese Pharmacopoeia version in 2010;

With octadecylsilane chemically bonded silica, be weighting agent, 0.1% potassium dihydrogen phosphate (phosphoric acid is adjusted pH2.5 ± 0.05) of take is mobile phase A, and acetonitrile is Mobile phase B, flow velocity is 1.0ml/min, 35 ° of C of column temperature, the detection wavelength is 251nm, according to the form below carries out linear gradient elution:

Time (minute)	Mobile phase A (%)	Mobile phase B (%)
			0	65	35
10	65	35
			40	50	50
52	23	77
			53	65	35
62	65	35

The preparation of need testing solution: get trial-product (for example material medicine of the present invention or the pharmaceutical composition that comprises this material medicine for example pharmaceutical preparation) appropriate, accurately weighed, add mixed solvent (mobile phase A: Mobile phase B=60:40) dissolve and dilute the solution of making in every 1ml containing formula I compound 0.4mg, as need testing solution; Precision measures in right amount, makes the solution that contains formula I compound 4 μ g in every 1ml, solution in contrast with thinner;

Get contrast solution 10 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at principal constituent peak be about 20% of full range;

Precision measures need testing solution and each 10 μ l of contrast solution again, and the injection liquid chromatography, record respectively need testing solution color atlas and contrast solution color atlas respectively;

Read peak area and the retention time at principal constituent peak in the contrast solution color atlas, and peak area and the retention time of principal constituent peak and each impurity peaks in the need testing solution color atlas;

For the need testing solution color atlas, the relative retention time of principal constituent chromatographic peak of take is 1, calculates the relative retention time of each impurity chromatographic peak;

For the need testing solution color atlas, for each impurity chromatographic peak, calculate the peak area ratio (this peak area ratio is larger means that the relative content of this impurity for main composition is lower) of principal constituent chromatographic peak and this impurity chromatographic peak;

Optionally, for the need testing solution color atlas, calculate the chromatographic purity of trial-product by area normalization method;

Optionally, for the need testing solution color atlas, calculate single contaminant with respect to the content of principal constituent (can referred to as the content of single contaminant content or single contaminant) and total impurities with respect to the content of principal constituent (can referred to as total impurities content), each single contaminant content sum is total impurities content, wherein with following formula, calculates the content of a certain impurity phase for principal constituent:

According to the described material medicine of the arbitrary embodiment of first aspect present invention, in wherein said [HPLC method A], select suitable chromatogram column length to make principal constituent go out peak between 25～31min.Select suitable chromatogram column length so that principal constituent goes out peak between 25～31min is that those skilled in the art easily realize, for example can select the chromatographic column of 15～30cm, for example can select the chromatographic column of 15cm, 20cm, 25cm, 30cm.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the peak area ratio of principal constituent chromatographic peak and described RRT0.88 impurity chromatographic peak is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.The inventor has been surprisingly found that, in the pharmaceutical composition of controlling material medicine of the present invention or being prepared into by it, the content of RRT0.88 impurity is below a threshold quantity, this material medicine or the pharmaceutical composition be prepared into by it have better stability, and particularly for example RRT1.74 impurity or total impurities increase slowly in the high temperature accelerated test for impurity wherein.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, be about 1.64～1.84 places in relative retention time and show an impurity (in the present invention, this impurity is called RRT1.74 impurity) peak.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the peak area ratio of principal constituent chromatographic peak and described RRT1.74 impurity chromatographic peak is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, in relative retention time, approximately 1.40～1.60 shows one or more impurity peaks for place.In the present invention, this one or more impurity can be described as RRT1.40～1.60 impurity.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the ratio that the peak area of principal constituent chromatographic peak and described relative retention time are about the peak area sum at all dirt peak that 1.40～1.60 places show is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtain, deduction solvent peak and/or auxiliary material peak wherein when the testing drug composition.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, except RRT0.88 impurity mentioned above and RRT1.74 impurity and RRT1.40～1.60 impurity, also optionally contain other impurity.Described other impurity phase can be less than or be greater than RRT0.88 impurity mentioned above, RRT1.74 impurity, RRT1.40～1.60 impurity for the content of principal constituent.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, and single contaminant content is ignored lower than any impurity of 0.01%.That is,, when calculating total impurities content, only calculate single contaminant content higher than those impurity of 0.01%.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, and described single contaminant content is no more than 1.0%.That is, maximum single contaminant content is no more than 1.0%.

According to the described material medicine of the arbitrary embodiment of first aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, and described total impurities content is no more than 2.0%.That is, all dirt content sum is no more than 2.0%.

Term of the present invention " material medicine ", it is the bulk drug that can be used for the preparation preparation, for example, two ones the 619th page " potassium dehydroandrographolide succinate " kind of recording of Chinese Pharmacopoeia version in 2010 (it is formula Ib compound of the present invention) is a kind of material medicine, and it can be used for preparing two the 619th page of pharmaceutical preparation recorded " Potassium DehydroandrograpolidSuccinate Succinate for Injection " kinds of version in 2010.Certainly; in the present invention; as a kind of material medicine; it also should meet other quality index as material medicine usually; for example, as the formula Ib compound of one of material medicine of the present invention, it also should meet in two ones the 619th page " potassium dehydroandrographolide succinate " kind of recording of Chinese Pharmacopoeia version in 2010 about " proterties ", " discriminating ", " inspection ", the lower set quota of " assay " item.And these indexs can by those skilled in the art when the raw materials medicine according to they experience and easily realize, for example when preparation material medicine of the present invention, can easily realize by final drying process the index of " weight loss on drying " under " inspection " item.

First aspect present invention provides the material medicine that can be used for the preparation preparation, and therefore, it is pharmaceutical preparation that the present invention can prepare with this type of material medicine the pharmaceutical composition that comprises them further.

Therefore, second aspect present invention provides a kind of pharmaceutical composition, wherein comprises the described material medicine of first aspect present invention any one, and the acceptable auxiliary material of pharmacy or carrier.

Specifically, second aspect present invention provides a kind of pharmaceutical composition, and it is prepared by material medicine and the acceptable auxiliary material of pharmacy or carrier; Described material medicine comprise as activeconstituents with the following formula I compound:

Wherein R1 and R2 are selected from hydrogen, potassium or sodium independently of one another.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, wherein said formula I compound is selected from the compound of following formula Ia to formula If:

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it measures in the need testing solution color atlas obtained according to following [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, be about 0.83～0.93 place in relative retention time and show an impurity peaks (in the present invention, this impurity is called RRT0.88 impurity);

[HPLC method A]:

According to two appendix VD high effective liquid chromatography for measuring of Chinese Pharmacopoeia version in 2010;

With octadecylsilane chemically bonded silica, be weighting agent, 0.1% potassium dihydrogen phosphate (phosphoric acid is adjusted pH2.5 ± 0.05) of take is mobile phase A, and acetonitrile is Mobile phase B, flow velocity is 1.0ml/min, 35 ° of C of column temperature, the detection wavelength is 251nm, according to the form below carries out linear gradient elution:

Time (minute)	Mobile phase A (%)	Mobile phase B (%)
			0	65	35
10	65	35
			40	50	50
52	23	77
			53	65	35
62	65	35

The preparation of need testing solution: get trial-product (for example material medicine of the present invention or the pharmaceutical composition that comprises this material medicine for example pharmaceutical preparation) appropriate, accurately weighed, add mixed solvent (mobile phase A: Mobile phase B=60:40) dissolve and dilute the solution of making in every 1ml containing formula I compound 0.4mg, as need testing solution; Precision measures in right amount, makes the solution that contains formula I compound 4 μ g in every 1ml, solution in contrast with thinner;

Get contrast solution 10 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at principal constituent peak be about 20% of full range;

Precision measures need testing solution and each 10 μ l of contrast solution again, and the injection liquid chromatography, record respectively need testing solution color atlas and contrast solution color atlas respectively;

Read peak area and the retention time at principal constituent peak in the contrast solution color atlas, and peak area and the retention time of principal constituent peak and each impurity peaks in the need testing solution color atlas;

For the need testing solution color atlas, the relative retention time of principal constituent chromatographic peak of take is 1, calculates the relative retention time of each impurity chromatographic peak;

For the need testing solution color atlas, for each impurity chromatographic peak, calculate the peak area ratio (this peak area ratio is larger means that the relative content of this impurity for main composition is lower) of principal constituent chromatographic peak and this impurity chromatographic peak;

Optionally, for the need testing solution color atlas, calculate the chromatographic purity of trial-product by area normalization method;

Optionally, for the need testing solution color atlas, calculate single contaminant with respect to the content of principal constituent (can referred to as the content of single contaminant content or single contaminant) and total impurities with respect to the content of principal constituent (can referred to as total impurities content), each single contaminant content sum is total impurities content, wherein with following formula, calculates the content of a certain impurity phase for principal constituent:

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, in wherein said [HPLC method A], select suitable chromatogram column length to make principal constituent go out peak between 25～31min.Select suitable chromatogram column length so that principal constituent goes out peak between 25～31min is that those skilled in the art easily realize, for example can select the chromatographic column of 15～30cm, for example can select the chromatographic column of 15cm, 20cm, 25cm, 30cm.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the peak area ratio of principal constituent chromatographic peak and described RRT0.88 impurity chromatographic peak is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.For example this peak area ratio is 200～4000,

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, be about 1.64～1.84 places in relative retention time and show an impurity (in the present invention, this impurity is called RRT1.74 impurity) peak.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the peak area ratio of principal constituent chromatographic peak and described RRT1.74 impurity chromatographic peak is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, is about 1.40～1.60 places in relative retention time and shows one or more impurity peaks.In the present invention, this one or more impurity can be described as RRT1.40～1.60 impurity.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it measures in the need testing solution color atlas obtained according to [HPLC method A], the ratio that the peak area of principal constituent chromatographic peak and described relative retention time are about the peak area sum at all dirt peak that 1.40～1.60 places show is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtain, deduction solvent peak and/or auxiliary material peak wherein when the testing drug composition.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, except RRT0.88 impurity mentioned above and RRT1.74 impurity and RRT1.40～1.60 impurity, also optionally contain other impurity.Described other impurity phase can be less than or be greater than RRT0.88 impurity mentioned above, RRT1.74 impurity, RRT1.40～1.60 impurity for the content of principal constituent.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, and single contaminant content is ignored lower than any impurity of 0.01%.That is,, when calculating total impurities content, only calculate single contaminant content higher than those impurity of 0.01%.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, and described single contaminant content is no more than 1.5%.That is, maximum single contaminant content is no more than 1.5%.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, wherein said [HPLC method A] measures in the need testing solution color atlas obtained, and described total impurities content is no more than 3.0%.That is, all dirt content sum is no more than 3.0%.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it is oral preparations or injection formulations.

According to the described pharmaceutical composition of the arbitrary embodiment of second aspect present invention, it is tablet, capsule, granule, injection (comprising injection liquid and lyophilize powder injection), suspensoid, pill.

Further, third aspect present invention provides the method for preparing the described material medicine of first aspect present invention any one, and it comprises the following steps:

(a) provide dehydroandrograpolide succinate;

(b) make described dehydroandrograpolide succinate be dissolved in 8 times of 35～40 ° of C amounts (, the solute 1kg solvent for use that for example often feeds intake is 8L) in ethanol-acetone-acetic acid-water mixed solution, amount by liquor capacity 0.5% (w/v) adds activated carbon, stir 30min, decarburization is filtered in insulation;

(c) make filtrate at the temperature of 2～8 ° of C standing 10～12 hours to carry out recrystallization, leach crystallization, drying, obtaining dehydroandrograpolide succinate is formula If compound; Optionally

(d) step (c) gained formula If compound is reacted with alkali metal compound in aqueous ethanol solution, obtains with the following formula I compound:

Wherein R1 and R2 are selected from potassium and sodium independently of one another.

The inventor has been found that, that compares processes in other method, after using above-mentioned steps (b) and step (c) crystallization treatment, the gained dehydroandrograpolide succinate is measured under [HPLC method A] of the present invention condition, in its this dehydroandrograpolide succinate, shows and has lower RRT0.88 impurity.In addition, in case of necessity, repeating step (b) and step (c) operation can continue to reduce the RRT0.88 impurity in dehydroandrograpolide succinate.Therefore, according to the described method of the arbitrary embodiment of third aspect present invention, also optionally repeating step (b) and step (c) operate again to carry out crystallization for they.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein ethanol-acetone-acetic acid-water mixed solution described in step (b) comprises acetone, 1～3% (v/v) acetic acid of ethanol, 10～20% (v/v) of 40～50% (v/v) and the water of surplus.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein described in step (d), aqueous ethanol solution is 40～60% aqueous ethanolic solutions.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein described in step (d), alkali metal compound is free: sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus or its combination.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein the molar weight of alkali metal compound described in step (d) is counted 1.0～1.1 times (this feed ratio can obtain single alkalimetal ion salt) or 2.0～2.2 times (this feed ratio can obtain two alkalimetal ion salt) of dehydroandrograpolide succinate molar weight with alkalimetal ion.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein described in step (d), alkali metal compound is free: potassium hydroxide, salt of wormwood or saleratus obtain being formula Ib compound or the formula Ie compound of monopotassium salt or di-potassium.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein described in step (d), alkali metal compound is free: sodium hydroxide, sodium carbonate or sodium bicarbonate obtain being formula Ic compound or the formula Id compound of single sodium salt or disodium salt.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein alkali metal compound described in step (d) is sodium hydroxide, sodium carbonate or sodium bicarbonate and potassium hydroxide, salt of wormwood or saleratus combination, obtains being the formula Ia compound of k-na salt.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein in step (d), make formula If compound doubly measure potassium hydroxide, salt of wormwood or saleratus and react with 1.0～1.1 moles in aqueous ethanol solution, obtain being the formula Ib compound of monopotassium salt; Then make this formula Ib compound doubly measure sodium hydroxide, sodium carbonate or reaction of sodium bicarbonate with 1.0～1.1 moles in aqueous ethanol solution, obtain being the formula Ia compound of k-na salt.

According to the described method of the arbitrary embodiment of third aspect present invention, wherein in step (d), make formula If compound doubly measure sodium hydroxide, sodium carbonate or reaction of sodium bicarbonate with 1.0～1.1 moles in aqueous ethanol solution, obtain being the formula Ic compound of single sodium salt; Then make this formula Ic compound doubly measure potassium hydroxide, salt of wormwood or saleratus and react with 1.0～1.1 moles in aqueous ethanol solution, obtain being the formula Ia compound of k-na salt.

Have been found that by step (b) and step (c) crystallization treatment and can effectively remove the RRT0.88 impurity in dehydroandrograpolide succinate, and this RRT0.88 impurity has no increase significantly in follow-up step (d).Therefore in the inventive method, step (b) and step (c) crystallization treatment can be removed formula Ia compound effectively to the RRT0.88 impurity in formula If compound.It should be noted that, as well known to those skilled in the art, under identical chromatographic conditions, formula If compound and their an alkali metal salt for example formula Ia compound are identical to their retention time of formula Ie compound.

While mentioning ethanol in the present invention, its concentration, refer to 98% ethanol if not otherwise specified.

Fourth aspect present invention provides that the arbitrary embodiment of first aspect present invention is described take material medicine that formula I compound the is activeconstituents purposes in the medicine for the preparation for the treatment of or preventing viral pneumonia, viral upper respiratory tract infection.

Arbitrary embodiment of either side of the present invention, can be combined with other embodiment, as long as they not there will be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they not there will be contradiction.

Below the invention will be further described.

All documents that the present invention quotes from, their full content is incorporated to this paper by reference, and if, when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to explain, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.

In the present invention, the implication of " % " can be determined according to concrete environment for use, and particularly it has as implication as described in " metering " lower the 28 (4) money in two notes on the use of version Chinese Pharmacopoeia in 2010.

In the present invention, if not otherwise indicated, determine various materials for example the formula I compound in material medicine or pharmaceutical composition for example during the content of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate, adopt following [HPLC method B] to be measured.

[HPLC method B]:

Get trial-product (material medicine or pharmaceutical composition) appropriate, accurately weighed, add moving phase and dissolves and dilute and make the solution that contains formula I compound 0.1mg in every 1ml, shake up, according to the method for [HPLC method A], precision measures 10 μ l injection liquid chromatographies, records color atlas, separately get the dehydroandrograpolide succinate reference substance (in the present invention, term " reference substance " has those skilled in the art's known implication usually, particularly can be used for measuring the content of principal constituent in sample to be tested, it can obtain by commercial sources usually, such as passing through to government organs or the purchases of other commercial undertaking such as National Institute for Food and Drugs Control, also can reach more than 99.9% and obtain by for example being purified to content, in the present invention, if not otherwise indicated, the reference substance of mentioning is all that the content/purity of related material is at the reference substance more than 99.9%), measure simultaneously, press external standard method with dehydroandrograpolide succinate (C in the calculated by peak area trial-product ₂₈h ₃₆o ₁₀) content, with the ratio of formula I compound and dehydroandrograpolide succinate molecular weight, multiply each other, obtain the content of trial-product Chinese style I compound.The ratio of above-mentioned dehydroandrograpolide succinate molecular weight, for example when formula I compound be formula Ib compound while being potassium dehydroandrographolide succinate, this ratio is 1.072; When formula I compound is formula Ia compound while being potassium sodium dehydroandroan drographolide succinate, this ratio is 1.1128; And when formula I compound be formula If compound while being dehydroandrograpolide succinate, this ratio is 1.

In the present invention, the chromatographic column that octadecylsilane chemically bonded silica used is weighting agent, the chromatographic column that the octadecylsilane chemically bonded silica that can easily obtain from the market various brands is weighting agent, its column length can be selected as required, can be typically the column length of 10～30cm, the chromatographic column internal diameter can be 4.6mm usually, and flow rate of mobile phase and column temperature also can be adjusted as required, typically flow velocity is 0.8～1.5min, and column temperature is selected the steady temperature between 20～40 ° of C; Especially, in the present invention, can suitably select column's length, flow rate of mobile phase, column temperature etc., so that the retention time at dehydroandrograpolide succinate peak is controlled in the scope of 25～31min, for example be controlled in the scope of 28～31min.Yet, in above-mentioned adjustment dehydroandrograpolide succinate to 25～31min scope, be for the ease of measuring, for example guaranteeing that each chromatographic peak separates the unlikely long recording time that makes color atlas in satisfactory situation, reasonably in the time, completing test.In addition, well-known, after above-mentioned such as chromatographic column brand, column length, flow velocity, column temperature etc. appropriately adjusts, typically each impurity peaks does not have large variation with respect to the relative retention time at principal constituent peak, and this is the ABC in liquid phase chromatography.

Generally speaking, the material medicine of the present invention of using as pharmaceutical raw material, wherein usually should be more than 98% as the content of the formula I compound of activeconstituents, and wherein the content of single impurity should be less than 1.0%, and the content of total impurities should be less than 2.0%.

Generally speaking, medicine as a kind of clinical use, the pharmaceutical composition of being made by material medicine of the present invention is its lyophilize powder injection for example, wherein usually should be in 90～110% scopes of labelled amount as the content of the formula I compound of activeconstituents, and wherein the content of single impurity should be less than 1.5%, the content of total impurities should be less than 3.0% (all for the content of formula I compound wherein).

" pharmaceutically acceptable carrier " used in pharmaceutical composition of the present invention can be the carrier of any routine in field of pharmaceutical preparations.The selection of specific support will be depended on administering mode or disease type and the state that is used for the treatment of particular patient.For the preparation method of the suitable drug composition of specific administration pattern fully in pharmaceutical field technician's ken.For example, can be used as thinner, carrier, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and the lubricant etc. that pharmaceutically acceptable carrier comprises the pharmaceutical field routine.In case of necessity, can also in pharmaceutical composition, add flavouring agent, preservative and sweetener etc.

Pharmaceutical composition of the present invention can be made the various ways such as tablet, pulvis, granule, capsule, oral liquid, paste, creme, injectable emulsion (aseptic powder needle for injection).The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.

The existing medicament of the andrographolidume derivative of list marketing (for example, aqueous injection, powder injection etc.), the effect that it has antiviral property pneumonia, viral upper respiratory tract infection, can be used for treatment or preventing viral pneumonia, viral upper respiratory tract infection.The invention provides a kind of new material medicine, wherein foreign matter content is low, and surprisingly impurity wherein increases slowly in sample prolonged preservation process, shows that this material medicine has satisfactory stability.

The accompanying drawing explanation

Fig. 1: material medicine prepared by the embodiment of the present invention is measured the typical need testing solution HPLC figure obtained through [HPLC method A].Show the about 30min of retention time at material medicine principal constituent of the present invention peak (being denoted as peak 0) in figure, occurred that in the drawings RRT is about 0.88 impurity peaks (be RRT0.88 impurity of the present invention, be denoted as peak 1); In addition, also being presented at RRT in figure is about 1.74 places impurity peaks (be RRT1.74 impurity of the present invention, be denoted as peak 2) is arranged; In addition, also being presented at RRT in figure is about 1.40～1.60 places two obvious impurity peaks (be RRT1.40 of the present invention～1.60 impurity, be denoted as peak 3, peak 4) is arranged.What in figure, after 54min, after sample of baseline fluctuation system test, the moving phase switching formed, do not count chromatographic peak.

Embodiment

By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although, for to realize that many materials and working method that the object of the invention is used are well known in the art, the present invention still does to describe in detail as far as possible at this.

In test below, use the present invention [HPLC method A], wherein concrete condition determination used is:

Chromatographic column: ZORBAX Eclipse XDB-C18 chromatographic column is (purchased from Agilent company, 250mm*4.6mm*5 μ m), flow velocity 1ml/min, the about 30min of formula I compound retention time, the auxiliary material peak that the pharmaceutical preparation of solvent peak and interpolation pharmaceutical excipient shows all eluted before 2.1min, the relative retention time of formula I compound of take is 1, the relative retention time of RRT0.88 impurity is in 0.83～0.93 scope, the relative retention time of RRT1.74 impurity is in 1.64～1.84 scopes, show and may show one or two impurity peaks between relative retention time 1.40～1.60, because of content different different.Term " relative retention time " refers to that take formula I compound peaks is benchmark, the value with the retention time of each chromatographic peak divided by the retention time gained of this formula I compound peaks, and this definition is well known to a person skilled in the art.

preparation example part: the preparation of dehydroandrograpolide succinate

Preparing material medicine of the present invention raw material used is dehydroandrograpolide succinate, and it can prepare by art methods, for example:

Preparation example 1: the method that is last 4 line descriptions of page 2 with reference to [0014] section of CN102584752A (Chinese Patent Application No. 201210033663.4, Kaifeng pharmacy) Instructions Page 2 prepares.

Preparation example 2: the method with reference to CN102617527A (Chinese Patent Application No. 201210051312.6, the Hubei lotus is general) specification sheets [0048] to [0049] section prepares.

Preparation example 3: with reference to CN1450059A (Chinese Patent Application No. 02113587.8, Chengdu San Kang) formula (III) compound that the method that Instructions Page 3 the reciprocal the 16th walks to the 11st line description reciprocal prepares is dehydroandrograpolide succinate.

the embodiment part: the material medicine of the present invention that formula I compound is activeconstituents is take in preparation

Below, in the example of the material medicine of preparation formula I compound of the present invention, take the dehydroandrograpolide succinate charging capacity as 1mol for every batch.

embodiment 1: the dehydroandrograpolide succinate of preparation formula If

Method for making: (a) provide dehydroandrograpolide succinate (preparation example 1 gained);

(b) described dehydroandrograpolide succinate is dissolved in 8 times of amount ethanol-acetone-acetic acid-water mixed solutions (containing the water of 45% ethanol, 15% acetone, 2% acetic acid and surplus) of 37 ° of C, amount by liquor capacity 0.5% (w/v) adds activated carbon, stir 30min, decarburization (0.22 μ m millipore filtration) is filtered in insulation;

(c) make filtrate at the temperature of 8 ° of C standing 11 hours to carry out recrystallization, leach crystallization, drying, obtain material medicine of the present invention, its activeconstituents is that dehydroandrograpolide succinate is formula If compound.

embodiment 2: the dehydroandrograpolide succinate of preparation formula If

Method for making: (a) provide dehydroandrograpolide succinate (preparation example 1 gained);

(b) described dehydroandrograpolide succinate is dissolved in 8 times of amount ethanol-acetone-acetic acid-water mixed solutions (containing the water of 40% ethanol, 20% acetone, 3% acetic acid and surplus) of 35 ° of C, amount by liquor capacity 0.5% (w/v) adds activated carbon, stir 30min, decarburization (0.22 μ m millipore filtration) is filtered in insulation;

(c) make filtrate at the temperature of 8 ° of C standing 10 hours to carry out recrystallization, leach crystallization, drying, obtain material medicine of the present invention, its activeconstituents is that dehydroandrograpolide succinate is formula If compound.

embodiment 3: the dehydroandrograpolide succinate of preparation formula If

Method for making: (a) provide dehydroandrograpolide succinate (preparation example 1 gained);

(b) described dehydroandrograpolide succinate is dissolved in 8 times of amount ethanol-acetone-acetic acid-water mixed solutions (containing the water of 50% ethanol, 10% acetone, 1% acetic acid and surplus) of 40 ° of C, amount by liquor capacity 0.5% (w/v) adds activated carbon, stir 30min, decarburization (0.22 μ m millipore filtration) is filtered in insulation;

(c) make filtrate at the temperature of 2 ° of C standing 12 hours to carry out recrystallization, leach crystallization, drying, obtain material medicine of the present invention, its activeconstituents is that dehydroandrograpolide succinate is formula If compound.

embodiment 4: the dehydroandrograpolide succinate of preparation formula If

Method for making: with the dehydroandrograpolide succinate of preparation example 2 gained, feed intake, the method according to embodiment 1, make material medicine of the present invention, and its activeconstituents is that dehydroandrograpolide succinate is formula If compound.

embodiment 5: the dehydroandrograpolide succinate of preparation formula If

Method for making: feed intake with the dehydroandrograpolide succinate of preparation example 3 gained, method according to embodiment 1, make material medicine of the present invention, its activeconstituents is that dehydroandrograpolide succinate is formula If compound (yield of meter is 95% from step (a)).

embodiment 51: the dehydroandrograpolide succinate of preparation formula If

Method for making: feed intake with the dehydroandrograpolide succinate of embodiment 5 gained, according to embodiment 1 step (b) and step (c) method recrystallization again, make material medicine of the present invention, its activeconstituents is that dehydroandrograpolide succinate is formula If compound (yield of meter is 89% from step (a)).

embodiment 52: the dehydroandrograpolide succinate of preparation formula If

Method for making: feed intake with the dehydroandrograpolide succinate of embodiment 51 gained, according to embodiment 1 step (b) and step (c) method recrystallization again, make material medicine of the present invention, its activeconstituents is that dehydroandrograpolide succinate is formula If compound (yield of meter is 83% from step (a)).

embodiment 53: the dehydroandrograpolide succinate of preparation formula If

Method for making: feed intake with the dehydroandrograpolide succinate of embodiment 52 gained, according to embodiment 1 step (b) and step (c) method recrystallization again, make material medicine of the present invention, its activeconstituents is that dehydroandrograpolide succinate is that (from step (a), the yield of meter is 56% to formula If compound; Although the foreign matter content of gained dehydroandrograpolide succinate is lower, the large reduction of its yield is low, therefore as industrial production, says also inadvisable).

embodiment 6: the POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE of preparation formula Ib (being potassium dehydroandrographolide succinate)

Get 40% dissolve with ethanol of embodiment 1 gained formula If compound by 5 times of amounts; (b) solution that contains 5% potassium hydroxide that to add with 40% ethanol be solvent preparation, stir and make reaction, and the two mol ratio of formula If compound-potassium is 1:1.1, stirring makes to react completely, add ethanol to determining alcohol making crystallization more than 80%, leach crystallization, use washing with alcohol, vacuum-drying, obtain.

embodiment 61: the POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE of preparation formula Ib (being potassium dehydroandrographolide succinate)

Get embodiment 2 gained formula If compounds, the method for shining CN102617527A (Chinese Patent Application No. 201210051312.6, the Hubei lotus is general) specification sheets [0050] section prepares.

embodiment 7: the dehydroandrograpolide succinate di-potassium of preparation formula Ie

Get 60% dissolve with ethanol of embodiment 2 gained formula If compounds by 5 times of amounts; (b) solution that contains 8% salt of wormwood that to add with 60% ethanol be solvent preparation, stir and make reaction, and the two mol ratio of formula If compound-potassium is 1:2.2, stirring makes to react completely, add ethanol to determining alcohol making crystallization more than 80%, leach crystallization, use washing with alcohol, vacuum-drying, obtain.

embodiment 8: the dehydroandrograpolide succinate list sodium salt of preparation formula Ic

Get 40% dissolve with ethanol of embodiment 3 gained formula If compounds by 5 times of amounts; (b) solution that contains 8% sodium bicarbonate that to add with 40% ethanol be solvent preparation, stir and make reaction, and the two mol ratio of formula If compound-sodium is 1:1.0, stirring makes to react completely, add ethanol to determining alcohol making crystallization more than 80%, leach crystallization, use washing with alcohol, vacuum-drying, obtain.

embodiment 9: the dehydroandrograpolide succinate disodium salt of preparation formula Id

Get 50% dissolve with ethanol of embodiment 4 gained formula If compounds by 8 times of amounts; (b) solution that contains 5% sodium hydroxide that to add with 50% ethanol be solvent preparation, stir and make reaction, and the two mol ratio of formula If compound-sodium is 1:2.0, stirring makes to react completely, add ethanol to determining alcohol making crystallization more than 80%, leach crystallization, use washing with alcohol, vacuum-drying, obtain.

embodiment 10: the PSDS of preparation formula Ia (being potassium sodium dehydroandroan drographolide succinate)

Get 40% dissolve with ethanol of embodiment 5 gained formula If compounds by 5 times of amounts; (b) adding with 40% ethanol is the solution that contains 5% sodium bicarbonate and saleratus that solvent is prepared, stirring makes reaction, formula If compound-sodium bicarbonate-saleratus three's mol ratio is 1:1.0:1.0, stirring makes to react completely, add ethanol to determining alcohol making crystallization more than 80%, leach crystallization, use washing with alcohol, vacuum-drying, obtain, the test that this sample is correlated with for the present invention.And its color atlas according to [HPLC method A] mensuration gained need testing solution as shown in Figure 1.

In addition, in supplementary test, when the mol ratio of using 60% ethanol instead or using formula If compound-sodium bicarbonate-saleratus three instead is 1:1.1:1.1, the k-na salt of the formula Ia that two samples that obtain and top method obtain is identical aspect the peak area ratio of peak area ratio, principal constituent chromatographic peak and the described RRT1.74 impurity chromatographic peak of principal constituent chromatographic peak and described RRT0.88 impurity chromatographic peak, maximum single assorted, total impurities, shows that the small adjustment of above-mentioned steps can not affect product property.

embodiment 101: the PSDS of preparation formula Ia (being potassium sodium dehydroandroan drographolide succinate)

Get embodiment 51 gained formula If compounds, the method for shining CN102617527A (Chinese Patent Application No. 201210051312.6, the Hubei lotus is general) specification sheets [0050] to [0051] section prepares.

embodiment 102: the PSDS of preparation formula Ia (being potassium sodium dehydroandroan drographolide succinate)

Get embodiment 52 gained formula If compounds, the method for embodiment 10 prepares.

embodiment 103: the PSDS of preparation formula Ia (being potassium sodium dehydroandroan drographolide succinate)

Get embodiment 53 gained formula If compounds, the method for embodiment 10 prepares.

embodiment 11: the PSDS of preparation formula Ia (being potassium sodium dehydroandroan drographolide succinate)

Get the POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE of embodiment 6 gained formula Ib, with 50% dissolve with ethanol of 5 times of amounts; (b) adding with 50% ethanol is the solution that contains 10% sodium bicarbonate that solvent is prepared, stirring makes reaction, the two mol ratio of formula Ib compound-sodium bicarbonate is 1:1.1, stirring makes to react completely, add ethanol to determining alcohol making crystallization more than 80%, leach crystallization, use washing with alcohol, vacuum-drying, obtain.

embodiment 12: the PSDS of preparation formula Ia (being potassium sodium dehydroandroan drographolide succinate)

Get the dehydroandrograpolide succinate list sodium salt of embodiment 8 gained formula Ic, with 50% dissolve with ethanol of 5 times of amounts; (b) solution that contains 10% salt of wormwood that to add with 50% ethanol be solvent preparation, stir and make reaction, and the two mol ratio of formula Ic compound-potassium is 1:1.0, stirring makes to react completely, add ethanol to determining alcohol making crystallization more than 80%, leach crystallization, use washing with alcohol, vacuum-drying, obtain.

embodiment 13: the PSDS of preparation formula Ia (being potassium sodium dehydroandroan drographolide succinate)

Get embodiment 1 gained formula If compound, the method for shining CN102617527A (Chinese Patent Application No. 201210051312.6, the Hubei lotus is general) specification sheets [0050] to [0051] section prepares.

reference examples 1: preparation POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE (it is formula Ib compound)

According to the method for CN102617527A (Chinese Patent Application No. 201210051312.6, the Hubei lotus is general) specification sheets [0048] to [0050] section, prepare POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE (it is formula Ib compound, i.e. potassium dehydroandrographolide succinate).

reference examples 2: prepare PSDS (it is formula Ia compound)

According to the method for CN102617527A (Chinese Patent Application No. 201210051312.6, the Hubei lotus is general) specification sheets [0048] to [0051] section, prepare PSDS (it is formula Ia compound, i.e. potassium sodium dehydroandroan drographolide succinate).

reference examples 3: prepare PSDS (it is formula Ia compound)

With reference to CN102584752A (Chinese Patent Application No. 201210033663.4, the Kaifeng pharmacy) specification sheets [0014] to [0015] section is the method that embodiment mono-describes, prepare PSDS (it is formula Ia compound, i.e. potassium sodium dehydroandroan drographolide succinate).

reference examples 4: prepare PSDS (it is formula Ia compound)

With reference to CN102382082A (Chinese Patent Application No. 201110264481.3, Zhou Xiaodong) method that specification sheets [0044] is described to [0046] section, prepare PSDS (it is formula Ia compound, i.e. potassium sodium dehydroandroan drographolide succinate).

the dehydroandrograpolide succinate of reference examples 5: preparation formula If (it is formula If compound)

With reference to the method for embodiment 1, different is that the middle aqueous solution used of step (b) is without acetone.

the dehydroandrograpolide succinate of reference examples 6: preparation formula If (it is formula If compound)

With reference to the method for embodiment 1, different is that the aqueous solution used in step (b) contains 5% acetone.

the dehydroandrograpolide succinate of reference examples 7: preparation formula If (it is formula If compound)

With reference to the method for embodiment 1, different is that the aqueous solution used in step (b) contains 30% acetone.

the dehydroandrograpolide succinate of reference examples 8: preparation formula If (it is formula If compound)

With reference to the method for embodiment 1, different is that the middle aqueous solution used of step (b) is without acetic acid.

the test example part

test example 1: the chemical constitution of measuring each sample

Measure above each preparation example according to the present invention [HPLC method A] and/or [HPLC method B] method, embodiment, reference examples gained sample, calculate in the need testing solution color atlas of each sample, the peak area ratio of principal constituent chromatographic peak and described RRT0.88 impurity chromatographic peak (meaning with " peak area ratio master/RRT0.88 "), the peak area ratio of principal constituent chromatographic peak and described RRT1.74 impurity chromatographic peak (meaning with " peak area ratio master/RRT1.74 "), the content (%) of maximum single contaminant (meaning with " maximum single assorted "), and all dirt content sum (%) (meaning with " total impurities "), result is as table 1.In the present invention, maximum single mixing may be RRT0.88, RRT1.74 or RRT1.40-1.60, also may not, therefore, when the present invention calculates the trial-product chemical constitution, needn't do explanation one by one to the single assorted retention time of this maximum.

Table 1:

From the table result known, preparation example 1,2,3 gained half esters-slightly have lower master/RRT0.88 value and master/RRT1.74 value, show that these samples RRT0.88 and RRT1.74 content are than the height of embodiment of the present invention sample, maximum single contaminant and total impurities also show that preparation example 1,2,3 samples are than the height of embodiment of the present invention sample.In addition, the formula I compound that reference examples 1-4 is used prior art to obtain, their RRT0.88 and RRT1.74 content are than the height of embodiment of the present invention sample, and maximum single contaminant and total impurities also show the height than embodiment of the present invention sample; Surprisingly, reference examples 5-7 is not used acetone or uses lower acetone or use too high acetone in step (b), perhaps in reference examples 8, do not use acetic acid, the formula I compound of these reference examples gained, their RRT0.88 and RRT1.74 content are than the height of embodiment of the present invention sample, and maximum single contaminant and total impurities also show the height than embodiment of the present invention sample.Containing appropriate acetone and acetic acid in the aqueous solution used in the visible step in the third aspect present invention method (b) is favourable for preparation material medicine of the present invention.

In addition, also calculated in the need testing solution color atlas, the peak area of principal constituent chromatographic peak and described relative retention time are about the ratio of the peak area sum at all dirt peak that 1.40～1.60 places show, result shows in the need testing solution color atlas of various embodiments of the present invention sample, this peak area ratio is all in 200～5000 scopes, this peak area ratio that this peak area ratio that for example this peak area ratio of embodiment 1 is 545, embodiment 5 is 225, embodiment 103 is 4250.

test example 2: preparation is not mixed containing the formula I raw materials of compound medicine of RRT0.88 and the RRT0.88 of substantially pure substantially matter

test example 21, prepare the formula I compound (formula If compound) of substantially pure

Feed intake with the dehydroandrograpolide succinate of embodiment 53 gained, shine embodiment 1 step (b) and step (c) method recrystallization 4 times, obtaining desciccate is dehydroandrograpolide succinate (formula If compound).

test example 22, prepare the formula I compound (formula Ia compound) of substantially pure

Use-testing example 21 gained formula If compounds are raw material, according to embodiment 10 methods, prepare the PSDS (being potassium sodium dehydroandroan drographolide succinate) of formula Ia.

test example 23, prepare the formula I compound (formula Ib compound) of substantially pure

Use-testing example 21 gained formula If compounds are raw material, according to embodiment 6 methods, prepare the PSDS (being potassium dehydroandrographolide succinate) of formula Ib.

The formula I compound of above test example 21,22,23 gained, they are measured through [HPLC method A] respectively, and result shows, for these three products, the two peak area ratio of formula I compound and RRT0.88 impurity all is greater than 40000, can think that it is containing RRT0.88 impurity fully; The two peak area ratio of formula I compound and RRT1.74 impurity all is greater than 10000, and maximum single contaminant all is less than 0.005%, and total impurities all is less than 0.05%, and the content of formula I compound is between 99.94%～99.97%.These products can be thought the formula I compound of the present invention of substantially pure.

test example 24, prepare the RRT0.88 impurity of substantially pure

Using preparation example 3 gained dehydroandrograpolide succinates as raw material, use the chromatographic condition of [HPLC method A], the ZORBAX Eclipse XDB-C18 chromatographic column of use preparative (purchased from, Agilent company, 300mm*10mm*7 μ m), intercepting and RRT0.88 impurity phase are answered the elutriant of retention time chromatographic peak, the gained elutriant is desolventized, carry out recrystallization again in ethanol-acetone (4:1), obtain the RRT0.88 impurity of substantially pure, it is measured chromatographic purity with [HPLC method A] and all is greater than 99.3%, and formula I compound and other impurity do not detected.

test example 3: the formula I raw materials of compound medicine and the Performance thereof that contain different content RRT0.88 impurity

test example 31: the formula I raw materials of compound medicine that preparation contains different content RRT0.88 impurity

Get the test example 24 gained RRT0.88 impurity of 1 weight part, with the test example 21 gained formula I compounds of some weight fraction (formula I compound and RRT0.88 impurity the two, with " ratio of mixture ", mean, for example 1g test example 24 gained RRT0.88 impurity and 100g formula I compound, being somebody's turn to do " ratio of mixture " is 100), in the Chromatographic Pure Methanol of a little (can make the two fully mix), mix, solvent removed in vacuo, drying, obtain the formula I compound (two kinds of materials that this method can make content differ larger mix) that contains a certain amount of RRT0.88 impurity.The formula I raw materials of compound medicine that contains different content RRT0.88 impurity according to this method preparation, the ratio of mixture of their RRT0.88 impurity and formula I compound is in Table 2.

test example 32: the study on the stability with formula I raw materials of compound medicine of different content RRT0.88 impurity

The medicinal aluminum-plastic composite membrane bag hermetic package of the formula I raw materials of compound that test example 31 gained are contained to different content RRT0.88 impurity, be placed at 45 ° of C temperature and place March (can be described as in the present invention " 45 ° of C3 months are disposed " or " 45 ° of C3 months ").Then measure the two peak area ratio (they are greater than 15000 when disposing without these equal 45 ° of C3 months) of formula I compound in these samples and RRT1.74 impurity according to [HPLC method A], and calculate other total impurities except RRT0.88 impurity in each sample increment (that is, dispose 45 ° of C3 months after other total impurities content except RRT0.88 impurity deduct dispose 45 ° of C3 months before the difference of other total impurities content gained except RRT0.88 impurity).The results are shown in Table 2.

Table 2

No.	Ratio of mixture (formula If/RRT0.88)	Peak area ratio (master/RRT1.74)	Total impurities increment/%
				1	50	87	2.931
2	100	135	1.837
				3	150	205	1.011
4	200	320	0.423
				5	225	460	0.284
6	250	1980	0.093
				7	300	2135	0.084
8	350	2370	0.065
				9	500	2835	<0.05
10	750	3190	<0.05
				11	1000	3480	<0.02
12	1500	>5000	<0.02
				13	2500	>5000	<0.01
14	5000	>5000	<0.01
				15	10000	>5000	<0.01

Visible according to above result, the amount of RRT0.88 is larger, and for example formula If/RRT0.88 particularly is less than at 225 o'clock being less than 250, and RRT1.74 impurity and total impurities wherein can increase greatly, and for example RRT1.74 impurity approximately 0.22%; And If/RRT0.88 is being greater than 250 o'clock RRT1.74 impurity approximately 0.05%, the total impurities increasing amount is also equally very low.

The contriver, in supplementary test, repeats above test example 31 and test example 32, and different is to use formula I compound wherein instead test example 22 gained formula Ia compounds.The result demonstration is basic identical with the result in table 2, and data variation trend and table 2 result are identical, and the mixture peak area ratio (master/RRT1.74) that for example formula Ia/RRT0.88 is 225 is 452, and the total impurities increment is 0.291%.The mixture peak area ratio (master/RRT1.74) that Ia/RRT0.88 is 250 is 2010, and the total impurities increment is 0.095%.

The contriver, in supplementary test, repeats above test example 31 and test example 32, and different is to use formula I compound wherein instead test example 23 gained formula Ib compounds.The result demonstration is basic identical with the result in table 2, and data variation trend and table 2 result are identical, and the mixture peak area ratio (master/RRT1.74) that for example formula Ib/RRT0.88 is 225 is 465, and the total impurities increment is 0.288%.The mixture peak area ratio (master/RRT1.74) that Ib/RRT0.88 is 250 is 2075, and the total impurities increment is 0.092%.

test example 33: the study on the stability of each sample above prepared

Disposing above all preparation example (preparation example 1-3), whole embodiment (embodiment 1-5, embodiment 51-53, embodiment 6, embodiment 61, embodiment 7-10, embodiment 101-103, embodiment 11-13), whole resulting various forms of formula I compounds of reference examples (reference examples 1-8) 45 ° of C3 months according to the study on the stability method in test example 32.Calculate increasing amount (increasing amount=March this foreign matter content-0 month this foreign matter content of each sample RRT0.88 impurity before and after dispose 45 ° of C3 months, this increasing amount more means that this impurity increase is larger, lower same), calculate the increasing amount of each sample RRT1.74 impurity before and after disposing 45 ° of C3 months, calculate the total impurities increment (%) of each sample before and after dispose 45 ° of C3 months (total impurities increment=March total impurities amount-0 month total impurities amount, this total impurities increment more means that this all dirt increase is faster).

Result shows, (1) with regard to the increasing amount of RRT0.88 impurity, all the RRT0.88 impurity increasing amount of preparation example, whole embodiment, whole reference examples is all in 0.15～0.3% scope, for example preparation example 1 sample RRT0.88 impurity increasing amount is 0.27%, for example embodiment 1 sample RRT0.88 impurity increasing amount is 0.21%, and for example reference examples 1 sample RRT0.88 impurity increasing amount is 0.23%.(2) with regard to RRT1.74 impurity increasing amount, all the RRT1.74 impurity increasing amount of embodiment sample is all in 0.10～0.25% scope, for example embodiment 2 sample RRT1.74 impurity increasing amounts are that 0.16%, embodiment, 5 sample RRT1.74 impurity increasing amounts are 0.21%; All all, in 0.75～1.5% scope, for example preparation example 2 sample RRT1.74 impurity increasing amounts are 1.13% to the RRT1.74 impurity increasing amount of preparation example sample; All all, in 0.6～1.2% scope, for example reference examples 5 sample RRT1.74 impurity increasing amounts are 0.95% to the RRT1.74 impurity increasing amount of reference examples sample.(3), with regard to the total impurities increment, all, in 0.25～0.50% scope, for example embodiment 6 sample total impurities increments are that 0.36%, embodiment, 7 sample total impurities increments are 0.29% to the total impurities increment of embodiment sample; All all, in 2.5～3.5% scopes, for example preparation example 3 sample total impurities increments are 3.05% to the total impurities increment of preparation example sample; All all, in 1.6～2.3% scopes, for example reference examples 6 sample total impurities increments are 1.87% to the total impurities increment of reference examples sample.

From above result, in the stability test of disposing above-mentioned 45 ° of C3 months, although in the sample of different RRT0.88 foreign matter contents, the increase of RRT0.88 foreign matter content is all more consistent and lower.Yet surprisingly, the lower sample for the RRT0.88 foreign matter content, the sample of each embodiment of the present invention for example, wherein RRT1.74 impurity increasing amount and total impurities increasing amount are all less; And for

The sample that the RRT0.88 foreign matter content is higher, the sample of each preparation example mentioned above and reference examples for example, wherein RRT1.74 impurity increasing amount and total impurities increasing amount are all larger, these results show, it is useful that the RRT0.88 foreign matter content is controlled at the quality control for material medicine of the present invention in certain limit, and for example it is useful for RRT1.74 impurity wherein and/or the control of total impurities.

the formulation example part

formulation example 1: the pharmaceutical preparation that preparation comprises potassium dehydroandrographolide succinate

Formula:

embodiment 6 gained potassium dehydroandrographolide succinates	100g,
		n.F,USP MANNITOL	100g,
water for injection (removing after freeze-drying)	to 2000ml.

The preparation method:

(1) take main ingredient and the N.F,USP MANNITOL of recipe quantity, be placed in stainless steel cask, add approximately 90% water for injection of recipe quantity, make to dissolve, then add the gac of 0.2% (w/v) by liquor capacity, stir 30 minutes, filtering decarbonization, add water for injection to approaching the prescription full dose.

(2) filtrate sampling, measure pH value (7.0), uses in case of necessity pH adjusting agent (1M hydrochloric acid or 1M sodium hydroxide) to be adjusted to prescribed value, then add water for injection to the full dose of writing out a prescription.

(3) liquid is first used the 0.45um filtering with microporous membrane, then uses the 0.22um filtering with microporous membrane 2 times.

(4) filling in the 7ml cillin bottle with every bottle of liquid drug 2ml, the false add plug.

(5) lyophilize to moisture lower than 3%; Freeze-drying is carried out hydraulic pressure and is jumped a queue after finishing; Prick aluminium lid, obtain being the pharmaceutical composition of powder injection form.

formulation example 2: the pharmaceutical preparation that preparation comprises potassium dehydroandrographolide succinate

With reference to the method for formulation example 1, different is that use embodiment 61 gained potassium dehydroandrographolide succinate material medicines are raw material.

formulation example 3: the pharmaceutical preparation that preparation comprises potassium sodium dehydroandroan drographolide succinate

With reference to the method for formulation example 1, different is that use embodiment 10 gained andrographolide bulk pharmaceutical things are raw material.

formulation example 4: the pharmaceutical preparation that preparation comprises potassium sodium dehydroandroan drographolide succinate

With reference to the method for formulation example 1, different is that use reference examples 2 gained andrographolide bulk pharmaceutical things are raw material.

Content and the impurity of above each formulation example gained powder injection of test, result shows that content is all in 98～102% scopes of labelled amount, total impurities for the principal constituent amount in 0.45～0.60% scope, in addition, the corresponding bulk drug that the peak area ratio (master/RRT0.88) of these formulation example gained powder injection is used with it is compared slightly reduction in a small amount, but difference is all in 30 units, for example use embodiment 6 raw material gained formulation example 1, its peak area ratio (master/RRT0.88) is 524, be worth 18 units of 542 reduction than the peak area ratio of the embodiment of its use 6 raw materials (master/RRT0.88), for example use again embodiment 10 raw material gained formulation example 3, its peak area ratio (master/RRT0.88) is 224, be worth 24 units of 248 reduction than the peak area ratio of the embodiment of its use 6 raw materials (master/RRT0.88), in addition, the corresponding bulk drug that the peak area ratio (master/RRT1.74) of these formulation example gained powder injection is used with it is compared slightly reduction in a small amount, but difference is all in 40 units, for example use embodiment 10 raw material gained formulation example 3, its peak area ratio (master/RRT1.74) is 452, than the peak area ratio of the embodiment of its use 6 raw materials (master/RRT0.88), is worth 24 units of 476 reduction.

According to the stability testing method of test example 32 above, the powder injection of investigating 4 formulation example is the content of activeconstituents and the variation of related substance in sample after disposing through 40 ° of C3 months.Result shows, after disposing through 40 ° of C3 months, the content of formulation example 1～3 is still at more than 95% of labelled amount, and the content of formulation example 4 is labelled amount 88%, the level of having stipulated lower than general standard.In addition, after disposing through 40 ° of C3 months, the maximum single contaminant of formulation example 1～3 is in 0.2～0.4% scope, and total impurities is in 0.7～0.9% scope; And the maximum single contaminant of formulation example 4 is 1.14%, total impurities is 2.24%, has exceeded the general acceptable level of pharmaceutical industry.

Claims (10)

1. a material medicine, comprising as activeconstituents with the following formula I compound:

Wherein R1 and R2 are selected from hydrogen, potassium or sodium independently of one another.

2. material medicine according to claim 1, wherein said formula I compound is selected from the compound of following formula Ia to formula If:

3. material medicine according to claim 1, it measures in the need testing solution color atlas obtained according to following [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, is about 0.83～0.93 place in relative retention time and shows an impurity peaks, and this impurity is called RRT0.88 impurity;

[HPLC method A]:

According to two appendix VD high effective liquid chromatography for measuring of Chinese Pharmacopoeia version in 2010;

With octadecylsilane chemically bonded silica, be weighting agent, 0.1% potassium dihydrogen phosphate (phosphoric acid is adjusted pH2.5 ± 0.05) of take is mobile phase A, and acetonitrile is Mobile phase B, flow velocity is 1.0ml/min, 35 ° of C of column temperature, the detection wavelength is 251nm, according to the form below carries out linear gradient elution:

Time (minute) Mobile phase A (%) Mobile phase B (%) 0 65 35 10 65 35 40 50 50 52 23 77 53 65 35 62 65 35

The preparation of need testing solution: get trial-product (for example material medicine of the present invention or the pharmaceutical composition that comprises this material medicine for example pharmaceutical preparation) appropriate, accurately weighed, add mixed solvent (mobile phase A: Mobile phase B=60:40) dissolve and dilute the solution of making in every 1ml containing formula I compound 0.4mg, as need testing solution; Precision measures in right amount, makes the solution that contains formula I compound 4 μ g in every 1ml, solution in contrast with thinner;

Get contrast solution 10 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at principal constituent peak be about 20% of full range;

Precision measures need testing solution and each 10 μ l of contrast solution again, and the injection liquid chromatography, record respectively need testing solution color atlas and contrast solution color atlas respectively;

Read peak area and the retention time at principal constituent peak in the contrast solution color atlas, and peak area and the retention time of principal constituent peak and each impurity peaks in the need testing solution color atlas;

For the need testing solution color atlas, the relative retention time of principal constituent chromatographic peak of take is 1, calculates the relative retention time of each impurity chromatographic peak;

For the need testing solution color atlas, for each impurity chromatographic peak, calculate the peak area ratio (this peak area ratio is larger means that the relative content of this impurity for main composition is lower) of principal constituent chromatographic peak and this impurity chromatographic peak;

Optionally, for the need testing solution color atlas, calculate the chromatographic purity of trial-product by area normalization method;

Optionally, for the need testing solution color atlas, calculate single contaminant with respect to the content of principal constituent (can referred to as the content of single contaminant content or single contaminant) and total impurities with respect to the content of principal constituent (can referred to as total impurities content), each single contaminant content sum is total impurities content, wherein with following formula, calculates the content of a certain impurity phase for principal constituent:

4. material medicine according to claim 1, it measures in the need testing solution color atlas obtained according to [HPLC method A], the peak area ratio of principal constituent chromatographic peak and described RRT0.88 impurity chromatographic peak is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.

5. material medicine according to claim 1, it measures in the need testing solution color atlas obtained according to [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, is about 1.64～1.84 places in relative retention time and shows an impurity peaks, and this impurity is called RRT1.74 impurity; Further, the peak area ratio of described principal constituent chromatographic peak and described RRT1.74 impurity chromatographic peak is 100～10000, and for example this peak area ratio is 150～7500, and for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.

6. material medicine according to claim 1, it measures in the need testing solution color atlas obtained according to [HPLC method A], the relative retention time of principal constituent chromatographic peak of take is 1, be about 1.40～1.60 places in relative retention time and show one or more impurity peaks, this one or more impurity can be described as RRT1.40～1.60 impurity; Further, the ratio that the peak area of described principal constituent chromatographic peak and described relative retention time are about the peak area sum at all dirt peak that 1.40～1.60 places show is 100～10000, for example this peak area ratio is 150～7500, for example this peak area ratio is 200～5000, and for example this peak area ratio is 250～2500.

7. a pharmaceutical composition, wherein comprise the material medicine of claim 1-6 any one and the acceptable auxiliary material of pharmacy or carrier.

8. a pharmaceutical composition, it is prepared by material medicine and the acceptable auxiliary material of pharmacy or carrier; Described material medicine comprise as activeconstituents with the following formula I compound:

Wherein R1 and R2 are selected from hydrogen, potassium or sodium independently of one another; Further, it has the described feature of embodiment as arbitrary as the specification sheets second aspect.

9. prepare the method for the described material medicine of claim 1-6 any one, it comprises the following steps:

(a) provide dehydroandrograpolide succinate;

(b) make described dehydroandrograpolide succinate be dissolved in 8 times of 35～40 ° of C amounts (, the solute 1kg solvent for use that for example often feeds intake is 8L) in ethanol-acetone-acetic acid-water mixed solution, amount by liquor capacity 0.5% (w/v) adds activated carbon, stir 30min, decarburization is filtered in insulation;

(c) make filtrate at the temperature of 2～8 ° of C standing 10～12 hours to carry out recrystallization, leach crystallization, drying, obtaining dehydroandrograpolide succinate is formula If compound; Optionally

(d) step (c) gained formula If compound is reacted with alkali metal compound in aqueous ethanol solution, obtains with the following formula I compound:

Wherein R1 and R2 are selected from potassium and sodium independently of one another; Further, the method has feature as described in embodiment as arbitrary as the specification sheets third aspect.

10. the purposes of the described material medicine of claim 1-6 any one in the medicine for the preparation for the treatment of or preventing viral pneumonia, viral upper respiratory tract infection.

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