DE1802569C3 - Baicalein esters and process for their preparation - Google Patents

Description

- -P
i \
O OH

■ - S -OH

ji

means, and their pharmacologically vettntuliche trial

.'water-soluble salts. ' ■ '. ■■, ■.'. ■ "■ '■■., -.'"'■ .., ■ ■ ·' · - ..: ■.

2. .Process for establishing the connections according to Ansprüelj ' ⁱ l ..;.'' ^I äa'dureh: - .. gckcrinzeichn. dal! % o Table I, Baiealein is esterified in a manner known per se with a phosphorylating agent or a SuI-ID ,, (mg kg) fatierungsmitte) and the resulting phosphoric acid or partial acidic acid partial ester of Bai, calein, optionally by treatment with a base pharmacologically acceptable, water-soluble salt transferred ".:>;: V ■ '-: ■. ν ■

4 "

water-soluble salts and a process for their preparation.

Baiealein (5,6. ⁷ -Trih \ drox \ tlavon) is the predominant component of Seutellariae iadi \. a crude medicament which has been used for years as a remedy for diarrhea or sweating, and as such is sparingly soluble in water.

f-s has now been found that Baiealeinestei the obe'ii besieiiebencn general formula and its ίο pharmaceutically acceptable water-soluble. Sal? E have remarkable antiallergenic effects and, for example, as anti-inflammatory agents Means ueecri asthma and dermatoses effective mihI. There are no undesirable side effects

'S on.

The pharniacological properties of the invention Connections are illustrated by the following experiments.

TeM 1
Acute Toxi / ilü'l

\ Erichstiere: Mause (lCR-ICl.-Siamm.

4 weeks aiii:
Veisiich ^ d.iuer '7 T.isie

("«.-Checked manager Jim; .. '

Oiri.ilriurrwi, I / from N., η · ..! B.iicalein-6-ι: itono ■ Β.! '·. "■' phosphate Wed! ; '. ΓΗΓ, icuic f.l!

π>: ΐη: ι1κΙι ucihlii'h in.innlicl · «οι Wich

The discovery concerns Baicalein-Lister the general intravenous

my formula

IK)

AO

in the A the group

Av. -A

HO

OH

s <> iι

bodeutct. ' and their .phitnuakoloüisch

Om! 550

• njek'.ion In.ra (ierit-oneale .SJfI
injection

Intradcrmal. . ¹ M (I.
injection

2S 50

53 "
TH)
S7D
275 (!

350

'fi (i

6S (!

7SU

5000

\ request 2

Dic-cut / üniliingshemmeiide Wtikiüü '. dot connection

.. fertilize '> viirile after four Metliodo, .du' in Archives im Internationals de I'li.uuUK.'udvn.iiniv · ei dc I Ik'iap.ie, '

12V 7 | ji ') 5') |. bf-cliiiobe »'is. untci · 'usage from Aiuir, iiicn \ fi um v.nn K.ini'nchv'it, il- phiciOiicnc- · Means iiuii \ on m.iimliv.hen-Rallen tW-si.ir-S.tiiinm.) from | c sth, ι '. Is) e. aU VvisiiclHiica · '· t'njtillclt. D.ic '

(Λ. Ί eslvfibiiuliiinieir winden'- den M, aisv: ii-. Mli.tvenös ID \ .liiiuten vor. J ₁ 1 iMiiviiii'iriuK'n 111 j ο K11 «> 11 .des

■ ■ -plilnyoiieikMi using vv'i.ilM'i.tlt !! . The l'.i'i'ebnisM. ' snui

in. I abelle 2 Zws.tnmu'-i'iresti'ill: .- · ■ '".' ■ ':'

Table 2

llcprufltf dose Ver, Insecurity Inhibition '5 links Miths- ■ the the / ahl Inflammation Ent / umlimg 5 (mg / kg) 1%) control O 12th 70.3 ±. 1.33 Dinairium 5.0 ■ 12 ■ 4WJt 2.36 29.3 ί 2.37 ^l0 bailelein- 6 mono phosphate Sodium- 5.0 12- 54.7 -L 2.38 22.2 j. 2.61 baicalern- 6 mono .sulfate

Comparative tests with known anti-asthmatics

I Influence on the passive kutunc anaphvlaue (PCA)

in guinea pigs

Λ. method

The experiments were carried out according to the method of

II a rad a and employees (Allergv (Japanese), 15 [i ') 6ft] 1) carried out an improvement the Ovar-Mcthodc (Journal of Lxperiment Medicine. J17 (N63) represents 95I.

B. Results

The effect of the uni-addicted, administered intravenously Substances on the PCA in guinea pigs can be derived from the values in the following labile '

Influence of the test substances on the PCA in guinea pigs (percentage inhibition)

Table 3

Tested connection

Sharkein-ft-monophosphate
(Bl ¹ Si

HaiciliMii-ft-monosulfate (HSSl

I.3-Dimeth> l. \ Anthinäthvlen-

diamine (Al (known)

Di - l- (3.4-Dihvdro \) phen> I) -

2-isopropyl aminoethanol (H)

(known ι

Prednisolone (PRD)

(known)

HPS was named Dmalrimmal /. HSS as Mononairium / used (HPSNa, Ivw. HSSNa): dose-.niL'abeii are each based on the active ingredient

The results show that both HPS, ils, un.h HSS has a remarkable inhibition of administration icluing of 5 mg kg, which is considered to be the usual clinical Dose of these compounds viewed wild, and dall the inhibition at doses of IO or 50 mg ki;

20th

Doms I ¹ CA : 6.33 (my kg) r 6.S 2 5 6S.6 : 7.05 IO 74.2 - 7.43 50 73.7 i 7.32 5 37.S : 4.27 10 49.6 P.79 50 59.3 P.55 5 4.3 ι ί 6.21 IO 5.1! : 5.51 5 30.3 : 12/0 IO 27.S • lit.36 5 30.4 H) 30.5

is even stronger. In particular, BPS has the effect of KontrolKvcrt of Smg'ksi an inhibition of about 70%.

(A) shows hardly any inhibition of PCA when using 5 mg / kg, and the inhibition by (B) and PRD entrusted with the KontrolKvcrt of 5 msrkii only 30%.

C. Summary

BPS, BSb show a better inhibiting action against the comparison substances PCA in guinea pigs.

II. Toxicity

The LD, _(J (mg.kg) values of BPSNa, i-disodium sal / of baicalein-6-monophosphate) and BSSNa (sodium spleen of baicalein-6-monosulf.it) when administered orally to mice are given in Table I. .

Comparable LD _5fI (mg kg) values for the administration of the comparative drugs are contained in the literature or these were determined by our own experiments. They are the following-

.1 °

V crgleiths-
v .Tbindun |! LI) ,,, din: ki!)
at (irjlcr
ViT.ihtcichuiid
.in K.titen I i'cr.iinr IA) 540 Meick Index IB) 3675 loMcologv and
Applied Pharma
cologv. IS,! S>
(1971) Prednisolone
IPRD) > 5 (KM) own experimental
ernehnissc

Prednisolone seems to be just as low vu have like PHSNa, and HSSNa. However, prednisolone has a much stronger subacute toxicity and cannot be administered continuously. Same can generally be said of steroid hormones

4S can be said. This can be seen from experiments in which all rats are fed a commercial food for 5 weeks daily continuously PBSNa ,, BSSNa or prednisolone is added. In these attempts, all are nut

«, O Rats fed food containing prednisolone with an administration of only 5 mg kg day prednisolone died after 10 to 15 days, choosing the _{hitter treated with BPSNa 2} and BSSNa containing no anomalies! in your

ss showed demise and lived far more than ^ 1 rage.

although they resent these connections' ·.

A dose of 650 mg per day was administered From the experiments it appears that the fatigue

painted connections vori ilh.iftei a! -> known

ho antrallergenc or vv untiasthmai mine! like Di - I - (3,4 - Dihvdro \ vphcnvl) - 2 - ls'opropvl.iminoäth.mol or also 2 -. \ 1eihvlainmo-I-phui \ ll-pri> panol (which often cause heart damageI and Prednisolone Ulic im other disorders are often endocrine cause) As the tested salts ertindiingsgemallen showed no unerwiiiiscluen Nelvnwnkungen, it can be assumed dal * they have an effect char.iktensiische manner si _L h -.on

that of the previously known anti-allergic or anti-asthmatic agents.

The connections according to the requirements can be found in usual pharmaceutical preparations in dci form of tablets. Capsules. Supposiioricn, syrups or injection fluids can be used.

The effective daily dose for the treatment of Inflammation in adult adults is about 50 to 200 mg, but is common when administered orally about 50 to KK) mg, of the relevant free baicalein ester, choosing the dose in the case of injection approximately 20 to 200 mg. is generally about 30 to 50 mg.

The baicalein esters of the general ones given above Found and its pharmacological contract κ Borrowed water-soluble salts are prepared by mil Baicalein in a manner known per se esterified with a phosphorylating agent or a sulfating agent and the phosphoric acid obtained or sulfuric acid components of baicalein if necessary by treatment with a base into a pharmacologically acceptable, water-soluble salt uberfi'ihil

The baicaleiii using al ·, starting material / ti can be obtained by extraction and isolation from a plant. /, B. Seutelbrai baiealensis Georg.,. Or from a raw drug, ζ. B. Seutellariae radix. have been received in the usual way. The synthetically produced compound is also suitable. The 'Atisgauys material must now be' och keisi-purified Bai- jo caleiii.. ■ -... '' -. ■; ... . ,: '^;---; ^: "■ · '' .. .- -.- '■

Suitable phosphorylating agents are, for example, phosphoric acid. Phosphoric anylride. halogenated phosphorus compounds, for example, phosphoroxy. chloride. Phosphorox \ b: omid. Teträchlorpyrophos ^ s phat. Dtphenylphosphochlondai. Ditei / ylphosphochloridat and Phosphortriehioridl. .! ;; ; '. ^:

They are suitable as sulfating agents; for example chlorosulphonic acid, the diovanic bond of sulphuric acid anhvdnd. tertiary basic compounds, /. B. Pyridiniumsulfatrioxid and Tnäthylammoniumsulf.itriö'.xyd. Sulfuric acid is also suitable; Sulfuric anhydride. Sulfuyl chloride. I-alkoxy vinyl sulfals. The esterification can in the absence of .'Lösungsmittels, in particular 'when using a 4', the above-mentioned halides as Verestcrungsniitt ^'- l. be carried out. It can also be carried out in the presence of a solvent. Examples of suitable solvents are tertiary amines..; B. puidin and trimethylamine. " Amides ,; / .. B Di- so i'.uihylfo'rmamid and formamide, aromatic hydrocarbons, e.g. benzene and ToUh) L and ethers, e.g. Diaih>! Äihet. T.etrah \ drv.ifu'ran and Dioxuii, as well as _: as ■ -mixture ·: · ^ ι named »'solvents Of these solvents the tertiary" aliwe "y <.or the amides act equally / hastily as a catalyst' or as ';'Neii.tTa'Iisioruiigs'ntittc-i to 'bond, .the yebiklcten with forlsebreitetuic Reukiinn: The acid ■' ^reac: 'may, ion basks bc> chieuüii · »· earth) if such u!.': fij.ue-. Λίητη oiler A;!> ui -is used. Fs (<> ..ist. 'iVsoncicrs / w-cvkrüäUia. the subjecteiuk · »Aniuic bei. der'Siiif'.iin;! aiv yii vcrvv. Cnifcr ¹ :: ■■ '.. ".- ■■' ■ -.- ■■ *; .. pu ^% '' reaction. Wiüi: m, -iifgemeinen.- t> c * Tempera-, vuixti \ i> ii ..- ■: ■ 1-0 to elw.:i ^: 40 ('' carried out -.:.;. : r ...,. The received 'i'c'i'es'tcr mmi Baicitieui tn! f -Pl ₁ K) S 'vs phorsäitri'-uviör'Sc'iv'.u'ici.sätire'sare as sVitchfi!.! water leich:! «", hch üü.-! k'.XTne:'. ais' McdikamtiP.k 'Λ01 ■: ■' ■ vvendei .-. wciüei ';-' Λαί 'vjfür.d'lisecr'-disso

Acid group, however, can easily handle the most diverse, to form water-soluble salts with various bases. The pharmaceutical seilräglidien and stable water-soluble salts are obtained by neutralization or double reaction with one corresponding base or a corresponding salt without prior isolation of the window concerned from the reaction mixture or after its isolation by evaporation to dryness. As bases are for example Alka'ihydroxyde, z. B. Natniimhyoro.xsd, Potassium Hydroxide and Lithium Hydroxide. Ammonium hydroxide and amines, such as monruthanolamine and triethanolamine and alkali carbonates and -bicarbonate, ζ. B. sodium carbonate, sodium bicarbonate and potassium carbonate. i'nd strongly acidic cation exchange resins suitable in the form of a corresponding salt of the desired base.

Phosphorylation can vary depending on the. Conditions for the mono-, di- or triphosphate of Baiealine. or from several of these compounds, for example, if letrachloropyrophosphoric acid is used as phosphorus, the (i- \ 1onophosphhal) is obtained , phorylierungsmittels mainly the 6.7-Diphosphal or 5.6,7-triphosphate obtained in the sulfation Baieaiein-d monosulfate is mainly obtained - as solvent can vary depending on the Reaktionsbedingiingcn 1. B. the amount of Pho · used -.... In the case of baicalein-6-iiionopliosphate, a rearrangement of the pliosphono group from the ii-position to the 7-position with formation of the 7-phosphate or the cyclic 6,7r-monophosphate can take place during the purification or recirculation.

In the following examples, parts of the weight deteriorate to rauintcilen like grams - to milliliters.

. ■ lic is ρ i e I 1

. ' 100 parts by volume of baicalein are gradually added to Λ () 0 parts by volume of teirachloropyrope phosphite, while stirring and cooling with ice. The addition takes about 1 hour. The mixture is then stirred for a further 1 hour, whereupon the reaction mixture is poured into 4,000 parts of ice water while the temperature is kept below 30 ° C. The aqueous mixture is centrifuged and the precipitate which has separated off is washed with water and dried Solid is dissolved in 1 * 00 parts by volume of tetrahydrofuran with stirring and concentrated under reduced pressure. HK) parts of water are added to the concentrate. The remaining tetrahydrofuran is then completely removed. • leaving a syrup after adding 2IH) O room divider! In water, the syrup is ground, causing a precipitation in water: The '..'F'ällang-, is- separated by centrifugation, -two -.-. m, i! wash with water and stir again! ■ suspended in 3 (KK) R.iimiieilen water The suspension is now rhi! a 'concentrated''aqueousNatruinihvdnix'ydlö.siing'i.iuf pll (\ 0 set wu \ /entfiiiigiert-.'.woiiei one above Lösuiu. erh.il · "teuvvral Dse Lä'iung wud separated and washed twice MTT j.e'2 (X>-;kaunjteil'en washed water. The washing liquids "" are. 'with the örxmste'hendeir solution' ■ • .ernnigi |) the solution is 'u! er!' a 'k at a temperature wr,'nicii't'morethan.-5'I (

20th

'.'cihgeengCHyo ^

■ remains, '· ■': while a "! If necessary ^ cbUdcitf ^ 'gcI ^^' ■ iariig ^ substance ^ bfiliriertAvird ^ -Da ^ concentration is; ^! Iniit" 5W Raüroteilm ^ thäriöl ^ :;
i.; '"gciühr: ii ^ i> ie ^.' ^ Vhaiten ^
vZeritrifu ^ ieren Äbgelrenri ^
^ anh, ^ irnal'irniti ^

iNiiQJ! -örajiulätlget rocknet ;; HierbctiWery ^^ r ^ G ^ li ; \ vichtstenea r ^

ΐ "1 50 parts by weight of seals: YohehiMicalciWsälze ^;.;

VsCerdcn; ih 300 volumes of water dissolved "and; A OMi £ ΐ

nuten with stirring cooked after the;, cooling; «J

be / u the mixture / 200 rooms' Äthanolijg

■ prayerful. The fillings deposited in the process

centrifuged off: / and the solid substance; first with -:>; ■ /.

SO ^ aqueous aqueous ethanol. Then with ethanol and: -;

then twice / with ethyl ether washing,; o

■ where; 32 parts by weight; purified // pihatmimbai- _; ; ailein-6-monophösphat get; en wcrdeiv ^ ;; ;:

Qcvvichtsanalysc in% Γύτ ^: C, <!! ^ PNaV ) \ 2 Tj; Q

y ^l calculated ..ν JC 41VKS, H 3.05. Ρ; 7,20νΥ. _: /^//.'-,/, ■ ■. ' ^ - \; βέ | ϊιηϋ _Β η ^ /: ·: ^ 4ί / 16; Ίί · 2; 73; Ίν7 ^ 2 ./'-^ ·: ^ ·. · ;;; ί · _: - ·

-. ·. ;. '/..."-"VV ■, "■.'. ' . " ■:., '' ■ - ■■. ■. ■ - ■■. ■ '"■■■■; ■ _-}' " ■ - '. ■■■■■ ".- J?

:. Uitraviolcite absorption: .. ■ ';■■' ■ '■ -'"/ v ■ Λ, ¹ V

^{1 ;} λ ^ 2Ί1 ην.ι, 327 mx "/ ■ - ^: - Λ" ■■ '-. ■;.: ■■■ .... ^: / _: ^ f ^Nj ' ^1M 269 mu. 3 / i! must ^: . ":.. \

This connection becomes .as follows in its mono. ;; _; , V ■■ älhanolariiinsal / .umgewandclt: '. ^;; . ; ; - :; ;>, '

! Face! of (ibigen Dinatrmmbaicaiein-6-monophosphate is suspended in 5 parts by volume of water to 'suspension is a with Monoalha olamine y laden, strongly acidic pcrlförmiges cation. _5; given austauschhirz The resin is abfiltnert and the filtrate is concentrated and recrystallized from ethanol.. 0.53 parts by weight of the monoathano / amine salt of baicalein-6-monophosphate as noodle-shaped crystals with a temperature of 159 to 163 ° C (Zcrs.).,. ·. ". '■.'. ■.

Weight anise in% door CV (II ₂₅ O ₁₀ N ₂ P;:;.

Calculated .'. .C4S.31. H 5.34. N 5.95, P 6; 56; \

uefundcn .... C 48.37. H 5.71. N 6.13, P 6.68. .

'■■ - "■■■: · ■■; ■; -"> ..:: \ Example 2 ■ ·. - ■ ■, '

To a solution of Ί 00% Baicalein in a mixture of 714.3 parts by volume Ietrahyd.ro-

■ furan and 178.5 parts by volume of dimethylformamide svic in the example! 107.2 parts by weight of methylammonium sulfate trioxide and after 3 hours a further 10 parts of this compound were added. The Mixture takes about 5 hours of reaction at room temperature left with stirring. Then _ 357 2Raumieile water are used for the Rc'aktionsgem.iscliι

■ ■ L ^; -ibe: i and the mixture with: concentrated aqueous ammonia adjusted to pH 6.5. The solvent is then evaporated under reduced pressure. After adding 2 (K) room dividers - water to the back -, the mixture is stirred. And then overnight

-. kept in a refrigerator. The secluded Precipitation is filtered off and four times with a germ ge π WasscrmenjL-e washed. The lalliing so treated Avi.rd suspended in 26 (H rough part of water.

'- ■ -pension' - "Wcrden- KKX) Raumtcile of a siaik acidic KaiiinH-nausuitic resin of the; Na type πι pearl form ^^! Cbin ^ Since & iQemisch: is stirred for 40 minutes and?; Ϊ! Äjii ^ aii ijrJcinvÄVasserbaduhit50 ^r 'Ccrcrit ,; WObeiisich "illjK ^ JhffigilöstilDas I iHarz: w will: abfiltricrt uri <f die ': fPallfiiin ^ illl ^ ciiil ^ cmjxirätur ^

tieijn ^ i | g ||| j | te ^! | iückstand ;: is in 700 Rätirrrteilcn \ _: s | tthantJll ^ eflfeStigtiitmd _; % bfilteredS ^ By washing ^ ■; äe | i | fieiet | Chla | i ^ niit / .Äthiino | ^: 'urid Äthy! iithe ^': | v <ir- "S || ^ 5CN | c ^ CM ^ hurry! slatriiJm

i ^ laltSrlllif ^ Öt ^^ iteres'i.Wasch ^ ^ ί ^ || ιηϊί ||| ϊί »η (χί ) are 90GcWiChIsIeIIe gefcinigje ^s

^; 1Verl | iny! Ü ^ i | iiiaHem ' ^: S .. ¥;: ■';^;.:;':"■; .yΐν: ν ''■: ■ ': ν'ΐ * 4ίί '? Ί ^ Geyfwlilirillse ^ v. ^^' fiir ^ Cijl ^^^

| v | efundp ^ gcj; 43,} 7 ;; _; jt: 2.96; - ^^, [^^ B ^ m:; ^ ^ HtrayiMeitjii _0jptjqilen: \;.; ^: \ ~ ' ^: ^.! ί'ίΡ- ^: '. '' ^: ^ ^: Ά: -. ί% ',

{This connection; wild svic follows Monoi in it ättianoliiniinsalz or Triaüianoiaminsjlz unViicwan-

'■' ■ · ':''-'. To a vSolution; of 2 parts by weight of the above ⁷ sodium baicalein - 6 - nibnösulfats in 50 Raumiciien water / becomes a ίιιίι. Ntonoaihanolamine-laden 'cation exchange resin is added during stirring. The hat / is filtered off and the' filtrate 'is concentrated.' that melt above 240 C .. "", ■ .. '■''.;.■;■' .- .. ^;

Face analysis in % for C ₁ -IIj-U ₁ NS; ■ 11.5'H _; O: ;;.

Calculated. C 48.57. H 4.32. ?.. N'3.33.-S ^63: '-.'- ^{/: ..;} found.-;,.;. C 48.72. Il 4JX). N 3-33.-S 7, <n:>

The experiment described above is repeated, but using a cation exchange resin which is bulky with thiithane oil amine made from the resin coated with ylonoalhanolaniin: 1 the triethanolamine salt of baicalein-6-monosulphate is obtained

fiir C _{11 H:} <

, NS -Ό.5 H, C);

₅₅

Weight analysis in

Calculated ...: C 49.60. H 5.15, N 2.75. S 6.31; found .... C 49.42. H 4.97. N 2.72, S 6.79. ^

■■■■. Be is ρ ic 1 3-.

To a solution of 2 parts by volume of baicalein in a mixture of 8 parts by volume of dimeths / formamide, 1.08 parts of triethylammonium sulfate dioxide are added as in Example 1, and the mixture is left to stand for about 5 hours at room temperature, with stirring . The reaction mixture is then adjusted with dilute 'aqueous ammonia to pH 5 and then mixed with J.53 _f Gc-.wichtsteilen barium acetate, Bariurhbaicaleinmonosulfat svodureh ausgefällt'wird. The precipitate is separated off by centrifugation and washed with water. The product obtained is then washed with the Na type of an acidic ion exchange resin in parts of the volume of water and thereby converted into the water-soluble sodium salt. The resin is separated off and the aqueous solution obtained is concentrated ..-. With crude sodium baicalciri-- .: 6-monosulfate (the .sodium sulfate as inorganic

((P "6 102

\ erunremiiMin ») is obtained. Because- »Rohpioijuki is recirculated twice from water. where .175 Wiched purified NaU.umhavale.n · (xnonosulfat erhalle «.

Weight analysis in% for

Calculated ... C 42.56. Il 3.54. S 152;
found .. C 42.22, H 3.19. S 7.43

Example;"

To a solution of 0.2S (jcwicfuttcilen Baicaiciis in a mixture of 4 rauintcilen tetrahydrofuran and 2 parts by volume of oxymeth \! Example 1 0.72 parts by weight of triethylammonium sulfite trioxide and the mixture is allowed to stand at room temperature for about 3 hours with stirring The reaction mixture is then as in the example 2 described worked up. The received potassium salt / is recrystallized from water, giving 1,202 parts by weight of potassium baicalein-6-monosulfate receive.

Example 5

/ u of a solution containing 0.56 parts by weight of baical cm 6 parts of dimethylformamide are 0.64 parts by weight P \ ridiniumsulfatriox> d given The mixture is then 8 hours at room temperature touched. The pH of the reaction mixture is then determined adjusted to pH 5 with aqueous ammonia. whereupon the reaction mixture to the im The manner described in Example 3 is worked up by recrystallization of the crude product obtained 0.41 parts by weight of ammonium baicalein-6-mi) nosu! fat are obtained from water receive.

In all relevant examples, the commercial product "Ambeihie IR-120" in the form indicated was used as the acidic potassium ion exchange
use /

Some preparations are shown below described, which includes the sodium baicil contain monophosphate

Preparation I.

. I ₁₁₀ ^ ₁ UK) nip

3-benzyl alcohol,. 2U πΐ £

All ingredients are dissolved in water in such an amount that the total volume is 2.0 ml. The resulting mixture is doing a pH of 7.5 to un · * serves as Injcktionslösung.

Preparation 2

! Dinatriiimsal / \ t »n Haicaiein- I.iMc.tc

r «; 6-m «» noph (»sphai 5t;

2 1 acto »e» 5

3 corn starch {2n

4 microcrystalline cellulose 3n

5. Magnesium Mearate 5

The Nerbiruiuiiüen I. 2. 3 and ^? ₃ of compound i and half of compound 5 are mixed well. '' ¹ ^ mixture ^{x is} granulated. After adding the rest of the borrowed third of compound 4 and half of the compound 5 to the granules, these / u tablets are pressed. These tablets can then be coated with sugar, for example

Preparation 3

I. Dmatruimsa! / From Baicalein- ^Β ' ^{? Γ} '" * ^Λ ^" ·

6-monopho * phat 50

2 lactose 12

is 3 microcrystalline cellulose. TM

4 Magnesium stearate S

\ "- ^iy "

The connections i. 2. 3 uiui the H.ilfie the \ e: -

40. bmduüg. 4 are well .mixed., And the Gi mix is granulated! After adding the / large half of the .Connection of 4 mm granules, this is in - "- ine Gelatinek; tp'se! ge

Claims (1)

1. M.iit ilci'.t-lNtcT tier general formula HO Λ Ο HO in the Λ the group OH