JPS6034911A - Medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to a pharmaceutical composition and a method for producing the same.

Japanese Patent Application No. 52-106879 describes and claims a pharmaceutical composition comprising andocyanidin in admixture with a pharmaceutically usable diluent or carrier. In particular, the specification of the above-mentioned patent application describes pharmaceutical compositions containing anthocyanidins obtained by hydrolysis of natural glycosides known as anthocyanins. Specific examples of these anthocyanidins include cyanidin, peonidin, derefinidin, betunidin, malvinidin and belargonidin, which can be represented by the following formula.

OH In this formula, R1= R”= −OH and R”=
1-1 (cyanidin), R'=-OMe, R"=-OH
and R”=H (peonidine), R’=R”=R”=O
H (Derefinigi 7), R"= OMeo!HiR"
=R"=R"=OIl (hetsu=shiy), R"=R"=-
(Thfe and R'= -OH (malvidin), R''
=-OH and R1=R''=H (belargonidine).

The inventors have discovered that a group of Fujibirirum compounds that are structurally similar to the anthocyanins described above also have useful pharmacological activity. In particular, these compounds have a pronounced scarring, epithelial characteristic tE, which makes them useful in the treatment of skin I'f7 wounds, paralytic pains and external and internal ulcers. It has also been found that Fujibiriram compounds exhibit distinct anti-inflammatory, vasoprotective, antilipidemic, cholesterol-lowering and hypoglycemic activities.

According to the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically usable diluent or carrier and, as active ingredient, a flavylium salt having the formula:

In the formula, Y is the same or different and represents -OH or -R (R is an alkyl group having 1 to 6 carbon atoms), muD or an integer from 1 to 6, and n is 0 or is an integer from 1 to 5, and the sum of m and n is 1 to 11
, and (Y),, Rs (a) R'=R"-10H, and R'=H(b) R
'=-OMe, R"=-OH1 and R"=H(c)
B 1= r, t÷Rj=OH(d)R'=-OMe
, R''=R'=OH(e)RI=R'=OMe
, and R''=OH or (f) R2-OH1 and R
When weight=Rs=H, it indicates a group having S, and in this case, each of Y3, Y5 and Y7 has the previously centered ys portion y)<L,, Y3, Y
At least one of 5 and Y7 is a group other than -OH.

A particular detail of the pharmaceutical composition according to the invention is a composition containing a salt having the formula:

(Y)n Therefore, a more preferred group of compounds according to the present invention are those having the following formula.

2 in the above formula. Hy is preferably HlOH and OMe
selected from.

Therefore, when a flavylium compound is represented by the formula %, where % represents Ha and B represents (Y)n, the group A is preferably selected from the following: 0][ The OMe flavylium compound may be associated with any pharmaceutically acceptable anion X, such as chloride, sulfate, phosphate, acetate, hydroxy, and the like. Particularly preferred compounds of this type are compounds in which at least one of the 3.5 and 7 positions is unsubstituted.

Flavilium compounds suitable for incorporation into pharmaceutical compositions according to the invention can be prepared according to known methods, such as A. Robertson and R. Robertson. J-Chem-8OC・ by Robertson,
1526 (1928): A. Robertson, R. Robertson and Cedarwood, l: Lisiei Kemusoku, 1
533 (1928): Murakami and R# Lopertson, 1537 (1928): W
The condensation reaction 1+i> can be prepared as reported in Bradley and R. Robertson, J. Chem., 1541 (1928), respectively.

More specifically, the flavylium salt of formula (1) having a substituent at the 3-position can be PLed by condensing salicylaldehyde having the formula or its Mm form with ω-acyloxyacetophenone having the formula or a derivative thereof. , in the above formula Ylm and n6 are as defined above, and AC
is an acyl group.

Similarly, the 7-ravillium compound of formula (I) which does not have a seed moiety at the 3-position is a salicylaldehyde of formula (It) defined above or a derivative thereof (wherein Y and n are defined above). It can be produced by condensation with acetophenone or its derivatives having If desired, any hydroxyl groups representing groups Y that can inhibit the reaction can be retained and then converted into free hydroxyl groups in a manner known per se.

Thus, the production of 3-hydroxy 7-ravillium chloride and 7-hydroxy 7-ravillium chloride is illustrated by the following formula.

I-Ac The above condensation reaction is generally carried out in the presence of a strong mineral acid,
Intermediate products are salts of these acids. Salts can be converted to other acid salts by conventional methods.

The particular galenic form of the compositions of the invention will depend on the intended route of administration and the condition to be treated; the form may be amorphous or in the form of a shaped dosage unit. Examples include sterile liquids suitable for parenteral administration, forms suitable for oral administration (e.g. tacks, capsules, solutions, suspensions), forms suitable for insertion into body cavities (e.g. anus or ’full opening), forms suitable for topical administration (e.g. soft,
1. ? , creams, gels, bath solutions or suspensions) and dentifrices.

It will be appreciated that a wide variety of excipients may be used in formulating the compositions according to the invention, and the nature of these agents will depend on the intended mode of application of the composition. Examples include preservatives, buffers, thickeners, suspending agents, stabilizers, wetting agents, emulsifiers, colorants and flavoring agents, especially carboxyvinyl polymers, phlopylene gellicol, ethyl alcohol, water, cetyl Alcohol, saturated vegetable triglycerides, fatty esters or propylene glycol, triethanolamine, glycanol, starch, sorbitol, bentonite, carboxymethylcellulose, lauryl sulfate, dicalcium phosphate, powdered silica, lecithin, etc. can be used.

It is often advantageous to use more than one diluent or carrier.

The compositions of the invention have been found to be particularly useful in the treatment of wounds, gastric and duodenal ulcers, inflammation of the oral cavity and throat, pathological conditions of the vascular system and diseases caused by disorders of lipid and carbohydrate metabolism.

The present invention also provides a compound of formula (1) comprising a pharmaceutically usable form suitable for administration, e.g. combining the active ingredient with one or more excipients and/or Also encompassed is a process for the preparation of a formulation as defined above consisting of a change in one of the above galenic forms.

The present invention also provides a subject with an effective amount of the 72 biryum salt of formula (1), preferably from 1 to 9 in 100 s, most preferably in s.
The present invention provides a method for producing a fatigue, anti-epithelial, anti-inflammatory, vasoprotective, antilipidemic, fresterol-lowering and hypoglycemic response in a subject, which comprises administering ~sorny/Ky/day. be.

Compositions according to the invention preferably contain at least 0.2 M% and most preferably at least 0.5 M% of the flavylium salt of formula (1). More concentrated compositions, particularly those containing at least 1% by weight of flavylium salt, and even at least 5% by weight, are suitable for internal (ie, parenteral as well as enteral) administration. The composition contains a flavylium salt of 1 to 100 μ/l, preferably 5 to 5 (1; +/
is administered at a daily dosage ratio of 9 to 9.

Next, the production of the substituted 7-labyrium compound of formula (1), which can be used as an active ingredient in the production of the pharmaceutical composition according to the present invention, will be specifically explained with reference to production examples.

122 g of dosalicylaldehyde and 136 g of 4-hydroxyacetophenone were dissolved in a four-eye 11 flask equipped with a mechanical stirrer and containing 400 g of anhydrous ethyl acetate. At room temperature with stirring, a stream of dry hydrochloric acid gas was passed through the solution in such a way that saturation was completed in 1 hour, and the mixture was left under stirring for 24 hours, during which time the reaction products began to precipitate. and the product in the presence of KOH for 40
It was dried at °C and then recrystallized twice from methanol. 4′
-Hydroxyflavylium chloride 179I is obtained and the corresponding molecular ion of the quinolinesilyl derivative: M/e
293 Experimental value: C, 68, 99: H, 4, 54: C1, 12,
92C1s H■':l Ox NiJsuKfM:c,
6964 ;H.

4.29; C1,15,70 79 g of 2,4-dihydroxybenzaldehyde was dissolved in 800 g of anhydrous ethyl acetate at room temperature, 106 g of ω-acetoxyacetophenone was added to the bath liquid, and the mixture was stirred at 0°C. After adding hydrochloric acid gas to saturation and leaving it for 24 hours at room temperature, the product began to crystallize, and was filtered and dried at 40°C in the presence of NaO [(Mo3.7-hydroxy-7 Labyrium). Chloride 95, j7 was obtained.

Molecular ion of the corresponding quinolinesilyl derivative: m/
e 581 experimental value: C, 64, 72: H, 4, 19;
Calculated value for C1,11,83C1gH1xC103: c, 6s, s9:H,4,o4;C1,12,91 Salicylaldehyde 88F was bath-dissolved in 3001 nt of anhydrous ethyl acetate with 162 g of ω-acetoxyacetophenone, and the solution was dissolved at 0°C. Cool to , start saturation with HCl gas,
This took about 1 hour and the mixture was then left at 4°C for 48 hours and the crystallized solid was collected, which consisted of 106 g of 6-hydroxyflavylium chloride. Molecular ion of derivative: m/
e 293 experimental value: C, 6B, 72:II, 4.17
:C1,12,86 (calculated value for 45H11C102: C,69,tS4:)1,4.29:C1,13,
70 Manufacturing Example 4. -5.4'-dihydroxyflavylium chloride salicylaldehyde 232 g and ω-acetoxy-(
Dissolve 4-acetoxin-acetophenone 41 in 300+++ g of anhydrous ethyl acetate, cool the c0 solution to -5°C,
It was saturated with hydrochloric acid gas and left at 4° C. for 48 hours. 3,4'
A total of 35.117 crystallized products consisting of -dihydroxyfrapyrium chloride were collected.

Molecular ion of the corresponding quinolinesilyl derivative: m/
e 381 experimental value: C, 6382; H, 3,97; C
Calculated value for 1,1184CHHI CI O3: C
, 65,59:H,4,04:C1,12,91 (2-6--<nzoyl)-2,4,6-dolyhydroxybenzaldehyde 70 g and (ω-acetoxy)
A solution containing 95 g of -5,4,5-)rimethoxyacetophenone in 1600 g of anhydrous ethyl acetate was saturated with HCl gas at room temperature. After 24 hours of standing at room temperature, product 10
4II, redissolved in 5.5 g of methanol, added 680 g of concentrated aqueous hydrochloric acid, and the mixture was left under reflux for 12 hours, then cooled and concentrated in vacuo until crystallization occurred at 4°C. After standing for 24 hours, it was filtered and the product was washed with 200% acetone and dried. The title compound 76I! was gotten.

Molecular ion of equivalent quinolinesilyl derivative: nn
/ e 559 experimental value: C, 55, 83: H, 4, 32
:C1,8,96C1 color H1? Calculated value for CI Or: c, 5a7s:n, +, so:Cl, 9.5
1 Manufacturing example 6. -47.4' -) 4-Hydroxy-ω- lyhydroxy7-ravillium chloride dissolved in anhydrous ethyl acetate 11I
Acetoxyacetophenone 96.6p, L2,4
-dihydroxybenzaldehyde 657y at room temperature
saturated with l gas. Leave the solution at room temperature under the sun for 3 hours.
Then, it was left at 4°C for 12 hours. The number of crystallized solids is 3,44'-trihydroxyflavylium chloride 142! i was obtained.

Molecular ion of the corresponding chimerin silyl derivative: m/
e 469 experimental value: C, 59,75: H, 3,96:
C1,1174C15Hl 10a Calculated value for C1: c, 61.98:H,3,81:C1,12
, 20 Production example 7. -3.5.7-) Lihydroxyflavylium chloride (2-0-benzoyl)-2,4,(S-)dihydroxybenzaldehyde S! 40 l and 178 g of ω-acetoxyacetophenone were dissolved in 3A' double-hydrated ethyl acetate. HCl was bubbled to saturation with stirring, and the solution was allowed to stand for 24 hours to obtain 175 g of a crystalline product. The resulting solution, redissolved in methyl alcohol 7', was refluxed for 20 hours, then concentrated until crystallization and left at 4°C for 24 hours.
-) 98 g of lyhydroxyflavylium chloride was obtained.

Molecular ion of the corresponding quinolinesilyl derivative: m/e
469 experimental value: C, 62, 31: H, 369; C1,
Calculated value for 119NC1sH1104C1: c, 5
t2s:u, 3. el: C1, 12, 20 Next, the pharmacological properties of representative examples of 7-lapyrium salts that can be incorporated into the pharmaceutical composition of the present invention will be specifically explained using experimental data.

Fasted for 16 hours and received 2 doses of olive oil 3 hours before slaughter.
Hyperlipidemia was induced in rats by oral administration at 1 nl/hg.

The test substance was administered intraperitoneally (ip) 1 hour before rat sacrifice in the experiments in Tables 1 to 4 and 2 hours before slaughter in the experiments in Table 5.
The results of these tests, in which the concentrations of non-esterified fatty acids (NEFA) and triglycerides in plasma were measured in experimental animals administered orally (O3) and in control rats administered 09% sodium chloride, are as follows: Shown in Tables 1 to 5.

(2) Hyperlipidemia induced by dryoid y (Triton) WRl 339 in male Spragut °urei (Spr
ague-DaW le Y) and C0s/<
(C, River) 8 hours before sacrifice, Triton WR1339 was administered intraperitoneally at 225 my/Ky to induce hyperlipidemia, and two test substances were administered intraperitoneally. . That is, the first administration - immediately after Triton, the second administration - after 41 Samurai ■].

The results of the test are shown in Table 6 below.

Table 6 - Significant difference from the effect on hyperlipidemia induced by Triton WR1339 (p<0.05) [Note] The percentage difference from the comparison control is shown in parentheses.

The pharmaceutical composition according to the present invention can be manufactured according to the following recipe.

3.4'-dihydroxy 7-ravillium chloride 1
125 da Solvent: double distilled water (pyrogen color first) 3 ml capsule 3-hydroxyne biryum chloride 50 dacia aminotetraacetate, lactose, methylcellulose, magnesium stearate) With χ 200 dacapsules 3.4'-dihydroxyflavylium loraik"
1nnr,.

Excipients (mannitol, citric acid, sodium chloride, thiourea, sodium ethylenediaminotetraacetate, lactose, methylcellulose, magnesium stearate) 2501n9 Tablet 3.4'-Dihydroxy7 Labyrium Chloride 25■ 25R9 excipients (mannitol, Sodium chloride, sodium ethylenediaminotetraacetate, thiourea) in appropriate amounts 125~ Solvent double distilled water (pyrogen-free) Flavylium chloride 0.25g Excipients [cetyl alcohol, saturated vegetable triglyceride, ester of polyethylene glycol 2000 and Cl2 - Cl4 fatty acids, Tween 80, paraoxybenzoate, sorbitol, carboxyvinyl polymer, sodium sulfite, Triethanolamine, lecithin, purified water, lactic acid] Appropriate amount 100g Dental gel 3.5.7-)rihydroxy-5', 4', 5'-trimethoxyflavylium chloride 0.125g Excipient (carboxyvinyl polymer , sorbitol, propylene glycol, sodium sulfite, ethyl alcohol, roseoxybenzate, sodium lauryl sulfate) in appropriate amounts 100.9 Patent Applicant Inverni, Della, Beffa, Varnish.

Hee, Knee / Patent Attorney Takashi Yoshino 4.・'-j Procedural Amendment C Method) % Formula % 1 Display of the case 1982 Patent Application No. 233754 2 Name of the invention Pharmaceutical composition 3 Person making the amendment Relationship with the case Patent applicant name Inverni della Vetufanis beanie
\Name Patent attorney (6323') Ryoji Yose 1. 5 Date of sending of the amendment order ``'':, 1ll=;,,: Submit the entire specification as attached. However, there are no amendments to the content.

Claims (1)

[Scope of Claims] 1. A pharmaceutically usable diluent or carrier and an active ingredient (Y)n [wherein each Y is the same or different (, -
OH or 10R (R is an alkyl group having 1 to 6 carbon atoms), m is 0 or an integer of 1 to 6, n is 0 or an integer of 1 to 5, m and n is 1 to 11, and X is a cation that can be used as a pharmaceutical, provided that Y) 9 is a group having the formula, and in this formula (a) =-OH, and R''=H(b)
R"=OMe, R"=-OI(,+shi-r R"=
H(c) R'= R"= R'=OH (d) R"=-OMe and R"= Rj= OH(e
) R'li"=-OMe, and R"=OHt Taha (
f) When R"=OH1+L and R"=R"=H, θ represents a group having the formula Y5, in which each of Yl, Y5 and Y7 represents the Y moiety defined above, and Y3, A pharmaceutical composition comprising a flavylium salt in which at least one of Y5 and Y7 has -0 [a group other than 1]. The pharmaceutical composition according to claim 1, wherein the flavylium salt has the formula: 3. The pharmaceutical composition according to claim 1, in which the flavylium salt has the formula. 4. The pharmaceutical composition according to claim 1, in which the flavylium salt has the formula.
A pharmaceutical composition according to claim 1, wherein the flavylium salt has the formula: The pharmaceutical composition according to claim 1, wherein the Z flavylium salt has the formula: 8. The pharmaceutical composition according to claims 1 to 6, wherein the flavylium salt has the formula: A pharmaceutical composition according to claims 1 to 6, wherein the 97 labyrium salt has the formula. 11. The pharmaceutical composition according to claims 1 to 6, wherein each Y is selected from H, -OH and 10Me. 7. A pharmaceutical composition according to claims 1 to 6, wherein the 127 labyrium salt has the structural formula: (Y)nO!(orIi)Me. 7. A pharmaceutical composition according to claims 1 to 6, wherein the 137 labyrium salt has the structural formula: wherein B is selected from: 14. Pharmaceutical composition according to claim 1, in which the active ingredient is 4'-hydroxyfumbillirum salt - 15. Claim 1, in which the active ingredient is 3,7-hydroxyfrapyrium salt Pharmaceutical composition according to item 1. 16. The pharmaceutical composition according to claim 1, wherein the active ingredient is 3-hydroxyfumbillirum salt. 17. Medical use n according to claim 1, item 11&, wherein the active ingredient is 3,4'-dihydroxyflavylium salt.
1 product. 18 The active ingredient is 3,5.7-)lihydroxy-3/,
41. s/ -\ Claim 1 which is trimethoxyfunbillirum salt
The pharmaceutical composition described in . 19 Active ingredient?3. The pharmaceutical composition according to claim 1, which is Otsu 4'-trihydroxyfunbillirum salt. 20. The pharmaceutical composition according to claim 1, wherein the active ingredient is 3.5.7-doryhydroxyflavylium salt. 22. Pharmaceutical composition according to claim 1(d), wherein the active ingredient is a 5,7-cyhydroxyflavylium salt.23.
, Xd-clonoid, sulfate, phosphate, acetate and hydroxy ion. 24. The pharmaceutical composition according to claims 1 to 23, which contains a preservative or buffering agent, a thickening agent, a clouding agent, a stabilizer, a wetting agent, an emulsifier, a coloring agent, or a flavoring agent. 25, carboxyvinyl polymer, clopylene glycol, ethyl alcohol, water, heptylalcohol ~ 21, saturated plants (1, triglyceride, fatty acid ester, propylene glycol, triethanolamine, glycerol,
Pharmaceutical compositions according to claims 1 to 24 containing excipients selected from starch, sorbitol, pen)-1-ite, carboxymethyl cellulose, lauryl sulfate, dicalcium phosphate, powdered silica and lecithin. thing. 26. The pharmaceutical composition according to claims 1 to 25, which contains at least two types of excipients. 27. Pharmaceutical compositions 2a according to claims 1 to 26 containing two or more types of fumbillirum salts of formula (I) Claims 1 to 26 in a form suitable for parenteral administration
Pharmaceutical composition 29 according to claim 27 Claims 1 to 2 in a form suitable for oral administration
Pharmaceutical composition 5a according to claim 7. The pharmaceutical composition according to claims 1 to 27, which is in a fully opened form. 31 Claim 1 in a form suitable for local administration
The pharmaceutical composition according to claims 1 to 27 is also in the form of a toothpaste.65 The pharmaceutical composition according to claims 1 to 27 is in the form of a dosage unit.
Pharmaceutical composition according to item 7. 34. A pharmaceutical composition according to claims 1 to 33 containing at least a2% by weight of fumbillirum salt. 35, 1 to 50) ff (% by weight) of 72 biryum salt. 36. The pharmaceutical composition of claim 34 containing at least 5 weight % biryum salt Pharmaceutical composition according to scope item 35.