JPS5855418A - Remedy for hyperlipemia - Google Patents

Abstract

PURPOSE:A cholesterol depressant that contains, as an active ingredient, a salt of monacholin K carboxylic acid or ML-236B carboxylic acid with an anion- exchanging basic macromolecular compound, thus showing high pharmacological activity, stability and safety. CONSTITUTION:The objective remedy contains a salt of monacholin K carboxylic acid of formulaIor ML-236B carboxylic acid of formula II with an anion-exchanging basic macromolecular compound such as basic protein or base polypeptide as an active ingredient. Preferable examples of the above macromolecular compound are protamine, lysozyme, cytochrome C, tripsin, papain and ficin. The above compound is novel and obtained by reaction between monacholin K carboxylic acid or ML-236B carboxylic acid and the macromolecular compound in an aqueous medium and the weight ratio of the former to the latter is 0.1-1.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the compound monacolin, carbovin, and ML-23.
This invention relates to a 4Ji polymer compound having an ion exchange ability equal to that of 6B calzenic acid, and a treatment for treating myelinemia, which contains 4-4 as an active ingredient.

The present invention 6α Monacolin K and ML-266Blr' were previously discovered as cholesterol synthesis inhibitors.
WJ is an approximate compound with the chemical structure of F (
@ Kaisho 55-111790, Kaisho 50-155690].

f YX, Monacolin, Calhanjo and M It-2
36B Cal Ni71 Hamonacolin K and ML-2368
It can be easily cracked by saponification with a weak alkali, and has the following structure.

It is well known that monacolin carboxylic acid and ML-266B carboxylic acid also have a blood cholesterol lowering effect.

The present inventor, Tamokoro et al., continued to conduct exploratory research on related compounds that are superior to known compounds in terms of pharmacological action, stability, and safety.
2. The present invention found that the combination with a monobasic molecule compound having anion exchange disorder of phosphoric acid has the characteristic Y as a first generation F reduction of cholesterol. One piece completed.

In the present invention, carbic acid and ML-2 are added to monacolin.
Around 36B Calzenbato? As a salt-bridgeable polymer compound capable of ion exchange to form a, a basic protein or a raw polypeptide, primary, secondary, or 6
There are a large number of resistant anion exchangers with M as a base and a quaternary amino group.

As a basic 46 molecule compound, clT is added to the water bath solution.
Suitable general 1-injection protein molecules include highly active polypeptides, among which derotami, lysozyme, cytochrome O1) resonone, papain, ficin, and the like are preferred. Monacolin is a 14-dimensional compound of calcinic acid and ML-236B calcinic acid and these basic proteinaceous acids and polypeptides, for example, prepared by reacting both in an aqueous solution. be able to. At this time, if necessary, the formation of a weir can be promoted by adding PI-1w acidic or neutral water bath solution to alkaline water. The ratio of monacolin to calzenic acid and ML-2368 calcinic acid to basic protein's value and basic volibedetyl at the time of formation can be carefully adjusted. However, it is generally preferable that the ratio of the former to the latter (the ratio) is from 0.1 to 1.

Among the four-group ion exchangers, there are various 11-group ion exchangers, including 14 & amines, secondary amines, and 6-group ion exchangers. This, n, etc. ion exchanger has cellulose yarn, dextran yarn, agarose type and resin yarn due to 14 of the carrier bonded to the 4y:ho group. ! -Introduction to synthesis- Molecular threads are known, and the representative one is the one called "F".

Namely, T-KAE-cellulose, QAFli-cellulose, DiiiAB-cellulose, BCTg□LA-cellulose, BD-cellulose, A-cellulose, PA
B-Cellulose, BND-Cellulose, QAE-Sephadex (A-25 and A-50'), D, K A
, 1! i-Sephadex (A-25 and A-50>,
D In A, ll! Ni Sepharose 0L-68,
DEAFJ-Sephacel, DB Hachihe-Dextran, Lysine-Sephrose 4B, DOWEX 1, DOWEX 2, DOWEX 11, DOWEX MWA-1, DOWEX BBR-P, DOWEX WGfi, DOWEX M8A-i , DOWEX M8A-2, AGI-
x2, AGI-X4, A'G1-X f3, AC3
-x8, AC3-X10. AGMP-1, B10-R8
X9, B10-R41X 5, AC3-X4A, Dff
iAj! :Bi(J-GelA, Amberlight IFj
A-400, Amberlite HA-410, Amberlite R-4B, and Amberlite R-45# are available. Unibasic polymer compounds such as chitosan, basic polyamino acids, and 44-polyamines having anion crosslinkers related to these ion crosslinkers can also be used. As mentioned above, the basic ion parent compound Potopete is a well-known substance and is easily available.

Monacolin was combined with carboxylic acid 1'rML-236B carboxylic acid and cm4iaps ion exchanger with 0-related compounds #r#1. It is a substance whose formation can be carried out in accordance with the commonly known usage of σ ion exchanger. That is, a warm ion parent body pre-combined with a suitable anion is formed into a shell, and then monacolin and Calzenvin 1-j M L-236B cal? It can be made by using a bath liquid. Also, both by punch method? It can also be made by mixing.

Calzenbin rx M L -236B to monacolin, le, tenoic acid and anionic crosslinker j'3! When forming a carbic acid or rtM L- to chemonacolin, some of the exchange groups are related to chemonacolin.
256B carboxylic acid.

As will be described later, the terms of carboxylic acid in monacolin and ML-266B carboxylic acid and basic polymer compound having anion exchange ability have a higher cholesterol content than monacolin K and ML-256B@Binikorin et al.'s enzyme conductor. There is much concern about it as a depressant.

The ambiguous effects of these 1 carboxylic acids and ML-236B on monacolin are unpredictable. Therefore, Cal, +? The terms of aphrodisiac acid, σML-236B caldic acid, and aphrodisiac compound having anion exchange ability are extremely effective as a treatment for aphrodisiacs.

Next is Karzen I for Monacolin! i! and ML-266B
Choles'tyrol-lowering effect of a bottle of calcinic acid and a basic polymer compound having an ion-containing compound,
Indicates toxicity.

(1) Cholesterol 1 F action 1 Misaki 5 male rats (approximately 250 g) 4 C world I @ activator 1 Triton WR-1339J (song product name) (hon-
m'ji [It has the effect of raising the cholesterol in the rat dish by 1 liter> 40 oq/*n, and at the same time, monacolin and Calzan #! x is orally administered to ML-236 with 3-carzonic acid and a resistant polymer compound with anion exchange ability, killed after 20 hours, and spherical and blood/*Y
As a precaution, serum cholesterol levels were measured using a conventional method. In addition, in order to facilitate the comparison with the administration control in the table,
Calzen Il is added to monacolin, which is included in the rS term.
The results are shown in Table 1, expressed as # and ML-2368 carboxylic acid size.

Cloth 1 Cholesterol lowering effect on hyperlipidemic rats caused by Triton d*1 Reduction rate of pancreas administered with Triton wR-1339 compared to I1.

*2 The manufacturing method and properties of the salt used in this experiment are as described in the Examples below.

*6 Monacolin with carboxylic acid and M L-236B
The carboxylic acid itself is converted into a lactone. For this reason, the respective sodium salts and lactonized monacolin K and ML-236B were used as controls.

As is clear from &1, monacolin has calcinic acid and ML-236B acid and skin ionic acid exchange ability? have 1
-2368 to control monacolin, 1 monacolin, sodium carbenzene, and MI, in order of monolithic polymer compound, -2368
It is clear that it has an extremely strong cholesterol-lowering effect compared to %ML-2368 Sodium Carzenate.

(2) Acute toxicity to mice of 12 dan salt listed in Table 1
The binding, LD, was tested by oral administration. (Used T
Half of these animals die t) Kill 2000'l1
As is clear from the test examples with extremely low toxicity of 9/lc9 or higher and 0 or higher, monacolin contains carzanic acid and ML.
The combination of -23168 calzanic acid and a basic macromolecular compound containing an ion-synthetic function can be conveniently used by doctors as a cholesterol-lowering and arteriosclerosis preventive agent.

This drug can be administered orally or parenterally, for example in the form of capsules, injections, injections, etc., but it is preferable to use a medicinal drug. It is. Administration for adults: 0.5 to 1000 #I/day, for example, 5 to 1,000 doses per day, depending on the machine, number of doses, and type of cliff.
~500111g is preferable.

Next, embodiments of the present invention will be explained.

Actual opening 1 Protamine/sulfuric acid! ≦(Salmon whitebait) 5g 0,005
M IJ Potassium acid acid solution (...7.4) An aqueous solution containing 1.8 g of monacolin and calzene in a bath of 100 g (pH 7.4 tic adjusted with caustic soda) 6
A white precipitate was formed by annealing constantly while stirring for 0.1 m of cold acetone was added to the precipitate.
-C-.

- After cooling, the sediment was collected by centrifugation, purified with acetone, and dried by suction.6. Calzebe 1 protamine salt yx * r,: OI white powder monacolin.

Example 2 Egg white risotchi 1. (Seikagaku Corporation) 6009-101117 was dissolved in cold water. This is an aqueous solution of 559 monacolin and calzenic acid (P & 4 with caustic soda).
7.6) When 1 yrl was added, a white precipitate formed. Collected by sedimentation and centrifugation, suspended in 10M water and lyophilized, a white powdery monacolin K.
Door team t3i590r/v4.

Example 3 Downick, Su 11 5g (4.0 millimeters/l') was treated with alkali and acid in a conventional manner, and then made into QM form with approx.
00 (dissolved in 1 liter of water.) Here, 6-mic acid IJ-11 (1.27 g) of monacolin was mixed with carvone Yf.
fmrnl#Ethyl welding (immediately after taxidermy) 12111
Wash thoroughly with acetone, dry, and add 5.2 g of Monaco, phosphoric acid, DOWEX 114Y (1
7,-〇 Example 4 TJIliAfC-cellulose powder (1.02 mm/g) was treated with acid and alkali by the 59-ton method and then made into acetic acid I cedar. This AY is d good luck to last g, and it is a column, and this
, VCio (<4.2 g) of monacolin was passed through 100 g of calcaric acid water solution (adjusted to -7.6 with caustic soda), and the column was added to -? The sand was washed by passing water through it.

What is the contents of that column? It was taken out, suspended in about 5 Qml of water, and then freeze-dried.

Calanoic acid/TKAE-cellulose 45.2 gw f4Dca Example 5 A K-M+! Lurose (0.31 mm fit/fl
) 59 After treatment with acid and alkali using the capillary method, Ql (cedar).

It was suspended in about 300 ml of water. Then, according to Example 6, 1.1 ml of ethyl acetate bath containing 1 ml of monacolin and carzanyl # was added and thoroughly stirred.The solid Y was collected by filtration, washed thoroughly with acetone, and dried. did. Monacolin, a white powder, contains 44.8.9% carboxylic acid and AK-cellulose.

Implementation Gallo LlEAK-Sephadex A-25 (3.5 mm*/9) 51? Treated with acid or alkali using a conventional method (J
It was made into an R shape and was submerged in water at a depth of approximately 400m.

In addition to this, 6.2 mm of monacolin and calzenate are added.
12 ml of the ethyl phosphate bath solution was stirred well for 8 times.

Water? In addition, all types are approximately 100+
++l and freeze-dried.White monacolin and carboxylic acid.DKAg-Sephadex 1!4.9 g
I got it.

Example 7 Fruit! ! f4 Same as Example 1 Protamine/sulfuric acid 100'
nl<5qM*)Ic 1.7gOML-736B
Cal-Honic acid aqueous solution 3Qa+/(p'7 with caustic soda
．． 44'C tone 1111>) χ While stirring,
The resulting precipitate was separated by the same method as in Example 1, and 6.1
White powdered ML-256B Calic acid/protamine.

Center 1ffA Example 8 Same as Example 2 <600# egg whites/t team water#
g 10#LjK5 o*oML -236B Cal r
ML-236B carboxylic acid/lysozyme 4 in the white powder bed from 582 by performing the same operations as in example 2. Ta.

4-+11N 9 Dowex 1 (X2.3.5 Mi Ij 6/11
) Treated with acid or alkali using the 3g'xg method to obtain OEi
The shape is immersed in water of 300 i/m. Add to this 9 milliliter (3.7 g) of ML-236B calcium acid? 28 ml of an In tube ethyl solution was added with stirring, and the solids were collected by χ filtration. Solid food? After thoroughly washing with acetone and drying, apply 4.3.9 ML-2368 Cargonic Acid/Dowex 14 N47. -Q Example 10 DKAg-cellulose (1 t/, 9 per 1.04 mm)
5g was treated with acid and alkali using the phthalate method to form a liquid of approximately 300ml as QH type.To this, 5ml of ML-236B calzenate Y was treated with ethyl ethyl @liquid 8 rnl. w While stirring, it was mixed.Solid matter pt r
5. Drain through a filter, thoroughly wash with acetone, and dry.
12. ! i+ white powder ML-236B Kaluzunjo D
EAf! ;-Cellulose Shiokai Samurai 1ko@jikuyo] 11 Amberlight IR-45 (5 mm per t/F) 10,
@v Treated with acid or alkali according to the usual method to form 0) i form,
It was suspended in about 400 ml of water. In this case, 1 part of ML-2") 5B carboxylic acid per 10 milliliter of ethyl acetate @
3rnl of solution 2F was added with stirring. The insoluble matter was removed by passing through the kF, washed with acetone and dried to give pale yellow granular M.
L-236B Carzanic acid/Ryotenperlite R-454
I got 9.9 yen.

'48mGa12 EcTh: □LA-Cellulose (1t/0.35mm)
g) It was treated with acid and alkali using the 5g zero method to form an OR type. Packed into column, 4mm dazzling CR)
M L -236B force"'te 7 acid water bath g18m14
50ml of FJ 50ml
It was soaked in water and freeze-dried. White powder ML
-266B phosphoric acid-1'rI! X□L& -Cellulose 44.6yn 4# friend.

Actual power example 13 D B3 A W --? "Kist5 y (molecule t
4g50J5.2.3mm-it/,! 7. oh cedar) 5
．． ! i' (D water + 4
Add 770 mL of ethyl acid (dissolved in ethyl acid) and react for 60 minutes at room temperature. ML of that t & freeze-freeze drying new performance 9.49
-23<SB carboxylic acid/DmAFJ-dextran 1
I got it.

Example 14 HPTMA (2-hydroxypropyl trimethylammonyl 11)-dextran (molecular breakdown 40,000, 1.9
per millimeter t/, V, 01i type) 5g of water bath solution (60m
l) VC7,5 mm current nL-2368 force A/
yK 7 acid (4,6 Inl of ethyl acetate ic $) Y
Use for -30 minutes at room temperature for 6 times. Thereafter, lyophilization was performed to obtain 8.19 ML-236B carpic acid/HPTMA-dextran.

1 person who submitted the above. Written amendment of chapter procedure (voluntary) 1981 1t'15t1 Commissioner of the Patent Office Kazuo Wakasugi 1 Indication of the case 1981 Patent Application No. 151620 2 Name of the invention Hyperlipidemia therapeutic agent 3 Amendment Relationship with the case of the applicant 4 Agent voluntarily 6. Column 7 of “Detailed description of the invention” of the specification to be amended, Contents of the amendment (1) Page 2 of the specification, Monaprin In the expression [

Claims (1)

[Claims] 1. Carbobin yl M L-25 in monacolin
6B Cal has an acidic acid ion father's character and an annotated high juice. Cure and cure pigeon lipemia with child compound and 1M young component. 20. A bottle-based rope molecular compound having 4 ions of acetic acid is
monobasic protein - when the father is a 44i polypeptide f
fs Seishui Range 1st Engineering Cosmetic Pigeon Lipidemia Jiri Bank Ja6
, Claim 2, wherein the basic polypeptides of the 44 protein fibers are protamine, su-l-zyme, cytochrome O,) lysosin, papain, ficin, polylysine, polyarginine, and polyornithine. Eliminated high guard plate. 4.1 Weir-based polymer compound field with ion father encyclopedia is the first
class, 2nd #l&, 6th class and (also) quaternary amine group r
The hyperlipidemia cure according to claim 1, which is a tetrabasic anion exchanger that acts as a single agent.