JPH01139587A - Basic amino acid and organic amine salt of 3-oxygermylpropionic acid polymer, production thereof and immunopotentiator containing said compound as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is basic amino acid or organic amine; n is a positive integer). EXAMPLE:3-Oxygermylpropionic acid polymer.L-lysine salt. USE:An immunopotentiator. PREPARATION:A 3-oxygermylpropionic acid polymer expressed by formula II is reacted with a basic amino acid (e.g., lysine, arginine or ornithine) or organic amine (e.g., ethanolamine or ethylenediamine), preferably in an aqueous medium at 5-36 deg.C for 5-60min.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a basic amino acid and organic amine salt of 3-oxygermylpropionic acid polymer, a method for producing the same, and an immunostimulant containing the compound as an active ingredient. Related.

(Prior art) The 3-oxygermylpropionic acid polymer itself is represented by the formula % formula %) (wherein n means a positive integer) as disclosed in Japanese Patent Publication No. 57-53800. It is publicly known. However, this patent publication does not contain any equivalent description regarding the salt.

On the other hand, as related compounds, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, and methylamine salt of 3-trihydroxygermylpropionic acid are disclosed in Japanese Patent Publication No. 58-44677, and Basic amino acid salts of carboxyethyl germanium sesquioxide and its derivatives are disclosed in JP-A No. 62-252794.
Disclosed in the official gazette.

(Problems to be Solved by the Invention and Objectives of the Invention) The 3-oxygermylpropionic acid polymer disclosed in Japanese Patent Publication No. 57-53800 is excellent in physiological activity, but it is an acidic substance and is not suitable for living organisms. It has the disadvantage of being irritating and having low water solubility.

On the other hand, the basic amino acid salt of carboxyethyl germanium sesquioxide and its derivatives disclosed in JP-A No. 62-252794 is a salt of a low-molecular compound represented by the formula A certain carboxyethyl germanium sesquioxide itself is a substance that exhibits almost no immunostimulatory effect.

In the above-mentioned Japanese Patent Application Laid-Open No. 62-252794, Example 1 shows a method for producing the L-lysine salt of the above compound, and FIG. 1 shows its rR spectrum. The substance is an L-lysine salt according to the invention (manufactured by IM
As is clear from a comparison of IR spectrum charts and the like, they are completely different substances.

Therefore, an object of the present invention is to reduce the bioirritation properties of 3-oxygermylpropionic acid polymers having excellent immunostimulatory effects and to improve their water solubility.

(Means and Uses for Solving the Problems and Achieving the Objectives) According to the present invention, the above problems are solved by the formula % () (where ^ means a basic amino acid or an organic amine). ,
n means a positive integer) A basic amino acid and an organic amine salt of a 3-oxygermylpropionic acid polymer solves the problem and achieves the above object.

According to the method of the present invention, the above salt of formula I is prepared by combining a 3-oxygermylpropionic acid polymer with a basic amino acid having the formula % (in which n has the meaning given above). Alternatively, it can be produced by reacting with an organic amine.

That is, the present invention neutralizes 3-oxygermylpropionic acid polymer, which is an acidic substance, by forming it into a salt with a basic amino acid or an organic amine, thereby reducing its irritation to living organisms and reducing its water solubility. It is something that improves sexuality.

It has also been surprisingly found that the salt according to the present invention has a significantly enhanced immunostimulatory effect when compared with 3-oxygermylpropionic acid polymer.

The basic amino acids used in the method of the present invention include optically active forms and racemic forms of lysine, arginine, orthinine, histidine, tryptophan, oxylysine, oxydialginine, homoarginine, oxyhomoarginine, giartine, lysine norleucine, indospisine, etc. Examples of organic amines include ethanolamine, ethylenediamine, and meglumine. Note that these basic amino acids and organic amines have a high affinity for living organisms, and therefore, the salts according to the present invention are also excellent in use safety when administered as medicines.

When carrying out the process of the invention, a 3-oxygermylpropionic acid polymer and a basic amino acid or organic amine are mixed in an aqueous solvent at a temperature of 5-36°C for 5-60°C.
The desired salt is synthesized by reacting for a minute. Since 3-oxygermylpropionic acid polymer is poorly soluble in an aqueous solvent, it may be suspended in an aqueous solvent and reacted by adding a basic amino acid or an organic amine to this suspension.
In this case, the suspension gradually transforms into a solution. Incidentally, the desired salt can also be synthesized by making the individual reaction participants into a solution and mixing both warm solutions.

Regardless of the synthesis method used, the reaction mixture should be freeze-dried or dried under reduced pressure and treated with an appropriate solvent such as acetone, dioxane, dimethylformamide, ethanol, methanol, diethyl ether, etc. For example, it can be made into a crystalline powder, or it can be left to crystallize after freeze-drying or drying under reduced pressure.

(Dosage form and dosage) The salt according to the present invention can be made into various preparations for oral or parenteral administration by blending with pharmaceutical diluents or excipients. There are no restrictions on the dosage form when preparing a formulation, and it can be made into tablets, capsules, granules, injections, etc.

Although the dosage as an immunostimulant depends on the dosage form, symptoms, etc., 50-400 mg of the salt as an active ingredient is appropriate.

(Production Examples, etc.) Next, the present invention will be explained in further detail in relation to production examples, pharmacological effect test examples, and formulation examples of salts according to the present invention.

848 mg of 3-oxygelmylpropionic acid polymer and 80 mg of water. Dissolve L-lysine 7 in Onl, and add L-lysine 7 to this aqueous solution.
A solution of 31 mg in 10.0 ml of water was added.

The reaction mixture was lyophilized and the residue was treated with acetone to yield 16 g of a white crystalline powder.

Melting point: 160-170℃ (decomposition) Elemental analysis: (CgH1gGeN205.5 ・1.5
H20) TI calculation: )I, 6.47. C, 31,
53, N, 8.17 actual measurement: H, 6, 17, C, 31
,44,N, 7.91IR spectrum < Xy, );
l) C, -I.

As shown in the chart of FIG.

1) 1-NMR spectrum (O20, extTMS) δ
ppo+: 1.65-2.65 (6H, m, L-
Lysine C, -t+2゜C4-)12 and C5-1(2
) 2.02 (2H, t, J = 7.0Hz
.

GeCll-CH2CO2H) 2.95 (2H,t, J = 7.0Hz
.

G e CH2C! iiCO□H) 3.35-3.7 (2)1. m, L-lysine C6-O2) 4.1 -4.35 (18, ra, L
-C2-H of lysine) [α17・+5.58°(C”
1.86. t+20) 848 mg of 3-oxygermylpropionic acid polymer was suspended in 10.0 ml of water, and 731 mg of L-lysine was added to this suspension while stirring.

The resulting clear solution was lyophilized and the residue was treated with acetone to obtain 1.21 g of white crystalline powder.

Melting point: 160-170°C (decomposition) Elemental analysis: (CgH1gGeN205.s ・1.
5H20) n calculation: H, 6, 40, C, 31, 95,
N, 8.29 Actual measurement: )l, 6.06. C, 31
,91,N, 8.04IR,lh)le(!/”sua
l) C11-′:j! A1 1580 (C=0), 840. 775 (
Ge-0)'H-NMR spectrum (O20, extT
Ms) δppm: 1.65-2.65 (6H, tx
, C, -112°C4-O2 and C5- of L-lysine
O2) 2.02 (2H,t, J
Two 7. Ohz.

G e C! LICt(2C02H) 2.95 (2H,t, J = 7.0Hz
.

G e CH2C! ! iCO2H) 3j5-3.7 (2H, ta, C6 of L-lysine
-82) 4.1 -4j5 (IH, Sono, C2-H of L-lysine) [112]￥ = +5.80° (c
・1.93. O20) Setmotoe [848 mg of 3-oxygermylpropionic acid polymer was dissolved in 80.0 ml of water, and L-lysine 7 was dissolved in this aqueous solution.
A solution of 31 mg in 10.0 ml of water was added.

The reaction mixture was concentrated under reduced pressure on a rotary evaporator.
Treat the residue with acetone to obtain 1.28 g of white crystalline powder.
I got it.

Melting point: 160-170'c (decomposition) elemental content! fr:
(C9Ht, GeN2O5, s・O20)n calculation:
H,6j4. C, 32.3g, N, 8.39 Actual measurement: H, 6,12, Ni 32.28. N, 8.17I
R spectrum (C:;;') C11-': 1580
(C:0), 840.775 (Ge-0)+H-
NMR spectrum (extTMS) δp
p.m.

1.65-2.65 (6H, tx, C of L-lysine
, -1t2゜C4-O2 and C5-O2) 2.02 (21(,t, J = 7.0)
1z.

G e CHCH2C02H) 2.95 (2H, t, J = 7.
0Hz.

G e CH2CLmCO2) 1) 3.35-3.7 (2H, m, C6 of L-lysine
-O2)4.1 -4j5 (IH, rs, C2-11 of L-lysine>[α]':= +6.09°(c:
1.93. tlzo) In the same manner as in Production Example 1, except that L
- Treatment was performed using 71 mg of L-arginine δ instead of lysine to obtain 1.57 g of white crystalline powder.

Melting point: 195-220℃ (decomposition) Elemental analysis: (CgH1gGeN405.5- O20
) n calculation: H, 5, 85, C, 29, 11? , N,
15.48 Actual measurement: H, 5.7g, C, 29,96
,N, 15.53IR spectrum (Xu5el)c
,−,.

p+AX 1630 (C=0), 840.775 (Ge-0)
'H-NMR spectrum (020, extTMs) δP
PI: 1.8 -2.7 (4H, m, C, -O2 and C4-O2 of L-arginine) 2.02 (2H, t, J =
7.0Hz.

GeC1(iCt(2CO211) 2.95 (28,t, J;7.
0Hz.

G5Cll2C]C02H) 3.71 (211, m, J = 6.0H
z, C5-H2 of L-arginine) 4.1 -'4.35 (IH, m, C2-old of L-arginine [(Z)2: : +7.3 p (c
= 1.86. 1120) Same as Production Example 2, except that L-arginine 87bn was used instead of L-lysine.
1.61 g of white crystalline powder was obtained.

Melting point: 195-220℃ (decomposition) Elemental analysis: (CgH1gGeN405.5 ・[20
) n calculation: 11.5.85. C, 29, 87, N,
15.48 Actual measurement: H, 5, ♂4. C, 30, 23
,N, 15.49IR spectrum (ν″u5ol)C
11-1.

7th course X +630 (C;o), 840.775 (Ge-0
)'II-NMR spectrum (H2O, extTMs)
δppm: 1.85-2.65 (4)1. m,
C3-H2 and C4-112 of shearginine) 2.05 (2tl, t, J
= 7.011z.

G e CHCH2CO□It ) 2.97 (2H, t, J = 7.
0Hz.

G e CH2CHlCO□H) 3.73 (211,t, J・6.011z
, C3- of L-arginine) + 2) 4.1 -4.45 (IH, m, C2-H of L-arginine) [ctl; = +7.42° (c ・2
．． 10. H2O)W'L'3-oxygelmylpropionic acid polymer 848B in water 10. While stirring the suspension, 731 mg of lysine was added thereto.

The resulting clear solution was freeze-dried and then left under an argon atmosphere to crystallize, yielding 80 g of white crystals 1.

Melting point: 190-200℃ (decomposition) Elemental analysis: (CgH1gGeN205.5 ・3H2
0) 11 calculations: H, 6, 81, C, 29, 22, N,
7.57 Actual measurement: H, 6, 93, C, 29, 20, N
, 7.40IR spectrum (shikodama') cm-'
:1630 (C=0), l1g5. 805
(Ge-0)1B-NMR spectrum (020, ex
tTMs) δppm: 1.65-2.65 (6L
C3-H2゜C4-H2 and C5- of m, L-lysine
H2) 2.00 (2H,t+' J =
7.0Hz.

GeClUiCH2CO□H) 2.92 (2H, t, J =
7.0Hz.

cecu2cL, co□o> 3.35-3.7 -(2H, m, C6 of L-lysine
-H2)4.1 -445 (IH, m, C2-11 of L-lysine) Ia]" = 45.56° (c = 1
．． 85. H2O) In the same manner as in Production Example 3, except that 871 mg of L-ornithine was used instead of L-lysine to obtain white crystalline powder 1. 11 g was obtained.

Melting point: 145-155°C (decomposed) IR spectrum <Schiff "50') CIll-1 near az 1580 (C:o), 840.775 (Ge-0
) IH-NMR spectrum (mouth 20. extTMs
) δppm: 1.11 -2.6 (6H, m,
L-ornithine') C3-H2, C4-H2 and C6-
H)2.06 <2)1. L, J・7.1
)llz.

G death c! iic)l 2CO□1I)2.97
(2H, t, J = 7.0Hz.

GeCll2CH2CO21() 3.3 -3.8 (2H, m, C6-H2 of L-ornithine) 4.1 -4j5 (III, rn, 02-Old production example 3 of L-ornithine, except that L - Treatment was carried out using 976 mg of meglumine instead of lysine to obtain 1.75 g of white crystalline powder.

Melting point: 218-225℃ (decomposition) IR spectrum (,:l/,%l)am-'.

1595 (C:o), 840.760 (Ge-0
)'H-NMR spectrum (020, extTMS) δ
ppm +2.07 (2H,t,
J = 7.0Hz.

G e CN2. , CH2C02N ) 2.97
(2H, t, J = 7.0Hz
.

GeCH2CLLCO2H) 3.28 (3H,s, N-CN5) 3.5
-4.8 (8H,m, Meglumine-H) 305 mg of white crystalline powder was obtained in the same manner as in Production Example 3, except that 305 mg of ethanolamine was used instead of L-lysine.

Melting point: 60-80°C (decomposition) IR spectrum (S27; l) C, t.

1580 (C=O), 830. 765 (
Ge-0)'I-NMR spectrum (020,ext
TMs) δppm +2.00 (2)1
．． t, J・7.0Hz.

G e CLLCt12 CO211) 2.94
(211,t, J・7.0Hz.

G e CH2C! LmC02H) 3.87. 4.25 (4H, entered 2B2.N
C11,C)1,0) In the same manner as in Production Example 3, except that L-
Treatment was performed using ethylenediamine 120B instead of lysine to obtain 918 mg of white crystalline powder.

Melting point: 130- +50°C (decomposition) IR spectrum <Synopsis>, II"l: 11X 1580 (C=0), 840.770 (Ge-0)
IH-NMR spectrum (D20. extTMs) δ
ppm: 2.0g (2H, t, J near, 0l-1z.

G e CLLCH2CO2H) 2.99 (2H,t, J = 7.0Hz
.

GeCH2Cll-CO211) 3.90 (4+1.S, NCji
iCH, 0) l2 and Jul Compounds obtained from production examples and Japanese Patent Publication No. 57-5380
The pH of the 3-oxygermylpropionic acid polymer disclosed in No. 0 was measured as a 55.5mM aqueous solution at 20°C, and the results were as shown in Table 1 below.

Furthermore, the solubility of the compound according to the present invention in water is about 1.
It ranges from 5% to 10% or more, which is significantly higher when compared with the compound disclosed in Japanese Patent Publication No. 57-53800.

- The immunological action of the compounds according to the present invention was demonstrated in sheep red blood cells (SR).
This was investigated using a delayed hypersensitivity reaction (DTH reaction) using BC) as an antigen.

ICR male mice (7 withdrawn) were used as experimental animals in a group of 10 mice, and after 10' Sarcoma-180HA vesicles were intraperitoneally implanted, 106 antigen 5RBCs were administered into the tail vein to sensitize them.

Four days after sensitization, 10 pieces of 5RBC2 were injected into the paw skin of the right hind leg to induce a DTH reaction, and 24 hours later, the thickness of the heel was measured. The test drug was orally administered 4 days before sensitization.

The results are shown in Table 2 below, and the compound according to the present invention has the effect of activating the immune response that has decreased due to cancer-bearing, and its activity strength is as disclosed in Japanese Patent Publication No. 57-53800. It was found to be more than 10 times that of oxygelmylpropionic acid polymer.

Kawarayu Test for tumor-bearing control group Significant difference in Zero zero: p < 0.001 Ne: p<0.05 Made in Japan 1mokushu 4 (tablets) The following ingredients were mixed and tablets were manufactured by a conventional method.

Compound of Production Example 1 100 (mg) Crystalline Cellulose 20 Milk N41 Corn Starch 30 Hydroxypropyl Cellulose 6 Suarin Magnesium
200 mg per 31 tablets (W<capsules) The following ingredients were blended and capsules were manufactured by a conventional method.

Compound of Production Example 2 100 (mg) Crystalline cellulose 25 Silicic anhydride
lsteer1n magnesium
128 mg per 21 capsules Reifu Salmon Yu (granules) The following ingredients were blended and granules were produced by a conventional method.

Production Example 3 f-hi compound 150 (mg) Milk? 97 Corn starch 45 Polyvinylpyrrolidone
7 Silicic anhydride 300+ng per 11 packets "K Shinsho" (injection) The following ingredients were blended, an injection was made by a conventional method, and the injection was aseptically loaded into a vial.

Compound of Production Example 4 50 (mg) Distilled water for injection 5 q Benzyl alcohol 51 per vial 105 mg (Effects of the invention) The compound according to the present invention is a compound of the present invention in which a known 3-oxygermylpropionic acid polymer is mixed with a basic amino acid salt 1 Or an organic amine salt, but as a result, the aqueous solution becomes almost neutral and less irritating to living organisms, so it can be administered even to patients with gastric disorders, and its solubility in water is significantly improved. Therefore, the dosage forms are expanded, and furthermore, the importance of immunostimulation is significantly enhanced.

[Brief explanation of the drawing]

The figure is an IR spectrum chart regarding the L-lysine salt of the 3-oxygermylpropionic acid polymer obtained in Production Example I. Patent applicant: Sanwa Kagaku Institute Co., Ltd.

Claims (10)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, A means a basic amino acid or organic amine,
(n means a positive integer) A basic amino acid and organic amine salt of a 3-oxygermylpropionic acid polymer. (2) The basic amino acid salt of 3-oxygermylpropionic acid polymer according to claim 1, wherein A represents L-lysine. (3) The basic amino acid salt of 3-oxygermylpropionic acid polymer according to claim 1, wherein A represents L-arginine. (4) The basic amino acid salt of 3-oxygermylpropionic acid polymer according to claim 1, wherein A represents L-ortinine. (5) The organic amine salt of 3-oxygermylpropionic acid polymer according to claim 1, characterized in that A means ethanolamine. (6) The organic amine salt of 3-oxygermylpropionic acid polymer according to claim 1, characterized in that A represents ethylenediamine. (7) The organic amine salt of 3-oxygermylpropionic acid polymer according to claim 1, characterized in that A represents meglumine. (8) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, n means a positive integer) 3-oxygermylpropionic acid polymer and a basic amino acid or organic amine are combined. There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (I) (where A means a basic amino acid or an organic amine,
n has the above-mentioned meaning) A method for producing a basic amino acid and organic amine salt of a 3-oxygermylpropionic acid polymer. (9) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, A means a basic amino acid or organic amine,
(n means a positive integer) An immunostimulant characterized by containing a basic amino acid and an organic amine salt of a 3-oxygermylpropionic acid polymer as active ingredients. (10) The active ingredients are a) 3-oxygermylpropionic acid polymer/L-lysine salt, b) 3-oxygermylpropionic acid polymer/L-arginine salt, c) 3-oxygermylpropionic acid polymer/L - ortinine salt, d) 3-oxygermylpropionic acid polymer ethanolamine salt, e) 3-oxygermylpropionic acid polymer ethylenediamine salt, and f) 3-oxygermylpropionic acid polymer meglumine salt. The immunostimulant according to claim 9, which is at least one type of compound.