JPS5910515A - Immune adjusting agent and its preparation - Google Patents

Abstract

PURPOSE:An immune adjusting agent effective for remedying and preventing malignant tumor, etc., having powerful immune adjusting action, showing low toxicity and safety, containing a compound such as 3-iodo-2-propynyl p-toluenesulfonate, etc. as an active ingredient. CONSTITUTION:An agent containing a compound shown by the formula I (R is triiodovinyl group, iodoethynyl, or ethynyl) as an active ingredient. The compound is used in the same dosage form and by administration method as those of common immune adjusting agent, carcinostatic agent, etc. Properly a daily dosage is usually 0.001-1mg per kg weight in the case of oral administration, and 0.0001-1mg in the case of hypodermic and intramuscular administration. In the synthesis of the active ingredient, a compound shown by the formula III as a raw material obtained from 2-propyne-1-ol shown by the formula II is treated with iodine in the presence of an alkali reagent to give a compound shown by the formula IV among the compound shown by the formula I , which is further reacted with iodine to give a compound shown by the formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an immune amJD characterized in that the active ingredient is a compound represented by the following general formula (in which R represents a triiodovinyl group, an iodoethynyl group, or a kingtinyl group). The purpose and point of this article is to use immunogens as immunomodulators in patients suffering from various cancer diseases, infectious diseases, or immunodeficiency in which immunodeficiency is recognized. Providing legally effective drugs1
(-is to do.

Many attempts have been made to develop Mine's chemotherapeutic agents,
Combination therapy and combination with other surgical operations are also often performed. However, many of the chemotherapeutic agents for aneurysms contain substances that damage not only the 6III cells but also the permanent cells, and no commercial drug that is effective in treating aneurysms has yet to be found. Not yet. In addition, many of these highly toxic chemotherapeutic agents have the side effect of further reducing the immune function of II91 patients, who have essentially decreased immune function. As a result of the decline in IJ, each apple is more likely to suffer from infections as complications, and as a result, there are many cases in which the layer condition worsens.

In recent years, great advances have been made in immunology, and a great deal of knowledge has been gained about the host's biological defense mechanism against infections and aneurysms. As a result, we have developed a concept different from the conventional chemical rapid-determination concept of so-called selective toxicity, which expects drugs to act directly on cancer cells, namely (1. The idea of using the immune response mechanism to indirectly exert anti-cancer effects has attracted attention as the so-called anti-tumor therapy. In addition, by activating the non-specific acidic or cellular functions of the immune system and restoring the immune function to normal or near normal levels, cancer cells are recognized as foreign to the host and the immune response mechanism is activated. In addition to suppressing the death, proliferation, or metastasis of cancer cells, we are also trying to prevent the decline in immune function due to chemotherapy, surgery, physical therapy, radiation therapy, etc. The purpose is to improve the therapeutic effect.In addition to cancer, drugs are useful for restoring or enhancing normal immune function, or for restoring immune function to a normal level.

In addition to cancer, cases in which the immune system is more likely to occur include aging, cases where the immune function has decreased due to 41 JJK human diseases, 11 = Heka, or immunodeficiency syndrome, etc. Even in such cases, immune activation or preparation M is required. Some immunostimulants against cancer have already been discovered and put into practical use, such as the Corsicolor versicolor extract, the BCG bacterial preparation, and the extract of the 9 human type M nucleophiles in the Yuseizono formulation. However, these are foreign organisms to the human body,
lI Table 1J] Since it is ranked 1st, it contains other types of problems. In particular, these are not single components, but mixtures of polymeric components with complex compositions. It is difficult to provide the agent with optical usability and properties, and there are problems such as the absorption is generally not good.

In order to solve these problems, we will prepare a low-molecular-weight non-throw codfish used as a seed crystal.
, can be done. Levamisole is expressed as a low-molecular weight-free viscosity obtained as a pure product [Cancer Research J (Cancer 14es,) 35 Contains +92
7 Sada (1975 August) Volume 103, 6
82A (1977 noon)]. However, levamisole has relatively widespread toxicity, a long safety margin, and clinical
1. ．． It has been reported that the side effect of thickening occurs in the heart rate as well. For example, individual I #military itch.

Unpleasant side effects such as rubella, hair loss, and gastrointestinal irritation occur.The present inventors have developed a drug that is easy to use as a low-molecular, single-substance substance, has strong immunofA modulating action, and is low in oligogenicity and has a wide safety margin. After conducting a wide search for a leading compound 1, we found compounds #fll, compound (2), and compound (3) shown below as having these properties, and completed the present invention.

Compound 11: 2,3.3-triiodo-2-propenyl p-)luenesulfonate compound? +21: 3-iodo 2-propynyl p-toluenesulfonate (H3CO802-0-CH2-C:C-I) Compound f31: 2-70 vinyl p-toluenesulfonate (H,C-<=>-8o, - 0-CH2-CmiC)I compounds (+1, +21 and 13) are all known compounds. Compound (1) is an intermediate for the synthesis of an antiseptic compound (% Kosho 49-24445) - [, Compound I2)
is a synthetic intermediate for anti-difficult compounds (West German public pi attached [22
63121 (26.

Jul., 1973)) and as a fungicide (Japanese Patent Application Laid-Open No. 54-1.22727), but it has never been known to have immune-stimulating properties. Compound (3) is also a known compound
igsAnnale;1der Chemie) 5
96, vol. 25-38) (1955), but similarly, nothing is known about its effect on dispensation and regulation.

The immunostimulant IO of the present invention can be used in the same dosage form and administration method as ordinary immunostimulants, analgesic agents, and various chemotherapeutic agents for infectious diseases, and can be used alone or in combination with other drugs.
Used in I. Oral preparations include: usually powders with excipients, capsules, gunpowders, and fine granules9
It is used as a tablet thickener, syrup cup, and dry syrup agent. Suppositories may be used for rectal administration. As an injection, it can be used subcutaneously, intramuscularly, or by other intravenous injections. For topical use, it is used as a tincture or cream.

Diseases of overuse of the drug of the present invention include, for example, malignant diseases such as gastric cancer, medicinal cancer, canine intestinal cancer, rectal cancer, uterine cancer, liver cancer, leukemia, lung cancer, malignant pigmented melanoma, osteosarcoma, and lintural sarcoma. M
Treatment and prevention of infectious diseases caused by bacteria and fungi in the hospital and other buildings, as well as rheumatoid arthritis, polymyositis, metal lupus erythematosus, etc., which are associated with decreased or abnormal complete pitch function. The adjustment and normalization of immune system in autoimmune diseases etc. can be accelerated. It can also be used as a reagent for diagnosis and assay of various types of immunocompetence. The dose of the immune-stimulating FM agent of the present invention is 1
The daily dose per gram is usually 0.
001~1~, 0.01 for subcutaneous or intramuscular administration
J 01-179 are excessive. For topical administration, I3.0001-0.1% softeners or tinctures are usually used.

The toxicity of the compounds of the present invention to mice is that the LD5o value is 100 m97 kg or more when administered orally, which is extremely high compared to the effective dose, and the compounds have a wide range of safety. The administration method, formulation, administration frequency, etc. are appropriately selected depending on the type and condition of the disease. Other immunostimulants, 11
By using υF with various antibacterial agents including +11 cancer drugs or antibiotics, a synergistic effect with these drugs is expected. Tablets, granules, capsules, etc. are formulated with excipients, lubricants, disintegrants, etc., and are formulated into their respective dosage forms using conventional methods. Examples of excipients include starch, lactose, gelate/magnesium stearin, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, and wax. As the lubricant, boric acid, sodium benzoate, polyethylene glycol, etc. are used. Disintegrants include starch, methylcellulose, alginates, carboxymethylcellulose,
Sodium lauryl or the like is used. Examples of the pestle III activator used in the 70-pound formulation include gum arabic, carboxymethyl cellulose, and the like. Flavoring agents, color-degrading agents, stabilizing agents, and the like may be appropriately added to the above-mentioned oral preparations. Injectables may contain salt, glucose, various preservatives, and the like.

Formulation example 1゜Compound + 11 50 mf stearinated magnesium 50~lactose
50 l Blend each component in the above proportions and press into a tablet of 1 t J150 TNi 0 Preparation Example 2 Compound (1150 ~ Magnesium stearate 100 rng) Mix the above ingredients and press into tablets 1 control 50 mg It was made into tablets.

Preparation Example 3゜Compound + 2) 1 nv Stearin Soaked Magnesium 100■ Each component was mixed in the above ratio and compressed into tablets with a weight of 100~.

Formulation Example 4゜Compound+,'(11m9 Crystalline Cellulose 201L9 Starch 3Q++y Lactose
30■ Magnesium Stearin 20q Each component was mixed in the above ratio and compressed into a tablet of 11 dlOOki.

Formulation example 5゜Compound f11 5 m9 milk
sugar 200
119 Sudarin song Magnesium 6 ■ Corn starch 50 ~ Cho crystal cellulose
50#v of the above ingredients were mixed and filled with light into an acid capsule to form a capsule.

Next, the results of enhancing cellular immunity of the compound which is the active ingredient of the immunomodulator of the present invention will be shown.

Test Example 1 Test on effects on cellular immunity in normal animals: Compound +1 on 4111 cellular immunity in normal animals
1, 121, and +31, using sheep blood cells as an antigen, and injecting them into mouse footprints produces delayed skin dregs bLLt) (1) layered type cut
aneous hypersensitivity -5ity
) as an index (Lagrange, P, H, + G,
B, Mackanessand 'l'', FoMl
lle: J, Exp, Med, 139. 15
29-1539.

(1974)).

Test method: 0.05 - 1 mT of physiological saline was applied to a 10 - 8 week old female CDF mouse, which was equipped with a syringe under light. , compound (11,
+21, [31 respectively 10 TnVkg CM
Object nta') ), I WAq, 0.1rn
g/kg'1. Three mouthfuls of 0.2 ml of the sample prepared with 25 thiethyl alcohol static solution to give 0.0 and 0.01 rIv'kq were administered to each mouse. 24 hours after secondary sensitization by subcutaneous injection to 108 quotient sheep red dish f*1, the a degree of eye opening (thickening of the foot opening) that occurs in the foot opening was measured using Calibus, and the Compared with the foot thickening degree, the foot binding J9 rate (average foot jump thickness of compound-administered animals/average foot heel JI, I height of control animals) x 100 ((6)) The results are shown in Table 1.Table 1 Effect on delayed-type hypersensitivity (D, T, H) in compound +I+, 121, (3+) (1 out of 5 animals, (transdermal administration) Compounds fll, +21, +31 are clearly qd
It strengthened the main cell-mediated immunity 11, but especially the compound (+1
is 176 tny in Q, lq/W amount, 172% in I Q/kW fIL, 1 at the foot of compound (2) ore 0.1 tny/yq
67% and 1 qAq* resulted in high foot fertilization rates of 160%, respectively, and a remarkable immunoenhancing activity effect was observed in the solid compound.

Test Example 2゜Anti-IIIJ! Test on the effect of +1111M immune Vt deletion in tumor animals: Test method: 12-week-old female CDF□ mice were used, 6 mice per group.

10 Ascites 5arco+na 180 #III
Embrace C1) F, -r usu H1: Inside #jo (o B)
L,, 1120 wm for 24 hours, i.e. 1st H of the test.
x Width 21) m x 0.6-6% of I'iTr cotton cut into 2 mm pieces with a Komagome pipette.
Add vicryl chloride ethanol solution and mix it with Vincerato.
l ljJ 15 tm 17) rt\sani hair I
CIj superior Mautuma abdominal skin debris is reciprocated 3 times to disintegrate (
- Next sensitization) First, measure the thickness of both ears of the mouse at 088U.
Add mt+ with lthiekneaa gauge and set it as tiil sen of skin dregs reaction. Next, a 1% vinyl chloride olive oil solution was soaked in absorbent cotton measuring 10 x 4 w x lfi thick and applied to the superficial nests of both ears of the mouse (secondary sensitization). The thickness is measured and the value before secondary sensitization is subtracted to obtain the ear thickness increase (standard deviation above the average value of both ears of 6 animals). 10.1, o, 1. of 6 compounds. o,ot m
Ws4u samples were prepared by dissolving qy%c (animal body weight) in each 25% ethyl alcohol solution, and were administered once for 7 days x 6 days (2-day system) from the 1st H to the 8th day of the test. 0.3 dikX was orally administered to mice.

The control group was similarly transplanted, sensitized with vinyl chloride, administered with 25% ethanol/L solution as a solvent, and secondary sensitized with 1-chloride picryl-olive oil solution to reduce ear thickness. Measure. The average ear thickness increase rate of the control group was compared with that of the compound administration group, and the ear thickness increase rate was calculated from the formula (average ear thickness increase rate of the administration group/average ear thickness increase rate of the control group) x 100). , was used to determine the degree of cellular immunostimulation.

The results are shown in Table 2.

Table 2 Cellular immunity test using delayed skin reaction as an indicator in IIIm-bearing animals d): Mine P(0,1, Future P<0.05,
From these results, it is clear that the delayed skin reaction induced by sensitization with violyl chloride (]~butene antigen) is effective in reducing cells in tumor-bearing animals. The present compound (1) has a positive effect on sexual immunological function.

(2) was allowed to be used as a tax.

, Compound (1) Te is 1 m? Aq in group 134
2%, and 0.2% for compound (2). i w% 14 in rice group
A high rate of increase in ear thickness of 6.2 yen was observed in each case, indicating that both solid compounds clearly have the effect of activating the host's cellular immune capacity, which has been reduced by malignant lesions.

Next, the method for synthesizing the compound of the present invention will be explained.
As mentioned above, the compounds of the present invention are known compounds according to the above-mentioned literature, and the known synthesis methods thereof are summarized in FIG. 1 below.

Figure 1 Known synthesis method: Using 2-propyn-1-ol as a raw material, 3-iodo-
Compound (3) is obtained by treating 2-propyn-1-ol with p-)luenesulfonic acid chloride in the presence of an alkali. After removing 3-iodo-2-propyn-1-ol or further reacting with iodine without Jll#, 2.3.3-triiodo-2-propene-1-
Compound (1) is obtained by reacting p-)luenesulfonic acid chloride with ol in the presence of an alkali. Compound (3) can also be obtained by reacting 2-propyne-1-mer with p-)luenesulfone I)t chloride in the presence of an alkali.

Among the above synthetic methods, when looking at the method for synthesizing compound (2), 3-iodo-2-propyne-1 is synthesized using the synthetic intermediate.
- The ol is irritating, has erosive properties, and has a negative effect, and the yield when synthesizing this compound is low.
There is one problem, such as the operation being complicated. The reason for this idea is that when 2-propyn-1-ol is reacted with iodine in the presence of an alkali, the reaction does not stop at mono-iodination, but also adds 1 mole of iodine to 2-propyn-1-ol.
3. 3-triiodo-2-flopen-1-ol tends to form as a by-product, and 3-iodo-2-proquine LI-1-ol is extremely soluble in water, so the extraction bath In addition, the extraction efficiency is not good. Since these problems are 11 problems to be solved for industrialization, the present inventors developed a simple method for synthesizing compound (2) that does not pass through 3-iodo-2-brochin-1-ol. As a result of our investigations, we completed a new synthesis method for compound (2), shown in Figure 2. Furthermore, compound +11 can be efficiently extracted from compound (2).
We have also completed a synthesis route. Combine the above results 1 and -2 and press.

Figure 2 A new method for synthesizing compound CII, +21, i.e., using compound (3), which can be easily obtained in good yield by a method known from 2-propyn-1-ol, as a raw material, and adding iodine to it in the presence of an alkaline reagent. Surprisingly, only the selective reaction, that is, the 1-pleasant reaction due to the iodine system in the acetylenic water system (water system at the ethynyl position), is almost selectively swept away! ' , lik 'ffr-1
- It was found that the expected l1It substitution reaction of p-)luenesulfonyluogycy-A5 with the iodide atom hardly occurs. Through this reaction, compound (2) can be easily synthesized from compound (3) in a high yield. Furthermore, it has been found that by reacting the compound 2) with iodine, it is possible to easily form a chemical compound 'F-'J11) with a still high yield. When compound (2) is synthesized using the above method, the intermediate compound (3) does not necessarily need to be purified or isolated, and 2-propyl-7-1-ol i fc
(Ti 2-propynyl p-toluenesulfonate was prepared by a so-called one-pot operation.)
is swallowed. + point bhr. For example, the alkali sample used in the above-mentioned difficult synthesis method is waterpolymer.
Hina) l) Rum, hydroxide power 1 noum.

Water 11% can be added to alkali metals such as water II compounds, alkaline water sensitizers, alkali carbonates, and tertiary amines, but are not limited to these. Ascending self γ Lucari +: L addition is out'Kl ~ 2
Between the moles, Alka 11 raw paper system, yarn and compound side, 3) react 6) part of that trs sword 1j) f? Do not pretend to limit q □For example, the yo-system and the field ``1''
A method of reacting compound 13) with a bath solution containing a salt obtained by reacting with reagent 11,
Alternatively, a method of sequentially adding alkaline mulberry and iodine to the dissolved IK of compound (3), or a method of sequentially adding iodine and an alkali to dissolve compound 13). Both methods are applicable to 5J11. The solvent is not particularly limited, but may be used, such as a mixture of water and a conventional medium, such as a mixture of water and a conventional medium. Alcohol or mixture of water and alcohol 1]
A spear is used to steal a lamp. On the other hand, a hot hammer is usually heated in an ice-cooled room or in a room (1J with crystals, or depending on the scale of the reaction, a lower rHA (-20℃~-!i'C) is preferable. Problematic 3
-Iodo-2-propyn-1-ol A route and method for efficiently sweetening compound i21 without encountering it has been established, and a convenient synthetic method for compound (1) has also been established. ``I did it.

Next, 2,3゜3-triiodo-2-flobenyl p-
) luenesulfonate [compound 11)],] 3-iodo-2-propynyl p-toluenesulfonate [compound *
(21) and the method for synthesizing 2-propynyl p-1 luenesulfonate [compound (3)] will be shown as a synthesis example.

Synthesis example 1. 2,3.3-) Ryodo-2-gopenyl p-)luenesulfona) 1: Synthesis of compound (+) 2.3.3-Triiodo-2-propen-1-ol 102 was bathed in 20 ml of dioxane, While stirring this at room temperature, add 4.189 g of p-)luenesulfonyl chloride, then add 0.97 g of sodium hydroxide.
A solution of F in 5 ml of water is added dropwise over about 30 minutes. After stirring for an additional 30 minutes at room temperature, ice water was added and extracted with ethyl ether. Wash the ether layer with water, dry it,
When all the ether is distilled off, crystals remain. This is recrystallized from the tetrachloride reversion system to produce 2,3,3-triiodo-2-flobenyl as mostly colorless, slightly pale colored crystals.
p-toluenesulfonic acid) 11.19 is obtained. Melting point: 114°C to 116°C Analysis value: Total of 311 candies, (C,o
)L, C)3Si2.589.94)C2o,3
6.

H1, 54; Experimental value C20, 62, H2, 20 (@ t
M Example 2. 3-iodofurovinyl p-toluene i
sulfonate [synthesis of compound *t211 2-propyne-
1-all 562 to water 2507! nir = rudder, under water cooling,
Sodium hydroxide 100? Add the iodine 2542 in small amounts at a time for about 1 hour. Stir in 100ml of water at 01:00. Extract twice with chloroform, resist the chloroform extraction with a small amount of water, dehydrate with anhydrous magnesium sulfate, distill off the solvent, and leave the residue at 50 °C to form crystals of 3-iodo-2-propyn-1-ol 110
When recrystallized from 0 ether containing t, the melting point is 43°C.
~44°C. Of the 3-iodo-2-propyn-1-ol obtained here, 36.6 F was bathed in 100 me of t-dioxane, cooled on ice, and while stirring, 43.2 F of p-toluenesulfonic acid chloride was added. Next, a solution of 9.452 ml of sodium hydroxide in 30 ml of water was subjected to rITIi for about 1 hour using a trowel, and the mixture was stirred at room temperature for 30 minutes. Add 150 ml of water, extract with 300ml of ethyl ether, wash the ether with water, dehydrate with anhydrous magnesium sulfate, and boil the solvent at below 30°C to crystallize the resulting oily residue.

Recrystallization from ligroin gives 3-io)'-2-flobinyl p-)luenesulfonate (compound 'F/I+2)) exhibiting a temperature of 79 to 81°C at one point. Collection: 56.2f.

Elemental analysis value (Ct.) (,IO,S, 336.14
): Calculated value C35,73, H2,70; Experimental value C35,44, H1,80 (@Synthesis example 3. '2-
Propynyl p-)luenesulfonate [Compound (3)
] Synthesis of 2-propyn-1-ol 11.2 f in dioxane 5
00 tnt, and add p-toluenesulfoyr to this.
Add 76.29 g of 1N chloride, then 25.2 g7! of sodium hydroxide! About 1 liter of bath solution made by soaking
Drip in time. After 2 days at room temperature, the solvent was distilled off under reduced pressure, the residue was extracted with 1 t of ethyl ether, the ether extract was precipitated with water, and after dehydration over magnesium anhydride, the ether was distilled off and the resulting liquid was distilled off under reduced pressure. Glaze made by distillation, boiling point 1
04-109℃ (1,0 degrees Hg) and L-' (2
-;'Robinyl p-toluenesulfona-) [Compound +
31327 f is obtained. NMR spectrum (CI)
C/3-TMS) δ: 2.43 (-U, line + 3
H+ CH3) +2.50 (3-*+□, H(,
danC=C-) ; 4.68 (2M+!□, 21(
, -CH2-); AB four orders centered on 7.58 +
W (4H, benzene ring proton, JAB=8Hz)
Synthesis Example 141 2.3.3-) Ryodo 2-propenyl p-)luenesulfonate [Synthesis of compound (11) 3-iodo-2-propynyl p-toluenesulfonate (compound +21) 3.35 S' in chloroform Add 2.549 iodine to it, and irradiate it with sunlight for 2 hours while cooling with water and stirring.After most of the iodine color has disappeared, the solvent is distilled off, and the residue crystallizes. The compound 2,3.3-) Ryodo 2-propenyl p obtained in Synthesis Example 1 was recrystallized using about 70 ml of carbon tetrachloride and had a melting point of 114-116°C.
-Toluenesulfonate, 1! : Same (7) Compound 5
．． 32 was served (yield 90%).

Synthesis Example 5. Synthesis of 3-iodo 2-propynyl p-toluenesulfonate C compound +2+) 2-propynyl p-toluenesulfonate [compound +
31) Dissolve 10 r in 400 ml of methanol,
100 nm of a sodium chloride bath solution of N-water was added to the ice while stirring under water cooling. , then powdered iodine 12'? were added sequentially, stirred for 30 minutes under water cooling, and ice water was added to precipitate white crystals. As a result, 132 (yield: 81) of 3-iodo-2-propynyl p-toluenesulfonate ((14 product (21)) was obtained.

IR Spectrum)Nujol)cm': 22
00 (ko=C)NM)t spectrum (et+cL
3>δ(ppm): 2.45 (3H.

Takei F. Representative of Meiji Silk Manufacturing Company Masaru Kobori (and 2 others)

Claims (1)

[Claims] 1. An immunomodulator containing a compound represented by the following general formula (I) (wherein R represents a triiodovinyl group, an iodoethynyl group, or an ethynyl group) as an active ingredient. 2. A method for preparing an anti-inflammatory #J@ regulatory agent, which is characterized in that a compound is obtained by reacting 2-7'ropinyl p-)luenesulpote with an alkaline reagent and iodine. 3.3-iodo-2-propynyl p-toluene k;
1. A method for preparing an immunomodulator, characterized in that: 1) a compound is obtained by impregnating an iodine-based compound with an iodine-based compound;