JPS60156628A - Manufacture of 2,4,6-triiodophenol and therapeutic application - 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] [Industrial Application Field] Mokugo Akira is a strong ~1 anti-inflammatory agent and analgesic agent, as well as a strong anti-cirrhosis agent, press, teal lowering agent, and tower fat. blood drug 1
．． Regarding the products that have been disclosed as vasodilator, aggregation, concentration, and first-rate stimulant agents. Conventional brilliance reviews, points of interest],, 9. Dar 4.11 Knee 1: h;,,,, Lyodov, 1,000-knoll product is a yellow crystal, powder, powder of one point istη, 1, poorly soluble in water, 1, ethyl Organic solvents, such as acetone, sulfuric acid varnish, chlorine, alcohol, alcohol, acetone, sulfuric acid varnish, etc. It dissolves very well in water, etc., and it also dissolves well in alkaline solutions.

′・: “, detri 3-door”/-7+z is old, kukara・.

Example 'Gfmj'se Ryo'al'sr'Capuano
Pharm, “Acta Helv, 2/ (/941
4), PJJ! Although known as r, it has not currently found any practical application in the industrial or commercial field.

[Means for solving problems]

Therefore, one of the objects of the present invention is to provide a strong and effective anti-inflammatory and analgesic agent for veterinary medical treatment as well as human treatment, by intravenous administration. In the middle of the day,
The first step is to use 6-dryiodophenol.

This product, administered parenterally at a dose of 9 in /'#/, exhibits efficacy comparable to or superior to other typical anti-leumatis effects such as aspirin and indomethacin at therapeutic doses.

Preferred administration is parenteral, preferably intramuscular administration, but other routes such as oral, rectal, and transdermal administration are equally effective. Therefore, another object of the invention is to apply coe''*A-triiodophenol therapeutically as well as to
Pharmaceutical compositions containing t,-triiodo-5-enol as an active ingredient can be prepared individually and depending on the case, such as injections, tablets, syrups, loans, pills, suppositories, pomanid, and sapphire. The objective is to formulate the drug into a pharmaceutical form for administration.

Other objects of the present invention are the treatment of cerebrovascular insufficiency, ventricular and coronary insufficiency, hepatic insufficiency and portal hypertension, and chronic localized anemia of the lower extremities; 2. 'q,:t,,''
) by applying lyodophenol. Parenteral administration is preferred, especially intramuscular administration, but other methods are also effective, such as oral administration and
and rectal administration, etc.” □. Its = H and m
- The dose is ``1 kg body weight'' (7, s mg).

Finally, one object of the present invention is to catalyze the displacement of aromatic hydrogen (particularly benzene hydrogen) to iodine starting from phenol and using a relatively hydrated reaction medium and - According to the ability, 1.1□, Hiroshi directly iodines the phenol.

The method for producing 6-triiodophenol is as follows. - Iodination using peroxylic acid and potassium iodide in the presence of sulfuric acid also shows good results.

〔Example〕

The following examples illustrate the invention of methods of manufacturing this product, as well as methods of evaluating its pharmaceutical and pharmacological properties, and methods of preparing therapeutic dosage units. □ Example, 4, 4(,A-) Production of rhodophenol (1)
Direct iodination of phenol Phenol 'ffAIIt□ (6 soles □) and Metsutsukogdatictt' equivalent) were dissolved in tIooo resistant methanol and placed in a water bath, stirrer, reflux condenser, thermometer and Introduce into a three-day reactor equipped with a mixing funnel.

Add sulfuric acid and heat the mixture to 0.5cm. joqb hydrogen peroxide qo6yul at 60~□65℃
Add gradually at temperatures between. After mixing, the above temperature is partially heated under reaction for <C-S time. Stop heating, 21
Leave it for an hour. The obtained precipitate fa is filtered and air-dried. The resulting crude acid product is recrystallized from warm methanol and washed with methanol/water (?//).

Approximately /kot to t of product (melting point isg −is;
is obtained (yield: a37e+%). That R0N
6M spectrum and mass spectrum are J, q, x-)
Hibiki: iz, iii, peracetic acid (i, 33 mol) □
Cool it externally with ice, then dissolve it in 100% concentrated sulfuric acid.

S3. K/2,1 t of potassium iodide (3/6 mol) is added in portions, followed by K/2,1 t of phenol (72 t).
5 mol) is added. Leave it overnight while stirring. Pour onto ice and sift the resulting precipitate into powder to remove excess iodine with ethanol/ethanol.

□ A pure product (yield: 5 qb) with some of the same characteristics as the product obtained in the previous method is obtained by recrystallization in acetone/chloroform □ Example: cardiovascular system organs Clinical Effects on the Tube The technique used to demonstrate changes in blood circulation movement is non-invasive so that the test is repeatable and completely harmless to the patient. Of all the non-invasive diagnostic methods, we have chosen the most reliable in practice: ultrasound (echo and top 2 effects). Simultaneous-dimensional echocardiography combined with pulsating Doppler, and two-dimensional vascular echocardiography combined with pulsating Doppler of blood circulation motion, are capable of detecting histological changes and microscopic blood flow related to the organs of the cardiovascular system. Two of the most reliable non-invasive methods for studying cyclic motion. This is Ko, Q, A-) To study the clinical effects of rhodophenol, the Echodzuplar (TM) ATL (Mark V) C transmission frequency J Mj (z, and the continuation of da and ff MHz □
This is the reason why Doppler (trademark) 5ONICAID was used.

The following four vascular regions of the organ were selected.

a) Cerebral circulation b) Cardiac circulation C) Portal-empty venous circulation d) Peripheral circulation of the lower extremities Patients were divided into two statistically acceptable groups (50 patients in each group) to determine the benefits of this drug before and after treatment. Compare the results. Methodologically, we performed simultaneous echographic cross-sections of the heart, great vessels, superior aortic trunk, abdominal arteries, portal and empty venous systems, intestinal and femoral arteries, and examined all of the above-mentioned cardiac cavities and vessels. A Doppler of the flow sample is obtained to study the characteristics of flow direction, fluid outflow (flow) or volume, and circulatory motion of blood flow.

These studies are: 2. 4! , showed that 4-triiodophenol acts on &.

a) Mechanical properties of the carotid vessel wall in elderly patients with cerebrovascular insufficiency b) Flow velocity and flow related to the initial and internal carotid arteries (testing the cerebral circulation in patients with cerebrovascular insufficiency and studying its variations) c) Dilated hyperemia ventricular effects (thus showing circulatory changes in the heart in pre-load, during-load and post-load experiments) in patients with sexually or regionally anemic heart disease. d) liver failure or portal vein Characteristics of the portal vein/thread wall of a patient with hypertension ′ □ ・), the patient mentioned in (d)? r1 pulse system 1. , and liver,, town! in! ! ! , intrahepatic flow velocity and flow rate.

f) Intermittent ligament caused by femoral veins and femurs, and fan-shaped areas of the ilium and femur.g) Cotton anemia in the lower extremities. Old F: Branch flow rate and flow rate where 1.200 cardiovascular patients 2,4', A
- Shows the clinical results obtained after 3 months of administration of triiodophenol. ,,,,,.

The patients were divided into two groups. (1) JO people with cerebrovascular insufficiency, ix: i', (2) Japanese-style crown ↑ total 6 patients,' (3)
50 patients with liver failure, (4) 30 patients with distal heavy duct failure in the lower extremities, 2. A dose of 30rrq 7 days of Dow 6-dryiodoenol was administered and l
Month 1, Month 3: All vascular circulation and movement parameters from t6 to 3 months are controlled, and there are a total of 600 controls (each group/SO people after 3 months).

The results obtained are summarized statistically in the following table.

1□ 11 111 11 ・□Table 1・ ・ ・ , , □ Tissue: Blood vessel wall. Effect: Anti-athepamin arteriosclerosis□
,'11' □Distensibility of neck/arterial ostium...-+, 17chi +27%
+30% thoracic aorta distensibility +7% +11% +
/4'chi Abdominal aorta distensibility 11Ii% +29%
+3/%□;・・□・4・+2A% Portal vessel extensibility +/Schi +ko9.5chi+3.2%,
・,pe,1(,1,,,■:11''',/l:,,11
・,1:,.

°□Distensibility of the superior venous system, '+7chi +7kochi' Z cistern, -・, average value +, 211* Table ■ Tissue: Blood vessel surface. Effect: Vasodilation Blood vessel diameter at the carotid ostium 10/C 10/K +73-I!
Diameter of the 4-part aorta + 3 + 7 + □ 9 - Diameter of the abdominal aorta + 6% + 77% + 5% of the iliac artery of the I3 large vein +/J% + 137% Blood vessel Diameter of the portal venous system -13chi -23chi -ko6chi above r
IP vein diameter -? Chi -/4'% -134 Table 1 Function: Rapid generation. Effect: Fluidization - Dish tube am fortune telling.

Parameter fluctuation (Δchi) 1st month 2nd month 3rd month after drug treatment Carotid artery ostium flow velocity +l/chi +l Hirochi +/9% Thoracic-large-pulse flow velocity +2chi +3%+! - Abdominal aortic flow velocity
+j% +&9j +9%+//% Portal venous system flow rate +/As i/% +29superior venous system flow rate +1176 +/-% +/! 17 to average value +/cut table■ Function: Emission. Effect 2 Peripheral hyperemia.

□ Brain volume +3qb+27.4%, +741%
Cardiac drainage + Chichi + 6chi + l/chi Volume of vulva 110% +111% +30% Liver volume (venous) +241% 1/4%, ±JJ%□ Table V Function: Pressure. Effect: Lowers blood pressure.

□ Systemic arterial pressure -3--! r% -4%portal pressure -
11% -11% -/J96 Table ■ Function: Cardiac contractility. Change parameters of contractile force of two working muscles
Change (Δchi) 1st month 2nd month 3rd month after miliary treatment Volume in late cardiac systole +Zachi +/lchi +/J%'Volume in late cardiac diastole -3--3l-1T.

Gushing one product-,,,1Is-.

(BJICTON, VOL shout).

EJIi:CTl0NFRACTION-9,/% -
4.1% -t, l, % table ■ □ Function: Blood fat. Effect: Lowers cholesterol.

1 ・/< 9 i -1 7 legs, g7″ decacholesterol − □ −−−/3% triglyceride □ −+
-J -tKochi- Conclusion The values and results mentioned above are・′・“,・“−)! JEI-
Tonenol has a highly effective anti-atherosclerotic effect on all arteries and! Significantly improves the mechanical properties of the vein wall (26- and 29%, respectively)
. Mi's product number, mama, has a strong and effective hyperemic effect, as the blood flow rate increases by 11% in the arteries and by /7176 in the veins.
%), liver (Q?j), and lower 11f (3oC flow rate)
Increasing - Certain products, which are the subject matter of the present invention, produce no toxicity or clinically significant side effects in any patient after three months of administration. Other evidence suggests that the iodine levels in this product do not alter thyroid function.

V - Anti-inflammatory effect A), anti-inflammatory effect when stimulating the foot edema caused by injecting /% carrageenin solution O0/IIL into one foot of a white rat weighing approximately - I showed it□.

The control group consisted of 70 animals, the other group received orally 9 doses of indomethacin at 30/day in carboxymethyl cellulose suspension, and the other group of 10 rats received 1 dose of 9/day at t Iv/. The phenolic solution was administered orally, the other group received intramuscular injection of /In9/kP triiodophenol, and the other group received 0. S~ Chest triiodophenol was administered intramuscularly.

All medications were given at the same time as emulsion formation.

These sizes are mercury prestemoda2f (Pl@st1
0 o'clock, 3 o'clock, da o'clock, 5 o'clock, and 6 o'clock busy time were measured using mograph).

The following table shows the average values obtained.

B) Approximately 200 to 2,000 y If), <ty A group of rats in Sakai was impregnated with a known amount of drug sterilization solution, dried after drying, and... , (,, Marshal,,,,9q
) Insert subcutaneously into the back of the rat.

Dexameth, Ri, Nzon (Dexameth)
an-,...,) and throw, 4. 'M without is used.

After the time, the movement,, I killed the thing quickly, 1. Transplant? After drying, take the lumps formed around it, weigh them, weigh them, and calculate the amount of spring resistance ±'').
8.

□...,,:,.

, Texamethane Don /A 0 # -〇 2g 〃 DaQ JO Triiodophenol too iq # 200 2g 〃 Daθθ Gl Analgesic effect A) To control analgesic activity, mice weighing approximately 1,000 yen were used, Groups of 70 mice were subjected to the 56°C hot plate test.

The animal was given a drug solution containing aspirin with sodium bicarbonate. /- or pH? A chemical solution in which triiodophenol was dissolved in j. /- is injected.

Controls receive physiological serum.

The time the animal exhibits pain is measured with a chronometer.

The table below shows the results of testing animals 13 minutes and 30 minutes after dosing. Mean values are for each group.

After is minutes 30 minutes later Control 7.6 seconds Da, 6 seconds to acetylsalicylic acid 001n9/to 9 41.3 seconds
A, 11 seconds triiodophenol 10~/yu l/, 7
seconds //, g seconds triiodophenol/~/yu 6. !
f seconds 6.7 seconds B) @BIT) IING SYNDR
OM” test ’Irritant: 0,k injected intraperitoneally
% acetic acid.

1 These tensions and tensions are measured over a period of time and used as a measure of the pain stimulated.

Before testing, a mouse weighing 22 tons was used.
I made him abstinent for hours.

Mice were preselected on their individual response to pain elicited by intraperitoneal injection of θ, tatiacetic acid solution θ, Jtttl. Animals that are effective in cysting this test are those that respond within the limits of tS to 3S triggers approximately 3-11 minutes after injection □.

The remaining animals are not useful.

1st record Administer medication orally via deep-hole cannula Let's do it.

Empty funnel': For each body weight iot, l attack, da, 6- triodophenol lot 2/chi CM
Dosage of product aspirin-ricin lot (sulpirin) of 10 da/kl suspended in C: soo da/kl dissolved in lti? After administration of aspirin, wait 3 minutes to inject O, S% acetic acid θ, coynl intraperitoneally, and measure the number of withdrawals in S minutes. 60 min and ioo min after acetic acid injection, repeat 5
Measure the number of pulls per minute.

L ma- Nine mice were tested for each loft.

1o containing 10m9 of 6-triiodophenol as an active substance.
Prepare oo tablets as follows.

4I, A-) Rhodophenol/θ Microcrystalline cellulose igs t Silica 19g Magnesium stearate Af The homogenized and separated mixture was compressed at ℃, 0.0f
100 tablets of 0.2 t each containing t of active substance
Prepare 0 pieces.

Example S 7000 seven Latin capsules each containing 10 Da, 4 I, A-) rhodophenol were prepared as follows.

Co, da, 6-dryiodophenol iot Microcrystalline cellulose Tast Silica 3t Magnesium stearate 2t The sieved and homogenized mixture was divided into 70 m9 portions and filled into capsules using a suitable filling machine.

Example 6! fo my 2. 101 syrup containing A-triiodophenol (each month fit k I!113) was prepared with the following ingredients:

Co, da, 6-dryiodophenol 100 t Lysine Coot Zaccharose 'yooo t Glycerin Taoot Sodium chloride gθt Methyl P-hydroxybenzoate 101P-H) Isopropyl oxybenzoate Sorbic acid iot Distilled water Remainder of this syrup can also be chilled and flavored.

Example 7 Preparation 100 injection ampoules each containing 101v of co, da, 6-dryiodophenol were prepared with the following ingredients.

Ko, 41. A-tri-dophenol 101 lysine coppic sodium chloride solution was sterilized with water for injection at 1000 mA and divided into S-.

[Brief explanation of drawings]

FIG. 1 is a diagram showing the results of the analgesic effect of Example 3. Applicant's agent Kiyoshi Inomata

Claims (1)

[Claims] l Phenol in 1. Acids... and in the presence of hydrogen peroxide as a catalyst in difficult-hydration media,! 41. A-) Method for producing rhodophenol. Euphenol was treated in the presence of concentrated sulfuric fermentation in 1. Reacting with periodic acid and potassium iodide: A method for producing a Q, Q, 6-triiodo 7, enol having a q# character. j J, lI, 6-) Veterinary medicine containing Ryod:, Fujin, Ru or its addition salt, part active ingredient, etc.
,,l, ,-,,,,) Lyodov: anti-inflammatory agent containing an enol or a pharmacologically acceptable simple addition or salt, together with a vehicle and/or other drugs, and other acceptable components. analgesic, ko, shi, steroid, = le low, lower,
Anti-cirrhosis, blood fat lowering 1. Anti-aggregation therapeutic pharmaceutical composition. Suitable for oral, rectal, parenteral, or topical administration.
A patent that is characterized by the first group of circulating substances in drug history,
Leather texture material.