JPS5842191B2 - Dihydrofurancane - Google Patents

Description

[Detailed description of the invention] The present invention is based on the structural formula %formula% [In the formula, R is the formula represents a group selected from; n is O or l.

] and water-soluble pharmaceutically acceptable salts thereof.

The compounds of the invention are thus generally defined as: benzofuranyl-, benzopyranyl-, naphthofuranyl-, naphthopyranyl-acetic acid and salts of the above acids.

Examples of compounds according to the invention include: 2,3-dihydro-2-
Ether-benzofuran-5-yl-acetic acid: 2-ethylchroman-6-yl-acetic acid: 1,2-dihydronaphtho(2
, 1-bl furan-7-yl-acetic acid: naphtho[2,1-b
l-pyran-8-yl-acetic acid: as well as salts of the above acids.

It has been found that the compounds of the present invention have significant anti-inflammatory properties and low toxicity, which makes them particularly valuable for use as anti-inflammatory agents. It is well tolerated for long-term administration in doses and also has antipyretic and analgesic activity.

The present compound is produced by introducing an acid moiety into a heterocycle produced according to known methods.

The base of the heterocycle-substituted acetic acid can be prepared according to the following method: acetylation of the head heterocycle with acetic anhydride and aluminum chloride in nitrobenzene, subsequent treatment of the resulting ketone with sulfur and morpholine under reflux, and aqueous water. Hydrolysis of intermediate acet-thiomorpholide derivatives with sodium oxide.

Salts of acids according to the invention can be obtained by reaction of acids with the corresponding bases.

Preferred salts are alkali metal salts, especially sodium salts.

Particularly preferred organic base salts are those derived from triethanolamine, N-methyl-glucamine and arginine.

The following examples are presented to illustrate the novel compounds of this invention as well as methods of making them.

Example 1 Synthesis of 2.3-dihydro-2-ethylbenzofuran-5-yl-acetic acid- (compound I) 2°3- in acetic anhydride (112,3S': 1,1 mol)
Dihydro-2-ethelbenzofuran (148,2f; 1
．． 0 mol) solution to nitrobenzene (1100rILl) solution.
) in AlCl5 (266,7r; 2.0 mol)
Slowly added to the cold solution of while stirring.

After stirring overnight at room temperature, the mixture was treated with ice (200 g) and concentrated HCI (200 r/Ll).

After steam distillation of the nitrobenzene, the oily residue was taken up in ethyl ether.

The solution W was washed with water, dried (MgSO4) and the residue obtained after evaporation of the solvent was distilled under reduced pressure to 2.3
-dihydro-2-ethyl-5-acetylbenzofuran
5oy (79%) has a boiling point of 118-120 degrees C (0.3 m
mHg) as a colorless oil.

2.3-dihydro-2-ethyl-5-acetylhenschiffen (177,0f; 0.93-E-l), sulfur (
48,25'; 1.5 mol) and morpholine (130
, 7f; 1.5 mol) was refluxed for 16 hours.

The residue was triturated with ethanol and the crude 2,3-dihydro-2-ethylbenzofuran-5-acetylthiomorpholide thus obtained was refluxed with 2N NaOH (2.8 mol at 1400 m) for 6 hours.

The clear solution was washed with methylene chloride and 5N
Acidified with HCl.

The separated solid was collected, dried and treated with carbon tetrachloride (3
00ml).

Recrystallization from cyclohexane (2800WLl) yielded the compound Iso, or (42φ), white crystals, melting point 94-95.
I was given a degree C.

Elemental analysis Calculated value as Cl2H14o3 %: C69,88; H6,84 Measured value φ: C70,07; H6,72 Potency (0, IN KOH, E to H/in DMF)
:100±1% This compound has proper N, M, R and 1
．． R, spectrum, and T, L, C, [solvent system: benzene-dioxane-acetic acid (100: 10:4
); Rf=0.6 (silica gel)] migrated as a single spot.

Example 2 Synthesis of 2-ethylchroman-6-yl-acetic acid (compound ■) Starting from 2-ethylchroman and working according to the method of Example 1, the title compound was obtained, mp 88-90 degrees C.
(Cyclohexane): Elemental analysis: Calculated value as C13H1603 φ: C70,89; H7,32 Measured value %: C70,96; H7,41 Example 3 1.2-dihydronaphtho[2,lb,)furan-7 −
Synthesis of yl-acetic acid (compound ■) Starting from 2-aceto-1,2-dihydronaphtho[2,1-b)furan and working according to the method of Example 1, the title compound was obtained, melting point 181 -183 degrees C (benzene): Elemental analysis: Calculated value as C14H1□03 φ: C73,67; H5,30 Measured value φ: C73,83; H5,19 Example 4 IH-2,3-dihydronaphtho (2, Synthesis of 1-b,l]pyran-8-yl-acetic acid (compound ■) 2-acet-2
Starting from ,3-dihydronaphtho[2,1-b)bilane and working according to the method of Example 1, the title compound was obtained, melting point 165-166 degrees C (toluene): Elemental analysis" 15 HI3 o3 Conventional value: C44,36; H5,83 Measured value: C74,43; H5,79 The compound of the present invention can be administered orally (compressed tablets, capsules, pills) in solid form, and enterally (herbal medicine). They can also be formulated for liquid oral (oral) and transdermal administration.

Unit dosage forms are usually 25 mW to 250 mf per compressed tablet, capsule or pill, or 50 mf per 1 car side.
to 500 mf10 range.

Lower doses are also available for pediatric use.

Excipients and other carriers for use with the compounds of this invention in pharmaceutical formulations will be apparent to those skilled in the art.

Although the compounds of the invention are particularly suitable for solid oral (compressed tablets, capsules, pills), and enteral (cross-forming) administration, they may also be formulated for liquid oral (white tablets and transdermal) administration. can.

Unit dosage forms are usually 25- to 250-m2 per compressed tablet, capsule or pill. , and 50 to 5 per suppository.
It is within the range of 00mP.

Lower doses are also available for pediatric use.

Excipients and other carriers for use with the compounds of this invention in pharmaceutical formulations will be apparent to those skilled in the art.

Microcrystalline cellulose, starch, colloidal silica and magnesium stearate may be mentioned as excipients for solid forms.

Mixtures of triglycerides of saturated vegetable fatty acids, white wax, cocoa butter, macrogels are suitable bases for cross-agents.

A typical formulation of compound vAI) in capsules and cross-agents is shown below.

Capsule: Compound 'IMI)・・・・・・・・・・・・・・・・・・
・・・・・・・・・・・・100. omf microcrystalline cellulose 46.5
mV template・・・・・・・・・・・・・・・・・・
・・・・・・・・・・・・・・・ 1.5-Colloidal silica・・・・・・・・・・・・・・・ 1.0
Magnesium castearate 0.2 kg Suppository: Compound vAI)
・・・・・・・・・・・・ 0.25f Saturated vegetable fatty acid (having a chain length of C12 to C18) Triglyceride base... 2.50f Toxicity Acute toxicity The acute toxicity of the compounds of the present invention is as follows: Each test dose (250,500
, 1000 and 1500 m9Ag (last dose for rats only) was measured orally using 10 animals each.

Observations are carried out for 120 hours. 7'Q) The obtained LD values are shown in Table r and are compared with the anti-inflammatory drug phenylbutacin, selected as a control drug.

It is significantly less toxic than the control compound in both rats and mice.

Chronic Toxicity The compound 'IMI) was tested using 240 Wistar Wounds, divided into two groups of 20 animals (10 males and 10 females).

One group (control group) was housed normally, while the other groups of animals received daily oral administration of the test compound 60 mV/9.

Treatment lasted for 60 days. The following items were checked every 15 days: body weight, blood pressure [incre-end method].
nt rrlethod], heart rate, hemochromocytometry test (h emo -ch ano
cy tomet r ic ex ami na
t 1on), and urine analysis.

No fatal cases were observed. Food consumption was regular.

No differences were observed regarding weight gain or the above items.

At the end of treatment, all animals were sacrificed and subjected to further tests (hemochromocytometry, serum-biochemistry, enzyme, electrolysis and necropsy tests).

No significant changes were observed/7).

It can be concluded that long-term administration of compound (I) does not induce biologically relevant changes.

A test to detect the catabolic and fetotoxic effects, if any, was carried out using 30 m97 kg and 60 ml of compound (I).
It was performed in a conventional manner on Wistar rats that were orally dosed with mffAg.

No pregnancy disorders and/or toxic effects on the fetus were observed.

Pharmacology The anti-inflammatory and analgesic properties of the compounds of the invention were tested in mice and rats by various techniques commonly employed to evaluate non-steroidal anti-inflammatory drugs.

Carrageenin-induced edema assay In this test, activity is determined by carrageenan (1% suspension 0.
1r/Ll) was determined by the inhibition of murine hindlimb edema induced by subplantar injections.

This compound as the sodium salt was administered orally 1 hour before stimulus injection.

Limb edema was measured by the fluid displaced when the limb was immersed in a mercury dip.

Results were expressed as % inhibition compared to control 3 hours after administration of carrageenan; they were used as standards for phenylbutacin and 2-(4-inbutyl-phenyl)-propionic acid-sodium salt (isoprofen). It is also shown in Table 2.

These results suggest that the compounds of the present invention are superior to phenylphyntane and iprofen as anti-inflammatory agents.

Experimental polyarthritis assay Three groups of 10 Wistar rats were used.

Two groups each received a subcutaneous injection (
The animals were treated with compound (2) or phenylbutacin (200 mr/kg orally) 24 hours before the subplantar site of the hind paw.

Pharmacological treatment was carried out for 14 days, while the third group was used as a control.

Limb edema was measured as in carrageen-induced edema.

The results are reported in Figure 1 of the accompanying drawings as a large increase in limb volume immediately before injection of modified Freund's supplement.

In Figure 1, 〇-〇 indicates the group treated only with mycobacteria, and Muum indicates the group treated with phenylbutacin (200 m
Vkg, oral) and mycobacteria-treated groups;
kg, oral) and mycobacteria-treated groups.

Both compound (I) and phenylbutacin show significant activity in the experimental polyarthritis assay; it can be concluded that (I) is superior to the control drug at least during the first 9 days of treatment.

Compound (III) in experimental polyarthritis under the above conditions
) was completely similar to that of compound (I).

Anti-Writing Assay Male white Swiss Mus musculus mice, each weighing between 20 and 221 kg, were used.

Animals were fasted for 18 hours before pharmacological treatment.

Compounds of the invention and phenylbutacin (200m?A
9. 0.251 per animal 20 minutes after administration (orally)
rLl 3% acetic acid was injected intraperitoneally.

The number of abdominal distension was counted for 20 minutes after the acetic acid injection.

The reduction in tension φ from the control is reported in Table 3. From these results, the compounds of the invention appear to be superior to phenylbutacin as analgesics.

Clinical test compound (1) was used to treat painful bone and joint symptoms (hip and knee arthropathy, lumbar sciatic pain, cervical cancer, glenohumeral periarthritis,
etc.) and were orally administered to 25 patients aged 45 to 82 years.

Fourteen patients were treated with a dose of 100 mS' three times a day for 3 days; in a further 7 patients, treatment was given for 8-10 days at a dose of 200 mS' a day.
It was 300-.

The remaining 4 patients received doses of 200 mr 3 times daily for 3 to 5 days.

A significant analgesic-anti-inflammatory effect was confirmed with the administration of compound (1): in short, good or very good in 7 cases (68%), marginal in 5 cases (20%) and no effect in 3 cases (12%). It was determined that

Treatment was consistently found to be well tolerated and no side effects were observed.

Some treatment examples are listed below for illustrative purposes.

1) G.M., female, 62 years old.

Clinical pattern: lumbosacral arthropathy with acute, often painful exacerbations; the patient had already been treated repeatedly in the past with various anti-inflammatory drugs and physical therapy.

(I) 100m! Treatment was started with f 3 times a day.

Patients report significant symptom relief already on day 1; improvement persists on day 2 with increased likelihood of exercise and walking.

By the third time, the pain pattern had already completely regressed.

The treatment was very well tolerated and no side effects were observed.

2) N.M., female, 71 years old.

Clinical pattern: polyarthritis and diffuse rheumatic pain.

Pain symptoms are particularly evident in the right knee, which appears to be swollen, painful on palpation and passive motion, and kept in semi-flexion at the painful site.

Compound (I) is administered at roomf three times daily doses for 8 days without any other analgesic-anti-inflammatory treatment.

The patient reports a clear relief of symptoms; walking is easier on the 4th and 5th day, and knee joint motion is improved.

Clearly clinically effective.

No side effects. 3) P.M., female, 71 years old.

A pattern of cervical arthropathy with acute radiating pain in the nape and upper arms on a background of diffuse osteoporosis.

As the pain pattern worsens, (I)l OOd 1 day 3
administration was started.

Patients report relief, disappearance of headache, and ability to rotate the neck that was initially prevented by the pain.

The radiating pain in the shoulder and right arm persists, although the intensity decreases.

Patients are encouraged to continue treatment for 7 days until pain exacerbation has almost completely diminished.

No side effects. 4) FA, female, 54 years old.

Obese patient with radiogenic pattern of bilateral hip joint disease; right hip joint is very painful with severe motion restriction.

Upon re-emergence of pain patterns and functional incompetence after discontinuing treatment with indomethacin within a few days, the compound 'IMI
) 100mS'3 times a day 200mS on the 1st and 2nd day
M? The third dose was administered three times a day.

The result was a satisfactory response of the pain pattern with a progressive decrease in pain symptoms; on day 5, the patient still had some pain but was ambulatory.

Clearly favorable clinical response; no side effects.

5) M.C., male, 59 years old.

Examination reveals a pattern of arthrosis of the dorsal columns, particularly accentuated in the cervical and prelumbosacral regions.

Pain symptoms in the dorsal column with nerve root reactions.

Compound (I) is 1oOrrI! f Administer 3 times a day.

Patients report good analgesic effects, improved freedom of active and passive movements of the dorsal columns.

Treatment continues for 5 days without any side effects.

The present invention is summarized as the method of the claims, but includes the following embodiments.

(1) The acetylation reaction is carried out in nitrobenzene: treatment of the reaction product with sulfur and morpholine is carried out under reflux: and the hydrolysis of the intermediate acetothiomololide derivative is carried out in cold aqueous sodium hydroxide to 5% The method according to claim 1.

(2) A process for preparing a salt of a compound of formula I, wherein A method consisting of letting.

[Brief explanation of drawings]

FIG. 1 shows the effect of the compounds of the present invention on experimental polyarthritis, where the horizontal axis shows the number of days of treatment and the vertical axis shows the increase in limb volume φ in rats.

Claims (1)

[Scope of Claims] A method for producing a compound represented by the formula %; n is 0 or 1] and a water-soluble pharmaceutically acceptable salt thereof. A compound selected from the compounds of the formula (wherein n is as defined above) obtained by acetylation with total acetic anhydride (wherein n is as defined above) A process comprising treating with sulfur and morpholine at the reflux temperature of the reaction mixture and then with an aqueous alkali hydroxide to convert it into a compound of formula I above.