JP3000301B2 - 3- (bis-substituted phenylmethylene) oxyindole derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel 3- (bis-substituted phenylmethylene).
The present invention relates to an oxindole derivative and a medicine containing the same.

BACKGROUND ART In inflammation of organs or tissues and wound healing, it is a major clinical problem that fibrosis of cells causes dysfunction of organs and tissues. In joints, fibrosis of cells causes rheumatoid arthritis, and in the liver, as fibrosis of cells progresses, cirrhosis occurs, causing jaundice hypoproteinemia and liver failure. In addition, the blood vessel loses elasticity due to fibrosis of the blood vessel wall, leading to arteriosclerosis. The first stage of fibrosis is granulation, and it is considered that treatment of rheumatoid arthritis, cirrhosis, arteriosclerosis, and the like is possible if it can be suppressed.

In addition, compounds having hepatotoxicity in drug development pose a problem in the development. Nature, N
o. 283, 397-398 (1980), it is reported that hyperplasia of peroxisome, which causes liver hypertrophy, is a carcinogenic factor.

As described above, there is a strong demand for a drug that has an excellent granulation formation-inhibiting effect, has little hepatotoxicity, and is highly clinically useful.

Analogous compounds of the 3- (bis-substituted phenylmethylene) oxindole derivatives of the present invention include Berichte (Ber.), 96 (1963), 3328-37 and JP-B-43-3195.
And the compounds described in U.S. Pat. No. 3,428,649. Among them, particularly similar compounds are those represented by the following formula described in Berrichte (Ber.), 96 (1963), 3328-37. [Bisphenylmethylene] -oxindole (compound a) is known, but the compound is described only as a synthetic intermediate and has no description of pharmacological activity.

Further, Japanese Patent Publication No. 43-3195 describes an oxindole derivative represented by the following general formula (2) as a synthetic intermediate.

(Wherein R ¹ and R ² represent lower alkyl, aryl or pyridyl, and R ³ represents a hydrogen atom or lower alkyl.) However, such 3- (bis-substituted phenylmethylene)
As an oxindole derivative, only disclosure as a synthetic intermediate of a compound in which R ³ is a methyl group and R ¹ and R ² are unsubstituted phenyl groups is actually disclosed.

Accordingly, an object of the present invention is to provide a novel oxindole derivative which has an excellent granulation formation inhibitory action, has low hepatotoxicity, and is useful as a pharmaceutical.

DISCLOSURE OF THE INVENTION Under such circumstances, the present inventors have conducted intensive studies, and as a result, the 3- (bis-substituted phenylmethylene) oxindole derivative represented by the general formula (1) has an excellent granulation formation inhibitory action. And with little liver toxicity,
They have found that they are useful as pharmaceuticals, and have completed the present invention.

That is, the present invention provides the following general formula (1) (Wherein, R represents a methyl group or a methoxy group.) An oxindole derivative represented by the formula:

The present invention also provides a granulation inhibitor (excluding an intimal hyperplasia inhibitor) containing an oxindole derivative (1) as an active ingredient.

The present invention also provides a granulation inhibitor composition (excluding an intimal hyperplasia inhibitor composition) comprising the oxindole derivative (1) and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the oxindole derivative (crystal 1) of the present invention.
It is a figure which shows an IR spectrum.

FIG. 2 shows the oxindole derivative (crystal 2) of the present invention.
It is a figure which shows an IR spectrum.

BEST MODE FOR CARRYING OUT THE INVENTION The oxindole derivative of the present invention represented by the general formula (1) can be synthesized according to the following reaction scheme.

(In the formula, R is the same as described above.) The known compound represented by the general formula (3) and the general formula (4)
Is reacted in a suitable solvent in the presence of a base to give a compound represented by the general formula (1).

The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and dioxane. Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate and sodium carbonate, and organic bases such as piperazine, piperidine, pyrrolidine, and pyridine. In the reaction, it is preferable to use about 1 to 3 mol of the compound of the general formula (4) and about 1 to 10 mol of the base per 1 mol of the compound of the general formula (3). The reaction temperature is from room temperature to about 200 ° C., and the reaction time is preferably from about 1 to 24 hours.

The compound represented by the general formula (3) used herein is described, for example, in Journal of Medicinal Chemistry (J. Med. Chem.), 37, 2033 (1994). , Tetrahedron Lett., 2857 (197
9). Journal of the American Chemical Society (J. Am. Chem. Soc.), 5508 (1974). Journal of the American Chemical Society (J. Am. Chem. Soc.), 5512 (1974). , Tetrahedron, 24,6093 (1968). Or a method analogous thereto. Compounds represented by the general formula (4) include, for example, Organic Synthesis Collections (Org.Syn.coll.), Vol.I, p95, Journal
Of Chemical Society (J. Chem. Soc.), 529 (1
951) or a method analogous thereto.

Compound (1) of the present invention obtained by the above reaction scheme
Can be easily isolated as crystals or oils by ordinary separation and purification means, for example, recrystallization, distillation, column chromatography and the like.

The present compound (1) also includes a solvate represented by a hydrate or a polymorph.

The compound of the present invention represented by the above formula (1) has an excellent inhibitory effect on granulation formation and is effective as a medicament such as a therapeutic agent for various diseases related to granulation formation. Therefore, it is possible to provide a pharmaceutical composition comprising an effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.

When the compound of the present invention is used as a medicine, it can be prepared as a pharmaceutical composition according to a usual method using an appropriate pharmaceutical carrier. As the carrier, various types commonly used for ordinary drugs, for example, excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, surfactants and the like can be used.

The dosage unit form when the medicament according to the present invention is used for the treatment of mammals including humans is not particularly limited, and can be appropriately selected depending on the purpose of the treatment. Specifically, injections, suppositories, external preparations (ointments) Agents, patches and the like), parenterals such as aerosols, tablets, coated tablets, powders, granules, capsules, liquids, pills, suspensions, emulsions and other oral preparations.

The above various drugs are formulated by a formulation method generally known in this field.

Tablets, powders, granules and the like for solid oral preparations such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin Excipients, sodium alginate, gum arabic, etc., simple syrup, glucose solution, starch solution,
Gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, hydroxypropylcellulose, water, ethanol, potassium phosphate and other binders, dried starch, sodium alginate, agar powder, laminaran powder, carbonic acid Disintegrators for sodium hydrogen, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc., disintegrators for sucrose, stearic acid, cocoa butter, hydrogenated oil, etc., quaternary Absorption promoters such as ammonium base and sodium lauryl sulfate, humectants such as glycerin and starch, adsorption of starch, lactose, kaolin, bentonite and colloidal silicic acid Purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets and the like.

When formed into pill form, as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, binders such as gum arabic, powdered tragacanth, gelatin, ethanol, laminaran ,
Disintegrators such as agar can be used.

Capsules are prepared by mixing with the various carriers described above and filling in hard gelatin capsules, soft capsules, and the like.

In molding into suppositories, suitable carriers are, for example, polyethylene glycol, cocoa butter, lanolin, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, Witepsol (registered trademark Dynamite Nobel) and the like. An absorption enhancer can be added for use.

In the case of molding into an injection form, as a carrier, for example, diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and citric acid PH of sodium acid, sodium acetate, sodium phosphate, etc.
Adjusters and buffers, stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent may be used.
A soothing agent, a local anesthetic or the like may be added. By adding these carriers, injections for subcutaneous, intramuscular, and intravenous injections can be produced by a conventional method.

Liquid preparations include aqueous or oily suspensions, solutions, syrups,
Elixirs may be used and are prepared according to a conventional method using ordinary additives.

When preparing in the form of an ointment, for example, paste, cream and gel, commonly used bases, stabilizers, wetting agents, preservatives and the like are blended as necessary, and mixed and formulated by a conventional method. You. As a base, for example, white petrolatum, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicon, bentonite and the like can be used. As the preservative, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like can be used.

In the case of producing a patch, the above-mentioned ointment, cream, gel, paste or the like may be applied to a usual support in a conventional manner. As the support, a woven or nonwoven fabric made of cotton, cloth, or synthetic fiber, a film of soft vinyl chloride, polyethylene, polyurethane, or the like, or a foam sheet is suitable.

The amount of the compound of the present invention to be contained in the above-mentioned preparation varies depending on the dosage form, administration route, administration schedule and the like and cannot be stated unconditionally, and is appropriately selected from a wide range.
It is good to be about 70% by weight.

The administration method of the above formulation is not particularly limited, the form of the formulation,
Enteral administration, oral administration, rectal administration, buccal administration, depending on the patient's age, gender and other conditions, degree of patient's symptoms, etc.
An administration method such as transdermal administration is appropriately determined. For example, tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally, and in the case of suppositories, they are administered rectally. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid. Further, if necessary, it is administered alone, intraarterially, intramuscularly, intradermally, subcutaneously or intraperitoneally. The ointment is applied to skin, oral mucosa, and the like.

The dosage of the active ingredient of the preparation of the present invention is appropriately selected depending on the usage, the age of the patient, the sex, the state of the disease, the type of the compound according to the present invention to be administered, and other conditions. The amount should be about 300 mg / kg / day, preferably about 0.5 to 100 mg / kg / day. These preparations of the present invention can be administered once or twice or four times a day.

Examples Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 Synthesis of 3- [bis (4-methoxyphenyl) methylene] -oxindole (Compound 1A) (1) 10.0 g of oxindole was added to tetrahydrofuran 100
and 21.8 g of 4,4'-dimethoxybenzophenone at room temperature.
g was added to the mixture and the mixture was heated under reflux for 12 hours after generation of hydrogen was stopped. After completion of the reaction, the mixture was cooled, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over sodium sulfate and evaporated. The obtained crude product was recrystallized from methanol to obtain 22.8 g (yield: 85%) of yellow crystals (crystal 1). The physical properties are shown below.
FIG. 1 shows a chart of the IR spectrum.

Melting point: 176-179 ° C Elemental analysis value (%): Calculated value for CHN 77.29 5.36 3.92 Observed value 77.32 5.23 3.93 ¹ H-NMR (δppm) [solvent: CDCl ₃ ]: 3.84 (s, 3H), 3.88
(S, 3H), 6.51 (d, 1H), 6.65 (t, 1H), 6.70 (d, 1H), 6.
87 (d, 2H), 6.93 (d, 2H), 7.04 (t, 1H), 7.25 (d, 2H),
7.31 (d, 2H), 8.40 (s, 1H) 20 g of the compound A (crystal 1) obtained in the above (1)
Was suspended in 200 ml of n-undecane, heated at about 160 ° C. for 4 hours, and then cooled to 0 ° C. to obtain 19.6 g (yield 98%) of an orange polymorph (crystal 2) of compound 1A. . FIG. 2 shows a chart of the IR spectrum. Melting point was 203.5-205.5 ° C.

Example 2 Synthesis of 3- [bis (4-tolyl) methylene] -oxindole (Compound 1B) 4,4'-instead of 4,4'-dimethoxybenzophenone
The title compound was synthesized in the same manner as in Example 1 using dimethylbenzophenone. The physical properties are shown below.

Mp: two hundred forty to two hundred forty-one ° C. Elemental analysis (%): C H N Calculated 84.89 5.89 4.30 Found ^{85.00 5.75 4.24 1 H-NMR (} δppm) [ _{solvent: CDCl 3]: 2.37 (s} , 3H), 2.43
(S, 3H), 6.47 (d, 1H), 6.65 (t, 1H), 6.73 (d, 1H), 7.
07 (t, 1H), 7.13-7.26 (m, 8H), 7.79 (s, 1H) Reference Example 1 Synthesis of 3- [bis (4-chlorophenyl) methylene] -oxindole (compound c) 4,4′- 4,4'- in place of dimethoxybenzophenone
The title compound was synthesized in the same manner as in Example 1 using dichlorobenzophenone. The physical properties are shown below.

Melting point: 206-208 ° C Elemental analysis value (%): Calculated value for CHN 68.87 3.58 3.82 Observed value 69.09 3.29 3.79 ¹ H-NMR (δppm) [solvent: CDCl ₃ ]: 6.47 (s, 1H), 6.70
(T, 1H), 6.72 (d, 1H), 7.13 (t, 1H), 7.25 (d, 2H), 7.
32 (d, 2H), 7.33 (d, 2H), 7.42 (d, 2H), 8.05 (s, 1H) Test Example 1 Test for suppression of granulation formation induced by lipopolysaccharide (LPS) “Inflammation” vol.11 No. 4 The following tests were performed according to the method described in July 1991, 303-311. That is, under anesthesia, an air pouch (pouch) was prepared under the skin on the back of a 5-week-old male F344 rat, and serogen was injected the next day. The next day, lipopolysaccharide (LPS) was injected into the pouch at a rate of 5 ng / 0.5 ml / pouch. On the 5th day, the rats were dissected, the weight of granulation in the back pouch was measured, and the inhibition rate was calculated from the weight comparison between those treated with the test drug and those not treated. As test drugs, Compounds 1A (crystal 1) and 1B were suspended in 0.5% methylcellulose at a ratio of 10 ml / 100 mg body weight, and LPS injection 2 was used.
Oral administration once before time. Table 1 shows the results. Also,
Berichte (Ber.), 96 (1963), 3328-
37- (Bisphenylmethylene) -oxindole (compound a) according to 37, which has been developed as an antirheumatic drug (z) -3- [4- (acetyloxy) -5-ethyl-
3-methoxy-1-naphthalenyl] -2-methyl-2-
The same experiment was performed using propenoic acid (compound b: see JP-A-2-256645) and 3- [bis (4-chlorophenyl) methylene] -oxindole (compound c) obtained in Reference Example 1. Table 1 shows the results.

From the above results, the compound of the present invention has the same or higher effects as the comparative compound b, and has an excellent granulation formation inhibitory effect of about 2 to 4 times compared to the compound a or c which is a similar compound. Was. In addition, it has been confirmed that the compound of the present invention has an excellent granulation formation inhibitory effect about 10 to 15 times that of the compound of the formula (1) wherein R is an ethyl group or a compound wherein R is an ethoxy group. Was done.

Test Example 2 Liver toxicity test Test drug (compound 1A) suspended in 0.5% methylcellulose
(Crystal 1) and 1B) were administered to 4-week-old male SD rats at 300 mg /
Oral administration was performed at a rate of kg / 10 ml for 7 days. After the final administration, the rats were allowed to stand overnight under fasting. After weighing, the animals were exsanguinated and bled under anesthesia. The livers were removed and the liver weights were measured. Weight 100g
Per liver weight, and the hypertrophy rate was calculated from the liver weight of the group treated with the test drug relative to the liver weight of the untreated group. Table 2 shows the results. Similar experiments were performed using 3- (bisphenylmethylene) -oxindole (compound a) described in Berrichte (Ber.), 96 (1963), 3328-37 as a comparative compound. Table 2 shows the results.

From the above results, significant liver hypertrophy was observed in Comparative Compound a, but almost no liver hypertrophy was observed in Compounds 1A and 1B, which was about 1/6 to 1/3 of Comparative Compound a.

Formulation Example 1 Tablet Compound 1A (Crystal 1) 200 mg Corn starch 50 mg Microcrystalline cellulose 50 mg Hydroxypropyl cellulose 15 mg Lactose 47 mg Talc 2 mg Magnesium stearate 2 mg Ethyl cellulose 30 mg Stearic acid monoglyceride 4 mg Tablets were prepared.

Formulation Example 2 Granules Compound 1A (crystal 1) 300 mg Lactose 540 mg Maize starch 100 mg Hydroxypropylcellulose 50 mg Talc 10 mg At the above mixing ratio, 1000 mg of granules per packet were prepared according to a conventional method.

Formulation Example 3 Capsule Compound 1B 200 mg Lactose 30 mg Maize starch 50 mg Microcrystalline cellulose 10 mg Magnesium stearate 3 mg
g capsules were prepared.

Formulation Example 4 Injection Compound 1B 100 mg Sodium chloride 3.5 mg Distilled water for injection Appropriate amount (2 ml per ampoule) Injection was prepared in the above mixing ratio according to a conventional method.

Formulation Example 5 Syrup Compound 1B 200 mg Purified sucrose 60 g Ethyl parahydroxybenzoate 5 mg Propyl parahydroxybenzoate 5 mg Perfume Appropriate amount Colorant Appropriate amount Purified water Appropriate A syrup was prepared according to a conventional method at the above mixing ratio.

Formulation Example 6 Suppository Compound 1A (crystal 1) 300 mg Witepsol W-35 (registered trademark, mixture of mono-, di- and tri-glycerides of saturated fatty acids from lauric acid to stearic acid, manufactured by Dynamite Nobel) 1400 mg Suppositories were prepared at the mixing ratio according to a conventional method.

Industrial Applicability The compound of the present invention has an excellent granulation formation inhibitory action, has almost no liver toxicity, and is useful as a medicament,
It is useful for the prevention and treatment of rheumatoid arthritis, cirrhosis, etc., and also for osteoarthritis, psoriasis, gout, nephritis, vasculitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), bronchitis,
It can also be used for prevention and treatment of arthritis, chronic granulomatosis and the like.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 19/02 A61K 31/00 619A 29/00 629 35/00 635 43/00 643B A61K 31/404 31/40 607 (72) Inventor Yasuto Yamazaki 2-4-7 Toyooka, Iruma-shi, Saitama (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 209/34 A61K 31/40 CA, REGISTRY (STN)

Claims (3)

(57) [Claims] 1. The following general formula (1) (In the formula, R represents a methyl group or a methoxy group.) An oxindole derivative represented by the following formula: 2. A granulation inhibitor comprising the oxindole derivative according to claim 1 as an active ingredient (except for an intimal hyperplasia inhibitor). 3. A granulation inhibitory composition comprising the oxindole derivative according to claim 1 and a pharmaceutically acceptable carrier (except for an intimal hyperplasia inhibitory composition).