JPH0256341B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, when n is an integer of 2, R ¹ and R ³ are both halogen atoms, R ² is a hydrogen atom, or
When R ¹ and R ² are hydrogen atoms, R ³ means a halogen atom, and when R ¹ and R ³ are hydrogen atoms, R ² means a halogen atom. Further, when n is an integer of 3 to 4, at least one of R ¹ , R ² and R ³ consists of a hydrogen atom, and the other substituents are mono- or di-substituted with a halogen atom or a lower alkyl group. It means that. ) This relates to a novel 2,3-dihydroindene derivative represented by: To explain R ¹ , R ² and R ₃ in the general formula () more specifically, halogen atoms are fluorine, chlorine, bromine, and iodine, and lower alkyl groups are methyl, ethyl, n-butyl, and isobutyl. group, n-propyl group, and isopropyl group. Conventionally, 4-methyl-1-oxo-2,3-dihydro-2-
Indene acetic acid is Chemical Abstract (hereinafter abbreviated as CA) Vol.57.16430h, 5,6-ditomexy-1-
Oxo-2,3-dihydro-2-indenacetic acid
CA Vol.73.45192n, 5-methoxy-1-oxo-2,3-dihydro-2-indenacetic acid is CA
Vol.67.11673k, 4,7-dimethyl-1-oxo-2,3-dihydro-2-indenacetic acid is CA
Vol.74.88156s, 5-chloro-1-oxo-2,
3-dihydro-2-indenacetic acid is CA
Vol.88.104975e, 5-bromo-1-oxo-2,
3-dihydro-2-indenacetic acid is CA
Vol.90.72131z also contains 4-methoxy-1-oxo-2,3-dihydro-2-indenbutyric acid
Described in Vol.88.104979i. However, all of these compounds are disclosed as intermediates for certain target compounds, and of course, there are no reports of medicinal uses, nor are there any descriptions suggesting such use. Moreover, there is no mention of pharmacological effects such as anti-inflammatory effects, analgesic effects, antipyretic effects, anti-allergic effects, anti-complement effects, anti-platelet aggregation effects, and anti-hypercholesterol effects, and there are no reports on the manufacturing methods or chemical reactions of the compounds. Only. The compound of the present invention is a new compound that has not been described in any literature, and has remarkable anti-inflammatory effects, that is, anaphylactic, cytotoxic, Arthus-type, and cell-mediated antiallergic effects, and has particularly strong pharmacological activity in the Arthus-type. It is a compound useful as a prophylactic and therapeutic agent for allergic inflammation such as arthritis, rheumatism, knee disease, and autoimmune diseases. Furthermore, it also has platelet aggregation inhibiting action, anti-inflammatory action, analgesic action, antipyretic action, anti-hypercholesterol action, etc., making it a useful compound as a pharmaceutical. To explain in more detail, conventional nonsteroidal drugs with anti-inflammatory effects, such as indomethacin, are frequently used for rheumatic diseases, but they require long-term use and large doses. In addition, there is a problem in that it causes side effects such as gastrointestinal, liver, and kidney disorders. In addition, treatment for nephritis includes antihypertensive drugs such as α-methyldopa and β-blockers when hypertension is present, diuretics such as furosemide when swelling is severe, and nephrosis when accompanied by nephrosis. Since hypercholesterolemia occurs, anti-hypercholesterol drugs are used, but these are only general symptomatic treatments and are not fundamental treatments. Therefore, the present inventors searched for a new nonsteroidal compound that is effective against immune-related inflammatory diseases, and as a result of various studies, found that 2,3-dihydro- As a result of synthesizing an indene derivative and conducting various studies on its pharmacological effects, it was discovered that it suppresses Arthus-type reactions that are not suppressed by currently widely used anti-inflammatory agents, and has remarkable pharmacological effects. This medicinal effect is expressed in inflammation involving the immune system, and it is very different from existing non-steroidal anti-inflammatory drugs. Among the broad range of anti-allergy concepts, the fact that a particularly strong suppressive effect on Arthus-type inflammatory reactions was observed suggests that it can be used as a preventive and therapeutic agent for complement-related diseases such as arthritis, rheumatism, knee disease, and autoimmune diseases. Among these, it is a compound that exhibits excellent effects on rheumatism, that is, rheumatoid arthritis, and has a completely different mechanism of action from conventional non-steroidal anti-inflammatory drugs. Furthermore, it also has platelet aggregation inhibiting, anti-inflammatory, analgesic, antipyretic, and anti-hypercholesterol effects, and it also shows low toxicity values in acute toxicity tests, making it industrially useful as a drug with a very high margin of safety. It is a chemical compound. The compound of the present invention can be mixed with a pharmaceutical carrier or excipient according to a conventional method to prepare capsules, powders, granules, pills, tablets, suspensions, emulsions, syrups, liquids, etc.
It can be administered orally or parenterally as a preparation such as an ointment, cream, gel, aerosol, injection, suppository or external patch. Next, a method for producing the compound of the present invention will be described.
The compound of the present invention can be obtained in good yield by the methods described below, but these production methods are merely examples, and of course it can also be produced by other chemically similar methods. However, in the formula, R ¹ , R ² and R ³ have the same meanings as above, R ⁴ is a hydrogen atom, a lower alkoxy group, a lower alkoxycarbonyl group, X is a halogen atom, and Y is a cyano group, a lower alkoxy group. In the carbonyl group, n represents an integer of 2 to 4. However, in the formula, R ¹ , R ² , R ³ and Y have the same meanings as above, and R ⁵ is a pyrrolidino group, a piperidino group,
Represents a morpholino group. However, in the formula, R ¹ , R ² and R ³ have the same meanings as above, and n ¹ means an integer of 3 and 4. These manufacturing methods will be explained in more detail. Production method A involves combining the compound () and an alkylating agent with an alkali (e.g., sodium methylate, sodium ethylate, potassium t-butyrate, sodium amide, sodium hydride, etc.) and an organic amine (triethylamine, trimethylamine, N,
N-dimethylaniline, etc.) in a solvent (e.g., methanol, ethanol, tetrahydrofuranbenzene, toluene, xylene, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylenephosphotriamide, etc.) for 3 to 48 hours at room temperature or as necessary. It is obtained by heating and then performing a hydrolysis reaction using a mineral acid (eg, hydrochloric acid, sulfuric acid, etc.). In addition, during the hydrolysis reaction,
An organic solvent such as acetic acid may be used for the purpose of maintaining reaction uniformity. Production method B involves mixing the compound () and acrylonitrile or lower alkyl acrylate in an organic solvent (e.g., methanol, ethanol, tetrahydrofuran, dioxane, benzene, dimethylformamide, etc.) for 1 to 48 hours while blowing nitrogen gas if necessary. After heating to ~120°C, it may be hydrolyzed with a mineral acid (eg, hydrochloric acid, sulfuric acid) in an organic solvent such as acetic acid, or with diluted hydrochloric acid, diluted sulfuric acid, etc. in the absence of a solvent. Production method C involves hydrolyzing compound () using an alkali (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.) or mineral acid (e.g., hydrochloric acid, sulfuric acid, etc.) to lead to compound (). Compound () may be isolated if necessary, but may be directly subjected to the next reaction without being isolated. Compound () can be ring-closed all at once using a condensing agent (e.g. polyphosphoric acid, phosphoric anhydride, sulfuric acid, tin tetrachloride, phosphorus oxychloride, and hydrobromic acid and acetic acid, etc.) or first closed with a halogenating agent (e.g. chloride thionyl, phosphorus trichloride, phosphorus pentachloride, and phosphorus dibromide) and then dehydrohalogenating agents (e.g., aluminum chloride, stannic chloride, and chloride) in an inert solvent (e.g., carbon disulfide, nitrobenzene, etc.). The reaction may be carried out in the presence of zinc, etc.). Furthermore, the compound () which is the starting material of the present invention,
() and () are e.g. ES, Stratford, journal
Journal of Pharmaceutical Sciences, 67,
80 (1978), E., D., Bergman (ED.
Bergmann, Journal of Organic Chemistry
Chemistry), 26, 3555, (1961), C.K.
CKIngold Journal of
Journal of Chemical Society
Society), 1954, 1204. Examples of the present invention will be shown below. Example 1 2.2 g of 6-fluoro-1-oxo-2,3-dihydro-2-indenecarboxylic acid ethyl ester was dissolved in 20 ml of dimethylformamide, 0.53 g of 50% sodium hydrogen was added, and the mixture was stirred at room temperature for 2 hours. Next, 3.9 g of ethyl 3-bromobutyrate was added, and after stirring at 90°C for 3 hours, the solvent was distilled off under reduced pressure. 20ml of acetic acid to the residue
Add 15 ml of 20% sulfuric acid and reflux for 3 hours. After the reaction is complete, add 100 ml of ice water to the reaction solution and collect the precipitated crystals by filtration. The crystals were washed with water, dried, and then recrystallized from isopropyl ether to produce colorless needle-shaped 6-fluoro-1-oxo-2,3-dihydro-2-indenbutyric acid.
Obtained 1.45g. The melting point, infrared absorption spectrum, and molecular ion peak of the mass spectrum of this substance were as follows. Melting point: 106-107°C Infrared absorption spectrum νc=o: 1705 cm ^-1 molecule ion peak M ⁺ (m/e): 236 Example 2 6-chloro-1-oxo-2,3-dihydro-
2.93 g of ethyl 3-bromobutyrate was added to a mixture of 2.4 g of 2-indenecarboxylic acid ethyl ester, 1.82 g of triethylamine, and 20 ml of benzene, and the mixture was refluxed for 10 hours.
Thereafter, the solvent was distilled off under reduced pressure, and 20 ml of acetic acid and 15 ml of 20% sulfuric acid were added to the residue, followed by reaction under reflux for 3 hours. After the reaction was completed, 100 ml of ice water was added to the reaction mixture and the precipitated crystals were collected by filtration. The crystals were washed with water, dried, and then recrystallized from ethyl acetate to form colorless needle-like 6-chloro-1-
Oxo-2,3-dihydro-2-indenbutyric acid
Obtained 1.0g. The melting point, infrared absorption spectrum, and molecular ion peak of the mass spectrum of this substance were as follows. Melting point: 141-142℃ Infrared absorption spectrum νc=o: 1706cm ^-1 molecule ion peak M ⁺ (m/e): 252 Example 3 2-oxocyclohexanecarboxylic acid ethyl ester 19.2g, p-fluorobenzyl bromide
After refluxing a mixture of 21.4g, sodium ethoxide, 7.7g and 200ml of ethanol for 2 hours, 500ml of water was added.
and extracted with ethyl ether. The ether layer was distilled off with ether, and the residue was converted into 70% ethanol.
Dissolve in 500 ml, add 16.1 g of potassium hydroxide, reflux for 3 hours, and hydrolyze to obtain 26.5 g of colorless needle-like crystals of 1-(4-fluorobenzyl)-1,5-pentanedicarboxylic acid with a melting point of 80-81°C. Ta. Then 1-(4
A mixture of 26 g of -fluorobenzyl)-1,5-pentanedicarboxylic acid and 300 g of polyphosphoric acid is stirred at 100°C for 3 hours. After the reaction was completed, ice water was added and extracted with ethyl acetate. The organic layer was washed with water, dehydrated, the solvent was distilled off, and the residue was recrystallized from isopropyl ether to give colorless needle-like crystals of 6-fluoro-1-oxo-
18.2 g of 2,3-dihydro-2-indene valeric acid was obtained. The melting point, infrared absorption spectrum, and molecular ion peak of the mass spectrum of this substance were as follows. Melting point: 122-123℃ Infrared absorption spectrum νc=o: 1705, 1690cm
^-1 molecule ion peak M ⁺ (m/e): 250 The following compounds were obtained by the methods of Examples 1 to 3. Example 4 4-fluoro-1-oxo-2,3-dihydro-2-indenepropionic acid Melting point: 103-105°C Infrared absorption spectrum νc=o: 1710 cm ^-1 molecule ion peak M ⁺ (m/e): 222 Example 5 4-chloro-1-oxo-2,3-dihydro-
2-indenepropionic acid Melting point: 107-110℃ Infrared absorption spectrum νc=o: 1705cm ^-1 molecule ion peak M ⁺ (m/e): 222 Example 6 4-chloro-1-oxo-2,3-dihydro-
2-indenepropionic acid Melting point: 184-186℃ Infrared absorption spectrum νc=o: 1710cm ^-1 molecule ion peak M ⁺ (m/e): 238 Example 7 4,6-dichloro-1-oxo-2,3- Dihydro-2-indenepropionic acid Melting point: 142-145℃ Infrared absorption spectrum νc=o: 1720, 1700cm
^-1 molecule ion peak M ⁺ (m/e): 272 Example 8 4-chloro-1-oxo-2,3-dihydro-
2-indenbutyric acid Melting point: 102-103℃ Infrared absorption spectrum νc=o: 1705cm ^-1 molecule ion peak M ⁺ (m/e): 252 Example 9 6-bromo-1-oxo-2,3-dihydro-
2-indenbutyric acid Melting point: 155-157℃ Infrared absorption spectrum νc=o: 1707cm ^-1 molecule ion peak M ⁺ (m/e): 296 Example 10 4,6-dichloro-1-oxo-2,3-dihydro -2-indenbutyric acid Melting point: 114-116℃ Infrared absorption spectrum νc=o: 1710, 1700cm
^-1 molecule ion peak M ⁺ (m/e): 286 Example 11 4-chloro-1-oxo-2,3-dihydro-
2-indene valeric acid Melting point: 79-80℃ Infrared absorption spectrum νc=o: 1710, 1690cm
^-1 molecule ion peak M ⁺ (m/e): 266 Example 12 5-chloro-1-oxo-2,3-dihydro-
2-indene valeric acid Melting point: 108-110℃ Infrared absorption spectrum νc=o: 1705, 1690cm
^-1 molecule ion peak M ⁺ (m/e): 266 Example 13 6-chloro-1-oxo-2,3-dihydro-
2-indenevaleric acid Melting point: 138-139℃ Infrared absorption spectrum νc=o: 1708, 1692cm
^-1 molecule ion peak M ⁺ (m/e): 266 Example 14 6-bromo-1-oxo-2,3-dihydro-
2-indenevaleric acid Melting point: 161-163℃ Infrared absorption spectrum νc=o: 1710, 1694cm
^-1 molecule ion peak M ⁺ (m/e): 310 Example 15 4,6-dichloro-1-oxo-2,3-dihydro-2-indenevaleric acid Melting point: 104-106°C Infrared absorption spectrum νc=o :1710, 1695cm
^-1 molecule ion peak M ⁺ (m/e): 300 Example 16 6-methyl-1-oxo-2,3-dihydro-
2-indenevaleric acid Melting point: 123-124°C Infrared absorption spectrum νc=o: 1702 cm ⁻¹ molecule ion peak M ⁺ (m/e): 232 Next, the results of pharmacological experiments on the compound of the present invention are shown. Experimental example 1 Effect on passive Arthus response in rats Using a group of 5 to 7 male Wistar rats weighing 135 to 155 g, the method of Denk et al [Z.
Immun; Taetsforsch, 138, 169 (1969)]. That is, anti-BSA rabbit serum (precipitated antibody titer 32 times) was applied to rats that had been fasted for 18 hours.
Sensitization was carried out by injecting 0.3 ml of a 10% solution of the same into the tail vein.
0.025% bovine serum albumin (BSA) 30 minutes after sensitization
Induction was performed by subcutaneously injecting 0.1 ml of the solution into the right hind foot pad of each individual. Three hours after the induction, the paw volume was measured according to Fujihira's method [Oyoyaku 5169 (1971)], and the edema suppression rate was calculated according to the following formula. Both the test compound and the comparative drug indomethacin were suspended in a 0.5% aqueous solution of gum tragacanth, and 100 mg/Kg and 5 mg/Kg, respectively, were orally administered 1 hour before BSA induction. In addition, a control group was administered a vehicle. Edema rate (%) = Foot volume 3 hours after BSA induction - B
Foot volume before induction of SA/Volume of foot before induction of BSA x 100 Edema suppression rate (%) = Edema rate of control group - Edema rate of drug administration group/Edema rate of control group x 100 The results are shown in the following table.

[Table] Experimental Example 2 Acute toxicity in mice DDY male mice weighing 22 to 26 g were used in groups of 6 mice. After oral administration of the test compound suspended in 0.5% gum tragacanth aqueous solution and the comparative drug indomethacin to mice, the mice were observed for one week and the mortality rate was determined. The results are shown in the table below.

[Table] From the above pharmacological experiment results, the compound of the present invention is clearly a compound involved in the keratomycosis system, and it also has more pronounced pharmacological activity and lower toxicity than indomethacin, which is typified by the comparative non-steroidal drug. It is clear that

Claims (1)

[Claims] 1 General formula () (In the formula, when n is an integer of 2, R ¹ and R ³ are both halogen atoms, R ² is a hydrogen atom, or
When R ¹ and R ² are hydrogen atoms, R ³ means a halogen atom, and when R ¹ and R ³ are hydrogen atoms, R ² means a halogen atom. Further, when n is an integer of 3 to 4, at least one of R ¹ , R ² and R ³ consists of a hydrogen atom, and the other substituents are mono- or di-substituted with a halogen atom or a lower alkyl group. It means that. ) 2,3-dihydroindene derivative represented by