JPS58213732A - Novel 2,3-dihydro-indene derivative - Google Patents

Abstract

NEW MATERIAL:The 2,3-dihydro-indene derivative of formula I (n is 2-4; R<1> and R<2> are H, halogen, nitro, lower alkyl or lower alkyloxy; provided that R<1> and R<2> are not H at the same time). EXAMPLE:6-Fluoro-1-oxo-2,3-dihydro-2-indenebutyric acid. USE:Pharmaceuticals. It has low toxicity, and antiallergic activity to anaphylactic, cytotoxic and Arthus allergies. Especially exhibiting strong pharmacological activity to Arthus allergy, and useful as a preventive and remedy for allergic inflammation such as renal diseases, rheumatism, collagen disease, autoimmune diseases, etc. It has blood platelet coagulation inhibiting activity, etc. PROCESS:The compound of formula I can be prepared, e.g. by reacting the compound of formula II (R<3> is H, lower alkoxy, etc.) with the alkylating agent of formula III (X is halogen; Y is cyano or lower alkoxycarbonyl) in the presence of an alkali and an organic amine in a solvent, and hydrolyzing the reaction product with a mineral acid.

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (where n is an integer of 2 to 4, and R and R each represent a hydrogen atom, a nitro group, a lower alkyl group, or a lower alkyloxy group). However, the present invention relates to novel 2,3-dihydro-indene derivatives represented by the formula (except when R and R are both hydrogen atoms).

], R2 in the general formula (1) will be explained in detail. Haloken atoms are fluorine and chlorine.

Bromine and iodine, and lower alkyloxy groups include menaloxy, enaloxy, and n-propyloxy groups.

etc., and the lower alkyl group represents a methyl group, an ethyl group, an n-butyl group, an isobutyl group, an n-propyl group, an isopropyl group.

Conventionally, 4-methyl-1-oxo-2,3-cyto-al-1-indenacetic acid has been reported as a compound similar to the compound of the present invention in Chemical Abstracts (hereinafter abbreviated as CA) Vol. 57.16430:, 5,6. -Siftquin-1-oxo-2,3-dihydro-2-indenacetic acid CAVo1.73.45192n, 5-methoxy-1
-oxo-2,3-onehydro-2-indenacetic acid is CA
Vol.

67, 116'73, 4. '/-Dimethyl-1-oxo2,3-ShihiFlow-2-indenacetic acid (diA V
ol, 74.88156s, 5-chloro-1-oxo-3-dihydro-2-indenbutyric acid CA Vol,
R8,104975e, 5-bromo-l-oxo-
2,3-dihydro-2-indenacetic acid is CAνof, 9
0.72131z, also 4-mexyl-1-oxo-2
, 3-dihydro-1-indenbutyric acid is CA Vol,
88.1049'/9i. However, all of these compounds have been published as intermediates for certain target compounds, and of course there are no reports of their medicinal uses, nor are there any descriptions that suggest them. Furthermore, tnI et al. have not mentioned pharmacological effects such as anti-inflammatory effect, analgesic effect, antipyretic effect, anti-allergic effect, Ik complement effect, anti-coagulation effect, and anti-cholesterol effect. There are only reports on manufacturing methods or chemical reactions.

The compound of the present invention is a novel compound that has not been described in any literature, and has remarkable anti-inflammatory effects, including anaphylactic-type, cytotoxic-type,
It has Arthus-type and cell-mediated anti-allergic effects, and is particularly useful as a preventive and therapeutic agent for allergic inflammation such as gastritis, rheumatism, Fujiwara's disease, and autoimmune diseases. It is a compound that is useful as a pharmaceutical, as it also has blood aggregation inhibiting, anti-inflammatory, analgesic, antipyretic, and anti-cholesterol effects.

To explain in more detail, indomethacin is typified as a conventional non-steroidal drug having an anti-inflammatory effect. It is frequently used for rheumatic diseases, etc., but it has drawbacks such as the need for long-term continuous use and the need to take it as an introductory dose. The cause of this problem has become a problem. In addition, treatment for nephritis includes antihypertensive drugs such as α-menaltopa and β-filIi when commercial blood pressure is present, diuretics such as furosemide when swelling is severe, and diuretics such as furosemide when accompanied by infurose. Anti-nylsterol drugs are used because it causes cholesterolemia, but this is no more than a general symptomatic treatment, and is it a fundamental problem? (It's not treatment.

Therefore, the Ministry of the Invention and others have been searching for new compounds with non-steroidal compounds to treat inflammatory diseases involving the immune system, and as a result of various studies, we have found that the compound expressed by the general formula (1) As a result of synthesizing 2,3-dihydro-indene 1-force conductor and conducting various tests on its pharmacological effects, it was found that it suppressed the Arthus-type reaction, which is not suppressed by the currently widely used anti-inflammatory 1M agents, and showed a remarkable effect. It has been shown to have pharmacological effects.

This medicinal effect is expressed in inflammation related to the immune system, and is very different from existing non-skeleoid anti-inflammatory drugs. Among the wide range of anti-retroviral concepts, it has been shown to have a particularly strong suppressive effect on the Arthus-type inflammatory reaction, and is a preventive and therapeutic agent for nephritis, rheumatism, Fujiwara's disease, autoimmune diseases, etc. involving the body. Among these, it has an outstanding effect on rheumatoid arthritis. I7 (,, conventional non-scale U
Anti-inflammatory agents are completely different mechanisms of action than anti-inflammatory agents.

Its history includes: - aggregation inhibitory effect, anti-inflammatory effect, analgesic effect,
It also has antipyretic action, antibacterial cholesterol action, etc. (1) It also shows low toxicity values in acute toxicity tests, making it an industrially useful compound as a pharmaceutical with a very high safety margin.

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, tablets, suspensions, emulsions, syrups, liquids, injections, and suppositories. Alternatively, it can be administered orally or parenterally as a preparation such as an 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 only examples.
Naturally, it can also be produced by other chemically similar methods.

Manufacturing method A R2R2 (II) (
1) However, in the formula, R1 and R2 have the same meaning as above,
R3 represents a hydrogen atom, a lower alkoxy group, or a lower alkoxycarbonyl group, X represents a halogen atom, Y represents a cyano group or a lower alkoxycarbonyl group, and n represents an integer of 2 to 4.

Production method B (III) (I) However, in the formula, R', R2 and Y have the same meanings as above, and R"
represents a pyrrolidino group, a biheridino group, or a morpholino group.

Production method C 2 (■) (V) 2 (1) However, in the formula, R1 and ♂ have the same meanings as above, and +1'
means the integers 3 and 4.

These manufacturing methods will be explained in more detail.

Production method A uses compound (if) and alkylating agent with an alkali.
Presence of organic amines (e.g., sodium methylate, sodium ethylate, potassium-t-butylade, sodium amide pentahydride, etc.) and organic amines (triethyl-memine, trimenalamine, N,N-dimethyl-r-niline, etc.) solvent (e.g. methanol, ethanol,
Tetrahydrofuran.

Heating at room temperature or as necessary for 3 to 48 hours in a solution of 100 ml (Henzene, toluene, xylene, dioxane, dimethylborumamide, cymenal sulfoxide, hexamenalene phosphotriamide, etc.), and then heating in a mineral solution (e.g. hydrochloric acid, sulfuric acid, etc.) It can be obtained by a hydrolysis reaction using During the hydrolysis reaction, an organic compound such as acetic acid is added to ensure uniformity of the reaction.
You can also use connecting lines.

Production method B is compound (III): L acrylonitrile or acrylic acid lower alkyl ester in an organic solvent (e.g., methanol, ethanol, tetrahydrofuran, soybean, Hensen, cymenalborum amide, etc.), with a minimum of 90%
j! If so, pass nitrogen for 1 to 48 hours at 30 to 120 hrs.
After heating to a temperature of 1.5°C, it may be hydrolyzed with a mineral acid (e.g., hydrochloric acid, sulfuric acid) in an organic solvent such as acetic acid, or it may be hydrolyzed with diluted hydrochloric acid, diluted sulfuric acid, etc.

Production method C is to hydrolyze compound (IV) 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 form compound (V). ). At this time, compound (V) is separated from li° (or ti
! It may be used as is for the next reaction. Compound (V) can be ring-closed all at once using a method (e.g. polyphosphoric acid, phosphoric anhydride, sulfuric acid, soot tetrachloride, phosphorus oxychloride, hydrobromic acid and acetic acid, etc.) or first treated with a halogenating agent ( treatment with a dehydrohalogenating agent (e.g. aluminum chloride, sulfur chloride, etc.) in an inert solvent (e.g. carbon disulfide, nitrohenzene, etc.). It is only necessary to react with the presence of chloride and chloride (other ships, etc.).

In addition, the compounds (It), (■) and (1v) which are the starting materials of the present invention are, for example, E, Nis, Stratford (1!, S, 5tratford) + Charnal of Pharmaceutical Sciences (Jo).
Urnal of Pharmaceutical 5
sciences), 6”/+80 (1978)
, E, D, Berkunn (li, D.

11ergmann), Journal of Organic Chemistry
ganic chemistry).

26, 3555. (1961), Shi, Qi. In Cold (C, K, 1Bold) Journal O7”r・i;/J Jl/Society (Jor
nal of CI+emical 5ociety)
+1954, can be easily obtained according to Cal of 1204.

The following describes the embodiments of the present invention.

Example 1 2.2 g of 6-fluoro-1-oxo-2,3-dihydro-2-intencarphonic acid ethyl ester was dissolved in 20 ml of dinonalporum amine I, and 53 g of 1 lium U was hydrogenated to 50%. and stirred at room temperature for 2 hours. Next; 3
- Add 3.9 g of ethyl butyrate and stir at 90°C for 3 hours, then distill off each section under reduced pressure of 1. 20ml of acetic acid for residual fragrance
Add 15 ml of 2% sulfuric acid and reflux for 3 hours. After reaction route r, add 100 ml of ice water to reaction final 1k and filter the precipitated crystals. The crystals are washed with water, dried, and then crystallized from isoprepyl 1 l, giving 6-fluoro a-1 in the form of a sword-like product.
-o1-so23-nohydro2-indenbutyric acid 1.
45g is tj7.

The melting point, infrared absorption spectrum, and molecular ion peak of this substance's mass spectrum are as follows.

Melting point: 016 107"C, Ai outside 1 spring absorption 1 diagram spectrum vc*o: 1'7
05cm molecular ion dimension M (m/e):
236 Example 2 2.4 g of ethylnisyl 6-chloro-1-oxo-2,3-dihydro-2-indenecarphonate, 1.82 g of Ninalamine and 20 ml of Hensen's 3-benzene. Add 2.93 g of enal mubutyrate and reflux for 10 hours.

Then, the solvent is distilled off under reduced pressure to leave a residue! 1: Add 20 m of acid and 20% sulfuric acid piml and react for 3 hours under reflux.
It was.

Add 100 ml of ice water to the reaction path rl&, anti) core temperature mixture and collect the precipitated crystals by filtration. The crystals were washed with water, dried, and then recrystallized from ethyl acetate to give colorless sword-like crystals of 6-chloro-1-oxo-23-
Shishi lζ rho 2 ~ indenbutyric acid 1. Og'& got it.

The melting point, infrared absorption spectrum, and molecular ion peak of the mass spectrum of this substance were as follows: Melting point: 141 142°C Infrared absorption spectrum vcmo: 1706 cmMolecular ion peeling M” (m/e): 252 Example 3 22 g of 3-pyrrolisino-5-chloro-indene and 18 g of acrylic acid menal ester were dissolved in 70 ml of dioxane, refluxed for 5 hours, the solvent was distilled off, and #St was added to the remaining lh.
Add 100ml and 100ml of hydrochloric acid and heat for 3 hours. Reaction route J'l&, the solvent was distilled off under reduced pressure, ice water was added, and the precipitated crystals were collected by filtration. The crystals were washed with water, dried, and then recrystallized from ethyl acetate to give colorless needle-like crystals of 6-chloro 1-oxo-2,
16g
I got it.

The melting point, infrared absorption spectrum, and molecular ion peak of the WJM spectrum of this substance were as follows.

Melting point: 171-173'C Infrared absorption spectrum vc=o: l'/10cm
Molecular ion peeling M (m/e): 238 Example 4 19.2 g of ethyl nisfur 2-oxo-hexanecarboxylate, 21.
4g of sodium ethoxide, 1.1g of sodium ethoxide, and 2001111 ethanol.The mixture was refluxed for 2 hours, then 500ml of water was added and extracted with ethyl ether. Ethyl 1
- was distilled off with ether, the residue was dissolved in 500 ml of 70% ethanol, 16.1 g of potassium hydroxide was added, and the mixture was refluxed for 3 hours. When hydrolyzed, colorless needle-shaped 1-(4-fluoro 26.5 g of (pencil)-1,5-pentansocarboxylic acid was obtained. Then 1-(4
A mixture of 26 g of -fluorohensyl)-1,5-pencunzocarboxylic acid and 300 g of polyphosphoric acid (7) was 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, and the solvent was distilled off. The residue was recrystallized from isopropyl ether to give colorless needle-like crystals of 6-fluoro-■-oxo-2,3-dihylene.
2 g of -2-indene 1% tlB was obtained.

The melting point, infrared absorption spectrum, and molecular ion peak of the quality 1 spectrum of this substance were as follows: Melting point: 122-123°C Infrared absorption spectrum νC = 0: 1705.16
90cm molecular ion peak M (m/e): 250 or more The following compounds were obtained by the method of Examples 1 to 4.

Example 5 4-Fluoro-1-oxo-2,3-dihydro-2-indenepropionic acid Melting point: 103-105°C Infrared absorption spectrum vc=o: l i l O
c+n molecular ion peak M (m/e): 222 Example 6 6-F/Ju-1-oxo-2,3-dihydro-2indenepropionic acid Melting point: 109-110.5°C Infrared absorption spectrum υc=o: 1112crn
Molecular ion peak I (m/e): 222 Example 7 4-chloro-1-oxo-2,3-dihydro-2 melting point:
107-110°C Infrared absorption spectrum vc=o: 1705cmMolecular ion peak M (m/e): 222Example 8 5-chloro-1-oxo-2,3-dihydro-2-indenpropionic acid Melting point: 184- 186°C Infrared absorption spectroscopy C"0: 1710 cm Molecular ion peak M (m/e): 23B Example 9 6-ditriol: 1-1-oxo-23-dihydro-2-indenepropionic acid Melting point: 125- 127°C Infrared absorption spectrum υc=o: 1716c+n
Molecular ion peak M (m/e); 249 Example 1
0 46-cyclol-oxo-2ph-3-dihydro-2-
Indene propionic acid melting point: 142-145°C Infrared absorption spectrum υ””: l'/20. l
'700cm molecular ion peel M" (m/e)
: 2'12 Real LM Example 11 4-chloro-1-oxo-23-dihydro-2indenbutyric acid Melting point: 102-103°C Infrared absorption spectrum νC-=0: 1705 cm min-
r-ion peeling M (rn/e): 252
Example 12 6-from-l-oxo-2,3-dihydro-2indenbutyric acid Melting point: 155-157°C Red one-line absorption spectrum C=O: 1707 cm Molecular ion peeling M (m/e): 296 implementations Example 13 46-SikuU-Rule-Oxo-23-Sihi!・Low, 2
-Indene butyric acid Melting point: 114-116°C Infrared absorption spectrum vc=o: 1710°17
00cI11 molecular ion peak M (m/e)
: 286 Example 14 6-chloro-1-oxo-2,3-dihydro-2-indene valeric acid Melting point: 9-80°C Infrared absorption spectrum vC”O: 1710.1690
cu+molecular ion peak li (m/e):
266 Example 15 5-chloro-1-oxo-2,3-cycht Ll -2-
Indenic acid melting point: 10B -110℃ Infrared absorption vector νc=o: 1705.16
90c+++Molecular Ion Pill M (m/e)
: 266 Example 16 Rhochloro-l-oxo-2,3-dihydro-2-indene valeric acid Melting point: 138-139°C Infrared absorption spectrum vC=0: 170B + 16
92cm molecular ion peak M (m/e):
266 Example 17 Lobromo ■-oxo 2,3-dihydro-2-indene valeric acid Melting point: 161-163°C Infrared absorption spectrum VC”O: 1710+ 169
4cm molecular ion peeling M (m/e):
310 Example 18 46-fuchloro-l-oxo-2,3-dishidro-2-indene valeric acid Melting point: 104-106°C Infrared absorption spectrum vc=o: 1710+1
695cm molecular ion peak M (m/e): 30
06-Methyl-1-oxo-2,3-dihydro2-
Indene vallic acid Melting point: 123-124℃ Infrared absorption spectrum vc=o: 17+12cu
+Molecular ion peak M (m/e): 232 Next,
1 shows the results of pharmacological experiments on the compound of the present invention.

Experimental Example 1 Effect on passive ^rthus response in rats One group of 5 Wistar Itoo rats weighing 135 to 155 g.
Using ~7 animals'ζ, 1lenk eL at method (Z,
1mmun; taeLsforsch, 138.1
69 (1969)) was applied and tested (i.e., rats fasted for 18 hours were given a 10% solution of anti-13sA rabbit serum (precipitated antibody 1 dli 32 times).
．． Sensitization was carried out by injecting 3 ml into the tail vein. 30 minutes after sensitization, 0. +125% bovine serum albumin (13sA) was injected into the right hind leg at a dose of 0.1 ml/individual through the skin. After 3 hours of prayer, Fujihira's method (applied pharmacology)
5.169 (1971)), and the edema suppression rate was calculated according to the formula described above. The test compound and the comparative drug, indomethacin, were both 0.5% tragan 1-
Suspended in rubber aqueous solution, 100mg/kg and 5+og/kg, respectively, of BSA3 and ASA3 were added 1 hour before development.
I did it.

In addition, a control group was administered a vehicle.

11 Tumor rate (%) - ISA induction - USA induction 3 Hiro - 1 ---- 11--------- x io.

Constant volume l' tumor suppression rate (%) before induction of BSA - T mematoma rate of Ta 1 Sho 411 - l'JHdt of drug administration group
Rate − −−−−−−−−−−−− −−− −−−−−
----1------X 100 illusion Q, :4
The 14Z 1lii rate results for 111' are shown in the table below.

Table Effect on passive ^r thus reaction in rats Experimental example 2 Acute toxicity in mice Groups of 6 ddY Itoo mice weighing 22-26 g.
(Used. Mice were suspended in 0.5% tragacanth aqueous solution. After oral administration of IX (acclimated compound and comparative drug indomethacin), the mice were observed for -week and the mortality rate was determined.

The results are shown in the table below.

Table: Based on the results of pharmacological experiments with acute toxicity or higher in mice, the compound of the present invention is clearly a compound involved in the immune system.
・It is clear that it has a more prominent pharmacological effect than indomethacin, which is commonly known as a drug, and has lower toxicity.

Patent applicant: Hisamitsu Pharmaceutical Co., Ltd. (company representative: Takashi Nakashojin) 3/z Neichi J, 1E (LiJ Patent Office Commissioner, Yohito Wakasugi 1, Case Report: 1982 Patent Application No. 98986 2) , Title of the invention: New 2.3-dihydro-indene exclusive patent 3, Relationship with the case of the person making the amendment Patent applicant address: 408-4 Tashiro Daikan-cho, Tosu City, Saga Prefecture, [1-i] of the supplementary order j b, 17I old typed copy of the full statement of contents of the amendment (no change in content) Procedure?City J-E letter (self-motivated) September 1988 G Patent Office District Officer Wakasugi Yoto 1, Indication of the incident 1981 Patent Application No. 98986 2, Title of the invention: New 2,3-dihydro-indene derivative 3, Relationship with the 11-year-old case Patent applicant 4, 1# Date of positive order Voluntary action 5, Amendment l) In the specification [the engraving in the procedural amendment W (method) dated October 27, 1982], in the column [3. Detailed explanation of the invention], from the fourth line from the top of the second page The phrase “23-dihydro-indene derivative” on the fifth line has been replaced with “2.
3-dihydro-indene derivative”.

2) Same book, page 2, line 5 from the bottom (7) rVol,
57.16430: 'Vo1.57.16
430h J Correct.

3) In the same book, page 4, lines 7 to 8 from the top [represented by indomethacin]. ” is corrected to r, represented by indomethacin, and j.

4) In the same book, from the 5th line to the 4th line from the bottom of page 4, the words ``anticholesterol agent'' are corrected to r anticholesterol agent j.

5) In the same book, in the 5th line from the top of No. 6, after “liquid,” r
Insert ointments, creams, gels, and aerosols.

6) In the same book, page 7, line 6 from the top (however, the chemical structural formula is counted as one line, and the same shall apply hereinafter), the chemical structural formula () % formula % is corrected.

7) In the same book, in the 8th line from the top of the 7th line, the phrase 1-pyheridino group is corrected to read ``piperidino group j.

8) Same book, chemical structural formula in the first line from the top of No. 8 [ %formula% Correct it to 1.

9) “While passing nitrogen” in the 7th line from the top of No. 9 of the same book.
I corrected it by saying, ``Don't blow in nitrogen gas.''

10) In the same book, in the 6th line from the bottom of No. 9, the phrase ``to a compound'' is corrected to r compound j.

11) “6-chloro-1-oxo-2,3-dihydro-” in the same book, page 12, lines 2 to 3 from the top
2-indenecarboxylic acid ethyl nisyl” is replaced with “
Corrected to 6-chloro-1-oxo-2,3-dihydro-2-indenecarboxylic acid ethyl ester j.

12) In the same book, from the 12th line directly above the 1θth line to the 11th line, [6-li1col-1-oxo-23-dihydro-2-indenbutyric acid J] is replaced with “6-chloro-1 −
oxo-2,3-dihydro-2-indenbutyric acid".

13) In the same book, "46-dichloro-1-oxo-2,3-dihydro-2-indenepropionic acid" from the second line to the third line from directly above No. 17 is r4,6-
dichloro-1-oxo-2,3-dihydro-2-indenepropionic acid".

14) In the same book, page 18, from the second line to the third line from the top, the term 146-dichloro-1-oxo-2,3-dihydro-2-indenbutyric acid is replaced with ``4.6~dichloro~
Correct to 1-oxo-2,3-dihydro-2-indenbutyric acid j.

15) "1-6-chloro-1-oxo-2,3-dihydro-2-indenenevaleric acid" in the same book, page 18, lines 8 to 9 from the top, is replaced by r4-chloro- 1-
6r pressure.

16) The text "46-dichloro-1-oxo-2,3-dihydo-1co-2-indenevaleric acid" from the 5th line to the 4th line from the bottom of page 19 of the same book is r4.6 -Dichloro-1-oxo-2,3-dihydro-2-indene Valericusa @j.

17) In the same book, page 21, line 4 from the top, 1 "aqueous solution of gum tragacanth" is corrected to r aqueous solution of gum tragacanth j.

1B) In the same book, in the second line from the bottom of No. 23, the phrase "aqueous tragacanth solution" is corrected to r gum tragacanth aqueous solution j.

Claims (1)

[Claims] General formula (1) (1) (In the formula, n is an integer of 2 to 4, and R and R are hydrogen atoms. A novel 2゜3-sichth U-indene dispecialty represented by (except when R1 and R2 are both hydrogen atoms).