JPS5879919A - Antiphlogistic, analgesic and antipyretic - Google Patents

Abstract

PURPOSE:An antiphlogistic, analgesic and antipyretic showing low toxicity and improved action, comprising a 3,5-di-tert-butyl-4-hydroxystyrene derivative as an active ingredient. CONSTITUTION:The titled agent comprising a compound shown by the formula{R<1> is COR<3>[R<3> is OR<4>(R<4> is H or alkyl), alkyl, (substituted)phenyl, NHR<5> (R<5> is R<4>)], NO2, SO2R<6>(R<6> is alkyl); R<2> is H, alkyl, hydroxyalkyl, CN, COR<7> (R<7> is alkyl)}or its salt, such as beta-carboxy-beta-(2-hydroxyethyl)-3,5-di.tertiary. butyl-4-hydroxy-styrene, as an active ingredient. Any pharmaceutical preparation of oral medication, medication through the intestine and parenteral medication may be selected as pharmaceutical preparation.

Description

[Detailed description of the invention]

The present invention relates to anti-inflammatory, analgesic and antipyretic agents. More specifically, the present invention relates to the following general formula (1) (where R
1 is a group represented by the general formula COR'(R' is OR'(R' represents hydrogen or a lower alkyl group). Lower alkyl group, unsubstituted or substituted phenyl group, NHR
' (R5 represents hydrogen or a lower alkyl group) represents an amino group], a nitro group or an allele group represented by 5O2R6 (R6 represents a lower alkyl group) 3,5-di- Tertiary spotted M-4-
Hydroxystyrene derivative 1 is an anti-inflammatory, analgesic, and antipyretic agent containing its physiologically acceptable salt as an active ingredient. Since its first use, numerous compounds have been synthesized or extracted from nature that have been used for therapeutic purposes. However, there are 11. Drugs that have strong anti-inflammatory effects and weak toxicity tend to have relatively weak anti-inflammatory effects, and no drug has yet been found that satisfies both. The present inventors have discovered an anti-inflammatory drug with strong anti-inflammatory effect and low toxicity.
As a result of intensive research aimed at developing analgesic and antipyretic agents,
The compound represented by the above general formula (1) has low toxicity and good anti-inflammatory, analgesic, and antipyretic effects. The invention has been completed.The anti-inflammatory, analgesic, and antipyretic agent according to the present invention has the general formula (1).
3,5-di-tert-butyl-4- represented by
The active ingredient is a physiologically acceptable salt of hydroxystyrene derivative 1 or 11, which will be explained in more detail below. That is, R1 in the general formula (1) is represented by the general formula COR,3(R
3 is a group represented by 0R4 (R4 is hydrogen 1 & represents a lower alkyl group), a lower argyl group, an unsubstituted, substituted phenyl group, an amine group represented by NHR (R is hydrogen or a lower alkyl group) A group represented by ],
21. represents an argylsulfonyl group represented by 21.
The lower alkyl group of R is a methyl group, an ethyl group, a butyl group,
Hexo/1/ group, etc., as substituted phenyl group 1・l)
) group, chlorophenyl group, bromophenyl group, etc.; lower argyl group for R5 includes methyl group, ethyl group, butyl group, hexyl group, etc.;
Examples of the lower argyl group include methyl group, ethyl group, butyl group, hexyl group', and q. Further, examples of the lower argyl group of R2 include methyl group, ethyl group, butyl group, hexyl group, etc., and examples of the lower hydroxyargyl group include hydroxymethyl group, hydroxyethyl group, hydroxybutyl group, hydroxyhexyl group, etc. Examples of the lower argyl group of IF include methyl group, ethyl group, butyl group, hexyl group, etc. Compounds ff not represented by general formula (1): Specific examples include the following: β-carbogycy β-(2-human

[''Gin'ech/L/)
-3,5-tert-buna-4-hy-1-yloxystyrene (hereinafter abbreviated as compound 1), β-mer-I-
oxycarbonyl-β-(2-hydroxyethyl)-3,
5-tert-butyl-4-hydroxystyrene (hereinafter referred to as compound 11), β-carboxy-β-ethyl; 3,5-tert-butyl-4-hydroxystyrene (hereinafter referred to as compound 1)
(abbreviated as ■), β-1-oxycarbonyl-β-acetyl-3. 5-Si-ternary-butyl-4-hydroxystyrene (hereinafter abbreviated as compound 1v), β-acetyl-3,
5-di-tert-butyl-4-hydroxystyrene (hereinafter abbreviated as compound V), β-acetyl-β-methyl-3,5-tert.
・Butyl-4-hydroxystyrene (compounds ~11 below)
), β-benzoyl-3,5-di-tert-butyl-
4-hydroxyethylene (hereinafter abbreviated as compound Ⅰ), β-carbamoyl-3,5-tert-butyl-4-hydroxystyrene ([1” Compound '41h Vl
(abbreviated as compound IX), β-carbamoyl-β-cya2:3,5-tert-butyl-4-hydroxystyrene (hereinafter abbreviated as compound IX), β-nitro-3,5-oneΦ- Noyari Buchi/L/-
4-Hydroxystyrene (hereinafter abbreviated as compound X). β-methylsulfonyl β-thia/-:(,5-cy・
A compound v; 1, salt, (can form a salt with 1. As a base, the general formula (
1) The compound represented by
You can choose. Specific examples of salts include (1) metal salts, especially alkaline earth metals, alkaline earth metals,
Salt with aluminum, (2) ammonium1. a b(
3) Amine salts, especially salts with dimethylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, piperidine, morpholine, menalimine, aniline, pyridine, etc., as anti-inflammatory, analgesic, and antipyretic agents, from these salts Just choose one that is physiologically acceptable. All of the above compounds and their salts have excellent anti-inflammatory, analgesic, and antipyretic properties! It is a compound with a long history and low toxicity, and can be said to meet the purpose of the present invention. The above compound can be prepared by the following method (1): 3.5-tert-butyl-4-hydroxybenzaltehyto general formula (where Ar is an aryl group, R8 is the general formula OR9)
[R9 is Ofe 10 (RIO represents a lower argyl group)
It is represented by an alkyl group, a lower argyl group, an unsubstituted or substituted phenyl group, NHR5 (R5 represents all hydrogen or lower argyl groups), an amino group] group, 21・mouth block or 502R6 (R
6 represents a lower alkyl group), R2 is hydrogen, a lower argyl group, a lower hydrogyne argyl group, a Noano group, or COR (R represents a lower argyl group). The acyl group represented is
Also, R and R may be combined, and RR is 1-C-0-C2H3.R (R represents a lower γrugyl group)
ylide expressed as 0. 15ter et al.'s method [Helvetica Gimme Power Association Acta 40, 1242 (1957)
), and if necessary, the ester or amide of Compound 1 can also be obtained by hydrolyzing the entire ester or amide of Compound 1 with a suitable acid solution once a month. synthesis). This synthesis method uses the so-called Witzteig reaction, and the ylide to be reacted with the benzaldehyde 1- is, in addition to the compounds listed in -, 1-1, trigylphosphine, tria! Regirposu Fight, Triary! Ylide derived from realcin can be used as well. 1, f
The acids and bases that can be used to hydrolyze the esters or amides present in the compound are sulfuric acid, p-toluenesulfonic acid. Examples include acids such as 1 to lifluoroacetic acid, and bases such as phosphorium hydroxide, potassium hydroxide, barium hydroxide, and pyrrolidine. (2) Among the compounds represented by the general formula (]), the general formula (2) shown in 1.
5 represents a lower argyl group)
an amine group represented by N0R5 (R5 represents a hydrogen atom or a lower argyl group), a 21-ro group or an alkylsulfonyl group represented by 5O2R (R represents a lower argyl group) R1'' is hydrogen, a cyano group, or COR7 (R7 is a hydroxyl group or a lower alkyl group);
L combination #l/JIri can also be synthesized as follows. That is, 3,5-Si turn yearly spot/L/-4-
Hydrogenic benzaldehyde 6 General formula R-CH2-R (where, 12 is the general formula COR14 (R14 is OR
A group represented by I5 (R15 represents a lower alkyl group) or an amine group represented by NH'R5 ('R' represents hydrogen or a lower argyl group), 21・Represents an argylsulfonyl group represented by 5O3R (R represents a lower alkyl group),
R is hydrogen, cyano, or group. Alternatively, it is synthesized by reacting a compound represented by COR17 (R17 represents a group represented by a hydroxyl group or a lower alkyl group) with a base catalyst. This reaction uses a reaction known as the so-called Knoeffenagel reaction, and bases that can be used as catalysts include ammonia, -class or secondary amines, or salts thereof. Specific examples of bases and their salts that can be used include piperidine, pyrrolidine, ammonium acetate, and piperidinium acetate. When a compound represented by the general formula R-CH2-R is mixed with malonic acid monoamide or the like, it may be decarboxylated to produce a compound in which R is hydrogen. (3) Among the compounds represented by the general formula (]), the compound v represented by the following general formula (3) (R18 represents a lower argyl group)
/Ji is 3,5-di-tert-butyl-4-hydroxybenzaltehyde, (R18CH2CO)
20 (R18 represents a lower alkyl group) and RCH2C0CH2C0O are lower alkyl groups 5
It can be synthesized by subjecting an organic acid alkali metal salt represented by (M represents an alkali metal) to a Perkin reaction. Alkali metals that can be used here include sodium, potassium, and the like. (4) Among the compounds represented by the general formula (1), the compound represented by the following general formula (4) (R19 represents a lower alkyl group or a lower hydroxyalkyl group) is a 3゜5-di-tertiary group. Butyl-4-hydroxybenzaldehyde and a malonic acid derivative represented by 119-CH(C0OH)2 (R19 is lower argyl group) are mixed with pyridine or the like as a solvent.
Anti-L-1 using a base such as piperidine or pyrrolidine as a catalyst
・Can be synthesized by making it -1. Anti-inflammatory, analgesic, and antipyretic action The anti-inflammatory, analgesic, and antipyretic agent according to the present invention contains a compound represented by the general formula (1) or a salt thereof as an active ingredient. The pharmacological action and toxicity of these compounds are as shown in the experimental examples below. In addition, the anti-inflammatory effect of carrageenan to suppress footprint edema is C.
The method of A. Winter et al.
19 (i 2 )), the granulation growth inhibitory effect was determined by the method of Yukio Hara et al. [Japanese Pharmacological Journal, 1±, 557 (1977)],
Adjuvant arthritis inhibitory effect, T, Wal
The Method of Pharmacology and Experimental Therapeutics,
178.223 (1971)). The antipyretic effect is determined by the method of Yoshikazu Yanagi et al. [Japanese Pharmacological Journal, Jyu, 735
(1978)], and the analgesic effect was determined by the method of R. Koster et al. [Federation Proceedings, 18, 412].
(1959)]. From the results shown in Tables 1 to 6, it is clear that the anti-inflammatory, analgesic, and antipyretic agent according to the present invention has excellent pharmacological effects and high safety. Note that the compound numbers shown in Tables 1 to 6 correspond to the above compound numbers. Anti-inflammatory effect (1) Carrageenin foot edema suppressive effect Wistar male rats (body weight 150-180 g) were used, with 6 rats per group. A test compound suspended in a 2.5 aqueous gum arabic solution was orally administered at a rate of % 1.0 mt/100 g body weight. One hour later, 0.1 ml of 1% carrageenan was subcutaneously injected into one hind limb to induce inflammation. The swelling volume of the paw of the hind paw was measured at 3 and 5 hours after the onset of inflammation, and the inhibition rate was calculated using the following formula. The results are shown in Table 1. It can be seen that Compound 1 according to the present invention has a strong carrageenan float 1 inhibitory effect. Table 1 Carrageenin foot edema inhibitory effect (2) Granulation growth inhibitory effect Wistar male 1 year old rat 1~ (not in print 150~180g)
The number of animals per group was 6. Under anesthesia, after removing hair from the back, the skin is opened approximately lαnU along the midline, and one sterilized antibiotic assay paper disc (29 ± 1 my) is inserted under the skin in front of both shoulders, and the incision is made. was sutured. The test compound was suspended in a 2.5 gum arabic aqueous solution,
1ynt/10 (IQ percentage of body weight, paper
The drug was administered orally for 7 days from the day the disc was inserted. The animals were sacrificed 7 days after paper disc insertion, and the granulation tissue containing the paper disc was excised. . The excised granulation tissue (i
After drying at 0°C for 24 hours, it was weighed, and the dry weight of granulation was determined by subtracting the weight of the paper φ disk, and the inhibition rate was determined using the following formula. The results are shown in Table 2. It can be seen that the compounds according to the present invention have a strong granulation growth inhibiting effect. Table 2 Granulation growth inhibitory effect (3) Adjuvant arthritis inhibitory effect One SD male rat 1- (body weight 190-230IlI) was used, with 8 rats per group. As an adjuvant, Mycobacterium bacterium (Mycobacterium
utilicum) at 10 nlQ/
0.05 ml of the suspension was injected into the concavity of the hind paw on the - side. From the day of adjuvant treatment, once a day for 21 consecutive days, the test compound was suspended in 25 #) gum arabic water bath solution (1,5?〃e/1
00 fl Administered "Jun 1" according to body weight and no. After the adjuvant treatment, the swelling volumes of both hind limbs in the 144th and 211th layers were measured, and the inhibition rate was calculated using the following formula. Table 3 Ashban 1 - Arthritis inhibitory effect I11 analgesic effect Using ddY strain I mouse (body weight 20-25 g),
There were 10 animals in each group. The test compound (25 cycles) suspended in an aqueous solution of gum arabic was added at 0.1 ynt/l OQ.
(Administered intraperitoneally at a rate of 4.0 kg.) One hour later, intraperitoneal injection was performed at a rate of 0.1 me/l (l Q body weight). The number of strokes in the control group was compared with the number of strokes in the control group, and the inhibition rate was calculated from the following formula.The results are shown in Table 4. I understand. Table 4 Analgesic effect Antipyretic effect Male Wistar rat (body weight 150-180 Q)
5 animals per group. Dried yeast was suspended in physiological saline and injected subcutaneously into the back at a ratio of 20% suspension and 1 liter of soybean powder/100 g of body weight. After 18 hours, rectal temperature was measured using a thermistor thermometer, and only rats whose body temperature rose to 386°C or higher were selected for use in the experiment. Immediately after body temperature measurement, a suspension of the test compound in an aqueous solution of 25% gum arabic was orally administered at a rate of 1 me/100 f body weight. After administration. 1. Rectal temperature was measured at 3 and 5 hours, and the inhibition rate was calculated using the following formula. The results are shown in Table 5. It can be seen that the compound Va according to the invention has a strong antipyretic effect. Table 5 Antipyretic effect acute 14: Toxic ICR female mice (weight 20-25 g) were used.
There were 6 animals in the group. A test compound suspended in an aqueous solution of 25% gum arabic was orally administered at a rate of 0.1 me7101 body weight. General symptoms were observed for two weeks after administration, and the number of deaths/number of test cases was determined. The lethal dose LD50 (2IzQ/kq) was estimated. The results are shown in Table 6. It can be seen that all the compounds of the present invention have low toxicity. Table 6 Acute Toxic Preparation and Administration J■ As the anti-inflammatory, analgesic and antipyretic formulation according to the present invention, it is also possible to select formulations for oral, rectal or parenteral administration. Specific formulations include tablets, capsules, granules, syrups, crude drugs, and ointments. Carriers for the anti-inflammatory, analgesic and antipyretic formulations according to the invention include organic or inorganic solid or liquid, usually inert pharmaceutical carriers suitable for oral, rectal or other oral administration. material is used. Specifically, 1/i,
For example, Crystal I! t-cellulose, gelatin, lactose, starch,
Magnesium stearate, lyleph, vegetable and animal fats and oils, gums, boriaflexilene gellicol. The proportion of the anti-inflammatory, analgesic, antipyretic agent according to the invention to the partner in the formulation can vary between 0.2 and 100 parts. Furthermore, the anti-inflammatory, analgesic, antipyretic agent according to the present invention may include other anti-inflammatory, analgesic, antipyretic and other pharmaceuticals that are compatible therewith. In this case, the loss due to the present invention,
It is needless to say that inflammatory, analgesic, and antipyretic agents do not have to be the main ingredients in the formulation. The anti-inflammatory, analgesic, antipyretic agents according to the invention are generally administered at dosages that achieve the desired effect without side effects. The specific value should be determined by a doctor's judgment, but in general, 10 mQ ml OQ per day for adults,
Preferably, it will usually be administered in an amount of about 20 m9 to 5 g. In addition, the anti-inflammatory, analgesic, and antipyretic agent of the present invention contains i yptQ ~ 5 g as an active ingredient, preferably tri
It can be administered as a pharmaceutical preparation in units of 3 my to 1 g. Examples of the present invention will be described below. Example 1 Synthesis of Compound I 3.18 g of 5-tert-butyl-4-hydroxybenzaldehyde and 27. t/ and was dissolved in 150 tnl of dimethylsulfogizod (]) MS O) and reacted for 200 hours with stirring at 80°C on a hot water bath. After the reaction was completed, 800 ml of chloroform was added to the cooled reaction solution, and the mixture was washed 5 times with the same amount of water. The solvent DMSOk was removed. After separating the chloroform layer, it was concentrated to dryness under reduced pressure to remove chloroform. Ethanol was added to the residue to perform crystallization, followed by recrystallization from the same solvent to obtain 18 g of α-(3,5-di-tertiary-4-hydroxybenzylidene)-γ-butyrolactone. Next, 1.5 g of α-(:(,5-di-ternary-buty)v-4-hydroxybensylidene)-γ-butyrolactone obtained here was added to 100 ml of 1O,01N sulfur and lithium hydroxide aqueous solution, The hydrolysis reaction was carried out for 1 hour while stirring at 90-10°C (1°C) in a nitrogen stream. After the reaction, the cooled reaction solution was
Sulfuric acid was added little by little to make it acidic and to form a precipitate. The precipitate was separated by tP and washed well with water. Dissolve the precipitate in benzene 1~, perform crystallization, and obtain the desired compound■
1.0g of was obtained. Example 2 Synthesis of Compound (1) 3.2.3 g of 5-di-tert-butyl-4-hydroxybenzaldehyde and 45Q of 5-di-tert-butyl-4-hydroxybenzaldehyde were dissolved in DMSO2OmJ.
and reacted for 400 hours with stirring in a hot water bath at 1.80'C. After the reaction was completed, chloroform 200a+t was added to the cooled reaction solution, and the mixture was washed 10 times with the same 111 water.
The solvent DMSO was removed. The chloroform layer was separated, then the chloroform was removed under reduced pressure, and the residue was dissolved in aqueous alcohol/L/ (Alecol/Water-7/3) for crystallization. Next, the obtained crystals were dissolved in acetone, and all of jlirL and n-hegisan were added to precipitate crystals again. Yield 2. OQ. Example 3 Synthesis of compound (1) Ethanol/l/3. 3.
5g. 1.3 g of cyanoacetamide and piperidine l rl
Add It, mix, and add this mixture to 4()''~50'
Stir at C. After a while, the solution became homogeneous, and the reaction was further continued for 4 hours with stirring. After the reaction was completed, the solvent was removed under reduced pressure, and the remaining IIE was dissolved in chloroform and washed three times with diluted hydrochloric acid. After separating the chloroform layer, remove the chloroform under reduced pressure. The residue was dissolved in ethanol and crystallized. Yield: 3.5g. Example 4 After kneading a mixture of 1100 g of the compound, 55 g of lactose and dried potato starch 41Q with 20 ml of water. Extrude through a 16-mesh screen at 40°C.
It was dried and granulated. Next, it was mixed uniformly with 4 g of magnesium stearate and compressed into tablets by a conventional method to give 2 tablets per tablet.
A tablet containing 100 mQL7) compound 'ImI in 00 ml was obtained. Example 5 Example 1 was carried out using compound ■ instead of compound ■ of Example 1.
In the same manner as above, add 10% of compound ■ in 200 ml of one tablet.
All tablets containing 0 ml were included. Example 6 196 g of granules obtained in exactly the same manner as in Example 1 were mixed with 4 g of magnesium stearate, and then mixed with 200 n
A hard capsule containing 1 (10ynQ) of compound ■ was obtained. Example 7 Compound IX was prepared in the same manner as in Example 3, using compound ■ instead of compound ■. Hard capsules containing 100 ynQ were prepared. Example 8 Compound I 10. Oy Lactose 8
5.0 g Crystalline cellulose 45 g Magnesium stearate 0.5 g The above components were thoroughly mixed to obtain a powder containing 100 mQ of compound (1) in IQ. Example 9 Compound '16/I IX 10 (l
A powder containing mfl was obtained. Patent applicant Kanebuchi Chemical Industry Co., Ltd. Agent Patent attorney Sada Asano - Continued from page 10 Inventor Yutaka Ariki 141-40 Tenjin, Oshio-cho, Himeji-shi Author Toshiaki Yamashita 8-16 Shinjinno, Kakogawa-shi No. 1 No. 0 Inventor: Kiyoshi Watanabe, 5-15-41, Matsugaoka, Akashi City, Procedural Amendment (Order 9, 1947), February 3, 1981, Saisei Kogo Application No. 179949, 2. Name of the invention: Anti-inflammatory, Published pain, Kado 7cho Gekkoku 711'f
U” 3-2-4 Nakanoshima, Kita-ku, Osaka Address Representative: Takashi B1 Taku 4, Agent 5, Date of amendment order 6 Number of inventions to be increased by amendment 7, number subject to amendment) Ii-cho Mineno Beta ￥ β ￥ 蛸 蛸 蛸 蛸 蛸。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。. (2) No. 8 shell, second line from the bottom, ++ (R11 is a lower alkyl group" is corrected to "(R11id: hydrogen or t-class argyl group"). (3) No. 1 O member, ]1 In line 11, correct ``R7 hydroxyl group or lower alkyl'' to ``11 R7i lower alkyl''. (4) In line 11, line 6, ``Reaction 1 using a base catalyst
′°°′Baojijie or salt III! Correct reaction P using as medium II. (5) Same No. 251゜(, i.6, if X I 11
to "X ++" and "xu" to "XI", respectively. (6) Same page 26'jt, s line 1'', ``powder agent'' is corrected to ``fine powder agent.'' (7) Same page 27, line 122, ``Example I n'' Manufacturer side 1II 4. ζ City 11-ch. (8) Same No. 28 shell, line 8 1-1, seal), 01N sodium hydroxide" is reduced to "IN sodium hydroxide". (9) 28th Ft, 1/' to 5E 111, ``Example 2'';j'jL (Evening 1i 2
" if 11-', t'; 6. (ILIj same page 29, line 9 l", "Example 3"
is corrected to “Manufacturing Example 3”. (11) Same page 30, line 1, “Example 4” is corrected to “Example 111.” (12) Same page 30, line 9 l”, “Act h111, i.
, F C ``Correct ``Example 2'' to ``Example 2.''
(14) On page 30 of the same, the second line from the bottom IL''-, Example 7" is corrected to "Example 4" of 111. (15) On page 31 of the same, 1 Line 1\1, using the same force θ as P, correct compound IX u to ``in the same way, compound IX in 1 kub - 1 dol''. (16) Same j31st member, line 3]'', ``Example 8'' is also added to ``Example 5'' for a total of 7 times. (17) 31st member, line 10 “1. “Example 9””
Example 6'' is made into n-type.

Claims (1)

[Scope of Claims] 1. Anti-inflammatory and analgesic product containing as an active ingredient a 3,5-jeta-shari-butyl-4-hydroxystyrene derivative represented by the following general formula or a physiologically acceptable salt thereof;
Antipyretic agent. (Here, R1 is the general formula COR'(R" is OR'(R
Is ' hydrogen or lower alkyl group? ), lower alkyl M group, unsubstituted or substituted phenyl group, NH
an amino group represented by R5 (R5 represents hydrogen or a lower alkyl group), a nitro group or an alkylsulfony M group represented by SO□R' (R6 represents a lower alkyl group) and R2 is hydrogen, a lower alkyl group, a lower hydroxyalkyl group, a cyano group, or an acyl group represented by COR (R represents a lower alkyl group)? represent. )