JPH024584B2 - - Google Patents
Info
- Publication number
- JPH024584B2 JPH024584B2 JP33434588A JP33434588A JPH024584B2 JP H024584 B2 JPH024584 B2 JP H024584B2 JP 33434588 A JP33434588 A JP 33434588A JP 33434588 A JP33434588 A JP 33434588A JP H024584 B2 JPH024584 B2 JP H024584B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- inflammatory
- analgesic
- antipyretic
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- ZMRCFZFFKWFWSK-UHFFFAOYSA-N 2,6-ditert-butyl-4-ethenylphenol Chemical class CC(C)(C)C1=CC(C=C)=CC(C(C)(C)C)=C1O ZMRCFZFFKWFWSK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 30
- 230000003110 anti-inflammatory effect Effects 0.000 description 22
- 239000002221 antipyretic Substances 0.000 description 13
- 230000001754 anti-pyretic effect Effects 0.000 description 11
- 230000000202 analgesic effect Effects 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 229940125716 antipyretic agent Drugs 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- DOZRDZLFLOODMB-UHFFFAOYSA-N 3,5-di-tert-Butyl-4-hydroxybenzaldehyde Chemical compound CC(C)(C)C1=CC(C=O)=CC(C(C)(C)C)=C1O DOZRDZLFLOODMB-UHFFFAOYSA-N 0.000 description 7
- 239000000730 antalgic agent Substances 0.000 description 7
- 239000002260 anti-inflammatory agent Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 231100000053 low toxicity Toxicity 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 244000215068 Acacia senegal Species 0.000 description 4
- 229920000084 Gum arabic Polymers 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000205 acacia gum Substances 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 235000010418 carrageenan Nutrition 0.000 description 4
- 229920001525 carrageenan Polymers 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 230000001760 anti-analgesic effect Effects 0.000 description 3
- 230000036760 body temperature Effects 0.000 description 3
- 239000000679 carrageenan Substances 0.000 description 3
- 229940113118 carrageenan Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
- GCODEPGAPILMQG-UHFFFAOYSA-N 4-hex-1-enylphenol Chemical group CCCCC=CC1=CC=C(O)C=C1 GCODEPGAPILMQG-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- -1 amine salts Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- XVJKSGJGHGOBSI-FMIVXFBMSA-N (e)-4-(3,5-ditert-butyl-4-hydroxyphenyl)-3-methylbut-3-en-2-one Chemical compound CC(=O)C(\C)=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 XVJKSGJGHGOBSI-FMIVXFBMSA-N 0.000 description 1
- DIZAPZDIMTYXQE-UHFFFAOYSA-N 2-[(3,5-ditert-butyl-4-hydroxyphenyl)methylidene]butanoic acid Chemical compound CCC(C(O)=O)=CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 DIZAPZDIMTYXQE-UHFFFAOYSA-N 0.000 description 1
- JDYOMWDXAAPCEE-UHFFFAOYSA-N 3-(triphenyl-$l^{5}-phosphanylidene)butan-2-one Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=C(C)C(=O)C)C1=CC=CC=C1 JDYOMWDXAAPCEE-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010060891 General symptom Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 238000003684 Perkin reaction Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009529 body temperature measurement Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
２
で表わされる特許請求の範囲第１項記載の３，５
―ジ・ターシヤリー・ブチル―４―ヒドロキシス
チレン誘導体またはその生理的に許容される塩。2 3 and 5 of claim 1 expressed as
-Di-tertiary butyl-4-hydroxystyrene derivative or a physiologically acceptable salt thereof.
＜産業上の利用分野＞
本発明は、抗炎症、鎮痛、解熱作用を有する
３，５―ジ・ターシヤリー・ブチル―４―ヒドロ
キシスチレン誘導体または、その生理的に許容さ
れる塩に関する。さらに詳しくは、下記の一般式
(1)で表わされる３，５―ジ・ターシヤリー・ブチ
ル―４―ヒドロキシスチレン誘導体またはその生
理的に許容される塩に関するものである。
（ここで、R1はヒドロキシ基または低級アル
キル基を示し、R2は低級アルキル基を示す。）
＜従来の技術＞
炎症は最も一般的な病態の一つでサリチル酸
が、その治療に用いられて以来、数多くの化合物
が合成され、あるいは天然から抽出され、治療に
用いられて来た。しかし、それぞれ一長一短があ
り、一般に抗炎症の強い薬物は毒性も強く、毒性
の弱い薬物は抗炎症作用も比較的弱い傾向があ
り、その両者を十分に満足し得るものは未だ見出
されていない。
＜発明の解決すべき課題＞
本発明者等は、抗炎症作用が強く、毒性の低い
抗炎症、鎮痛、解熱剤の開発を目差し、鋭意研究
を重ねた結果、上記の一般式(1)で表わされる３，
５―ジ・ターシヤリー・ブチル―４―ヒドロキシ
スチレン誘導体が低毒性で良好な抗炎症、鎮痛、
解熱作用を有することを見出し、本発明を完成し
た。
＜課題を解決するための手段＞
本発明による新規化合物、前記の式(1)で表わさ
れる３，５―ジ・ターシヤリー・ブチル―４―ヒ
ドロキシスチレン誘導体または、その生理的に許
容される塩は、抗炎症作用、解熱・鎮痛作用を有
し、毒性が低い。
一般式(1)中、R1はヒドロキシ基または低級ア
ルキル基で表わされる基、R2は低級アルキル基
を示す。R1の低級アルキル基としては、メチル
基、エチル基、プロピル基、ブチル基、ヘキシル
基等が、R2の低級アルキル基は、メチル基、エ
チル基、プロピル基、ブチル基等を挙げることが
できる。
式(1)に属する化合物の具体例としては、β―カ
ルボキシル―β―エチル―３，５―ジ・ターシヤ
リー・ブチル―４―ヒドロキシスチレン（以下化
合物と略称する）、β―アセチル―β―メチル
―３，５―ジ・ターシヤリー・ブチル―４―ヒド
ロキシスチレン（以下、化合物と略称する）な
どがある。一般式(1)で表わされる化合物は、塩基
と塩を形成することが可能であり、塩基としては
一般式(1)で表わされる化合物と造塩可能な任意の
ものを選ぶことができる。具体的塩の例として
は、例えば(1)金属塩、特にアルカリ金属、アルカ
リ土類金属、アルミニウムとの塩、(2)アンモニウ
ム塩、(3)アミン塩、特にメチルアミン、エチルア
ミン、ジエチルアミン、トリエチルアミン、ピロ
リジン、ピペリジン、モルホリン、ヘキサメチレ
ンイミン、アニリン、ピリジン等との塩がある
が、抗炎症、鎮痛、解熱剤としては、これらの塩
のうちから生理的に許容されるものを選べばよ
い。
上記の化合物およびその塩は、いずれも優れた
抗炎症、鎮痛、解熱作用を有し、しかも毒性の低
い化合物であり、本発明の目的に合致するもので
あると言える。上記の化合物は、次のような方法
により合成できる。
(1) ３，５―ジ・ターシヤリー・ブチル―４―ヒ
ドロキシベンズアルデヒドと一般式
〔ここで、Arはアリール基を、R3は低級アル
キル基、低級アルコキシ基またはNHR4（R4は水
素または低級アルキル基を示す）で表わされるア
ミノ基を示し、R2は低級アルキル基を表わす〕
で表わされるイリドとを0.Isterらの方法〔ヘルベ
テイカ・キミカ・アクタ40，1242（1957）〕に従つ
て反応させることにより合成される。この合成方
法は、いわゆるウイツテイヒ反応を用いるもので
あり、上記ベンズアルデヒドと反応させるイリド
としては、上記の化合物以外に、トリアルキルホ
スフイン、トリアルキルホスフアイト、トリアリ
ールアルシンから誘導されるイリドも同様に用い
ることができる。また、得られた化合物中に存在
するエステルまたはアミドを加水分解するには、
硫酸、トリフルオロ酢酸等の酸や水酸化ナトリウ
ム、ピロリジン等の塩基が用いられる。
(2) 一般式(1)で表わされる化合物のうち、下記一
般式(3)
（R2は低級アルキル基を示す）で表わされる
化合物は、３，５―ジ・ターシヤリー・ブチル―
４―ヒドロキシベンズアルデヒドと、
（R2CH2CO）2O（R2は低級アルキル基を示す）
で表わされる酸無水物とR2CH2COOM（R2は低級
アルキル基、Ｍはアルカリ金属を示す）で表わさ
れる有機酸アルカリ金属塩とをパーキン反応に附
すことによつて合成することができる。ここで用
いることができるアルカリ金属にはナトリウム、
カリウム等がある。
(3) 一般式(1)で表わされる化合物のうち、下記一
般式(4)
（R2は低級アルキル基を示す）で表わされる
化合物は３，５―ジ・ターシヤリー・ブチル―４
―ヒドロキシベンズアルデヒドとR2―CH
（COOH）2（R2は低級アルキル基を示す）で表わ
されるマロン酸誘導体とをピリジン等を溶媒とし
て、ピペリジン、ピロリジン等の塩基を触媒とし
て反応させて合成することができる。
抗炎症、鎮痛、解熱作用
本発明による抗炎症、鎮痛、解熱剤は前記一般
式(1)で表わされる化合物またはその塩を有効成分
とするものである。これらの化合物の薬理作用お
よび毒性は下記の実験例に示される通りである。
なお、抗炎症作用のカラゲニン足蹠浮腫抑制作用
はC.A.Winterらの方法〔プロシーデイング・オ
ブ・ソサイアテイー・フオア・エキスペリメンタ
ル・バイオロジー・アンド・メデイシン、111、
544（1962）〕、肉芽増殖抑制作用は原幸男らの方法
〔日本薬理学雑誌、73，557（1977）〕、アジユバン
ト関節炎抑制作用はD.T.Walzらの方法（ザ・ジ
ヤーナル・オブ・フアーマコロジー・アンド・エ
キスペリメンタル・セラピユテイクス、178、223
（1971）〕に準じて試験した。解熱作用は柳義和ら
の方法（日本薬理学雑誌、74、735（1978）〕、鎮痛
作用はR.Kosterらの方法（フエデレーシヨン・
プロシーデイング、18、412（1959）〕にそれぞれ
準じて試験した。
表１から表４に示された結果から、本発明によ
る抗炎症、鎮痛、解熱剤は優れた薬理効果と高い
安全性を有することが明らかである。なお表１か
ら表４に示した化合物番号は前記化合物番号に対
応するものである。
抗炎症作用
(1) カラゲニン足蹠浮腫抑制作用
ウイスター系雄性ラツト（体重150―180ｇ）を
用い、１群６匹とした。被検化合物を2.5％アラ
ビアゴム水溶液に懸濁したものを、1.0ml／100ｇ
体重の割合で経口投与した。１時間後、１％カラ
ゲニンを一側後肢足蹠皮下に0.1ml注射し、起炎
した。起炎後、３および５時間目に後肢足蹠腫脹
容積を測定し、下記の式により抑制率を求めた。
抑制率（％）＝（１−被検化合物投与群平均腫脹容積
／対照群平均腫脹容積）×100
結果を表１に示す。本発明による化合物は強い
カラゲニン浮腫抑制作用を有することが分る。
<Industrial Application Field> The present invention relates to a 3,5-di-tert-butyl-4-hydroxystyrene derivative or a physiologically acceptable salt thereof having anti-inflammatory, analgesic and antipyretic effects. For more details, see the general formula below
This invention relates to a 3,5-di-tert-butyl-4-hydroxystyrene derivative represented by (1) or a physiologically acceptable salt thereof. (Here, R 1 represents a hydroxy group or a lower alkyl group, and R 2 represents a lower alkyl group.) <Prior art> Inflammation is one of the most common pathological conditions, and salicylic acid is used to treat it. Since then, many compounds have been synthesized or extracted from nature and used for therapeutic purposes. However, each has its advantages and disadvantages; in general, drugs with strong anti-inflammatory properties tend to have strong toxicity, and drugs with weak toxicity tend to have relatively weak anti-inflammatory effects, and no drug has yet been found that fully satisfies both. . <Problems to be Solved by the Invention> The present inventors have conducted extensive research with the aim of developing anti-inflammatory, analgesic, and antipyretic agents with strong anti-inflammatory effects and low toxicity. 3 represented,
5-di-tertiary butyl-4-hydroxystyrene derivative has low toxicity and good anti-inflammatory and analgesic properties.
They discovered that it has an antipyretic effect and completed the present invention. <Means for Solving the Problems> The novel compound according to the present invention, a 3,5-di-tert-butyl-4-hydroxystyrene derivative represented by the above formula (1), or a physiologically acceptable salt thereof is , has anti-inflammatory, antipyretic and analgesic effects, and has low toxicity. In general formula (1), R 1 represents a hydroxy group or a lower alkyl group, and R 2 represents a lower alkyl group. Examples of the lower alkyl group for R 1 include a methyl group, ethyl group, propyl group, butyl group, hexyl group, etc., and examples of the lower alkyl group for R 2 include a methyl group, ethyl group, propyl group, butyl group, etc. can. Specific examples of compounds belonging to formula (1) include β-carboxyl-β-ethyl-3,5-di-tertiary-butyl-4-hydroxystyrene (hereinafter abbreviated as compound), β-acetyl-β-methyl -3,5-di-tert-butyl-4-hydroxystyrene (hereinafter abbreviated as compound) and the like. The compound represented by the general formula (1) can form a salt with a base, and any base that can form a salt with the compound represented by the general formula (1) can be selected. Examples of specific salts include (1) metal salts, especially salts with alkali metals, alkaline earth metals, and aluminum, (2) ammonium salts, and (3) amine salts, especially methylamine, ethylamine, diethylamine, and triethylamine. , pyrrolidine, piperidine, morpholine, hexamethyleneimine, aniline, pyridine, etc., and as an anti-inflammatory, analgesic, and antipyretic agent, a physiologically acceptable salt may be selected from these salts. The above-mentioned compounds and their salts all have excellent anti-inflammatory, analgesic, and antipyretic effects, and have low toxicity, and can be said to meet the purpose of the present invention. The above compound can be synthesized by the following method. (1) 3,5-di-tert-butyl-4-hydroxybenzaldehyde and general formula [Here, Ar represents an aryl group, R 3 represents a lower alkyl group, a lower alkoxy group, or an amino group represented by NHR 4 (R 4 represents hydrogen or a lower alkyl group), and R 2 represents a lower alkyl group. ]
It is synthesized by reacting the ylide represented by 0. Ister et al. [Helvetica Chimica Acta 40 , 1242 (1957)]. This synthesis method uses the so-called Witteigh reaction, and in addition to the above-mentioned compounds, ylides derived from trialkylphosphine, trialkylphosphite, and triarylarsine can also be used as the ylide to be reacted with the benzaldehyde. Can be used. Additionally, to hydrolyze the ester or amide present in the resulting compound,
Acids such as sulfuric acid and trifluoroacetic acid and bases such as sodium hydroxide and pyrrolidine are used. (2) Among the compounds represented by general formula (1), the following general formula (3) The compound represented by (R 2 represents a lower alkyl group) is 3,5-di-tertiary-butyl-
4-Hydroxybenzaldehyde and (R 2 CH 2 CO) 2 O (R 2 represents a lower alkyl group)
It can be synthesized by subjecting an acid anhydride represented by R 2 CH 2 COOM (R 2 is a lower alkyl group, M represents an alkali metal) to an organic acid alkali metal salt to a Perkin reaction. can. Alkali metals that can be used here include sodium,
There are potassium etc. (3) Among the compounds represented by general formula (1), the following general formula (4) The compound represented by (R 2 represents a lower alkyl group) is 3,5-di-tert-butyl-4
―Hydroxybenzaldehyde and R 2 ―CH
It can be synthesized by reacting a malonic acid derivative represented by (COOH) 2 (R 2 represents a lower alkyl group) in a solvent such as pyridine and a base such as piperidine or pyrrolidine as a catalyst. 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.
The anti-inflammatory effect of carrageenan to suppress footpad edema was determined by the method of CA Winter et al. [Proceedings of Society for Experimental Biology and Medicine, 111 ].
544 (1962)], the granulation growth inhibitory effect was determined by the method of Yukio Hara et al. [Japanese Pharmacological Journal, 73 , 557 (1977)], and the adjuvant arthritis inhibitory effect was determined by the method of DTWalz et al. (The Journal of Pharmacology). and Experimental Therapeutics, 178 , 223.
(1971)]. The antipyretic effect was determined by the method of Yanagi Yoshikazu et al. (Japanese Pharmacological Journal, 74 , 735 (1978)), and the analgesic effect was determined by the method of R. Koster et al.
Proceedings, 18 , 412 (1959)]. From the results shown in Tables 1 to 4, 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 4 correspond to the above compound numbers. Anti-inflammatory effect (1) Carrageenin footpad edema inhibitory effect Male Wistar rats (body weight 150-180 g) were used, with 6 rats per group. 1.0ml/100g of the test compound suspended in 2.5% gum arabic aqueous solution
It was administered orally in proportion to body weight. One hour later, 0.1 ml of 1% carrageenan was subcutaneously injected into the footpad of one hind leg to induce inflammation. The swelling volume of the hind paw was measured 3 and 5 hours after the onset of inflammation, and the inhibition rate was calculated using the following formula. Inhibition rate (%) = (1-average swelling volume of test compound administration group/average swelling volume of control group) x 100 The results are shown in Table 1. It can be seen that the compounds according to the present invention have a strong carrageenan edema inhibitory effect.
【表】
鎮痛作用
ddY系雄性マウス（体重20〜25ｇ）を用い、１
群10匹とした。被検化合物を2.5％アラビアゴム
水溶液に懸濁したものを0.1ml／10ｇ体重の割合
で経口投与した。１時間後に、0.6％酢酸を0.1
ml／10ｇ体重の割合で腹腔内注射し、直後より20
分間に生じるストレツチングの回数を測定した。
対照群のストレツチング回数と比較して、次式よ
り抑制率を求めた。
抑制率（％）＝（１―被検化合物投与群の平均ストレ
ツチング回数／対照群の平均ストレツチング回数）×10
0
結果を表２に示す。本発明による化合物は強い
鎮痛作用を有することが分る。[Table] Analgesic effect Using ddY male mice (weight 20-25 g),
The group consisted of 10 animals. A test compound suspended in a 2.5% gum arabic aqueous solution was orally administered at a rate of 0.1 ml/10 g body weight. After 1 hour, add 0.6% acetic acid to 0.1
Immediately after intraperitoneal injection at a ratio of ml/10g body weight, 20
The number of stretches occurring per minute was measured.
The suppression rate was calculated from the following formula by comparing with the number of stretches of the control group. Suppression rate (%) = (1 - average number of stretching times in test compound administration group/average number of stretching times in control group) x 10
0 The results are shown in Table 2. It turns out that the compounds according to the invention have a strong analgesic effect.
【表】
解熱作用
ウイスター系雄性ラツト（体重150〜180ｇ）を
用い、１群５匹とした。乾燥酵母を生理食塩水で
懸濁し、20％懸濁液としたものを１ml／100ｇ体
重の割合で背部皮下に注射した。その18時間後
に、サーミスター温度計を用いて直腸温度を測定
し、38.6℃以上に体温上昇したラツトのみを選ん
で実験に用いた。体温測定直後、被検化合物を
2.5％アラビアゴム水溶液で懸濁したものを１
ml／100ｇ体重の割合で経口投与した。投与後、
１，３および５時間目に直腸温度を測定し、下記
の式により抑制率を求めた。
抑制率（％）＝（１−被検化合物投与群の平均上昇体
温／対照群の平均上昇体温）×100
結果を表３に示す。本発明による化合物は強い
解熱作用を有することが分る。[Table] Antipyretic action Male Wistar rats (body weight 150-180 g) were used, with 5 rats per group. Dry yeast was suspended in physiological saline to make a 20% suspension and injected subcutaneously into the back at a rate of 1 ml/100 g body weight. After 18 hours, rectal temperature was measured using a thermistor thermometer, and only rats whose body temperature rose to 38.6°C or higher were selected for use in the experiment. Immediately after body temperature measurement, test compound
1. Suspended in 2.5% gum arabic aqueous solution
It was administered orally at a rate of ml/100g body weight. After administration,
Rectal temperature was measured at 1, 3 and 5 hours, and the inhibition rate was calculated using the following formula. Inhibition rate (%) = (1 - average increased body temperature of test compound administration group/average increased body temperature of control group) x 100 The results are shown in Table 3. It turns out that the compounds according to the invention have a strong antipyretic action.
【表】
急性毒性
ICR系雌性マウス（体重20〜25ｇ）を用い、１
群６匹とした。被検化合物を2.5％アラビアゴム
水溶液に懸濁したものを0.1ml／10ｇ体重の割合
で経口投与した。投与後２週間にわたり、一般症
状を観察して、死亡例数／供試例数を求め、50％
致死量LD50（mg／Kg）を測定した。結果を表４に
示す。本発明の化合物はいずれも低毒性であるこ
とが分る。[Table] Acute toxicity Using ICR female mice (body weight 20-25 g),
There were 6 animals in the group. A test compound suspended in a 2.5% gum arabic aqueous solution was orally administered at a rate of 0.1 ml/10 g body weight. Observe general symptoms for 2 weeks after administration, calculate number of deaths/number of samples, and calculate 50%
The lethal dose LD 50 (mg/Kg) was determined. The results are shown in Table 4. It can be seen that all the compounds of the present invention have low toxicity.
【表】
調剤および投与量
本発明による抗炎症、鎮痛、解熱剤の製剤とし
ては経口、経腸または非経口的投与による製剤の
いずれをも選ぶことができる。具体的製剤として
は錠剤、カプセル剤、細粉剤、シロツプ剤、坐
薬、軟膏剤等を挙げる事ができる。本発明による
抗炎症、鎮痛、解熱剤の製剤の担体としては、経
口、経腸、その他非経口的に投与するために適し
た有機または無機の固体または液体の、通常は不
活性な薬学的担体材料が用いられる。具体的に
は、例えば結晶性セルロース、ゼラチン、乳糖、
澱粉、ステアリン酸マグネシウム、タルク、植物
性および動物性脂肪および油、ガム、ポリアルキ
レングリコールがある。製剤中の担体に対する本
発明による抗炎症、鎮痛、解熱剤の割合は0.2〜
100％の間で変化させることができる。また、本
発明による抗炎症、鎮痛、解熱剤は、これと両立
性の他の抗炎症、鎮痛、解熱剤その他の医薬を含
むことができる。この場合、本発明による抗炎
症、鎮痛、解熱剤がその製剤中の主成分でなくて
もよいことはいうまでもない。
本発明による抗炎症、鎮痛、解熱剤は、一般に
所望の作用が副作用を伴うことなく達成される投
与量で投与される。その具体的な値は医師の判断
で決定されるべきであるが、一般に成人１日当り
10mgｇ〜10ｇ、好ましくは20mg〜５ｇ程度で投与
されるのが普通であろう。なお、本発明の抗炎
症、鎮痛、解熱剤は有効成分として１mg〜５ｇ、
好ましくは３mg〜１ｇの単位の薬学的製剤として
投与することができる。
以下に本発明の実施例について説明する。
実施例１ 化合物の合成
３，５―ジ・ターシヤリー・ブチル―４―ヒド
ロキシベンズアルデヒド2.3ｇと３―トリフエニ
ルホスホラニリデン―２―ブタノン4.5ｇとを
DMSO20ml中に入れ、湯浴上80℃で撹拌しなが
ら40時間反応させた。反応終了後、冷却した反応
液にクロロホルム200mlを加え、同量の水で10回
洗浄し、溶媒のDMSOを取り除いた。クロロホ
ルム層を分離し、次いでクロロホルムを減圧除去
し、残渣を水性アルコール（アルコール／水＝
７／３）に溶解し、晶析を行なつた。次いで、得
られた結晶をアセトンに溶解し、ｎ―ヘキサンを
加えて再度結晶を析出させた。収量2.0ｇ。[Table] Preparation and Dosage The anti-inflammatory, analgesic, and antipyretic formulation according to the present invention can be selected from oral, rectal, or parenteral administration. Specific formulations include tablets, capsules, powders, syrups, suppositories, and ointments. Carriers for the anti-inflammatory, analgesic and antipyretic formulations according to the invention include organic or inorganic solid or liquid, normally inert pharmaceutical carrier materials suitable for oral, enteral or other parenteral administration. is used. Specifically, for example, crystalline cellulose, gelatin, lactose,
Starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycols. The ratio of anti-inflammatory, analgesic and antipyretic agent according to the invention to the carrier in the formulation is from 0.2 to
Can be varied between 100%. 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, it goes without saying that the anti-inflammatory, analgesic, and antipyretic agent according to the present invention does not have to be the main ingredient in the preparation. 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, but in general it is
It will usually be administered at a dose of about 10 mg to 10 g, preferably about 20 mg to 5 g. In addition, the anti-inflammatory, analgesic, and antipyretic agent of the present invention contains 1 mg to 5 g as an active ingredient.
Preferably, it can be administered as a pharmaceutical preparation in units of 3 mg to 1 g. Examples of the present invention will be described below. Example 1 Synthesis of compound 2.3 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 4.5 g of 3-triphenylphosphoranylidene-2-butanone were added.
The mixture was poured into 20 ml of DMSO and reacted on a hot water bath at 80°C for 40 hours with stirring. After the reaction was completed, 200 ml of chloroform was added to the cooled reaction solution and washed 10 times with the same amount of water to remove the solvent DMSO. The chloroform layer was separated, then the chloroform was removed under reduced pressure and the residue was dissolved in aqueous alcohol (alcohol/water =
7/3) and crystallization was performed. Next, the obtained crystals were dissolved in acetone, and n-hexane was added to precipitate the crystals again. Yield 2.0g.
Claims (1)
ーシヤリー・ブチル―４―ヒドロキシスチレン誘
導体またはその生理的に許容される塩。 （ここで、R1はヒドロキシ基または低級アル
キル基を示し、R2は低級アルキル基を示す。）[Scope of Claims] 1. A 3,5-di-tert-butyl-4-hydroxystyrene derivative represented by the following general formula (1) or a physiologically acceptable salt thereof. (Here, R 1 represents a hydroxy group or a lower alkyl group, and R 2 represents a lower alkyl group.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33434588A JPH01230542A (en) | 1988-12-28 | 1988-12-28 | 3,5-di-tertiary butyl-4-hydroxystyrene derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33434588A JPH01230542A (en) | 1988-12-28 | 1988-12-28 | 3,5-di-tertiary butyl-4-hydroxystyrene derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17994981A Division JPS5879919A (en) | 1981-02-05 | 1981-11-09 | Antiphlogistic, analgesic and antipyretic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01230542A JPH01230542A (en) | 1989-09-14 |
| JPH024584B2 true JPH024584B2 (en) | 1990-01-29 |
Family
ID=18276327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP33434588A Granted JPH01230542A (en) | 1988-12-28 | 1988-12-28 | 3,5-di-tertiary butyl-4-hydroxystyrene derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01230542A (en) |
-
1988
- 1988-12-28 JP JP33434588A patent/JPH01230542A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01230542A (en) | 1989-09-14 |
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