JPH0326180B2 - - Google Patents
Info
- Publication number
- JPH0326180B2 JPH0326180B2 JP58034194A JP3419483A JPH0326180B2 JP H0326180 B2 JPH0326180 B2 JP H0326180B2 JP 58034194 A JP58034194 A JP 58034194A JP 3419483 A JP3419483 A JP 3419483A JP H0326180 B2 JPH0326180 B2 JP H0326180B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- phenyl
- compound
- lower alkyl
- ketoprofen
- 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 - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical class CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000005529 alkyleneoxy group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229960000991 ketoprofen Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- BYHBHNKBISXCEP-QPJJXVBHSA-N 4-acetoxycinnamic acid Chemical compound CC(=O)OC1=CC=C(\C=C\C(O)=O)C=C1 BYHBHNKBISXCEP-QPJJXVBHSA-N 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BYHBHNKBISXCEP-UHFFFAOYSA-N p-acetoxy-cinnamic acid Natural products CC(=O)OC1=CC=C(C=CC(O)=O)C=C1 BYHBHNKBISXCEP-UHFFFAOYSA-N 0.000 description 2
- 229940049953 phenylacetate Drugs 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 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 2
- UJZRIKWTEFFUEJ-UHFFFAOYSA-N 2,3-diphenylprop-2-enoyl chloride Chemical compound C=1C=CC=CC=1C(C(=O)Cl)=CC1=CC=CC=C1 UJZRIKWTEFFUEJ-UHFFFAOYSA-N 0.000 description 1
- RURHILYUWQEGOS-VOTSOKGWSA-N 4-Methylcinnamic acid Chemical compound CC1=CC=C(\C=C\C(O)=O)C=C1 RURHILYUWQEGOS-VOTSOKGWSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- -1 butanediol compound Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は新規なフエニル酢酸エステル誘導体に
関し、更に詳細には次の一般式()
〔式中、Rは水素原子、基COR1(ここでR1は
アルキル基、アルケニル基を示す)、
基
The present invention relates to a novel phenyl acetate derivative, more specifically, the following general formula () [In the formula, R is a hydrogen atom, a group COR 1 (here, R 1 represents an alkyl group or an alkenyl group), a group
【式】(ここでR2は水素原子、
ハロゲン原子、シアノ基、低級アルキル基、フエ
ニル基を、R3は水素原子、低級アルキル基、フ
エニル基を、R4は低級アルキル基、低級アルキ
ルオキシ基、アシルオキシ基、水酸基又はハロゲ
ン原子で置換されていても良いフエニル基を示
す)、基−CO−A−R5(ここでAは単結合、C1〜
2のアルキレン基、C1〜2のアルキレンオキシ
基を、R5は低級アルキル基、低級アルキルオキ
シ基、アシルオキシ基、水酸基、ハロゲン原子、
ニトロ基、ベンゾイル基、又はアルキレンジオキ
シ基で置換されていても良いフエニル基を示す)
を示す〕
で表わされるフエニル酢酸エステル誘導体に関す
る。
現在、ケトプロフエンは非ステロイド性消炎鎮
痛剤として、頭痛、歯痛、腰痛、筋肉痛及びリウ
マチ性疾患等の治療に繁用されている医薬であ
る。
しかしながら、ケトプロフエンを経口投与した
場合、潰瘍発生を伴なう胃腸障害等の副作用の発
生が知られていた。すなわち、ケトプロフエンは
リウマチ性疾患の治療の如く長期間投与が必要な
場合のみならず短期間投与の場合でさえ胃に充
血、出血等の好ましくない症状を惹き起すことも
少なくなく、その投与方法、投与量が制限されて
いるのが現状であつた。
そこで、本発明者らは、ケトプロフエンの上記
副作用を軽減すべく鋭意研究をおこなつた結果、
ケトプロフエンにブタンジオール化合物を反応さ
せて得られた前記式()で表わされるフエニル
酢酸エステル誘導体はケトプロフエンと同等の消
炎鎮痛作用を有しながらその副作用はケトプロフ
エンと比べ非常に軽微であることを見出し本発明
を完成した。
すなわち、本発明の目的は、非ステロイド性消
炎鎮痛剤として有用な新規なフエニル酢酸エステ
ル誘導体()を提供せんとするにある。
本発明の化合物()は、例えば次のいずれか
の方法により公知のエステル化反応を利用して製
造することができる。
ケトプロフエン()又はその反応性誘導体
に2,3−ブタンジオール()又はその反応
性誘導体を反応させてフエニル酢酸エステル
(a)を製造する。
で得られたフエニル酢酸エステル(a)
に、縮合剤存在下カルボン酸()又はその反
応性誘導体を反応させてフエニル酢酸エステル
誘導体(b)を製造する。
(式中R6は前記したR1、[Formula] (where R 2 is a hydrogen atom, halogen atom, cyano group, lower alkyl group, phenyl group, R 3 is a hydrogen atom, lower alkyl group, phenyl group, R 4 is a lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, or phenyl group optionally substituted with a halogen atom), group -CO-A-R 5 (where A is a single bond, C1 to
2 alkylene group, C1-2 alkyleneoxy group, R 5 is lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, halogen atom,
Indicates a phenyl group that may be substituted with a nitro group, benzoyl group, or alkylenedioxy group)
It relates to a phenyl acetate derivative represented by: Currently, ketoprofen is a nonsteroidal anti-inflammatory analgesic drug that is frequently used to treat headaches, toothaches, lower back pains, muscle pains, rheumatic diseases, and the like. However, when ketoprofen is orally administered, it has been known that side effects such as gastrointestinal disorders accompanied by ulcer formation occur. In other words, ketoprofen often causes undesirable symptoms such as gastric congestion and bleeding, not only when long-term administration is required such as in the treatment of rheumatic diseases, but even when administered for a short period of time. Currently, the dosage is limited. Therefore, the present inventors conducted intensive research to reduce the above-mentioned side effects of ketoprofen, and as a result,
The present inventor discovered that the phenyl acetate derivative represented by the above formula () obtained by reacting ketoprofen with a butanediol compound has an anti-inflammatory and analgesic effect equivalent to that of ketoprofen, but its side effects are very minor compared to ketoprofen. Completed the invention. That is, an object of the present invention is to provide a novel phenylacetate derivative () useful as a non-steroidal anti-inflammatory analgesic agent. The compound () of the present invention can be produced using a known esterification reaction, for example, by any of the following methods. Phenyl acetate (a) is produced by reacting ketoprofen () or a reactive derivative thereof with 2,3-butanediol () or a reactive derivative thereof. Phenyl acetate (a) obtained in
Then, carboxylic acid () or a reactive derivative thereof is reacted in the presence of a condensing agent to produce a phenyl acetate derivative (b). (In the formula, R 6 is the above-mentioned R 1 ,
【式】及
び−A−R5を意味する)
2,3−ブタンジオールモノエステル誘導体
()にケトプロフエン()又はその反応性
誘導体を反応させて、フエニル酢酸エステル誘
導体(b)を製造する。
(式中R6は前記と同じ)
叙上の方法において、ケトプロフエン()及
びカルボン酸()の反応性誘導体としては、酸
ハロゲニド、酸無水物、混合無水物等が挙げられ
る。
また、反応はピリジン、トリメチルアミン、ト
リエチルアミン等の第三級アミン;炭酸アルカ
リ、水酸化アルカリ、水素化アルカリ等の脱酸剤
の存在下行うのが好ましい。
更に上記反応は適当な反応溶媒中で行うことが
好ましく、反応溶媒としては、エーテル、テトラ
ヒドロフラン、ベンゼン、トルエン、クロロホル
ム、ジクロルメタン等の反応に関与しない溶媒が
好ましい。
縮合剤を用いる反応は、縮合剤としての2−ハ
ロ−1−アルキルピリジニウム塩とピリジン、ト
リエチルアミン、トリブチルアミン等の第三級ア
ミンの存在下行うか、又は縮合剤としてのジエチ
ルアゾジカルボキシレートとトリフエニルホスフ
インの存在下行うのが好ましい。また上記縮合反
応は適当な反応溶媒中で行うことが好ましく、反
応溶媒としてはエーテル、テトラヒドロフラン、
ベンゼン、トルエン、アセトニトリル、クロロホ
ルム、ジクロルメタン等の反応に関与しない溶媒
が好ましい。
斯くの如くして得られる本発明化合物()の
消炎作用及び起潰瘍性について試験した結果を示
す。
消炎作用
体重200g前後の雄性ドンリユウ系ラツトを一
群7匹とし、48時間絶食した後、被検化合物を1
%カルボキシメチルセルロースナトリウム水溶液
に懸濁して経口投与した。被検化合物投与60分後
ラツトの足蹠容積を容積測定器を用いて測定し、
次いで1%カラゲニン生理食塩水溶液0.1mlを右
後肢足蹠皮下に注入し、3時間後における浮腫強
度を1%カルボキシメチルセルロースナトリウム
水溶液を投与した対照群と比較して浮腫抑制率を
求めた。
この結果を第1表に示す。[Formula] and -A-R 5 ) 2,3-butanediol monoester derivative () is reacted with ketoprofen () or a reactive derivative thereof to produce a phenyl acetate derivative (b). (In the formula, R 6 is the same as above.) In the above method, examples of the reactive derivatives of ketoprofen ( ) and carboxylic acid ( ) include acid halogenides, acid anhydrides, mixed anhydrides, and the like. Further, the reaction is preferably carried out in the presence of a tertiary amine such as pyridine, trimethylamine, or triethylamine; or a deoxidizing agent such as an alkali carbonate, an alkali hydroxide, or an alkali hydride. Further, the above reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent is preferably a solvent that does not participate in the reaction, such as ether, tetrahydrofuran, benzene, toluene, chloroform, or dichloromethane. The reaction using a condensing agent is carried out in the presence of a 2-halo-1-alkylpyridinium salt as a condensing agent and a tertiary amine such as pyridine, triethylamine, or tributylamine, or in the presence of a tertiary amine such as diethyl azodicarboxylate and tributylamine as a condensing agent. Preferably, the reaction is carried out in the presence of enylphosphine. Further, the above condensation reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent is ether, tetrahydrofuran,
Solvents that do not participate in the reaction, such as benzene, toluene, acetonitrile, chloroform, and dichloromethane, are preferred. The results of testing the anti-inflammatory effect and ulcerative properties of the compound () of the present invention thus obtained are shown below. Anti-inflammatory effect A group of 7 male rats weighing around 200g were fasted for 48 hours, and then 1 dose of the test compound was administered.
% carboxymethylcellulose sodium aqueous solution and administered orally. 60 minutes after administration of the test compound, the rat's footpad volume was measured using a volumetric device.
Next, 0.1 ml of a 1% carrageenan saline solution was subcutaneously injected into the right hind footpad, and the edema intensity after 3 hours was compared with a control group administered with a 1% sodium carboxymethyl cellulose aqueous solution to determine the edema suppression rate. The results are shown in Table 1.
【表】
第1表から明らかな如く、本発明化合物はカラ
ゲニン浮腫に対し高い抑制効果を示した。
起潰瘍性
体重170〜200g前後のWistar系雄性ラツトを
1群7匹として24時間絶食後、試験化合物を0.5
%カルボキシメチルセルロースナトリウム水溶液
に懸濁し経口投与した。3.5時間後にラツトを撲
殺し、全胃を摘出した。直ちに5%ホルマリン溶
液を注入して胃壁を固定後胃を切開し、胃の潰瘍
発生を肉眼的に観察判定した。なお対照群には
0.5%カルボキシメチルセルロースナトリウム水
溶液のみを経口投与した。
この結果を第2表に示す。[Table] As is clear from Table 1, the compounds of the present invention exhibited a high inhibitory effect on carrageenan edema. Ulcerogenicity A group of 7 male Wistar rats weighing around 170 to 200 g were given 0.5 ml of the test compound after fasting for 24 hours.
% carboxymethylcellulose sodium aqueous solution and administered orally. After 3.5 hours, the rats were bludgeoned to death and the entire stomach was removed. Immediately after fixing the stomach wall by injecting 5% formalin solution, the stomach was incised and the occurrence of gastric ulcer was visually observed and determined. In addition, the control group
Only 0.5% sodium carboxymethyl cellulose aqueous solution was orally administered. The results are shown in Table 2.
【表】
第2表から明らかな如く、本発明化合物では潰
瘍発生は認められず、公知のケトプロフエン誘導
体である比較化合物1及び2に比較し副作用が低
いことが確認された。
次に本発明の実施例を挙げて説明する。
実施例1 (化合物1の合成)
ケトプロフエン50.80gをベンゼン600mlに懸濁
し、これに塩化チオニル80mlを加え6時間加熱撹
拌した。反応後、過剰の塩化チオニル及びベンゼ
ンを減圧留去して淡黄色液体のケトプロフエンの
酸クロリドを得た。
この酸クロリドを無水エーテル200mlに溶解し
2,3−ブタンジオール18g、ピリジン20ml及び
無水エーテル500mlの混液中に少しずつ滴下した。
滴下後室温にて5時間撹拌したのち、反応液を
水、10%塩酸、水、炭酸ナトリウム溶液、水の順
に洗い、無水硫酸マグネシウムにて乾燥した。エ
ーテルを留去した残渣をカラムクロマトグラフイ
ー(シリカゲル)にて精製し、無色液状の第3表
記載の化合物1 40.10g(収率61.5%)を得た。
実施例2 (化合物2の合成)
1.63gの化合物1を無水エーテル20mlに溶解
し、ピリジン1mlを加え、氷冷撹拌しながらカプ
ロン酸クロリド0.71gのエーテル溶液5mlを滴下
した。同温度で30分、更に室温に戻して4時間撹
拌後、反応液を、水、10%塩酸、水、炭酸ナトリ
ウム試液、水の順に洗い無水硫酸マグネシウムで
乾燥した。エーテルを減圧下留去した後、残渣を
カラムクロマトグラフイ−(シリカゲル)にて精
製し無色液状の第3表記載の化合物2 1.70g
(収率80.0%)を得た。
実施例3 (化合物32の合成)
2,3−ブタンジオール1.80gをテトラヒドロ
フラン40mlに溶解しこれにピリジン2mlを加え、
氷冷撹拌しながらα−フエニルケイヒ酸クロリド
2.42gのテトラヒドロフラン溶液10mlを滴下し
た。同温度で30分、更に室温に戻して5時間撹拌
後、溶媒を減圧留去し、残渣をエーテルに転溶し
た。エーテル層を水、10%塩酸、水、炭酸ナトリ
ウム試液、水の順に洗い、無水硫酸マグネシウム
で乾燥した。エーテルを減圧下留去し、残渣をカ
ラムクロマトグラフイー(シリカゲル)にて精製
し無色液状のモノエステル体2.01g(収率67.6
%)を得た。このモノエステル体を無水エーテル
20mlに溶解し、ピリジン1mlを加え、氷冷撹拌し
ながら、ケトプロフエンの酸クロリド1.85gのエ
ーテル溶液5mlを滴下した。同温度で30分、更に
室温に戻して一夜撹拌後、反応液を水、10%塩
酸、水、炭酸ナトリウム試液、水の順に洗い無水
硫酸マグネシウムで乾燥した。エーテルを減圧下
留去し残渣をカラムクロマトグラフイー(シリカ
ゲル)にて精製し、淡黄色液状の第3表記載の化
合物32 3.12g(収率86.8%)を得た。
実施例4 (化合物28の合成)
化合物1 1.63g、トリフエニルホスフイン
2.62g、p−アセトキシケイヒ酸2.06gをテトラ
ヒドロフラン60mlに溶解し、これにジエチルアゾ
ジカルボキシレート1.74gのテトラヒドロフラン
溶液10mlを滴下した。滴下後室温にて一夜撹拌し
たのち、溶媒を減圧留去して残渣にエーテルを加
えて不溶物を取した。液は減圧留去して残渣
をカラムクロマトグラフイー(シリカゲル)にて
精製し、淡黄色液状の第3表記載の化合物28
2.25g(収率87.5%)を得た。
実施例5 (化合物26の合成)
2−クロロ−1−メチルピリジウムアイオダイ
ド0.77gをトルエン10mlに懸濁し、これに化合物
1 0.82g、p−メチルケイヒ酸0.41g、トリブ
チルアミン1.1gをトルエン10mlに溶解した溶液
を加え、3時間加熱撹拌したのち、溶媒を減圧留
去して残渣をカラムクロマトグラフイー(シリカ
ゲル)にて精製し、淡黄色液状の第3表記載の化
合物26 0.36g(収率30.6%)を得た。[Table] As is clear from Table 2, no ulcer formation was observed with the compounds of the present invention, and it was confirmed that the side effects were lower than those of Comparative Compounds 1 and 2, which are known ketoprofen derivatives. Next, examples of the present invention will be described. Example 1 (Synthesis of Compound 1) 50.80 g of ketoprofen was suspended in 600 ml of benzene, 80 ml of thionyl chloride was added thereto, and the suspension was heated and stirred for 6 hours. After the reaction, excess thionyl chloride and benzene were distilled off under reduced pressure to obtain ketoprofen acid chloride as a pale yellow liquid. This acid chloride was dissolved in 200 ml of anhydrous ether and added dropwise into a mixed solution of 18 g of 2,3-butanediol, 20 ml of pyridine and 500 ml of anhydrous ether.
After the addition, the mixture was stirred at room temperature for 5 hours, and the reaction solution was washed with water, 10% hydrochloric acid, water, sodium carbonate solution, and water in this order, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the ether was purified by column chromatography (silica gel) to obtain 40.10 g (yield: 61.5%) of Compound 1 listed in Table 3 as a colorless liquid. Example 2 (Synthesis of Compound 2) 1.63 g of Compound 1 was dissolved in 20 ml of anhydrous ether, 1 ml of pyridine was added, and 5 ml of an ether solution containing 0.71 g of caproic acid chloride was added dropwise while stirring under ice cooling. After stirring at the same temperature for 30 minutes and further returning to room temperature for 4 hours, the reaction solution was washed with water, 10% hydrochloric acid, water, sodium carbonate test solution, and water in this order, and dried over anhydrous magnesium sulfate. After distilling off the ether under reduced pressure, the residue was purified by column chromatography (silica gel) to obtain 1.70 g of compound 2 listed in Table 3 as a colorless liquid.
(yield 80.0%). Example 3 (Synthesis of Compound 32) 1.80 g of 2,3-butanediol was dissolved in 40 ml of tetrahydrofuran, and 2 ml of pyridine was added thereto.
α-Phenylcinnamic acid chloride while stirring on ice.
A solution of 2.42 g in 10 ml of tetrahydrofuran was added dropwise. After stirring at the same temperature for 30 minutes and further returning to room temperature for 5 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in ether. The ether layer was washed with water, 10% hydrochloric acid, water, sodium carbonate test solution, and water in this order, and dried over anhydrous magnesium sulfate. The ether was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain 2.01 g of a colorless liquid monoester (yield 67.6).
%) was obtained. This monoester is converted into anhydrous ether.
1 ml of pyridine was added, and 5 ml of an ether solution containing 1.85 g of ketoprofen acid chloride was added dropwise while stirring under ice cooling. After stirring at the same temperature for 30 minutes, and then returning to room temperature and stirring overnight, the reaction solution was washed with water, 10% hydrochloric acid, water, sodium carbonate test solution, and water in this order, and dried over anhydrous magnesium sulfate. The ether was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain 3.12 g (yield: 86.8%) of Compound 32 listed in Table 3 as a pale yellow liquid. Example 4 (Synthesis of compound 28) Compound 1 1.63g, triphenylphosphine
2.62 g of p-acetoxycinnamic acid and 2.06 g of p-acetoxycinnamic acid were dissolved in 60 ml of tetrahydrofuran, and 10 ml of a solution of 1.74 g of diethyl azodicarboxylate in tetrahydrofuran was added dropwise thereto. After the dropwise addition, the mixture was stirred overnight at room temperature, the solvent was distilled off under reduced pressure, and ether was added to the residue to remove insoluble matter. The liquid was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain compound 28 listed in Table 3 as a pale yellow liquid.
2.25g (yield 87.5%) was obtained. Example 5 (Synthesis of compound 26) 0.77 g of 2-chloro-1-methylpyridium iodide was suspended in 10 ml of toluene, and 0.82 g of compound 1, 0.41 g of p-methylcinnamic acid, and 1.1 g of tributylamine were added to 10 ml of toluene. After heating and stirring for 3 hours, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel) to obtain 0.36 g of the compound 26 listed in Table 3 as a pale yellow liquid (yield). rate of 30.6%).
【表】【table】
【表】【table】
【表】【table】
【表】【table】
Claims (1)
アルキル基、アルケニル基を示す)、 基【式】(ここでR2は水素原子、 ハロゲン原子、シアノ基、低級アルキル基、フエ
ニル基を、R3は水素原子、低級アルキル基、フ
エニル基を、R4は低級アルキル基、低級アルキ
ルオキシ基、アシルオキシ基、水酸基又はハロゲ
ン原子で置換されていても良いフエニル基を示
す)、基−CO−A−R5(ここでAは単結合、C1〜
2のアルキレン基、C1〜2のアルキレンオキシ
基を、R5は低級アルキル基、低級アルキルオキ
シ基、アシルオキシ基、水酸基、ハロゲン原子、
ニトロ基、ベンゾイル基、又はアルキレンジオキ
シ基で置換されていても良いフエニル基を示す)
を示す〕 で表わされるフエニル酢酸エステル誘導体。[Claims] First-order general formula () [In the formula, R is a hydrogen atom, a group COR 1 (where R 1 represents an alkyl group or an alkenyl group), a group [formula] (where R 2 is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, phenyl group, R 3 represents a hydrogen atom, lower alkyl group, phenyl group, R 4 represents a phenyl group optionally substituted with a lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group or halogen atom), Group -CO-A-R 5 (where A is a single bond, C1~
2 alkylene group, C1-2 alkyleneoxy group, R 5 is lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, halogen atom,
Indicates a phenyl group that may be substituted with a nitro group, benzoyl group, or alkylenedioxy group)
A phenyl acetate derivative represented by
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3419483A JPS59161331A (en) | 1983-03-02 | 1983-03-02 | Novel phenylacetic ester derivative and its preparation |
US06/581,990 US4560785A (en) | 1983-03-02 | 1984-02-21 | Phenylacetic ester derivatives and process for preparing the same |
GB08404626A GB2137985B (en) | 1983-03-02 | 1984-02-22 | Phenylacetic acid esters |
IT47777/84A IT1199075B (en) | 1983-03-02 | 1984-02-29 | PHENYLACETIC ESTER DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION |
CH1015/84A CH659059A5 (en) | 1983-03-02 | 1984-03-01 | PHENYL ACETIC ESTER DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. |
CA000448629A CA1248118A (en) | 1983-03-02 | 1984-03-01 | Phenylacetic ester derivatives and process for preparing the same |
DE19843407806 DE3407806A1 (en) | 1983-03-02 | 1984-03-02 | NEW PHENYL ACETIC ESTER DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
FR8403255A FR2541994B1 (en) | 1983-03-02 | 1984-03-02 | NOVEL PHENYLACETIC ESTER DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3419483A JPS59161331A (en) | 1983-03-02 | 1983-03-02 | Novel phenylacetic ester derivative and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS59161331A JPS59161331A (en) | 1984-09-12 |
JPH0326180B2 true JPH0326180B2 (en) | 1991-04-10 |
Family
ID=12407360
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3419483A Granted JPS59161331A (en) | 1983-03-02 | 1983-03-02 | Novel phenylacetic ester derivative and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS59161331A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5447954B2 (en) * | 2007-09-19 | 2014-03-19 | 公益財団法人名古屋産業科学研究所 | Neurotrophic factor-like agent |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS543044A (en) * | 1977-06-07 | 1979-01-11 | Hisamitsu Pharmaceut Co Inc | Novel 2-(m-benzoyl)phenylpropionic acid ester derivatives |
JPS5536654A (en) * | 1978-09-08 | 1980-03-14 | Tsubakimoto Chain Co | Timing belt |
-
1983
- 1983-03-02 JP JP3419483A patent/JPS59161331A/en active Granted
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS543044A (en) * | 1977-06-07 | 1979-01-11 | Hisamitsu Pharmaceut Co Inc | Novel 2-(m-benzoyl)phenylpropionic acid ester derivatives |
JPS5536654A (en) * | 1978-09-08 | 1980-03-14 | Tsubakimoto Chain Co | Timing belt |
Also Published As
Publication number | Publication date |
---|---|
JPS59161331A (en) | 1984-09-12 |
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