JPH0635472B2 - Diethylenetriamine triacetic acid oxyalkyl ester compounds and processes for their production - Google Patents
Diethylenetriamine triacetic acid oxyalkyl ester compounds and processes for their productionInfo
- Publication number
- JPH0635472B2 JPH0635472B2 JP16836590A JP16836590A JPH0635472B2 JP H0635472 B2 JPH0635472 B2 JP H0635472B2 JP 16836590 A JP16836590 A JP 16836590A JP 16836590 A JP16836590 A JP 16836590A JP H0635472 B2 JPH0635472 B2 JP H0635472B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- diethylenetriamine
- acid
- triacetic acid
- processes
- 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
- -1 Diethylenetriamine triacetic acid oxyalkyl ester compounds Chemical class 0.000 title claims description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title description 5
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 11
- 201000001883 cholelithiasis Diseases 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 208000001130 gallstones Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- PCEDCPYBUFBHHW-UHFFFAOYSA-N acetic acid;n'-(2-aminoethyl)ethane-1,2-diamine Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.NCCNCCN PCEDCPYBUFBHHW-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 210000000941 bile Anatomy 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 2
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VIRWKAJWTKAIMA-UHFFFAOYSA-N 2-chloroethyl acetate Chemical compound CC(=O)OCCCl VIRWKAJWTKAIMA-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、ジエチレントリアミン三酢酸エステル化合物
に関し、更に詳しくは、胆石溶解作用を有するウルソデ
オキシコリジエチレントリアミン三酢酸エステル化合物
及びそれらの製造法に関する。TECHNICAL FIELD The present invention relates to a diethylenetriamine triacetate compound, and more particularly to an ursodeoxycolydiethylenetriamine triacetate compound having a gallstone-dissolving action and a method for producing the same.
従来の技術 胆石治療剤として繁用されている薬物としては、ウルソ
デオキシコール酸及びケノデオキシコール酸が知られて
いる。これらの胆汁酸は、純コレステロール石に対して
は有効であるが、他のコレステロール系胆石、例えば、
カルシウムを含有するコレステロール混成石又はコレス
テロール混成石、更には、ビリルビンカルシウム石又は
炭酸カルシウム石等に対しては、その溶解効果が疑問視
されている。BACKGROUND ART Ursodeoxycholic acid and chenodeoxycholic acid are known as drugs commonly used as therapeutic agents for gallstones. Although these bile acids are effective against pure cholesterol stones, other cholesterol gallstones such as
The dissolution effect of calcium-containing cholesterol mixed stones or cholesterol mixed stones, as well as bilirubin calcium stones or calcium carbonate stones, has been questioned.
これに対し、特願平１−２３５７９９号公報には、下記
構造式［Ｉ］ で示されるジエチレントリアミン三酢酸化合物が、カル
シウム含有胆石、特に炭酸カルシウム含有胆石を胆汁中
で協力に溶解する効果があることが報告されている。On the other hand, Japanese Patent Application No. 1-235799 discloses the following structural formula [I] It has been reported that the diethylenetriaminetriacetic acid compound represented by the formula (3) has an effect of cooperatively dissolving calcium-containing gallstones, particularly calcium carbonate-containing gallstones in bile.
発明が解決しようとする課題 しかしながら、上記ジエチレントリアミン三酢酸化合物
［Ｉ］は、カルシウム胆石溶解剤として投与された場
合、胆汁移行性は優れるが経口吸収性が悪いことが判明
した。DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention However, when the above-mentioned diethylenetriaminetriacetate compound [I] is administered as a calcium gallstone dissolving agent, it has been found that bile transfer is excellent but oral absorbability is poor.
また、ジエチレントリアミン三酢酸化合物［Ｉ］のよう
なキレート剤は、生体内へ投与されると生体内の共存金
属イオンによる不活性化を招き、薬効が低減する可能性
がある。In addition, a chelating agent such as diethylenetriaminetriacetate compound [I] may be inactivated by coexisting metal ions in the living body when administered into the living body, and the drug efficacy may be reduced.
本発明者らは、これらの観点から上記ジエチレントリア
ミン三酢酸化合物［Ｉ］の誘導体について鋭意研究した
結果、キレート形成能がなく、しかも体内で容易にジエ
チレントリアミン三酢酸化合物［Ｉ］に代謝され得るこ
れらのエステル化合物が、極めて経口吸収性に優れるこ
とを知り、本発明に到達した。From these viewpoints, the present inventors have earnestly studied the above-mentioned derivatives of diethylenetriaminetriacetic acid compound [I], and as a result, have no chelate-forming ability and are easily metabolized to diethylenetriaminetriacetic acid compound [I] in the body. The inventors reached the present invention by knowing that the ester compound has extremely excellent oral absorbability.
課題を解決するための手段 本発明によれば、下記一般式［II］ （式中、ｎ＝１〜２、Ｒは、水素又はアシル基を表わ
す。）で示されるジエチレントリアミン三酢酸エステル
化合物及びそれらの製造法が提供される。Means for Solving the Problems According to the present invention, the following general formula [II] (In the formula, n = 1 to 2, R represents hydrogen or an acyl group), and a diethylenetriamine triacetate compound and a process for producing them are provided.
上記一般式［II］のジエチレントリアミン三酢酸エステ
ル化合物の第１の製造法として、前記のジエチレントリ
アミン三酢酸化合物［Ｉ］と下記一般式［III］ ＨＯ（ＣＨ2）nＯ−Ｒ［III］ （式中、ｎ＝１〜２、Ｒは、水素又はアシル基を表わ
す。）で示されるアルコールを縮合させる方法がある。As a first method for producing the diethylenetriaminetriacetate compound of the general formula [II], the diethylenetriaminetriacetate compound [I] and the following general formula [III] HO (CH 2 ) n O—R [III] In the formula, n = 1 to 2 and R represents hydrogen or an acyl group.).
反応割合は、ジエチレントリアミン三酢酸化合物［Ｉ］
に対してアルコール［III］を３〜１００００倍モル量
とする。アルコール［III］としては、エチレングリコ
ールが挙げられる。縮合剤としては、酸触媒、１−エト
キシカルボニル−２−エトキシ−１，２−ジヒドロキノ
リン又はクロロギ酸エステル等が挙げられる。The reaction ratio is diethylenetriaminetriacetic acid compound [I]
On the other hand, the alcohol [III] is used in a 3- to 10,000-fold molar amount. Examples of the alcohol [III] include ethylene glycol. Examples of the condensing agent include acid catalysts, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, chloroformates and the like.
縮合剤として酸触媒を用いる場合、酸触媒としては、硫
酸若しくは塩酸等の鉱酸又はベンゼンスルホン酸若しく
はｐ−トルエンスルホン酸等の有機酸が適当である。反
応温度は、２０〜２００℃、好ましくは６０〜１６０℃
の範囲内とし、反応時間は、３０分〜５０時間、好まし
くは１〜３０時間程度とする。When an acid catalyst is used as the condensing agent, a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as benzenesulfonic acid or p-toluenesulfonic acid is suitable as the acid catalyst. The reaction temperature is 20 to 200 ° C., preferably 60 to 160 ° C.
And the reaction time is 30 minutes to 50 hours, preferably 1 to 30 hours.
縮合剤として１−エトキシカルボニル−２−エトキシ−
１，２−ジヒドロキノリンを用いる場合、反応溶媒は、
テトラヒドロフラン又は１，４−ジオキサン等が適当で
ある。反応温度は、−１０〜６０℃、好ましくは２０〜
５０℃の範囲内とし、反応時間は、３０分〜１０時間、
好ましくは１〜４時間程度とする。1-ethoxycarbonyl-2-ethoxy- as a condensing agent
When 1,2-dihydroquinoline is used, the reaction solvent is
Tetrahydrofuran or 1,4-dioxane is suitable. The reaction temperature is −10 to 60 ° C., preferably 20 to
Within the range of 50 ° C., the reaction time is 30 minutes to 10 hours,
It is preferably about 1 to 4 hours.
縮合剤としてはクロロギ酸エステルを用いる場合、クロ
ロギ酸エステルとしては、クロロギ酸エチル又はクロロ
ギ酸イソブチル等が適当である。反応溶媒は、テトラヒ
ドロフラン又は１，４−ジオキサン等が適当である。反
応温度は、−２０〜６０℃、好ましくは−１０〜３０℃
の範囲内とし、反応時間は、３０分〜２０時間、好まし
くは１〜５時間程度とする。When chloroformate is used as the condensing agent, ethyl chloroformate, isobutyl chloroformate, etc. are suitable as the chloroformate. Tetrahydrofuran or 1,4-dioxane is suitable as the reaction solvent. The reaction temperature is -20 to 60 ° C, preferably -10 to 30 ° C
And the reaction time is 30 minutes to 20 hours, preferably 1 to 5 hours.
上記ジエチレントリアミン三酢酸化合物［Ｉ］は、特願
平１−２３５７９９号公報に報告されている方法によっ
て製造することができる。The diethylenetriamine triacetic acid compound [I] can be produced by the method reported in Japanese Patent Application No. 1-235799.
ジエチレントリアミン三酢酸エステル化合物［II］の第
２の製造法として、下記構造式［IV］ で示されるカリウム塩と下記一般式［Ｖ］ Ｘ−（ＣＨ2）nＯ−Ｒ［Ｖ］ （式中、ｎ＝１〜２、Ｒは、水素又はアシル基を表わ
し、Ｘは、塩素、臭素、又はヨウ素を表わす。）で示さ
れるハロゲン化物を反応させる方法がある。As a second method for producing the diethylenetriamine triacetate compound [II], the following structural formula [IV] In potassium and the following general formula shown [V] X- (CH 2) n O-R [V] ( wherein, n = 1 to 2, R represents hydrogen or an acyl group, X is chlorine, There is a method of reacting a halide represented by bromine or iodine).
反応割合は、カリウム塩［IV］に対してハロゲン化物
［Ｖ］を３〜６０倍モル量とする。ハロゲン化物［Ｖ］
としては、ピバリン酸クロルメチル又は酢酸２−クロロ
エチル等が挙げられる。反応溶媒は、アセトン又はメチ
ルエチルケトン等が適当である。反応温度は、０〜８０
℃、好ましくは３０〜８０℃の範囲内とし、反応時間
は、５分〜４０時間、好ましくは１〜８時間程度とす
る。The reaction ratio is such that the halide [V] is 3 to 60 times the molar amount of the potassium salt [IV]. Halide [V]
Examples include chloromethyl pivalate or 2-chloroethyl acetate. Acetone or methyl ethyl ketone is suitable as the reaction solvent. The reaction temperature is 0 to 80
C., preferably in the range of 30 to 80.degree. C., and the reaction time is 5 minutes to 40 hours, preferably 1 to 8 hours.
上記カリウム塩［IV］は、前記のジエチレントリアミン
三酢酸化合物［Ｉ］とカリウムｔ−ブトキシド又は水酸
化カリウム等を反応させて製造することができる。The potassium salt [IV] can be produced by reacting the diethylenetriaminetriacetic acid compound [I] with potassium t-butoxide, potassium hydroxide or the like.
反応割合は、ジエチレントリアミン三酢酸化合物［Ｉ］
に対してカリウムｔ−ブトキシド等を３倍モル量とす
る。反応溶媒は、メタノール又はエタノール等が適当で
ある。反応温度は、０〜４０℃とし、反応時間は、１分
〜１時間とする。The reaction ratio is diethylenetriaminetriacetic acid compound [I]
On the other hand, potassium t-butoxide and the like are used in a 3-fold molar amount. Suitable reaction solvent is methanol or ethanol. The reaction temperature is 0 to 40 ° C., and the reaction time is 1 minute to 1 hour.
作用 本発明のジエチレントリアミン三酢酸エステル化合物
［II］は、経口投与における胆汁への排泄率の評価で、
優れた経口吸収性を具備していることが認められた。Action The diethylenetriamine triacetate compound [II] of the present invention is evaluated for the excretion rate in the bile upon oral administration,
It was confirmed that it had excellent oral absorbability.
発明を実施例をもって更に説明する。The invention will be further described with reference to examples.
実施例１（ジエチレントリアミン三酢酸トリ（２−ヒド
ロキシエチル）エステル化合物） Ｎ″−ウルソデオキシコリルジエチレントリアミン−
Ｎ，Ｎ，Ｎ′−三酢酸７００mg（１．０７ミリモル）、
ｐ−トルエンスルホン酸−水和物３００mg（１．５８ミ
リモル）及びエチレングリコール５．０ｍの混合物を
９０〜１００℃にて２時間加熱還流した。この反応液に
水を加え、０．５Ｎ水酸化ナトリウムにてpH９とし、酢
酸エチルで抽出した。この酢酸エチル層を水洗し、無水
硫酸ナトリウムにて乾燥し、ついで溶媒を留去した。得
られた残留物をクロロホルム−メタノール混合液（容量
比１００：１〜５：１）を展開液とするシリカゲルカラ
ムクロマトグラフィーに付し、油状のＮ″−ウルソデオ
キシコリルジエチレントリアミン−Ｎ，Ｎ，Ｎ′−三酢
酸トリ（２−ヒドロキシエチル）エステル１００mg（収
率１２％）を得た。Example 1 (Diethylenetriaminetriacetic acid tri (2-hydroxyethyl) ester compound) N "-ursodeoxycholyldiethylenetriamine-
700 mg (1.07 mmol) of N, N, N'-triacetic acid,
A mixture of 300 mg (1.58 mmol) of p-toluenesulfonic acid hydrate and 5.0 m of ethylene glycol was heated under reflux at 90 to 100 ° C for 2 hours. Water was added to the reaction solution to adjust the pH to 9 with 0.5N sodium hydroxide, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography using a chloroform-methanol mixed solution (volume ratio 100: 1 to 5: 1) as a developing solution to give an oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N. 100 mg (yield 12%) of'-triacetic acid tri (2-hydroxyethyl) ester was obtained.
赤外吸収スペクトル（ＫＢｒ，cm-1）； １７４５，１６４５ 核磁気共鳴スペクトル（ＣＤ3ＯＤ，ppm）δ； ０．７１（３Ｈ，ｓ），０．９６（３Ｈ，ｓ）０．９７
（３Ｈ，ｄ，Ｊ＝６Ｈｚ），１．０１〜２．３４（２６
Ｈ，ｍ），２．７１〜２．９０（６Ｈ，ｍ），３．２５
（２Ｈ，ｔ，Ｊ＝６Ｈｚ），３．４１〜３．５８（２
Ｈ，ｍ），３．５２（２Ｈ，ｓ），３．６４（４Ｈ，
ｓ），３．７４（６Ｈ，ｔ，Ｊ＝５Ｈｚ），４．１８
（６Ｈ，ｔ，Ｊ＝５Ｈｚ） 元素分析値（Ｃ40Ｈ69Ｎ3Ｏ12として）； 理論値(%)Ｃ，61.28Ｈ，8.87Ｎ，5.36 実測値(%) 61.08 8.82 5.30 実施例２（ジエチレントリアミン三酢酸トリ（２−ヒド
ロキシエチル）エステル化合物） Ｎ″−ウルソデオキシコリルジエチレントリアミン−
Ｎ，Ｎ，Ｎ′−三酢酸１４０mg（０．２１５ミリモ
ル）、１−エトキシカルボニル−２−エトキシ−１，２
−ジヒドロキノリン６０mg（０．２４３ミリモル）及び
テトラヒドロフラン１．４ｍの混合物を４０〜５０℃
にて３時間攪拌した。この反応液の溶媒を留去し、得ら
れた残留物をクロロホルム−メタノール混合液（容量比
１００：１〜５：１）を展開液とするシリカゲルカラム
クロマトグラフィーに付し、油状のＮ″−ウルソデオキ
シコリルジエチレントリアミン−Ｎ，Ｎ，Ｎ′−三酢酸
トリ（２−ヒドロキシエチル）エステル３１mg（収率１
８％）を得た。この物質の赤外吸収スペクトル及び核磁
気共鳴スペクトルは、実施例１に記載したものと一致し
た。Infrared absorption spectrum (KBr, cm -1 ); 1745, 1645 Nuclear magnetic resonance spectrum (CD 3 OD, ppm) δ; 0.71 (3H, s), 0.96 (3H, s) 0.97
(3H, d, J = 6Hz), 1.01 to 2.34 (26
H, m), 2.71 to 2.90 (6H, m), 3.25
(2H, t, J = 6Hz), 3.41 to 3.58 (2
H, m), 3.52 (2H, s), 3.64 (4H,
s), 3.74 (6H, t, J = 5Hz), 4.18.
(6H, t, J = 5Hz ) Elemental analysis (as C 40 H 69 N 3 O 12 ); theory (%) C, 61.28H, 8.87N , 5.36 Found (%) 61.08 8.82 5.30 Example 2 ( Diethylenetriamine triacetic acid tri (2-hydroxyethyl) ester compound) N "-ursodeoxycholyldiethylenetriamine-
140 mg (0.215 mmol) of N, N, N'-triacetic acid, 1-ethoxycarbonyl-2-ethoxy-1,2
A mixture of 60 mg (0.243 mmol) of dihydroquinoline and 1.4 m of tetrahydrofuran at 40-50 ° C.
It was stirred for 3 hours. The solvent of this reaction solution was distilled off, and the resulting residue was subjected to silica gel column chromatography using a chloroform-methanol mixed solution (volume ratio 100: 1 to 5: 1) as a developing solution to give an oily N ″- Ursodeoxycholyldiethylenetriamine-N, N, N'-triacetic acid tri (2-hydroxyethyl) ester 31 mg (yield 1
8%). The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were in agreement with those described in Example 1.
実施例３（ジエチレントリアミン三酢酸トリ（ピバロイ
ルオキシメチル）エステル化合物） Ｎ″−ウルソデオキシコリルジエチレントリアミン−
Ｎ，Ｎ，Ｎ′−三酢酸カリウム塩８２０mg（１．０７ミ
リモル）、ピバリン酸クロルメチル１．０ｍ（６．９
１ミリモル）、ヨウ化ナトリウム４００mg（２．６７ミ
リモル）、アセトン２０ｍの混合物を２時間加熱還流
した。この反応液の溶媒を留去し、得られた残留物をク
ロロホルム−メタノール混合液（容量比１：０〜５０：
１）を展開液とするシリカゲルカラムクロマトグラフィ
ーに付し、油状のＮ″−ウルソデオキシコリルジエチレ
ントリアミン−Ｎ，Ｎ，Ｎ′−三酢酸トリ（ピバロイル
オキシメチル）エステル１０２mg（収率１０％）を得
た。Example 3 (Diethylenetriamine triacetic acid tri (pivaloyloxymethyl) ester compound) N "-ursodeoxycholyldiethylenetriamine-
N, N, N'-triacetic acid potassium salt 820 mg (1.07 mmol), chloromethyl pivalate 1.0 m (6.9
A mixture of 1 mmol), 400 mg (2.67 mmol) of sodium iodide, and 20 m of acetone was heated under reflux for 2 hours. The solvent of this reaction solution was distilled off, and the obtained residue was mixed with a chloroform-methanol mixture (volume ratio: 1: 0 to 50:
Silica gel column chromatography using 1) as a developing solution gave 102 mg (yield 10%) of oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid tri (pivaloyloxymethyl) ester. Got
赤外吸収スペクトル（ＫＢｒ，cm-1）； １７６０，１６５０ 核磁気共鳴スペクトル（ＣＤＣｌ3，ppm）δ； ０．６８（３Ｈ，ｓ），０．９４（３Ｈ，ｄ，Ｊ＝６Ｈ
ｚ）０．９５（３Ｈ，ｓ），１．２１（２７Ｈ，ｓ），
１．００〜２．３３（２６Ｈ，ｍ），２．６５〜２．８
８（６Ｈ，ｍ），３．２７（２Ｈ，ｑ，Ｊ＝６Ｈｚ），
３．４６（２Ｈ，ｓ），３．６１（４Ｈ，ｓ），３．５
１〜３．６８（２Ｈ，ｍ），５．７６（６Ｈ，ｓ），
６．６４（１Ｈ，ｔ，Ｊ＝６Ｈｚ） 元素分析値（Ｃ52Ｈ87Ｎ3Ｏ15として）； 理論値(%)Ｃ，62.82Ｈ，8.82Ｎ，4.23 実測値(%) 62.83 8.98 4.21 実施例４（ジエチレントリアミン三酢酸トリ（２−アセ
トキシエチル）エステル化合物） ピバリン酸クロルメチル１．０ｍの代わりに、酢酸２
−クロロエチル０．８ｍ（７．５７ミリモル）を用い
た以外は、実施例３とほぼ同様に処理し、油状のＮ″−
ウルソデオキシコリルジエチレントリアミン−Ｎ，Ｎ，
Ｎ′−三酢酸トリ（２−アセトキシエチル）エステル８
２mg（収率８％）を得た。Infrared absorption spectrum (KBr, cm -1 ); 1760, 1650 Nuclear magnetic resonance spectrum (CDCl 3 , ppm) δ; 0.68 (3H, s), 0.94 (3H, d, J = 6H)
z) 0.95 (3H, s), 1.21 (27H, s),
1.00 to 2.33 (26H, m), 2.65 to 2.8
8 (6H, m), 3.27 (2H, q, J = 6Hz),
3.46 (2H, s), 3.61 (4H, s), 3.5
1-3.68 (2H, m), 5.76 (6H, s),
6.64 (1H, t, J = 6Hz) Elemental analysis value (as C 52 H 87 N 3 O 15 ); Theoretical value (%) C, 62.82H, 8.82N, 4.23 Measured value (%) 62.83 8.98 4.21 Implementation Example 4 (Diethylenetriamine triacetic acid tri (2-acetoxyethyl) ester compound) Chloromethyl pivalate 1.0m was replaced with acetic acid 2 instead of 1.0m.
The procedure of Example 3 was repeated except that 0.8 m (7.57 mmol) of chloroethyl was used, and an oily N ″-
Ursodeoxycholyldiethylenetriamine-N, N,
N'-triacetic acid tri (2-acetoxyethyl) ester 8
2 mg (yield 8%) was obtained.
赤外吸収スペクトル（ＫＢｒ，cm-1）； １７６０，１６５０ 核磁気共鳴スペクトル（ＣＤＣｌ3，ppm）δ； ０．６８（３Ｈ，ｓ），０．９５（３Ｈ，ｄ，Ｊ＝６Ｈ
ｚ）０．９５（３Ｈ，ｓ），１．０１〜２．３５（２６
Ｈ，ｍ），２．０９（９Ｈ，ｓ），２．６７〜２．９０
（６Ｈ，ｍ），３．２６（２Ｈ，ｑ，Ｊ＝６Ｈｚ），
３．４５（２Ｈ，ｓ），３．５８（４Ｈ，ｓ），３．５
１〜３．６８（２Ｈ，ｍ），４．１５（１２Ｈ，ｓ），
６．７０（１Ｈ，ｔ，Ｊ＝６Ｈｚ） 元素分析値（Ｃ46Ｈ75Ｎ3Ｏ15として）； 理論値(%)Ｃ，60.71Ｈ，8.31Ｎ，4.62 実測値(%) 60.52 8.60 4.57 発明の効果 本発明のジエチレントリアミン三酢酸エステル化合物
［II］は、カルシウムを含有する種々の胆石の溶解剤と
して、経口投与にて利用できる。Infrared absorption spectrum (KBr, cm -1 ); 1760, 1650 Nuclear magnetic resonance spectrum (CDCl 3 , ppm) δ; 0.68 (3H, s), 0.95 (3H, d, J = 6H)
z) 0.95 (3H, s), 1.01 to 2.35 (26
H, m), 2.09 (9H, s), 2.67 to 2.90.
(6H, m), 3.26 (2H, q, J = 6Hz),
3.45 (2H, s), 3.58 (4H, s), 3.5
1-3.68 (2H, m), 4.15 (12H, s),
6.70 (1H, t, J = 6Hz) Elemental analysis (as C 46 H 75 N 3 O 15 ); theory (%) C, 60.71H, 8.31N , 4.62 Found (%) 60.52 8.60 4.57 invention The effect of the diethylenetriamine triacetate compound [II] of the present invention can be orally administered as a solubilizer of various gallstones containing calcium.
フロントページの続き (72)発明者 坂倉 浩夫 埼玉県東松山市幸町12番19号 (56)参考文献 特開 昭60−161996（ＪＰ，Ａ) 薬学研究 Ｖｏｌ．38 Ｎｏ．12 Ｐ. 402〜421（1967)Front page continuation (72) Inventor Hiroo Sakakura 12-19 Sachimachi, Higashimatsuyama City, Saitama Prefecture (56) Reference JP-A-60-161996 (JP, A) Pharmaceutical Research Vol. 38 No. 12 P. 402 ~ 421 (1967)
Claims (3)
す。）で示されるジエチレントリアミン三酢酸エステル
化合物。1. A general formula (In the formula, n = 1 to 2, R represents hydrogen or an acyl group.) A diethylenetriaminetriacetic acid ester compound.
す。）で示されるアルコールを縮合させることを特徴と
する請求項(1)記載のジエチレントリアミン三酢酸エス
テル化合物の製造法。2. A formula Diethylenetriamine triacetate compound of the general formula HO (CH 2) n O- R ( where, n = 1 to 2, R represents. Hydrogen or an acyl group) represented in said condensing an alcohol represented by The method for producing a diethylenetriamine triacetate compound according to claim (1).
し、Ｘは、塩素、臭素、又はヨウ素を表わす。）で示さ
れるハロゲン化物を反応させることを特徴とする請求項
(1)記載のジエチレントリアミン三酢酸エステル化合物
の製造法。3. A formula In in the potassium salt represented with the general formula X- (CH 2) n O- R ( wherein, n = 1 to 2, R represents hydrogen or an acyl group, X represents chlorine, bromine, or iodine. ) Reacting a halide represented by
(1) A method for producing the diethylenetriaminetriacetate compound according to item (1).
Priority Applications (1)
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|---|---|---|---|
| JP16836590A JPH0635472B2 (en) | 1990-06-28 | 1990-06-28 | Diethylenetriamine triacetic acid oxyalkyl ester compounds and processes for their production |
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|---|---|---|---|
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