JPH0459792A - Diethylenetriaminetriacetic acid oxyalkyl ester compound and production thereof - Google Patents
Diethylenetriaminetriacetic acid oxyalkyl ester compound and production thereofInfo
- Publication number
- JPH0459792A JPH0459792A JP16836590A JP16836590A JPH0459792A JP H0459792 A JPH0459792 A JP H0459792A JP 16836590 A JP16836590 A JP 16836590A JP 16836590 A JP16836590 A JP 16836590A JP H0459792 A JPH0459792 A JP H0459792A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- acid
- diethylenetriaminetriacetic
- compound
- ester compound
- 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.)
- Granted
Links
- -1 Diethylenetriaminetriacetic acid oxyalkyl ester compound Chemical class 0.000 title claims description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 150000004820 halides Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 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
- 239000000126 substance Substances 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 abstract description 9
- 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 abstract description 5
- 239000003377 acid catalyst Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract description 4
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 3
- 230000005494 condensation Effects 0.000 abstract 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract 2
- 229940126062 Compound A Drugs 0.000 abstract 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 8
- 208000001130 gallstones Diseases 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- 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
- 201000001883 cholelithiasis Diseases 0.000 description 5
- 238000000034 method Methods 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
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000004575 stone Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 210000000941 bile Anatomy 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-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
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 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
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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 1
- VIRWKAJWTKAIMA-UHFFFAOYSA-N 2-chloroethyl acetate Chemical compound CC(=O)OCCCl VIRWKAJWTKAIMA-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 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
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 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
- 229940079593 drug Drugs 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 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
- 235000005985 organic acids Nutrition 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
- 150000003839 salts Chemical class 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000003756 stirring Methods 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)
Abstract
Description
【発明の詳細な説明】
り果よ五■艮方１
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
オキシコリル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。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a diethylenetriamine triacetate compound, and more particularly to a ursodeoxycholyl diethylenetriamine 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
テロール混合石、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 OF THE INVENTION Ursodeoxycholic acid and chenodeoxycholic acid are known as drugs frequently used as gallstone therapeutic agents. Although these bile acids are effective against pure cholesterol stones, they are effective against other cholesterol-based gallstones, e.g.
The dissolving effect of cholesterol-containing stone or cholesterol-mixed stone containing calcium, as well as bilirubin calcium stone or calcium carbonate stone, 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
で強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 states that a diethylenetriaminetriacetic acid compound represented by the following structural formula [I] has the effect of strongly dissolving calcium-containing gallstones, especially calcium carbonate-containing gallstones, in bile. It has been reported that.
Ｕ１１部」已Ｂ」擾１１
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。Part U11 "B" 11 However, when the diethylenetriaminetriacetic acid compound [I] was administered as a calcium gallstone dissolving agent, it was found that although it had excellent bile transferability, it had poor oral absorption.
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。Moreover, when a chelating agent such as diethylenetriaminetriacetic acid compound [I] is administered into a living body, it may be inactivated by coexisting metal ions in the living body, and its medicinal 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０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 conducted intensive research on the derivatives of diethylenetriaminetriacetic acid compound [I], and found that they do not have chelate-forming ability and are easily metabolized to diethylenetriaminetriacetic acid compound [I] in the body. The present invention was achieved based on the finding that these ester compounds obtained have excellent oral absorption properties.
本発明によれば、下記一般式［ＩＩ］
（式中、ｎ＝’ｌ〜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。According to the present invention, there are provided diethylenetriaminetriacetic acid ester compounds represented by the following general formula [II] (where n = 'l to 2, R represents hydrogen or an acyl group) and methods for producing them. Ru.
上記一般式ＩＩＩ］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［Ｉ［１］
％式％［］
（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 diethylenetriaminetriacetic acid ester compound of the above general formula III], the above diethylenetriaminetriacetic acid compound [I] and the following general formula [I[1] % formula % [ ] (where n = 1 to There is a method of condensing alcohols represented by 2.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［Ｉ［Ｉ］を３〜１００００倍モル
量とする。アルコール［Ｉ［Ｉ］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 rate is diethylenetriaminetriacetic acid compound [I]
The molar amount of alcohol [I[I] is 3 to 10,000 times that of alcohol. Alcohol [I[I] includes ethylene glycol. As the condensing agent, acid catalyst, 1-
Examples include ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and chloroformate.
縮合剤として酸触媒を用いる場合、酸触媒としては、１
ａ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。When using an acid catalyst as a condensing agent, as the acid catalyst, 1
Mineral acids such as a-acid or hydrochloric acid or organic acids such as benzenesulfonic acid or p-toluenesulfonic acid are suitable.
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。The reaction temperature is 20-200°C, preferably 60-160°C.
C., and the reaction time is about 30 minutes to 50 hours, preferably about 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
おる。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 using 1,2-dihydroquinoline, the reaction solvent is
Tetrahydrofuran or 1,4-dioxane are suitable. The reaction temperature is -10 to 60°C, preferably 20 to
The temperature is within the range of 50°C, and the reaction time is 30 minutes to 10 hours.
Preferably it is about 1 to 4 hours.
縮合剤として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℃、好ましくは一１０〜３０℃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 a chloroformate is used as a condensing agent, suitable examples of the chloroformate include ethyl chloroformate and isobutyl chloroformate. Suitable reaction solvents include tetrahydrofuran or 1,4-dioxane. The reaction temperature is in the range of -20 to 60°C, preferably -10 to 30°C, and the reaction time is about 30 minutes to 20 hours, preferably about 1 to 5 hours.
上記ジエチレントリアミン三酢酸化合物［ＩＩ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 diethylenetriaminetriacetic acid compound [II] 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［１ｖ］で示されるカ
リウム塩と下記一般式［Ｖ］Ｘ−（ＣＨ２）、０−Ｒ［
Ｖコ
（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。As a second manufacturing method of diethylenetriaminetriacetic acid ester compound [II], a potassium salt represented by the following structural formula [1v] and the following general formula [V]X-(CH2), 0-R[
Vco (wherein n=1-2, R represents hydrogen or an acyl group, and X represents chlorine, bromine, or iodine.
）で示されるハロゲン化物を反応させる方法がある。There is a method of reacting halides shown in ).
反応割合は、カリウムＩ［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 3 to 60 times the molar amount of halide [V] to potassium I [IV]. Halide [V]
Examples include chloromethyl pivalate and 2-chloroethyl acetate. Suitable reaction solvents are acetone, methyl ethyl ketone, and the like. The reaction temperature is 0 to 80
C, preferably within the range of 30 to 80 C, and the reaction time is about 5 minutes to 40 hours, preferably about 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［ＩＩとカリウムｔ−７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 [II with potassium t-7 toxide, 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［ＩＩ
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 rate is diethylenetriaminetriacetic acid compound [II
The molar amount of potassium t-butoxide etc. is 3 times that of the amount of potassium t-butoxide. Suitable reaction solvents are methanol, ethanol, and the like. The reaction temperature is 0 to 40°C, and the reaction time is 1 minute to
It will be 1 hour.
正月
本発明のジエチレントリアミン三酢酸エステル化合物［
■］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。New Year Diethylenetriaminetriacetate compound of the present invention [
■] was found to have excellent oral absorbability in evaluation of bile excretion rate upon oral administration.
発明を実施例をもって更に説明する。The invention will be further explained with examples.
ヌ」１例」−＜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 ＩＩ−ウルン
デオキシコリルジエチレントリアミン−Ｎ、Ｎ、Ｎ＝−
三酢酸７００Ｉｎｇ（１，０７ミリモル）、ｐ−トルエ
ンスルホン酸−水和物３００ｍ１（１，５８ミリモル）
及びエチレングリコール５．Ｏｄの混合物を９０〜１０
０℃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。Diethylenetriaminetriacetic acid tri(2-
hydroxyethyl) ester compound) N II-ulundeoxycholyldiethylenetriamine-N, N, N=-
700 Ing (1,07 mmol) of triacetic acid, 300 ml (1,58 mmol) of p-toluenesulfonic acid hydrate
and ethylene glycol5. Od mixture 90-10
The mixture was heated under reflux at 0°C for 2 hours. Add water to this reaction solution,
The pH was adjusted to 9 with 0.5N sodium hydroxide, and the mixture was extracted with ethyl acetate. This ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off.
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ーＮ、Ｎ、Ｎ’
−−三酢酸トリ（２−ヒドロキシエチル）エステル１０
０Ｍ＃（収率１２％）を得た。The obtained residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (volume ratio 100:1 to 5:1) as a developing solution to obtain an oily N"-ursodeoxycholyldiethylenetriamine-N,N,N. '
--triacetic acid tri(2-hydroxyethyl) ester 10
0M# (12% yield) was obtained.
赤外吸収スペクトル（ＫＢｒ、 ｃｎ−１） ；１７４
５．１６４５
核ｆｉｌ気共ＩＡスヘ’ｙ ト）Ｌｔ （ＣＤ３０Ｄ、
Ｉ）Ｉ）ｍ ＞δ：０．７１ （３Ｈ，ｓ）、０．９
６ （３Ｈ。Infrared absorption spectrum (KBr, cn-1); 174
5.1645 Nuclear filtration IA system) Lt (CD30D,
I) I) m > δ: 0.71 (3H, s), 0.9
6 (3H.
ｓ＞、０．９７ （３Ｈ，ｄ、Ｊ＝６Ｈｚ＞。s>, 0.97 (3H, d, J=6Hz>.
１．０１〜２．３４ （２６Ｈ，ｍ＞、２．７１〜２．
９０ （６Ｈ，ｍ＞、３．２５ （２Ｈ。1.01-2.34 (26H, m>, 2.71-2.
90 (6H, m>, 3.25 (2H.
ｔ、Ｊ＝６Ｈ７）、３．４１〜３．５８ （２Ｈ，ｍ＞
、３．５２ （２ｆ−１，Ｓ）、３．６４（４日、Ｓ）
、３．７４ （６Ｈ，ｔ、Ｊ＝５Ｈｚ＞、４．１８ （
６Ｈ，ｔ、Ｊ＝５Ｈｚ＞元素分析”（Ｃ４０Ｈ６９Ｎ３
０１２として）：理論値（％） Ｃ，６１，２８日、
８．８７ Ｎ、 ５．３６実測値（％） ６１
．０８ ８゜８２ ５．３０Ｗ＜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１４０ｒｒｔｇ（０，２１５ミリモル）、１〜
エトキシカルボニル−２−エトキシ−１，２ニジヒドロ
キノリン６０＃（０゜２４３ミリモル）、エチレングリ
コール０．２ｍ（３，６１ミリモル）及びテトラヒドロ
フラン１゜４−の混合物を４０〜５０°Ｃにて３時間攪
拌した。t, J=6H7), 3.41-3.58 (2H, m>
, 3.52 (2f-1, S), 3.64 (4th, S)
, 3.74 (6H,t, J=5Hz>, 4.18 (
6H, t, J=5Hz>Elemental analysis” (C40H69N3
012): Theoretical value (%) C, 61, 28 days,
8.87 N, 5.36 actual value (%) 61
．． 08 8゜82 5.30W<diethylenetriaminetriacetic acid tri(2-hydroxyethyl) ester compound) N -ursodeoxycholyldiethylenetriamine-N,N,N"
- 140 rrtg (0,215 mmol) of triacetic acid, 1~
A mixture of ethoxycarbonyl-2-ethoxy-1,2 dihydroquinoline 60 # (0°243 mmol), ethylene glycol 0.2 m (3,61 mmol) and tetrahydrofuran 1°4 was heated at 40 to 50°C for 3 hours. Stir for hours.
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。The solvent of this reaction solution was distilled off, and the resulting residue was used as a chloroform-methanol mixture (volume ratio 100:1 to 5:1).
The product was subjected to silica gel column chromatography using as a developing solution to obtain an oily N-ursodeoxycholyldiethylenetriamine-N,N.
Ｎ′−三酢酸トリ（２−ヒドロキシエチル）エステル３
１ ｍｌ （収率１８％）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。N'-triacetic acid tri(2-hydroxyethyl) ester 3
1 ml (yield 18%) was obtained. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were consistent with those described in Example 1.
１ｉ１（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ーＮ、Ｎ、Ｎ′−三酢酸三
カリウム塩８２０ＩＩｔｇ（１，０７ミリモル）、ピバ
リン酸クロルメチル１、Ｃ）ｄ（６，９１ミリモル）、
ヨウ化ナトリウム４００Ｉｎｇ（２，ロアミリモル）、
アセトン２０ｄ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−ｍ＝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。1i1 (diethylenetriaminetriacetic acid tri(pivaloyloxymethyl) ester compound) N-ursodeoxycholyldiethylenetriamine-N,N,N'-triacetic acid tripotassium salt 820 IItg (1,07 mmol), chloromethyl pivalate 1, C) d (6.91 mmol),
Sodium iodide 400 Ing (2,0 mmol),
A mixture of 20 d of acetone was heated to reflux for 2 hours. The solvent of this reaction solution was distilled off, and the resulting residue was dissolved in chloroform.
It was subjected to silica gel column chromatography using a methanol mixture (volume ratio 1:0 to 50:1) as a developing solution to obtain an oily N"-ursodeoxycholyldiethylenetriamine-N,N,N-m=tri(pivaloacetate). 102 mg (yield 10%) of (yield 10%) ester was obtained.
赤外吸収スペクトル（１（１３ｒ、ｃｍ’″１）：１７
６０．１６５０
核磁気共鳴スペクトル（ＣＤＣｌ ３ 、 Ｉ）ＤＩ
）δ：０．６８ （３Ｈ，ｓ）、０．９４ （３Ｈ，ｄ
。Infrared absorption spectrum (1 (13r, cm'''1): 17
60.1650 Nuclear Magnetic Resonance Spectrum (CDCl3, I) DI
) δ: 0.68 (3H, s), 0.94 (3H, d
.
Ｊ＝６Ｈｚ＞、０．９５ （３１−ｉ、ｓ）、１゜２１
（２７Ｈ，Ｓ）、１．００〜２．３３（２６）−１
，ｍ）、２．６７〜２．８８ （６Ｈ。J=6Hz>, 0.95 (31-i, s), 1°21
(27H,S), 1.00-2.33(26)-1
, m), 2.67-2.88 (6H.
ｍ＞、３．２７ （２１−１，ａ、Ｊ＝６ｔ−ｆｚ）。m>, 3.27 (21-1, a, J=6t-fz).
３．４６ （２Ｈ，ｓ＞、３．６１ （４Ｈ。3.46 (2H, s>, 3.61 (4H.
Ｓ）、３．５ｉ〜３．６８ （２Ｈ，ｍ＞、５゜７６
（６Ｈ，ｓ）、６．６４ （１Ｈ，ｔ、Ｊ＝６Ｈ２）
元素分析値（０５□Ｈ８□Ｎ３０１５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１．０ｄの代わりに、酸１！！２−クロロエチ
ル０．８ｍ１（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ーＮ、Ｎ、Ｎ”−三酢酸
トリ（２−アセトキシエチル）エステル８０ＩＩｒ！Ｊ
（収率８％）を得た。S), 3.5i ~ 3.68 (2H, m>, 5°76
(6H, s), 6.64 (1H, t, J = 6H2) Elemental analysis value (as 05□H8□N3015): Theoretical value (%) C, 62,82H, 8,82N, 4.23
Actual value (%) 62.83 8.98 4
．． 21 Example 4 (diethylenetriaminetriacetic acid tri(2)
-acetoxyethyl) ester compound) Instead of chloromethyl pivalate 1.0d, acid 1! ! The process was carried out in the same manner as in Example 3, except that 0.8 ml (7,57 mmol) of 2-chloroethyl was used, and oily N"-ursodeoxycholyldiethylenetriamine-N,N,N"-triacetic acid tri(2 -acetoxyethyl) ester 80IIr! J
(Yield: 8%).
赤外吸収スペクトル（ＫＢｒ、Ｃｍ’）；１７６０．１
６５０
核磁気共鳴スペクトル（ＣＤＣ１３、ｐｐｍ ） ６
：０．６Ｂ （３１−１，ｓ＞、０．９５ （３Ｈ，ｄ
。Infrared absorption spectrum (KBr, Cm'); 1760.1
650 Nuclear magnetic resonance spectrum (CDC13, ppm) 6
:0.6B (31-1,s>, 0.95 (3H,d
.
Ｊ＝６Ｈｚ＞、０．９５ （３Ｈ，ｓ）、１゜０１〜２
．３５ （２６Ｈ，ｍ＞、２．０９（９Ｈ，ｓ）、２
．６７〜２．９０ （６Ｈ。J=6Hz>, 0.95 (3H, s), 1°01~2
．． 35 (26H, m>, 2.09 (9H, s), 2
．． 67-2.90 (6H.
ｍ＞、３．２６ （２）１．Ｑ、Ｊ＝６Ｈｚ）。m>, 3.26 (2) 1. Q, J = 6Hz).
３．４５ （２１−１，ｓ＞、３．５８ （４）−１
゜ｓ＞、３．５’ｌ〜３．６８ （２１−１，ｍ＞、４
゜１５ （１２Ｈ，ｓ＞、６．７０ （１Ｈ，ｔ。3.45 (21-1, s>, 3.58 (4)-1
゜s＞, 3.5'l~3.68 (21-1, m＞, 4
゜15 (12H, s>, 6.70 (1H, t.
Ｊ＝６Ｈｚ）
元素分析値（０４６日７５Ｎ３０１５として）：理論値
（％） Ｃ，６０，７１Ｈ，８，３１Ｎ、 ４．６２
実測値（％） ６０．５２ ８，６０ ４
．５７Ｒ皿五ヱ呈
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。J=6Hz) Elemental analysis value (as 75N3015 on 046th): Theoretical value (%) C, 60, 71H, 8, 31N, 4.62
Actual value (%) 60.52 8,60 4
．． Diethylenetriaminetriacetate compound of the present invention [57R dish]
II] can be used orally as a dissolving agent for various calcium-containing gallstones.
Claims (3)
。）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) Diethylenetriaminetriacetic acid ester compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n = 1 to 2, R represents hydrogen or an acyl group.)
。）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) Diethylenetriaminetriacetic acid compound represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. .) The method for producing a diethylenetriaminetriacetic acid ester compound according to claim (1), which comprises condensing an alcohol represented by .).
、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) Potassium salt represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ and the general formula A claim characterized in that a halide represented by X represents chlorine, bromine, or iodine is reacted (
1) A method for producing the diethylenetriaminetriacetic acid ester compound described above.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16836590A JPH0635472B2 (en) | 1990-06-28 | 1990-06-28 | Diethylenetriamine triacetic acid oxyalkyl ester compounds and processes for their production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16836590A JPH0635472B2 (en) | 1990-06-28 | 1990-06-28 | Diethylenetriamine triacetic acid oxyalkyl ester compounds and processes for their production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0459792A true JPH0459792A (en) | 1992-02-26 |
| JPH0635472B2 JPH0635472B2 (en) | 1994-05-11 |
Family
ID=15866737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16836590A Expired - Lifetime JPH0635472B2 (en) | 1990-06-28 | 1990-06-28 | Diethylenetriamine triacetic acid oxyalkyl ester compounds and processes for their production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0635472B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7144877B2 (en) * | 2000-10-06 | 2006-12-05 | Xenoport, Inc. | Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs |
| US8893317B2 (en) | 2008-08-05 | 2014-11-25 | Zoe Smith | Toilet training device |
-
1990
- 1990-06-28 JP JP16836590A patent/JPH0635472B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7144877B2 (en) * | 2000-10-06 | 2006-12-05 | Xenoport, Inc. | Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs |
| US7678782B2 (en) | 2000-10-06 | 2010-03-16 | Xenoport, Inc. | Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs |
| US8893317B2 (en) | 2008-08-05 | 2014-11-25 | Zoe Smith | Toilet training device |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0635472B2 (en) | 1994-05-11 |
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