JPH02233692A - Novel n6,2'-o-disubstituted-adenosine-3',5'-cyclic phosphate and production thereof - Google Patents
Novel n6,2'-o-disubstituted-adenosine-3',5'-cyclic phosphate and production thereofInfo
- Publication number
- JPH02233692A JPH02233692A JP5284289A JP5284289A JPH02233692A JP H02233692 A JPH02233692 A JP H02233692A JP 5284289 A JP5284289 A JP 5284289A JP 5284289 A JP5284289 A JP 5284289A JP H02233692 A JPH02233692 A JP H02233692A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- camp
- adenosine
- group
- salt
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 239000002585 base Substances 0.000 claims abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 150000004820 halides Chemical class 0.000 claims abstract 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 13
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 17
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 2
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 abstract 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 abstract 1
- 238000004220 aggregation Methods 0.000 abstract 1
- 230000002776 aggregation Effects 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract 1
- 229940030600 antihypertensive agent Drugs 0.000 abstract 1
- 239000002220 antihypertensive agent Substances 0.000 abstract 1
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 150000001455 metallic ions Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- -1 alkali metal salt Chemical class 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 5
- 230000003472 neutralizing effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LSXKDWGTSHCFPP-UHFFFAOYSA-N 1-bromoheptane Chemical compound CCCCCCCBr LSXKDWGTSHCFPP-UHFFFAOYSA-N 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 2
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 125000006289 hydroxybenzyl group Chemical group 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、新規なＮ”，２’ −０−ジ置換一アデノシ
ン−３’， ５’一環状リン酸（以下Ｎ６， ２’ −
０一ジ置換−ＣＡＭＰと略称する）又はその塩、及びそ
の新規な製法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel N'',2'-0-disubstituted monoadenosine-3',5' monocyclic phosphoric acid (hereinafter referred to as N6,2'-
0-1 di-substituted-CAMP) or a salt thereof, and a novel method for producing the same.
７デノシン−３’， ５’一環状リン酸（以下ＣＡＭＰ
と略称する）及びその誘導体は、種４の生理活性を有し
、生化学的試薬や医薬としての種々の用途が期待されで
いる。本化合物は新規化合物であり、抗炎症作用、血小
板凝集阻害作用、血圧降下作用等の優れた薬理作用が期
待される。7denosine-3', 5' monocyclic phosphate (hereinafter referred to as CAMP)
) and its derivatives have Type 4 physiological activity and are expected to have various uses as biochemical reagents and medicines. This compound is a new compound and is expected to have excellent pharmacological effects such as anti-inflammatory action, platelet aggregation inhibiting action, and blood pressure lowering action.
Ｎ’，２’−０−ジ置換一ＣＡＭＰ並びにこれを得る方
法は知られていない。N',2'-0-disubstituted 1-CAMP and the method for obtaining it are unknown.
Ｎ’，２’−０−ジ置換一ＣＡＭＰを得る方法について
は未だ報告されておらず、本発明者らはこれらを得る方
法につ（・て鋭意検討を重ねた結果、ＣＡＭＰ又はその
塩を水酸化カリウム、水酸化ナトリウム、炭酸水素カル
シウム等のアルカリ金属又はアルカリ土類金属の水酸化
物、炭酸水素塩等あるいはナトリウムメトキシド等のア
ルコキサイド等の塩基存在下、有機・・ロゲン化物と反
応させることにより、Ｎ６， ２’ −０−ジ置換一Ｃ
ＡＭＰ ，又はその塩を効率良く製造し得ることを見出
した。A method for obtaining N',2'-0-disubstituted mono-CAMP has not yet been reported, and the present inventors have conducted intensive studies on methods for obtaining them. React with an organic logenide in the presence of a base such as an alkali metal or alkaline earth metal hydroxide such as potassium hydroxide, sodium hydroxide, calcium hydrogen carbonate, hydrogen carbonate, or an alkoxide such as sodium methoxide. By this, N6,2'-0-disubstituted -C
It has been found that AMP or its salt can be efficiently produced.
本発明者は、一般式
一般式
（式中Ｒ はアルキル基又はアラアルキル基を示し、Ａ
は水素イオン、アルカリ金属イオン、アンモニウムイ
オン又は有機アンモニウムイオンを示す）で表わされる
Ｎ”，２’ 一〇−ジ置換一アデノシン−３／． ５１
一環状リン酸又はその塩であり、又本発明は
（式中Ａ は水素イオン、アルカリ金属イオン、アンモ
ニウムイオン又は有機アンモニウムイオンを示す）で表
わされるアデノシン−３’， ５’一環状リン酸又はそ
の塩を、塩基存在下、一般式ＲＸ （厘）
（式中Ｒ はアルキル基又はアラアルキル基ヲ示し、Ｘ
はハロゲン原子を示す）で表わされる有機ハロゲン化物
と反応させることを特徴とする一般式
（式中Ｒ 及びＡ は前記の意味を有する）で表わされ
るＮ’，２’−Ｑ−ジ置換−７デノシンー３’， ５’
一環状リン酸又はその塩の製法である。The present inventor has proposed the general formula (where R represents an alkyl group or an aralkyl group, and A
represents a hydrogen ion, an alkali metal ion, an ammonium ion, or an organic ammonium ion).
The present invention is adenosine-3',5' monocyclic phosphoric acid or The salt is prepared by the general formula RX (厘) (wherein R represents an alkyl group or an aralkyl group,
represents a halogen atom) N',2'-Q-disubstituted-7 represented by the general formula (wherein R and A have the above-mentioned meanings) Denosine-3', 5'
This is a method for producing cyclic phosphoric acid or its salt.
以下、本発明を詳述する。The present invention will be explained in detail below.
本発明の出発物質として用いられるＣＡＭＰ又はその塩
は、例えば次のようにして製造できる。CAMP or a salt thereof used as a starting material in the present invention can be produced, for example, as follows.
アデニン、キシロースもしくはリポース及び無機リン酸
塩を含む培地を用いて、ミクロパクテリウＡＩに属し、
アデニン、キシｐ−スモシ＜ハリボースと無機リン酸塩
とがらＣＡＭＰを生産する能力を有する菌を培養し、培
養物よりＣＡＭＰを採取する（特許第６５１７８１号明
細書参照）。更ｔこ遊離のＣＡＭＰ にアルカリ金属又
はアルカリ土類金属の水酸化物、炭酸塩、炭酸水素塩等
あるいは有機アミン好ましくはトリアルキルアミンを作
用させると、ＣＡＭＰ のリン酸部におけるアルカリ金
属塩、例えばナトリウム塩、カリウム塩等、アルカリ土
類金属塩、例えばカルシウム塩、マグネシウム塩等、有
機アンモニウム塩、例えばトリエチルアンモニウム塩等
を得ることができる。belonging to Micropacteriu AI, using a medium containing adenine, xylose or lipose and inorganic phosphate,
A bacterium capable of producing CAMP from adenine, p-sumoshi<haribose, and inorganic phosphate is cultured, and CAMP is collected from the culture (see Patent No. 651,781). Furthermore, when free CAMP is treated with an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogen carbonate, etc. or an organic amine, preferably a trialkylamine, the alkali metal salt in the phosphoric acid moiety of CAMP, e.g. Alkaline earth metal salts such as sodium salts and potassium salts, such as calcium salts and magnesium salts, organic ammonium salts such as triethylammonium salts, etc. can be obtained.
一般式（厘）で表わされる有機・・ｐゲン化物における
Ｒ としては、炭素数１〜ｌ６、特に２〜ｌ４のアルキ
ル基、例えばメチル基、エチル基、プロビル基、イソプ
ロビル基、プチル基、イソブチル基、ペンチル基、イン
ベンチル基、ヘキシル基、イソヘキシル基、ヘプチル基
、オクチル基、ノニル基、デシル基、ドデシル基、テト
ラデンル基、ヘキサデシル基等の直鎖状もしくは分枝状
の７ルキル基、７ラアルキル基、例えばベンジル基、ニ
トロベンジル基、クロロペンジル基、メチルベンジル基
、ハイドロキシベンジル基、フェネチル基、フェニルプ
ロビル基等が挙げられる。In the organic p-genide represented by the general formula (R), R is an alkyl group having 1 to 16 carbon atoms, particularly 2 to 14 carbon atoms, such as a methyl group, an ethyl group, a probyl group, an isopropyl group, a butyl group, Straight chain or branched 7-alkyl groups such as isobutyl group, pentyl group, inventyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, tetradenyl group, hexadecyl group, 7 Raalkyl groups such as benzyl group, nitrobenzyl group, chloropenzyl group, methylbenzyl group, hydroxybenzyl group, phenethyl group, phenylprobyl group and the like.
本発明を実施するに際しては、式（Ｉｔ）の化合物を水
酸化カリウム、水酸化ナトリウム、炭酸水素カルシウム
等のアルカリ金属又はアルカリ土類金属の水酸化物、炭
酸水素塩等あるいはナトリウムメトキシド等のアルコキ
サイド等の塩基存在下、また、アルカリ金属又はアルカ
リ土類金属の水酸化物、炭酸水素塩を用いる場合、好ま
しくはｌ８−クラウン−６、 ｌ５−クラウン−５等の
対応するクラウンエーテル存在下、式（■）の有機ノ・
ロゲン化物と反応させて、式（１）の化合物を得る。In carrying out the present invention, the compound of formula (It) may be used in the form of an alkali metal or alkaline earth metal hydroxide such as potassium hydroxide, sodium hydroxide, calcium hydrogen carbonate, hydrogen carbonate, etc. or sodium methoxide, etc. In the presence of a base such as an alkoxide, and when using an alkali metal or alkaline earth metal hydroxide or hydrogen carbonate, preferably in the presence of a corresponding crown ether such as l8-crown-6 or l5-crown-5, Organic of formula (■)
A compound of formula (1) is obtained by reaction with a halogenide.
この反応は溶剤中で行ない、溶剤としては水、アルコー
ル類例えばメタノール、エタノール等、エーテル類、例
えばジオキサン、テトラヒドロフラン等、アミド類例え
ばジメチルホルムアミド、ジメチルアセトアミド等、有
機カルポン酸のエステル、例えば酢酸エチル等、又はジ
メチルスルホ午サイド等、単独で又は２種以上の混合物
として適宜用いられる。This reaction is carried out in a solvent, including water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide, and esters of organic carboxylic acids such as ethyl acetate. , dimethyl sulfonide, etc., may be used alone or as a mixture of two or more thereof.
式（ｒ１）の化合物に対する弐口１の有機・・ロゲン化
物の使用量は、通常２〜３０倍モル、好ましくは５〜２
０倍モル程度である。また、式（ＩＮ）の化合物に対す
る塩基の使用量は、通常２〜３０倍モル、好ましくは５
〜２０倍モル程度である０この反応は一般にｌＯ〜ｌ５
０゜Ｃ１好ましくは２０〜７０℃の温度において、静置
もしくは撹拌下に１時間以上、好ましくは３時間〜２日
間行なわれる。The amount of the organic halogenide used in No. 1 relative to the compound of formula (r1) is usually 2 to 30 times the molar amount, preferably 5 to 2 times the molar amount.
It is about 0 times the mole. The amount of base to be used is usually 2 to 30 times the mole of the compound of formula (IN), preferably 5 times
This reaction is generally about 10 to 15 molar
0° C1 Preferably, the reaction is carried out at a temperature of 20 to 70° C., with standing or stirring for 1 hour or more, preferably 3 hours to 2 days.
式（１）の目的化合物な単離、精製するには、例えばシ
リカゲル、アルミナ、イオン交換樹脂、活性炭等を用い
るカラムクロマトグラフイ、再結晶法、ｐＨ 調製に
よる析出法、食塩を用いる塩析法、有機溶媒を用いる抽
出法等の精製法を単独で又は適宜組み合わせて行なうこ
とができる。式（１）の化合物の遊離酸に、例えばアル
カリ金属又はアルカリ土類金属の水酸化吻、炭酸塩、炭
酸水素塩等あるいはアンそ二７又は有機アミン、例えば
トリエチルアミン、トリブチルアミン等の三級アミンを
作用させることにより、式（！）の化合物の環状リン酸
部における対応する塩に導くことができる。To isolate and purify the target compound of formula (1), for example, column chromatography using silica gel, alumina, ion exchange resin, activated carbon, etc., recrystallization method, precipitation method by pH adjustment, salting out method using common salt. Purification methods such as extraction methods using organic solvents may be used alone or in appropriate combinations. The free acid of the compound of formula (1) may be added, for example, to an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogen carbonate, etc., or an organic amine, such as a tertiary amine such as triethylamine or tributylamine. can lead to the corresponding salt at the cyclic phosphate moiety of the compound of formula (!).
本発明により得られる式（１）のＮ６， ２’ −０一
ジ置換−ＣＡＭＰ及びその塩の例としては、次のものが
挙げられ、Ｎ６． ２’−０−ジメチルーＣＡＭＰ ，
Ｎ６， ２’一〇−ジエチルーＣＡＭＰ ， Ｎ６２
′一〇一ジプロピルーＣＡＭＰ ， ＮＯ， ２’ −
０−ジイソプロピルーＣＡＭＰ ， Ｎ６， ２’ −
０−ジプチルーＣＡＭＰ ， Ｎ６， ２’−０−ジイ
ソブチルーＣＡＭＰ ，Ｎ６，２’−０−ジペンチルー
ＣＡＭＰ ， ＮＯ， ２’−０−ジイソペンチルーＣ
ＡＭＰ ， Ｎ６， ２’ −０−ジネオペンチルーＣ
ＡＭＰ ， Ｎ６， ２’ −０−ジヘキシル−ＣＡＭ
Ｐ ， Ｎ６， ２’一〇−ジイソヘキシルーＣＡＭＰ
， Ｎ６， ２’−０−ジヘプチルーＣＡＭＰＮ６．
２’一〇−ジオクチルーＣＡＭＰ ， Ｎ６， ２’−
０一ジノニルーＣＡＭＰ ＳＮ’， ２’ 一〇−ジデ
シルーＣＡＭＰ ， Ｎ８， ２’−０−ジウンデル−
ＣＡＭＰＮ６．２’−０−ジドデシルーＣＡＭＰ ，
Ｎ’， ２’−０一ジトリデシルーＣＡＭＰ ， ＮＢ
， ２’ −０−ジテトラデシルーＣＡＭＰ ， ＮＯ
， ２’ −０−ジペンタデシルーＣＡＭＰ ， Ｎ６
， ２’ −０−ジヘキサデシルーＣＡＭＰ ， Ｎ６
， ２’−０−ジペンジルーＣＡＭＰＮ６，２’−０−
ジニトロベンジルーＣＡＭＰ ， Ｎ６２′一〇一ジク
ーロベンジルーＣＡＭＰ ， ＮＯ， ２’０−ジメチ
ルペンジルーＣＡＭＰ ， Ｎ６， ２’ −０ −ジ
ハイドロキンペンジルーＣＡＭＰ ， Ｎ６， ２’
−０一ジー２−フエニルエチルーＣＡＭＰ ， Ｎ６，
２’−０−ジー３−フエニルプロピルーＣＡＭＰ等、
及びこれらのアルカリ金属塩、アンモニウム塩及び有ｌ
アンモニウム塩等である。Examples of N6, 2'-0 monodisubstituted -CAMP of formula (1) and salts thereof obtainable according to the present invention include the following: N6. 2'-0-dimethyl-CAMP,
N6, 2'10-diethyl-CAMP, N62
'101 dipropyl-CAMP, NO, 2' -
0-diisopropyl-CAMP, N6, 2'-
0-diptyl-CAMP, N6, 2'-0-diisobutyl-CAMP, N6,2'-0-dipentyl-CAMP, NO, 2'-0-diisopentyl-C
AMP, N6, 2'-0-dineopentyl-C
AMP, N6, 2'-0-dihexyl-CAM
P, N6, 2'10-diisohexyl CAMP
, N6, 2'-0-diheptyl-CAMPN6.
2'10-dioctyl CAMP, N6, 2'-
01 dinonyl CAMP SN', 2' 10-didecyl CAMP, N8, 2'-0-diundel-
CAMPN6.2'-0-didodecyl-CAMP,
N', 2'-0-ditridecyl-CAMP, NB
, 2'-0-ditetradecyl-CAMP, NO
, 2'-0-dipentadecyl-CAMP, N6
, 2'-0-dihexadecyl-CAMP, N6
, 2'-0-dipendylu CAMPN6,2'-0-
Dinitrobenzyl-CAMP, N62'101 dicourobenzyl-CAMP, NO, 2'0-dimethylpenzyl-CAMP, N6, 2' -0-dihydroquinepenzyl-CAMP, N6, 2'
-0-2-phenylethyl-CAMP, N6,
2'-0-di-3-phenylpropyl-CAMP, etc.
and alkali metal salts, ammonium salts and alkali metal salts thereof
Ammonium salts, etc.
また本発明によれば、新規化合物であるＮｂ２′一〇−
ジ置換−７デノシン−３’， ５’一環状リン酸及びそ
の塩を効率良く製造することができる。Further, according to the present invention, a new compound Nb2'10-
Disubstituted-7denosine-3',5' cyclic phosphoric acid and its salts can be efficiently produced.
本発明の新規なＮ６， ２’ −０−ジ置換−７デノシ
ン−３’， ５’一環状リン酸及びその塩は、例えば抗
炎症作用、血小板凝集阻害作用、血圧降下作用等の優れ
た薬理作用が期待されるものであり、また本発明は該化
合物を極めて効率良く提供することができるものであっ
て、本発明は産業上極めて有意義なものである。The novel N6,2'-0-disubstituted-7denosine-3',5' monocyclic phosphoric acid and its salts have excellent pharmacological properties such as anti-inflammatory action, platelet aggregation inhibiting action, and hypotensive action. The present invention is expected to have an effect, and the present invention can provide the compound extremely efficiently, making the present invention extremely meaningful industrially.
以下、実施例により本発明を具体的に示す。Hereinafter, the present invention will be specifically illustrated by examples.
実施例Ｉ
Ｎ６．２’−０−ジプロピルーＣＡＭＰの製造ＣＡＭＰ
のトリプチルアミン塩３．０８４ ，Ｓ！をジメチル
スルホキサイド５０ ｄに溶解し、これにナトリウムメ
トキサイド２．５６ｍ／を添加し、３０分後ニｎ−プロ
ビルブロマイド１．０９履ｌを加えて、室温で１日間撹
拌する。この間ナトリウムメトキサイドとｎ−プロビル
プロマイドを上記の方法と同様に５回添加する。次いで
、反応液を水浴中５０℃で１日間撹拌し、その間ナトリ
ウムメトキサイドと ｎ−プロビルプロマイドを上記の
方法と同様に５回添加する。反応液を２Ｎ−塩酸で中和
した後、溶媒を減圧留去した。残留する油状物質を少量
の水に溶解し、２Ｎ一塩酸を加えてｐＨ２に調整し、こ
れを活性炭カラム（２．Ｉ Ｘ ３４０》に吸着させ、
水洗後、エタノール／水／２８％水酸化アンモニウム（
容量比； ｔｏ： １０： ｌ）を用いて溶出する区
分を採取し、これを減圧乾固する。得られたカラメル状
物質を少量のメタノールに溶解し、２Ｎ−塩酸を加えて
ｐＨ ３に調整し、これをシリカゲル薄層クロマト
グラフイ （展１１｝ｆｌＦ［ ；メタノール／クロロ
ホルム、容量比；３：７》により分離精製し、目的化合
物のＷ吸収帯（Ｒｆ値０．４付近）をかき取り、メタノ
ールで抽出し減圧乾固すると、Ｎ６， ２’ −０−ジ
プーピルーＣＡＭＰを４２７ ｍｙ （収率ｌ７．２％
）得た。Example I Preparation of N6.2'-0-dipropyl CAMP
Triptylamine salt of 3.084,S! was dissolved in 50 d of dimethyl sulfoxide, 2.56 ml of sodium methoxide was added thereto, and after 30 minutes, 1.09 liter of di-n-propylbromide was added, and the mixture was stirred at room temperature for 1 day. During this time, sodium methoxide and n-provil bromide are added five times in the same manner as above. The reaction solution is then stirred in a water bath at 50° C. for 1 day, during which time sodium methoxide and n-provil bromide are added five times in the same manner as described above. After neutralizing the reaction solution with 2N hydrochloric acid, the solvent was distilled off under reduced pressure. The remaining oily substance was dissolved in a small amount of water, the pH was adjusted to 2 by adding 2N monohydrochloric acid, and this was adsorbed on an activated carbon column (2.I X 340》).
After washing with water, ethanol/water/28% ammonium hydroxide (
A fraction eluted using a volume ratio of (to: 10: l) is collected and dried under reduced pressure. The obtained caramel-like substance was dissolved in a small amount of methanol, 2N-hydrochloric acid was added to adjust the pH to 3, and this was subjected to silica gel thin layer chromatography (Example 11}flF[; methanol/chloroform, volume ratio; 3: 7), the W absorption band (Rf value around 0.4) of the target compound was scraped off, extracted with methanol, and dried under reduced pressure. .2%
)Obtained.
Ｕｖ ： λ０ニニ″： ”’ （ｇ ）
２６６ （１７２００） ｎｍｍｐ ： １５９
〜１６１℃
Ｒｆ値：０．４７（展開溶媒；メタノール／クロロホル
ム、容量比；４：６以下同じ）
実施例２
Ｎ６，２’−０−ジプチルーＣＡＭＰの製造ＣＡＭＰ
のトリブチルアミン塩３．０８４ ｇをジメチルスルホ
キサイド５０ ｍｌに溶解し、これにナトリウムメトキ
サイド２．５６履ｌを添加し、３０分後にｎ−プチルプ
ロマイド１．２９ａ＋＃を加えて、室温で１日間撹拌す
る。この間ナトリウムメトキサイドと ｎ−プチルプロ
マイドを上記の方法と同様に５回添加する。次いで、反
応液を水浴中５０℃で６時間撹拌し、その間ナトリウム
メトキサイドとｎ−ブチルブロマイドを上記の方法と同
様に３回添加する。反応液を２Ｎ−塩酸で中和した後、
溶媒を減圧留去した。残留する油状物質を少量の水に溶
解し、２Ｎ−塩酸を加えてｐＨ ２に調整し、これを活
性炭カラム（２．Ｉ Ｘ ３１ ｃｍ）會こ吸着させ、
水洗後、エタノール／水／２８％水酸化アンモニウム（
容量比； １０： １０： ｌ）を用いて溶出する区
分を採取し、これを減圧乾固する。Uv: λ0 Nini'': ”' (g)
266 (17200) nmmp: 159
~161°C Rf value: 0.47 (Developing solvent: methanol/chloroform, volume ratio: 4:6 or less, the same) Example 2 Production of N6,2'-0-diptylu CAMP
Dissolve 3.084 g of tributylamine salt in 50 ml of dimethyl sulfoxide, add 2.56 liters of sodium methoxide, add 1.29a+# of n-butyl bromide after 30 minutes, and dissolve at room temperature. Stir for 1 day. During this time, sodium methoxide and n-butyl bromide were added five times in the same manner as above. The reaction solution is then stirred in a water bath at 50 DEG C. for 6 hours, during which time sodium methoxide and n-butyl bromide are added three times in the same manner as described above. After neutralizing the reaction solution with 2N-hydrochloric acid,
The solvent was removed under reduced pressure. The remaining oily substance was dissolved in a small amount of water, the pH was adjusted to 2 by adding 2N-hydrochloric acid, and this was adsorbed on an activated carbon column (2.I x 31 cm).
After washing with water, ethanol/water/28% ammonium hydroxide (
A fraction eluted using a volume ratio of 10:10:1) is collected and dried under reduced pressure.
得られたカラメル状物質を少量のメタノールに溶解し、
２Ｎ−塩酸を加えてｐＨ ３に調整し、これをシリカゲ
ル薄層クロマトグラフイ（展開溶媒；メタノール／クロ
ロホルム、容量比；３：７）により分離精製し、目的化
合物のＷ吸収帯（Ｒｆ値０．４付近）をかき取り、メタ
ノールで抽出し減圧乾固すると、Ｎ６． ２’ 一〇−
ジブチルーＣＡＭＰを５３４ ｍｆ （収率２０．２％
）得た。Dissolve the resulting caramelized substance in a small amount of methanol,
The pH was adjusted to 3 by adding 2N-hydrochloric acid, and this was separated and purified by silica gel thin layer chromatography (developing solvent: methanol/chloroform, volume ratio: 3:7) to detect the W absorption band of the target compound (Rf value 0). .4) was scraped off, extracted with methanol, and dried under reduced pressure to obtain N6. 2' 10-
534 mf of dibutyl-CAMP (yield 20.2%
)Obtained.
ＵＶ ： λ ’＝Ａ″： ”” （ｇ ）
２６７ （１６４００） ｎｍｍｐ ： １５
６ 〜１５８℃
Ｒｆ値：０．５３
実施例３
Ｎ６，２’−０−ジベンチルーＣＡＭＰの製造ＣＡＭＰ
のトリプチルアミン塩３．０８４ ，９をジメチルス
ルホキサイド１００ ｍｌに溶解し、これにナトリウム
メトキサイド２．５６履ｌを添加し、３０分後にｎ−７
ミルブロマイド１．４８履ｌを加えて、室温で２１時間
撹拌する。この間ナトリウムメトキサイドとｎ−７ミル
ブロマイドを上記の方法と同様に５回添加する。反応液
を２Ｎ−塩酸で中和した後、溶媒を減圧留去した。残留
する油状物質を少量の水に溶解し、２Ｎ一塩酸を加えて
ｐＨ ２に調整し、これを活性炭カラム（２．Ｉ Ｘ
３４ ｃｍ＞に吸着させ、水洗後、エタノール／水／
２８％水酸化アンモニウム（容量比； １０： １０
： １）を用いて溶出する区分及びエタノール／水／２
８％水酸化アンモニウム（容量比； ｌＯ：５：ｌ）
を用いて溶出する区分を採取し、これを減圧乾固する。UV: λ'=A″: ”” (g)
267 (16400) nmmp: 15
6 to 158°C Rf value: 0.53 Example 3 Production of N6,2'-0-dibenzene CAMP
3.084.9 of triptylamine salt was dissolved in 100 ml of dimethyl sulfoxide, 2.56 liters of sodium methoxide was added thereto, and after 30 minutes, n-7
Add 1.48 l of milbromide and stir at room temperature for 21 hours. During this time, sodium methoxide and n-7 milbromide are added five times in the same manner as above. After neutralizing the reaction solution with 2N hydrochloric acid, the solvent was distilled off under reduced pressure. The remaining oily substance was dissolved in a small amount of water, the pH was adjusted to 2 by adding 2N monohydrochloric acid, and this was applied to an activated carbon column (2.
34 cm>, and after washing with water, ethanol/water/
28% ammonium hydroxide (volume ratio; 10:10
: 1) Elution segment using ethanol/water/2
8% ammonium hydroxide (volume ratio; lO:5:l)
Collect the eluted fraction using a 100% water filter, and evaporate it to dryness under reduced pressure.
得られたカラメル状物質を少量のメタノールに溶解し、
２Ｎ−塩酸を加えてｐＨ ３に調整し、これをシリカゲ
ル薄層クロマトグラフイ（展開溶媒；メタノール／クロ
ロホルム、容量比；３：７）により分離精製し、目的化
合物のＷ吸収帯（Ｒｆ［ ０．４５付近）をかき取り、
メタノールで抽出し減圧乾固すると、Ｎ６， ２’ ＝
Ｏ−ジベンチルーＣＡＭＰを８９０ １１ｇ（収率３ｌ
．６％）得た。Dissolve the resulting caramelized substance in a small amount of methanol,
The pH was adjusted to 3 by adding 2N-hydrochloric acid, and this was separated and purified by silica gel thin layer chromatography (developing solvent: methanol/chloroform, volume ratio: 3:7), and the W absorption band (Rf [ 0 .45) scrape off,
When extracted with methanol and dried under reduced pressure, N6, 2' =
890 11g of O-dibenthyl CAMP (yield 3l)
．． 6%) obtained.
Ｕｖ： λＯｓａｄＮ＆” ＜ｔ ） ２６７ （１
５９００） ｒｕｎｍｐ ： １５２ 〜１５３℃
Ｒｆ値：０．５８
実施例４
Ｎ６， ２’−０−ジヘプチルーＣＡＭＰの製造ＣＡＭ
Ｐ のトリプチルアミン塩３．０８４ ，ｐをジメチル
スルホキサイド１００ ａｔに溶解し、これにナトリウ
ムメトキサイド２．５６ｍ／を添加し、３０分後にｎ−
ヘプチルプロマイド１．８８ｍ／を加えて、室温で２０
時間撹拌する。この間ナトリウムメトキサイドとｎ−ヘ
プチルブロマイドを上記の方法と同様に３回添加する。Uv: λOsadN &” <t) 267 (1
5900) runmp: 152 to 153°C Rf value: 0.58 Example 4 Production of N6, 2'-0-diheptyl-CAMP CAM
Triptylamine salt 3.084, p of P was dissolved in 100 at of dimethyl sulfoxide, 2.56 m/s of sodium methoxide was added thereto, and after 30 minutes n-
Add 1.88 m/heptyl bromide and
Stir for an hour. During this time, sodium methoxide and n-heptyl bromide are added three times in the same manner as above.
反応液を２Ｎ−塩酸で中和した後、溶媒を減圧留去した
。残留する油状物質を少量の水に溶解し、２Ｎ＝塩酸を
加えてｐＨ ２に調整し、これを活性炭カラム（２．
Ｉ Ｘ ３２ｃｍ）に吸着させ、水洗後、エタノール／
水／ ２８％水酸化アンモニウム（容量比； １０：
１０： ｌ）を用いて溶出する区分、及びエタノール
／水／２８％水酸化アンモニウム（容量比；１０：５：
ｌ）を用いて溶出する区分を採取し、これを減圧乾固す
る。得られたカラメル状物質を少量のメタノールに溶解
し、２Ｎ−塩酸を加えて ｐＨ ３に調整し、これを
シリカゲル薄層クロマトグラフィ （展開溶媒；メタノ
ール／クロロホルム、容量比；２５ ： ７５）により
分離精製し、目的化合物のＷ吸収帯（Ｒｆ ｆｍ Ｏ．
４３付近）をかき取り、メタノールで抽出し減圧乾固す
ると、Ｎ”，２’−０−ジヘプチルーＣＡＭＰ を９８
５り（収率３１．３％）得た。After neutralizing the reaction solution with 2N hydrochloric acid, the solvent was distilled off under reduced pressure. The remaining oily substance was dissolved in a small amount of water, the pH was adjusted to 2 by adding 2N hydrochloric acid, and this was transferred to an activated carbon column (2.
I x 32 cm), and after washing with water, ethanol/
Water/28% ammonium hydroxide (volume ratio; 10:
10:1) and ethanol/water/28% ammonium hydroxide (volume ratio; 10:5:
Collect the fraction eluted using 1) and dry it under reduced pressure. The obtained caramel-like substance was dissolved in a small amount of methanol, the pH was adjusted to 3 by adding 2N-hydrochloric acid, and this was separated and purified by silica gel thin layer chromatography (developing solvent: methanol/chloroform, volume ratio: 25:75). Then, the W absorption band (Rf fm O.
43), extracted with methanol, and dried under reduced pressure to obtain 98% of N'',2'-0-diheptyl-CAMP.
5 (yield 31.3%) was obtained.
Ｕ′ｖ： λ 〇二二″： ”０Ｈ （ｇ ）
２６７ （１５２００） ｎｍｍｐ ： １１
８ 〜１２１ ”Ｃ
Ｒｆ値：０．６４
実施例５
Ｎ’，２’−０−ジベンジルーＣＡＭＰの製造水酸化カ
リウム５．２８ｐを溶解した水３０１ｌにＣＡＭＰ ３
．２９ ｇを溶解し、これに１８−クラウン−６を７．
９３ ｇ溶解したジオキサン１５０ ｄを添加する。次
いで、ベンジルブロマイド７． １４ ｍｌ ’ｋ 添
加し、水浴中５０゜Ｃで３時間撹拌する。反応液を ２
Ｎ一塩酸で中和した後、溶媒一を減圧留去した。残留す
る油状物質を少量の水に溶解し、２Ｎ−塩酸を加えてｐ
Ｈ ２に調整し１これを活性炭力ラム（２．６ Ｘ
２８σ）に吸着させ、水洗後、エタノール／水／２８％
水酸化アンモニウム（容量比； １０：１０：ｌ）を
用いて溶出する区分を採取し、これを減圧乾固する。得
られたカラメル状物質を少量のメタノールに溶解し、２
Ｎ−塩酸を加えてｐＨ ３に調整し、これをシリカゲ
ル薄層クロマトグラフ｛（展開溶媒；メタノール／クロ
ロホルム、容量比；４：６）により分離精製し、目的化
合物の間 吸収帯（Ｒｆ ＠Ｉ ０．５付近）をかき取
り、メタノールで抽出し減圧乾固すると、Ｎ６．２’−
０−ジベンジルーＣＡＭＰ を２１０７ ｍｇ（収率
４１６４％）得た。U′v: λ 〇22″: ”0H (g)
267 (15200) nmmp: 11
8 to 121 "C Rf value: 0.64 Example 5 Production of N',2'-0-dibenzyl-CAMP CAMP 3 was dissolved in 301 liters of water in which 5.28 p of potassium hydroxide was dissolved.
．． Dissolve 29 g and add 7.18-crown-6 to it.
Add 93 g dissolved dioxane 150 d. Then benzyl bromide 7. Add 14 ml'k and stir for 3 hours at 50°C in a water bath. 2 of the reaction solution
After neutralizing with N-hydrochloric acid, the solvent was distilled off under reduced pressure. Dissolve the remaining oily substance in a small amount of water and add 2N-hydrochloric acid to p
Adjust to 2 H and add it to activated carbon ram (2.6
28σ), and after washing with water, ethanol/water/28%
A fraction eluted with ammonium hydroxide (volume ratio; 10:10:l) is collected and dried under reduced pressure. The resulting caramelized substance was dissolved in a small amount of methanol, and 2
The pH was adjusted to 3 by adding N-hydrochloric acid, and this was separated and purified using silica gel thin layer chromatography (developing solvent: methanol/chloroform, volume ratio: 4:6), and an absorption band (Rf @I) was obtained between the target compound. 0.5), extracted with methanol, and dried under reduced pressure to obtain N6.2'-
2107 mg (yield 4164%) of 0-dibenzyl-CAMP was obtained.
ＵＶ ： λ ’ｍｉｍ ”” （ｔ ）
２６７ （１８４００） ｎｍｍｐ ： １５
３ 〜１５６℃
Ｒｆ値：０．５６UV: λ'mim"" (t)
267 (18400) nmmp: 15
3 ~ 156℃ Rf value: 0.56
Claims (2)
水素イオン、アルカリ金属イオン、アンモニウムイオン
又は有機アンモニウムイオンを示す）で表わされるＮ＾
６，２′−Ｏ−ジ置換−アデノシン−３′，５′−環状
リン酸又はその塩。(1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents an alkyl group or an aralkyl group, and A represents a hydrogen ion, an alkali metal ion, an ammonium ion, or an organic ammonium ion). expressed N^
6,2'-O-disubstituted-adenosine-3',5'-cyclic phosphoric acid or a salt thereof.
ウムイオン又は有機アンモニウムイオンを示す）で表わ
されるアデノシン−３′，５′−環状リン酸又はその塩
を、塩基存在下、一般式 ＲＸ（III） （式中Ｒはアルキル基又はアラアルキル基を示し、Ｘは
ハロゲン原子を示す）で表わされる有機ハロゲン化物と
反応させることを特徴とする一般式 ▲数式、化学式、表等があります▼（ I ） （式中Ｒ及びＡは前記の意味を有する）で表わされるＮ
＾６，２′−Ｏ−ジ置換−アデノシン−３′，５′−環
状リン酸又はその塩の製法。(2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) Adenosine-3',5'- (in the formula, A represents a hydrogen ion, alkali metal ion, ammonium ion, or organic ammonium ion) It is characterized by reacting a cyclic phosphoric acid or a salt thereof with an organic halide represented by the general formula RX (III) (wherein R represents an alkyl group or an aralkyl group and X represents a halogen atom) in the presence of a base. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ N expressed by (I) (in the formula, R and A have the above meanings)
A method for producing ^6,2'-O-disubstituted-adenosine-3',5'-cyclic phosphoric acid or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1052842A JPH07116213B2 (en) | 1989-03-07 | 1989-03-07 | Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1052842A JPH07116213B2 (en) | 1989-03-07 | 1989-03-07 | Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02233692A true JPH02233692A (en) | 1990-09-17 |
| JPH07116213B2 JPH07116213B2 (en) | 1995-12-13 |
Family
ID=12926098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1052842A Expired - Lifetime JPH07116213B2 (en) | 1989-03-07 | 1989-03-07 | Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07116213B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5346047A (en) * | 1990-09-20 | 1994-09-13 | Kabushiki Kaisha Nippon Conlux | Coin processing apparatus |
| WO2003104250A1 (en) * | 2002-06-07 | 2003-12-18 | Kylix, B. V. | New compounds for modulating the activity of exchange proteins directly activated by camp (epacs) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56148218A (en) * | 1980-04-18 | 1981-11-17 | Kikkoman Shoyu Co Ltd | Saccharide increasing method of vegetable |
-
1989
- 1989-03-07 JP JP1052842A patent/JPH07116213B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56148218A (en) * | 1980-04-18 | 1981-11-17 | Kikkoman Shoyu Co Ltd | Saccharide increasing method of vegetable |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5346047A (en) * | 1990-09-20 | 1994-09-13 | Kabushiki Kaisha Nippon Conlux | Coin processing apparatus |
| WO2003104250A1 (en) * | 2002-06-07 | 2003-12-18 | Kylix, B. V. | New compounds for modulating the activity of exchange proteins directly activated by camp (epacs) |
| JP2005532360A (en) * | 2002-06-07 | 2005-10-27 | キリックス・ベー・ヴェー | Novel compounds for modulating the activity of exchange protein (Epac) directly activated by cAMP |
| AU2003242672B2 (en) * | 2002-06-07 | 2009-12-17 | Universitair Medisch Centrum Utrecht | New compounds for modulating the activity of exhange proteins directly activated by camp (EPACS) |
| US7906491B2 (en) | 2002-06-07 | 2011-03-15 | Univisitair Medisch Centrum Utrecht | Compounds for modulating the activity of exchange proteins directly activated by cAMP (Epacs) |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07116213B2 (en) | 1995-12-13 |
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