JPH03240779A - New hetero-ring derivative and drug containing thereof - Google Patents
New hetero-ring derivative and drug containing thereofInfo
- Publication number
- JPH03240779A JPH03240779A JP3364890A JP3364890A JPH03240779A JP H03240779 A JPH03240779 A JP H03240779A JP 3364890 A JP3364890 A JP 3364890A JP 3364890 A JP3364890 A JP 3364890A JP H03240779 A JPH03240779 A JP H03240779A
- Authority
- JP
- Japan
- Prior art keywords
- agent
- acid addition
- addition salt
- active ingredient
- group
- 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.)
- Pending
Links
- 229940079593 drug Drugs 0.000 title description 5
- 239000003814 drug Substances 0.000 title description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 6
- 239000000043 antiallergic agent Substances 0.000 claims abstract description 6
- 239000000924 antiasthmatic agent Substances 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 239000013543 active substance Substances 0.000 claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 206010040070 Septic Shock Diseases 0.000 claims abstract description 4
- 230000001986 anti-endotoxic effect Effects 0.000 claims abstract description 4
- 230000002253 anti-ischaemic effect Effects 0.000 claims abstract description 4
- 230000001518 anti-nephritic effect Effects 0.000 claims abstract description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- 239000000126 substance Substances 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000004480 active ingredient Substances 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 150000001450 anions Chemical class 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 229940127218 antiplatelet drug Drugs 0.000 claims description 5
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 4
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 4
- 239000002220 antihypertensive agent Substances 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 39
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 2
- SUGNCCCDWYULCQ-UHFFFAOYSA-M [Cl-].C(CCCCCCCCCCCCCCC)OC(=O)N1CC(CCC1)C(C[N+]1=CSC=C1)SC Chemical compound [Cl-].C(CCCCCCCCCCCCCCC)OC(=O)N1CC(CCC1)C(C[N+]1=CSC=C1)SC SUGNCCCDWYULCQ-UHFFFAOYSA-M 0.000 abstract 1
- 230000002946 anti-pancreatic effect Effects 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- 238000012986 modification Methods 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 136
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- 238000003756 stirring Methods 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 238000001816 cooling Methods 0.000 description 40
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 238000010898 silica gel chromatography Methods 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- -1 nanodecyl Chemical group 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000843 powder Substances 0.000 description 21
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 150000004820 halides Chemical class 0.000 description 12
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 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 10
- ORECNKBJIMKZNX-UHFFFAOYSA-N 1,3-thiazol-3-ium;chloride Chemical compound Cl.C1=CSC=N1 ORECNKBJIMKZNX-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 230000000704 physical effect Effects 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 6
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 102000015439 Phospholipases Human genes 0.000 description 5
- 108010064785 Phospholipases Proteins 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 230000003042 antagnostic effect Effects 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000013076 target substance Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000004531 blood pressure lowering effect Effects 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000026030 halogenation Effects 0.000 description 4
- 238000005658 halogenation reaction Methods 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 4
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- YOMFVLRTMZWACQ-UHFFFAOYSA-N ethyltrimethylammonium Chemical compound CC[N+](C)(C)C YOMFVLRTMZWACQ-UHFFFAOYSA-N 0.000 description 3
- HOQUWXSARQBQCW-UHFFFAOYSA-N hexadecyl carbonochloridate Chemical compound CCCCCCCCCCCCCCCCOC(Cl)=O HOQUWXSARQBQCW-UHFFFAOYSA-N 0.000 description 3
- 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 3
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 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 2
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Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は新規なヘテロ環誘導体及びそれを含有する薬剤
に関し、詳しくは血小板活性化因子(platelet
activating factor、以下PAFと
略記する。)に対する拮抗作用、PAF様血圧降下作用
、ホスホリパーゼ(phospholipase)阻害
作用並びに腫瘍に対する増殖抑制作用または分化誘導作
用を有する新規なヘテロ環誘導体及びそれを有効成分と
して含有する医薬品に関する。Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel heterocyclic derivative and a drug containing the same.
activating factor, hereinafter abbreviated as PAF. The present invention relates to a novel heterocyclic derivative having an antagonistic effect on PAF-like blood pressure lowering effect, a phospholipase inhibitory effect, and a growth-inhibiting effect or differentiation-inducing effect on tumors, and a pharmaceutical containing the same as an active ingredient.
〔従来の技術、発明が解決しようとする課!I!]近年
、血小板からの白血球依存性の活性アミンの放出反応に
関する研究が精力的に進められている。その結果、血小
板の凝集を引き起こす非常に強力な物質が見出され、P
AFと命名された[J、 I+u+uno1.、106
巻、1244ページ(1971年)、J、Exp。[Conventional technology, the problem that the invention attempts to solve! I! ] In recent years, research on the leukocyte-dependent release reaction of active amines from platelets has been vigorously pursued. As a result, a very strong substance that causes platelet aggregation was discovered, and P
Named AF [J, I+u+uno1. , 106
Volume, 1244 pages (1971), J, Exp.
Med、、 136巻、1356ページ(1972年)
及びNature。Med, Volume 136, Page 1356 (1972)
and Nature.
249巻、581ページ(3974年)1゜その後、P
AFはヒトを含む各種動物生体内においてもその存在が
確認された。 1979年には、その構造が決定され[
J、 Biol、 Chew、、 254巻、9355
ページ(1979年)1、下記一般式で示される化合物
の混合物であることが判明した[J、 Biol、 C
heIjp、。Volume 249, page 581 (3974) 1゜After that, P
The existence of AF has also been confirmed in living organisms of various animals including humans. In 1979, its structure was determined [
J. Biol, Chew, vol. 254, 9355.
Page (1979) 1, it was found to be a mixture of compounds represented by the following general formula [J, Biol, C
heIjp,.
255巻、5514ページ(1980年)1゜0e
CL
(式中、nは15または17を表わす。)PAFの生理
的作用としては、当初知られていた強力な血小板凝集分
泌作用だけでなく、非常に強い血圧降下作用及び気管支
収縮作用をも有することが明らかになった。また、PA
Fは人間においても血小板凝集因子の1つであり、さら
にはアレルギー反応や炎症反応の起因物質の1つではな
いかと考えられている(J、 Biol、 Chew、
、 、2」Σ4ヨ9355〜9385(1979))。Volume 255, page 5514 (1980) 1゜0e
CL (In the formula, n represents 15 or 17.) The physiological effects of PAF include not only the initially known strong platelet aggregation and secretion effects, but also extremely strong hypotensive and bronchoconstrictive effects. It became clear. Also, P.A.
F is one of the platelet aggregation factors in humans, and is also thought to be one of the causative agents of allergic reactions and inflammatory reactions (J, Biol, Chew,
, , 2'' Σ4yo 9355-9385 (1979)).
従って、PAFに拮抗する(PAFの作用を阻害する)
化合物は、これまでとは異なる血小板凝集阻害剤、抗喘
息剤、抗アレルギー剤、抗炎症剤等となる可能性が大き
い、また、PAFの作用のうち降圧作用だけを分離する
ことにより、血小板凝集作用を持たない降圧剤として用
いられることも考えられる。これまでに上記作用を示す
化合物としてはグリセロール誘導体が知られているが、
特にその中でCV−3988(Life、5ci、、3
2巻、 1975ページ(19B3年L Prosta
glandins、+ 30巻、715ページ(198
5年)+ J、 Pharwacol、+ 109巻、
257ページ(1985年)〉等が知られている。Therefore, it antagonizes PAF (inhibits the action of PAF)
The compound has great potential to become a different platelet aggregation inhibitor, anti-asthma agent, anti-allergy agent, anti-inflammatory agent, etc. Also, by isolating only the antihypertensive effect of PAF, it is possible to improve platelet aggregation. It is also conceivable that it may be used as an antihypertensive agent without any action. Glycerol derivatives are known as compounds that exhibit the above effects, but
Among them, CV-3988 (Life, 5ci, 3
Volume 2, 1975 pages (19B3 L Prosta
grandins, + 30 volumes, 715 pages (198
5 years) + J, Pharwacol, + 109 volumes,
257 pages (1985)> etc. are known.
本発明は、PAFに拮抗する化合物またはPAF様血圧
降下作用を有する化合物を見出すため幅広い研究を行な
った結果、ある種のヘテロ環誘導体がその目的を達成す
ることを見出して完成されたのである。The present invention was completed after extensive research was conducted to find a compound that antagonizes PAF or a compound that has a PAF-like blood pressure lowering effect, and it was discovered that a certain type of heterocyclic derivative achieves the objective.
一般式(1)
〔式中、Xはメチレン基、ンN−E基(Eは炭素数1〜
8の直鎖または分岐したアルキル基を示す、)酸素原子
あるいはイオウ原子を示す。Aはカルボニル基あるいは
メチレン基を示し、Bは単結合、酸素原子、イオウ原子
、窒素原子あるいはりン酸基を示す、Cは単結合あるい
は炭素数1〜6のアルキレン基を示し、Dはアミノ基あ
るいは式−NHCOR’、−NHR”、−NCR”)z
マタハ” NCR”)IYo(式中、R′は炭素数1〜
6のアルキル基またはフェニル基を示し、Hlは炭素数
1〜6のアルキル基を示し、yeは酸の陰イオンを示す
、ただし、複数のR2が結合している場合にはそれらは
同一であってもまた、環部とAとの結合は単結合でAの
配位がα位あるいはβ位の光学活性体あるいは両配位の
混合物であるラセミ体を示す。]
で表わされるヘテロ環誘導体またはその酸付加塩及びそ
れを有効成分として含有する血小板凝集阻害剤、抗喘息
剤、抗アレルギー剤、抗炎症剤、血圧降下剤、抗エンド
トキシンショック剤、抗腎炎剤、抗膵炎剤、抗虚血性脳
血管障害剤並びに抗腫瘍剤を提供するものである。General formula (1) [In the formula, X is a methylene group, N-N-E group (E is a carbon number of 1 to
(8) represents a straight chain or branched alkyl group, represents an oxygen atom or a sulfur atom. A represents a carbonyl group or a methylene group, B represents a single bond, an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphoric acid group, C represents a single bond or an alkylene group having 1 to 6 carbon atoms, and D represents an amino group. group or formula -NHCOR', -NHR", -NCR")z
Mataha "NCR") IYo (in the formula, R' is a carbon number of 1 to
6 represents an alkyl group or a phenyl group, Hl represents an alkyl group having 1 to 6 carbon atoms, and ye represents an acid anion. However, if multiple R2s are bonded, they are not the same. In this case, the bond between the ring part and A is a single bond, and A is in an optically active form in which the coordination is at the α- or β-position, or a racemic form in which the combination of both coordinations is present. ] Heterocyclic derivatives represented by or acid addition salts thereof, and platelet aggregation inhibitors, anti-asthmatic agents, anti-allergic agents, anti-inflammatory agents, hypotensive agents, anti-endotoxic shock agents, anti-nephritis agents containing the same as active ingredients, The present invention provides an anti-pancreatitis agent, an anti-ischemic cerebrovascular disorder agent, and an anti-tumor agent.
上記一般式(1)で表わされる化合物において、「アル
キル基」、「アルキレン基」とは直鎖または分岐鎖の「
アルキル基」、「アルキレン基」を意味する。さらに、
一般式(1)の化合物においてRが炭素数2〜22のア
ルキル基である場合のアルキル基としてはエチル、プロ
ピル、ブチル、ペンチル、ヘキシル、ヘプチル、オクチ
ル、ノニル。In the compound represented by the above general formula (1), "alkyl group" and "alkylene group" are linear or branched "
"alkyl group" and "alkylene group". moreover,
In the compound of general formula (1), when R is an alkyl group having 2 to 22 carbon atoms, the alkyl group is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl.
デシル、ウンデシル、ドデシル、トリデシル、テトラデ
シル、ペンタデシル、ヘキサデシル、ヘプタデシル、オ
クタデシル、ナノデシル、エイコシル、ヘンリイコシル
、トコシル基及びそれらの異性体が挙げられ、好ましく
は炭素数14〜18のアルキル基であり、特に好ましい
基はヘキサデシル基である。Examples include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nanodecyl, eicosyl, Henriicosyl, tocosyl groups, and isomers thereof, preferably an alkyl group having 14 to 18 carbon atoms, and particularly preferred The group is a hexadecyl group.
一般式(1)の化合物においてCが炭素数1〜6のアル
キレン基である場合、アルキレン基としてはメチレン、
エチレン、トリエチレン、テトラメチレン、ペンタメチ
レン、ヘキサメチレン基及びそれらの異性体が挙げられ
、好ましくはエチレン、トリメチレンである。また、一
般式(1)の化合物においてDが式(−NHCOR’、
−NHR”、−N(R”)zまタハ−ΦN(R”)、Y
e) テアルトキ、R’ * タハp”カ示を炭素数1
〜6のアルキル基としてはメチル、エチル、プロピル、
ブチル、ペンチル、ヘキシル基及びそれらの異性体が挙
げられ、いずれの基も好ましい。また、一般式(1)の
化合物において、Eが炭素数1〜8のアルキル基である
場合のアルキル基としては、メチル、エチル、プロピル
、ブチル、ペンチル、ヘキシル、ヘプチル、オクチル及
びそれらの異性体が挙げられ、好ましくはメチル基であ
る。In the compound of general formula (1), when C is an alkylene group having 1 to 6 carbon atoms, the alkylene group is methylene,
Examples include ethylene, triethylene, tetramethylene, pentamethylene, hexamethylene groups and isomers thereof, preferably ethylene and trimethylene. Further, in the compound of general formula (1), D is of the formula (-NHCOR',
-NHR", -N(R")zmataha-ΦN(R"), Y
e) Tealtoki, R' * Tahap" indicates carbon number 1
~6 alkyl groups include methyl, ethyl, propyl,
Examples include butyl, pentyl, hexyl groups, and isomers thereof, and any group is preferred. In addition, in the compound of general formula (1), when E is an alkyl group having 1 to 8 carbon atoms, examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomers thereof. are mentioned, preferably a methyl group.
次に、一般式(1)で表わされる化合物において、ye
が酸の陰イオンである場合、薬学的に許容される無機酸
及び有機酸の陰イオンを意味し、例えば、塩酸、臭化水
素酸、ヨウ化水素酸、硫酸。Next, in the compound represented by general formula (1), ye
When is an acid anion, it means the anion of pharmaceutically acceptable inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid.
リン酸、硝酸のような無機酸あるいは酢酸、乳酸。Inorganic acids such as phosphoric acid, nitric acid or acetic acid, lactic acid.
酒石酸、安息香酸、クエン酸、メタンスルホン酸。Tartaric acid, benzoic acid, citric acid, methanesulfonic acid.
エタンスルホン酸、ベンゼンスルホン酸、トルエンスル
ホン酸、イセチオン酸のような有機酸の陰イオンが挙げ
られ、好ましい陰イオンはハロゲンイオン、すなわち塩
素イオン、臭素イオン、ヨウ素イオンまたはメタンスル
ホン酸、p−トルエンスルホン酸のような陰イオンであ
る。Anions of organic acids such as ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid may be mentioned, preferred anions are halogen ions, i.e. chloride ion, bromide ion, iodide ion or methanesulfonic acid, p-toluene. It is an anion like sulfonic acid.
(2)1個の窒素原子のみを有するか、あるいは1個の
窒素原子とそれ以外に1個または2個の窒素原子、酸素
原子またはイオウ原子を有しく但し、複素原子の合計数
は3以下とする。)、かつ少なくとも2個の炭素原子を
有し、
(3)単環または架橋された2環性であり、(4)環内
に二重結合を有するか、または有さない、あるいは芳香
性または非芳香性の複素環基であり、さらに
(5)環内に任意の位置(好ましくは窒素原子)が炭素
数1〜6のアルキル基、好ましくはメチル基1〜5個で
置換されていてもよい複素環を意味する。(2) Contains only one nitrogen atom, or one nitrogen atom and one or two other nitrogen, oxygen, or sulfur atoms, provided that the total number of complex atoms is 3 or less shall be. ), and at least 2 carbon atoms; (3) monocyclic or bridged bicyclic; (4) with or without double bonds in the ring; or aromatic or It is a non-aromatic heterocyclic group, and (5) any position (preferably a nitrogen atom) in the ring is substituted with an alkyl group having 1 to 6 carbon atoms, preferably 1 to 5 methyl groups. It means a good heterocycle.
さらに、このような複素環基は、環自体に4級のアンモ
ニウムイオンが存在するか、または環内の窒素原子がア
ルキル置換されて4級のアンモニウムイオンとなってい
る場合には、適当な前述した酸のアニオンと塩を形成す
ることができる。Furthermore, in the case where such a heterocyclic group has a quaternary ammonium ion in the ring itself or a nitrogen atom in the ring is substituted with alkyl to become a quaternary ammonium ion, the appropriate can form salts with the anion of the acid.
このような複素環基としては、例えば次のものが挙げら
れる。Examples of such heterocyclic groups include the following.
びそれらの異性体及び部分飽和体、
らのN−アルキル置換体。なお、複素環基が4級アンモ
ニウムイオンとなるとき、それらと塩を形成する陰イオ
ン(Y−)は前述のY−と同じである。and isomers and partially saturated forms thereof, and N-alkyl substituted forms thereof. In addition, when a heterocyclic group becomes a quaternary ammonium ion, the anion (Y-) which forms a salt with them is the same as Y- mentioned above.
一般式(1)で表わされる本発明化合物には少なくとも
1つの不斉炭素(Aが結合しているヘテロ環の炭素)が
存在し、さらにR,C,R’及びR2が示す種々の置換
基のアルキル部分が分岐鎖を示す場合には、他の不斉炭
素が生じる可能性がある。The compound of the present invention represented by the general formula (1) has at least one asymmetric carbon (carbon of the heterocycle to which A is bonded), and various substituents represented by R, C, R' and R2. When the alkyl moiety of represents a branched chain, other asymmetric carbon atoms may occur.
しかしながら、本発明の一般式(1)で表わされる化合
物は不斉炭素によって生じる各々の異性体及びそれらの
混合物をも含有するものである。However, the compound represented by the general formula (1) of the present invention also contains each isomer generated by an asymmetric carbon and a mixture thereof.
前述の一般式(1)で表わされる化合物は、以下のいず
れかの方法を用いて製造することができる。The compound represented by the above general formula (1) can be produced using any of the following methods.
A法ニ一般式(II)
(モルホリノ基)及びそれらの異性体並びに部分または
完全飽和体または不飽和体、
−OR
〔式中、Rは前記と同じ意味であり、Yはハロゲン原子
(例えば塩素、窒素、ヨウ素)あるいはアルキルスルホ
ル基、好ましくはメタンスルホニル基(すなわちメシル
基)あるいは置換または無置換のアリールスルホニル基
、好ましくはp−)ルエンスルホニル基(すなわちトシ
ル基)を示す。〕で表わされる化合物と一般式(DI)
HO−C−G (III)
あるいは一般式(IV)
R3−C−G (IV)
〔式中、Cは前記と同じ意味であり、Gはハロゲン原子
、水酸基、メルカプト基あるいはアルキルスルホニル基
を示す。〕で表わされる化合物を反に常法に従いアルキ
ルスルホニル化、ハロゲン化とすることにより容易に製
造できる。Method A general formula (II) (morpholino group) and their isomers and partially or completely saturated or unsaturated forms, -OR [wherein R has the same meaning as above, and Y represents a halogen atom (e.g. , nitrogen, iodine) or an alkylsulfol group, preferably a methanesulfonyl group (ie, mesyl group) or a substituted or unsubstituted arylsulfonyl group, preferably a p-)luenesulfonyl group (ie, tosyl group). ] and general formula (DI) HO-C-G (III) or general formula (IV) R3-C-G (IV) [wherein, C has the same meaning as above, and G is a halogen atom , represents a hydroxyl group, a mercapto group, or an alkylsulfonyl group. ] can be easily produced by alkylsulfonylation and halogenation using conventional methods.
A法の一般的製造の反応的は以下の通りである。The general production reaction of Method A is as follows.
品である4−ピペリジンメタノール、3−ピペリジンメ
タノールあるいは2−ピペリジンメタノールを出発物質
として水酸化ナトリウムを合せアルコール溶媒、好まし
くはメタノール、エタノール中においてクロルギ酸ア冷
しキルと反応させ、さらH
ooc
61(ff3
B法ニ一般式(V)
〔式中、R,Yは前記と同し意味である。〕でわされる
化合物と一般式(I[I)および(IV)と法と同様に
反応させることにより容易製造できなお、一般式(V)
で表わされる化合物は、文記載の方法(Chew、 P
harm、 Bull、 33(9) 3766(1あ
るいはJ、 Che+*、 Soc、 Perkin、
Trans、 I 2:(1985))により2−置
換あるいは3−置換モルオリンを製造し、A法と同様に
容易に製造でき光学活性体の場合は、グリセリンあるい
は光?性ア短ノ酸を出発原料にして常法による光学詐グ
リシドールを製造し、光学活性(V)へと七ことができ
る。Starting material is 4-piperidine methanol, 3-piperidine methanol or 2-piperidine methanol, which is combined with sodium hydroxide and reacted with chilled chloroformate in an alcohol solvent, preferably methanol or ethanol, and then H ooc 61 (ff3 Method B) A compound represented by the general formula (V) [wherein R and Y have the same meanings as above] is reacted with the general formula (I[I) and (IV) in the same manner as in the method. The general formula (V) can be easily manufactured by
The compound represented by
harm, Bull, 33(9) 3766 (1 or J, Che+*, Soc, Perkin,
Trans, I 2: (1985)) to produce 2-substituted or 3-substituted moroline, which can be easily produced in the same manner as method A. In the case of an optically active form, glycerin or light? Optical deglycidol can be produced by a conventional method using a basic amino acid as a starting material, and can be converted to optically active (V).
B法の一般的製造法の反応式は以下の通りでる。The general reaction formula of Method B is as follows.
ooc
H33
ooc
H33
COOC1&)133
COOC+1lhi
Nエエ1
COOC+hHsz
3位置換体
CH2Ph
C00C1683:1
COOC16H33
COOC1&H33
ttzph
COOC+dhz
COOC+Jz3
C法ニ一般式
(VI)
〔式中、R及びYは前記と同し意味である。〕で表わさ
れる化合物と一般式(I[I)あるいは(IV)とA法
と同様にして容易に製造できる。なお、般式(V[)で
表わされる化合物はアミノ酸であるシスティンを出発原
料にして、容易に製造できる。ooc H33 ooc H33 COOC1&)133 COOC+1lhi NAE1 COOC+hHsz 3-substituted product CH2Ph C00C1683:1 COOC16H33 COOC1&H33 ttzph COOC+dhz COOC+J z3 C method general formula (VI) [wherein R and Y have the same meanings as above. ] It can be easily produced using the compound represented by the general formula (I[I) or (IV) in the same manner as in Method A. Note that the compound represented by the general formula (V[) can be easily produced using cysteine, which is an amino acid, as a starting material.
C法の一般的製造法の反応式は以下の通りである。The reaction formula of the general production method of Method C is as follows.
C00C16833
COOC+J33
C00CI&H3:1
COOC+Jh:+
C00CI&)133
D法ニ一般式
(■)
〔式中、R及びYは前記と同し意味である。〕で表わさ
れる化合物と一般式(In)あるいは(IV)とA法と
同様にして容易に製造できる。なお、般式(■)は文献
記載の方法(Helv、 Chen+、 Acta、。C00C16833 COOC+J33 C00CI&H3:1 COOC+Jh:+ C00CI&)133 D-method general formula (■) [In the formula, R and Y have the same meanings as above. It can be easily produced using the compound represented by formula (In) or (IV) in the same manner as in Method A. The general formula (■) is based on the method described in literature (Helv, Chen+, Acta, etc.).
2383 (1962))により容易に製造できる。2383 (1962)).
D法の一般的製造法の反応式は以下の通りである。The general reaction formula of Method D is as follows.
本発明の一般式(1)で表わされる化合物のうち好まし
いものとしては、例えば以下の化合物を挙げることがで
きる。Among the compounds represented by the general formula (1) of the present invention, preferred examples include the following compounds.
N−(N”−(ヘキサデシルオキシカルボニル)2−ピ
ペリジニル−メチルチオエチルフチアゾリウムハライド
又はメシレート
N−(N’−(ヘキサデシルオキシカルボニル)3−ピ
ペリジニル−メチルチオエチルフチアゾリウムハライド
又はメシレート
N−(N’−(ヘキサデシルオキシカルボニル)4−ピ
ペリジニル−メチルチオエチル〕チアツリウムハライド
又はメシレート
11− (N’−(ヘキサデシルオキシカルボニル)−
2−ピペリジニル−メチルオキシエチルクチアゾリウム
ハライド又はメシレート
N−(N’−(ヘキサデシルオキシカルボニル)=3−
ピペリジニル−メチルオキシエチルクチアゾリウムハラ
イド又はメシレート
N−CN’−(ヘキサデシルオキシカルボニル)−4−
ピペリジニル−メチルオキシエチルクチアゾリウムハラ
イド又はメシレート
ハロゲン化 N−(N’−(ヘキサデシルオキシカルボ
ニル)−2−ピペリジニル−メチルチオ〕エチルトリメ
チルアンモニウム又はメシレートハロゲン化 N−[N
”−(ヘキサデシルオキシカルボニル)−3−ピペリジ
ニル−メチルチオ]エチルトリメチルアンモニウム又は
メシレートハロゲン化 N−(N’−(ヘキサデシルオ
キシカルボニル)−4−ピペリジニル−メチルチオ〕エ
チルトリメチルアンモニウム又はメシレートN−(N“
−(ヘキサデシルオキシカルボニル)−2−モルホニル
−メチルチオエチルフチアゾリウムハライド又はメシレ
ート
N−(N’−(ヘキサデシルオキシカルボニル)−3−
モルホニル−メチルチオエチルフチアゾリウムハライド
又はメシレート
ハロゲン化 〔N−(ヘキサデシルオキシカルボニル)
−2−モルホリニル−メチルオキシフエチル−トリメチ
ルアンモニウム又はメシレートN−[N’−(ヘキサデ
シルオキシカルボニル)−3−チオモルホリニル−メチ
ル千オニチル〕チアゾリウムハライド又はメシレート
N−(N’−メチル−N”−(ヘキサデシルオキシカル
ボニル)−2−ピペラジニル−メチルチオエチルフチア
ゾリウムハライド又はメシレートN−(N’−(ヘキサ
デシルオキシカルボニル)−2−インドリニル−メチル
チオエチルフチアゾリウムハライド又はメシレート
N−(N”−(ヘキサデシルオキシカルボニル)アミノ
メチル−2−エチルチオエチル〕チアゾリウムハライド
又はメシレート
また、本発明の式(I)で表わされる化合物は薬理上許
容される酸付加塩の形にすることができる。N-(N''-(hexadecyloxycarbonyl)2-piperidinyl-methylthioethyl phthiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)3-piperidinyl-methylthioethyl phthiazolium halide or mesylate N- (N'-(hexadecyloxycarbonyl)4-piperidinyl-methylthioethyl]thiaturium halide or mesylate 11- (N'-(hexadecyloxycarbonyl)-
2-Piperidinyl-methyloxyethylcutiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)=3-
Piperidinyl-methyloxyethylcutiazolium halide or mesylate N-CN'-(hexadecyloxycarbonyl)-4-
Piperidinyl-methyloxyethylcutiazolium halide or mesylate halogenation N-(N'-(hexadecyloxycarbonyl)-2-piperidinyl-methylthio]ethyltrimethylammonium or mesylate halogenation N-[N
"-(hexadecyloxycarbonyl)-3-piperidinyl-methylthio]ethyltrimethylammonium or mesylate halogenated N-(N'-(hexadecyloxycarbonyl)-4-piperidinyl-methylthio]ethyltrimethylammonium or mesylate N-( N“
-(hexadecyloxycarbonyl)-2-morphonyl-methylthioethyl phthiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)-3-
Morphonyl-methylthioethylphthiazolium halide or mesylate halogenation [N-(hexadecyloxycarbonyl)
-2-morpholinyl-methyloxyphethyl-trimethylammonium or mesylate N-[N'-(hexadecyloxycarbonyl)-3-thiomorpholinyl-methylthionityl]thiazolium halide or mesylate N-(N'-methyl-N "-(hexadecyloxycarbonyl)-2-piperazinyl-methylthioethyl phthiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)-2-indolinyl-methylthioethyl phthiazolium halide or mesylate N-(N ``-(hexadecyloxycarbonyl)aminomethyl-2-ethylthioethyl]thiazolium halide or mesylate In addition, the compound represented by formula (I) of the present invention may be in the form of a pharmacologically acceptable acid addition salt. I can do it.
薬理上許容される酸付加塩としては、例えば塩酸、硫酸
、リン酸等の無機酸または巣酸、p−)ルエンスルホン
酸、マレイン酸等の有機酸との酸付加塩等を挙げること
ができる。Examples of pharmacologically acceptable acid addition salts include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as p-)luenesulfonic acid and maleic acid. .
一般式(1)で表わされる本発明化合物は、前記の如(
PAFに対する拮抗作用、PAF様血圧降下作用を有し
ているが、さらにホスホリパーゼ(phosphol
1pase) A を及びCの作用をも阻害することが
見い出された。生体内のカルシウム依存性ホスホリパー
ゼA2及びCは、リン脂質からのアラキドン酸遊離機構
に関与している。生理的刺激によって遊離されたアラキ
ドン酸はプロスタグランジンの代謝経路に取り込まれ、
最終的には強力な血小板凝集作用を有するトロンボキサ
ンA2やその他のプロスタグランジン類に、また喘息発
作時における重要な気管支収縮物質である各種のロイコ
トリエン類に代謝されることが知られている。The compound of the present invention represented by general formula (1) is as described above (
It has an antagonistic effect on PAF and a PAF-like blood pressure lowering effect, but it also has a phospholipase (phospholipase) effect.
1pase) was found to also inhibit the effects of A and C. In vivo calcium-dependent phospholipases A2 and C are involved in the mechanism of arachidonic acid release from phospholipids. Arachidonic acid released by physiological stimulation is incorporated into the prostaglandin metabolic pathway,
It is known that it is eventually metabolized into thromboxane A2 and other prostaglandins, which have a strong platelet aggregation effect, and into various leukotrienes, which are important bronchoconstrictors during asthma attacks.
従って、アラキドン酸の遊離機構に関与するホスホリパ
ーゼA、及びCを阻害する化合物は、PAF拮抗剤とは
異なる作用メカニズムを有し、しかもシクロオキシゲナ
ーゼを阻害するアスピリンの様な従来の非ステロイド性
抗炎症剤とも異なるホリパーゼA2及びCを阻害するこ
とに基づく血小板凝集阻害剤、抗喘息剤、抗アレルギー
剤または抗炎症剤となることが考えられる。Therefore, compounds that inhibit phospholipases A and C, which are involved in the release mechanism of arachidonic acid, have a different mechanism of action than PAF antagonists, and moreover, compounds that inhibit cyclooxygenase such as aspirin, It is thought that the drug may become a platelet aggregation inhibitor, an anti-asthmatic agent, an anti-allergic agent, or an anti-inflammatory agent based on inhibiting different holipases A2 and C.
さらに、一般式(1)で示される本発明化合物は、腫瘍
細胞の増殖抑制作用あるいは文化誘導作用を示し、従っ
て抗腫瘍剤としての用途も期待できる。Furthermore, the compound of the present invention represented by the general formula (1) exhibits a tumor cell growth-inhibiting effect or a culture-inducing effect, and therefore can be expected to be used as an antitumor agent.
本発明の一般式(I)で示されるヘテロ環誘導体または
その酸付加塩を前記の目的で用いるには、通常全身的あ
るいは局所的に経口または非経口で投与される。投与量
は年令9体重、症状、治療効果、投与方法、処理時間等
により異なるが、通常成人1人当り、1回につきIg−
1g、好ましくは20■〜200■の範囲で、1日1回
から数回経口投与されるか、または底入1人当り、1回
につきlOOμg〜100■、好ましくは1■〜10■
の範囲で、1日1回から数回非経口投与される。To use the heterocyclic derivative represented by general formula (I) of the present invention or its acid addition salt for the above-mentioned purpose, it is usually administered systemically or locally, orally or parenterally. The dosage varies depending on the age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but it is usually an Ig-
1 g, preferably in the range of 20 to 200 μg, administered orally once to several times a day, or 10 μg to 100 μg per dose, preferably 1 to 10 μg per dose per person.
It is administered parenterally once to several times a day.
もちろん前記したように投与量は種々の条件で変動する
ので、上記投与範囲より少ない量で十分な場合もあるし
、また範囲を越えて投与する必要のある場合もある。Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases where it is sufficient to use an amount smaller than the above-mentioned dosage range, and there are also cases where it is necessary to administer the dosage beyond the range.
本発明による経口投与のための固体&lllI2物とし
ては、錠剤、散剤、顆粒剤等が含まれる。このような固
体組成物においては、1つまたはそれ以上の活性物質が
少なくとも1つの不活性な希釈剤例えば乳糖、マンニト
ール、ブドウ糖、ヒドロキシプロピルセルロース、微結
晶セルロース、デンプン、ポリビニルピロリドン、メタ
ケイ酸アルミン酸マグネシウムと混合される。Solid objects for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances may be present in at least one inert diluent such as lactose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminate metasilicate. Mixed with magnesium.
組成物は、常法に従って、不活性な希釈剤以外の添加剤
、例えばステアリン酸マグネシウムのような潤滑剤や繊
維素、グルコン酸カルシウムのような崩壊剤を含有して
いてもよい。錠剤または丸剤は必要により白糖、ゼラチ
ン、ヒドロキシプロピルセルロース、ヒドロキシプロピ
ルメチルセルロースフタレートなど胃溶性あるいは腸溶
性物質のフィルムで被覆してもよいし、また2つ以上の
層で被覆してもよい。さらに、ゼラチンのような吸収さ
れうる物質のカプセルも包含される。The compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as cellulose and calcium gluconate, in accordance with conventional methods. Tablets or pills may be coated with a film of gastric or enteric substances such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or may be coated with two or more layers, if necessary. Also included are capsules of absorbable materials such as gelatin.
経口投与のための液体組成物は、薬剤的に許容される乳
濁剤、溶液剤、懸濁剤、シロップ剤、エリキシル剤等を
含み、−船釣に用いられる不活性な希釈剤、例えば精製
水、エタノールを含む。この組成物は不活性な希釈剤以
外に湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、
芳香剤、防腐剤を含有していてもよい。Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. - inert diluents used in boating, e.g. Contains water and ethanol. In addition to inert diluents, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
It may contain aromatics and preservatives.
経口投与のためのその他の組成物としては1つまたはそ
れ以上の活性物質を含み、それ自体公知の方法により処
方されるスプレー剤が含まれる。Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se.
本発明による非経口投与のための注射剤としては、無菌
の水性または非水性の溶液剤、懸濁剤。Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions and suspensions.
乳濁剤を包含する。水性の溶液剤、懸濁剤としては、例
えば注射用蒸留水及び生理食塩水が含まれる。非水溶性
の溶液剤、懸濁剤としては、例えばプロピレングリコー
ル、ポリエチレングリコール。Includes emulsifying agents. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol and polyethylene glycol.
オリーブ油のような植物油、エタノールのようなアルコ
ール類、ポリソルベート80等がある。このような組成
物は、さらに防腐剤、湿潤剤、乳化剤9分散剤のような
補助剤を含んでもよい。これらは、例えばバクテリア保
留フィルターを通す濾過、殺菌剤の配合または照射によ
って無菌課される。これらはまた無菌の固体組成物を製
造し、使用前に無菌水または無菌の注射用溶媒に溶解し
て使用することもできる。These include vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They are rendered sterile, for example by filtration through bacteria-retaining filters, by incorporation of disinfectants or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.
非経口投与のためのその他の組成物としては、1つそれ
以上の活性物質を含み、自体公知の方法により処方され
る。外用液剤、軟コウのような塗布剤、直腸内投与のた
めの坐剤及び腔内投与のためのペッサリー等が含まれる
。Other compositions for parenteral administration, containing one or more active substances, are formulated according to methods known per se. These include liquid preparations for external use, liniments such as soft creams, suppositories for intrarectal administration, and pessaries for intracavitary administration.
以下、実施例により本発明を詳述するが、本発明はこれ
らの実施例に限定されるものではない。EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these Examples.
なお、実施例中のrNMRJ、 rlRJ 、[αIn
はそれぞれ「核磁気共鳴スペクトル」、「赤外吸収スペ
クトル」、「ナトリウムD線による比旋硬度」を表わす
。NMRは重クロロホルム(coc 1 g)溶液で測
定している。In addition, rNMRJ, rlRJ, [αIn
represent "nuclear magnetic resonance spectrum", "infrared absorption spectrum", and "specific rotational hardness by sodium D line", respectively. NMR was measured using a deuterated chloroform (coc 1 g) solution.
実施例1
水素化リチウムアルミニウム(2,2g、 58n+a
+o l )をテトラヒドロフランに懸濁した。15分
間還流した後、3−ピペリジンカルボン酸(57)(5
g、 39開of)を加えた。1時間還流した後、水酸
化カリウム溶液(20■tao l )を加えた。不溶
物質を濾過後、減圧濃縮し、3−ピペリジン−メタノー
ルを油状勧賞として4.0g(収率100χ)得た。Example 1 Lithium aluminum hydride (2.2g, 58n+a
+ol) was suspended in tetrahydrofuran. After refluxing for 15 minutes, 3-piperidinecarboxylic acid (57) (5
g, 39 hours) was added. After refluxing for 1 hour, potassium hydroxide solution (20 μl) was added. After filtering out insoluble substances, the mixture was concentrated under reduced pressure to obtain 4.0 g (yield 100x) of 3-piperidine-methanol as an oily substance.
3−ピペリジンメタノール(1,2g、 10mm+o
ffi)をメタノール2.4dを含む2Nナトリウム溶
液10d(20sso j! )に溶解し、水冷下n−
ヘキサデシルクロロホルメー) (3,0g、 10m
moi)を滴下した。水冷下2時間更に室温で1時間攪
拌した。 IN塩酸でpH3とした後、酢酸エチルで抽
出した。抽出液を硫酸マグネシウムで乾燥した後、減圧
濃縮し、残さをシリカゲルクロマトグラフィーに付し、
N−(ヘキサデシルオキシカルボニル)ピペリジン3−
メタノールを3.7g(収率96z)無色油状として得
た。この化合物の物性値を以下に示す。3-piperidine methanol (1,2g, 10mm+o
ffi) was dissolved in 10 d of 2N sodium solution (20 sso j!) containing 2.4 d of methanol, and cooled with water.
hexadecyl chloroforme) (3.0g, 10m
moi) was added dropwise. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature. After adjusting the pH to 3 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. After drying the extract over magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
N-(hexadecyloxycarbonyl)piperidine 3-
3.7 g (yield 96z) of methanol was obtained as a colorless oil. The physical properties of this compound are shown below.
IR:(νneat)cm−’ 3420.1680.
’H−NMR:δ(CDCf 3)0.88(38,
t J=6.23Hz)、1.26(28H,br)、
1.46J、94(5H,m)、2.57〜4.27(
7H,m)、 3.48(2H,d、 J=5.12
Hz)N−(ヘキサデシルオキシカルボニル)ピペリジ
ン−3−メタノール(3,3g、8.6+w+wo 1
)とトリエチルアミン(1,7g、 17sso j
2 )をジクロルメタンに溶解した。水冷下撹拌しなか
ら4−塩化トルエンスルホニル(2,5g、 13sI
lo l )をジクロルメタン10−に溶解して滴下し
た。室温で一晩撹拌した後、水と飽和食塩水で洗浄した
。ジクロルメタン層を硫酸マグネシウムで乾燥後、減圧
濃縮し、残さをシリカゲルクロマトグラフィーに付し、
ヘキサン−酢酸エチルでt容出し、N−(ヘキサデシル
オキシカルボニル)−3−ピペリジニル−メチル−P−
トルエンスルフェートを白色粉末として3.4g(収率
73z)得た。IR: (νneat)cm-' 3420.1680.
'H-NMR: δ (CDCf 3) 0.88 (38,
t J = 6.23Hz), 1.26 (28H, br),
1.46J, 94 (5H, m), 2.57-4.27 (
7H, m), 3.48 (2H, d, J=5.12
Hz) N-(hexadecyloxycarbonyl)piperidine-3-methanol (3.3g, 8.6+w+wo 1
) and triethylamine (1.7 g, 17sso j
2) was dissolved in dichloromethane. While stirring under water cooling, 4-toluenesulfonyl chloride (2.5 g, 13sI
lo l) was dissolved in dichloromethane 10- and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. After drying the dichloromethane layer with magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
Remove to volume with hexane-ethyl acetate, N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-P-
3.4 g (yield 73z) of toluene sulfate was obtained as a white powder.
IR: (v KBr) cw、−’ 1705.
’H−NMR:δ(C[lCf j)0.88(3H,
t J=5.62Hz)、1.26(28H,br)
、1.52〜2.03 (5H4)。IR: (v KBr) cw, -' 1705.
'H-NMR: δ(C[lCf j)0.88(3H,
t J = 5.62Hz), 1.26 (28H, br)
, 1.52-2.03 (5H4).
2.45(3H,s)、 2.40〜3.02(28
,m)、3.71〜4.26(4H,s+)。2.45 (3H, s), 2.40~3.02 (28
, m), 3.71-4.26 (4H, s+).
7.34(2H,d、 J=8.31 Hz)、7.
79(2H,d、 J=8.31 Hz)。7.34 (2H, d, J=8.31 Hz), 7.
79 (2H, d, J=8.31 Hz).
水素化ナトリウム(480■、 12++no l )
をヘキサンで洗浄した後、テトラヒドロフラン10dに
懸濁した。水冷下撹拌しなから2−メルカプトエタノー
ル(700■、 9.0m5o i! )を滴下した後
、30分間攪拌した。水冷下、N−(ヘキサデシルオキ
シカルボニル)−3−ピペリジニル−メチル−p−)ル
エンスルフエート(3,2g、 6.0mmo 12
)をテトラヒドロフラン10mに溶解して滴下した。6
0°Cで一晩攪拌した後、放冷し、次いで氷水を加えジ
クロロメタンで抽出した。ジクロロメタン層を減圧濃縮
し、残さをシリカゲルクロマトグラフィーに付し、ヘキ
サン−酢酸エチルで溶出しくN−(ヘキサデシルオキシ
カルボニル)−3−ピペリジニル−メチルコチオエチル
アルコールを油状として2.4g(収率68x)得た。Sodium hydride (480■, 12++no l)
After washing with hexane, it was suspended in 10 d of tetrahydrofuran. After stirring under water cooling, 2-mercaptoethanol (700 μ, 9.0 m5 o i!) was added dropwise, and the mixture was stirred for 30 minutes. Under water cooling, N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-p-)luenesulfate (3.2 g, 6.0 mmo 12
) was dissolved in 10 ml of tetrahydrofuran and added dropwise. 6
After stirring at 0°C overnight, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate to obtain 2.4 g of N-(hexadecyloxycarbonyl)-3-piperidinyl-methylcothioethyl alcohol as an oil (yield 68x) obtained.
IR:(νneat)aI−’ 3440.1685.
’H−NMR:δ(CDCj! り0.88(3H,
t J=5.49Hz)、1.26(28EI、 br
)、1.40〜2.04(5H,a+)、2.30〜3
.09(6H,a+)、 3.51〜4.26(711
,s)〔N−(ヘキサデシルオキシカルボニル)−3ピ
ペリジニル−メチルコチオエチルアルコール(1,8g
、 4.Oauwo 12 ) とトリエチルアミン
(800■、 8+++s+o l )をジクロルメタ
ンに溶解した。水冷下撹拌しながらメタンスルホニルク
ロライド(700■、6.0 m+no1滴下した。室
温で一晩撹拌した後、ジクロロメタンを留去し、残さを
シリカゲルクロマトグラフィーでヘキサン−酢酸エチル
で溶出し、N−(ヘキサデシルオキシカルボニル)−3
−ピペリジニル−メチル−クロロエチルスルフィドを油
状物質として1.7g(収率92χ)得た。IR: (νneat)aI-' 3440.1685.
'H-NMR: δ(CDCj! ri 0.88 (3H,
tJ=5.49Hz), 1.26(28EI, br
), 1.40-2.04 (5H, a+), 2.30-3
.. 09 (6H, a+), 3.51-4.26 (711
,s) [N-(hexadecyloxycarbonyl)-3piperidinyl-methylcothioethyl alcohol (1.8g
, 4. Oauwo 12 ) and triethylamine (800 μ, 8+++s+ol) were dissolved in dichloromethane. Methanesulfonyl chloride (700 μ, 6.0 m+no1) was added dropwise with stirring under water cooling. After stirring overnight at room temperature, dichloromethane was distilled off, and the residue was subjected to silica gel chromatography eluting with hexane-ethyl acetate. hexadecyloxycarbonyl)-3
1.7 g (yield: 92x) of -piperidinyl-methyl-chloroethyl sulfide was obtained as an oily substance.
IR:(νneat)cm−’ 1700. ’)l−
NMR:δ(coc i 、)0.88(3H,t
J=5.62Hz)、1.26(288,br)、1.
46〜2.07 (6H,m)。IR: (νneat)cm-' 1700. ')l-
NMR: δ(coc i ,)0.88(3H,t
J=5.62Hz), 1.26 (288, br), 1.
46-2.07 (6H, m).
3.50〜4.50(68,s)。3.50-4.50 (68,s).
N−(ヘキサデシルオキシカルボニル)−3−ピペリジ
ニル−メチル−クロロエチルスルフィド(1,0g、
2.1mmo j! )をチアソ゛−ル(1,9g、
22m5of)に溶解し、封管中100℃−晩反応させ
た。チアゾールを留去した後、残さをシリカゲルクロマ
トグラフィーに付し、クロロホルム−メタノール水で溶
出し、N−rN’−(ヘキサデシルオキシカルボニル)
−3−ピペリジニル−メチルチオエチル〕チアゾリウム
クロライドを淡黄色粉末として80k (収率66z)
得た。N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-chloroethyl sulfide (1.0 g,
2.1 mmo j! ) with thiasol (1.9g,
22m5of) and reacted in a sealed tube at 100°C overnight. After distilling off the thiazole, the residue was subjected to silica gel chromatography, eluted with chloroform-methanol water, and N-rN'-(hexadecyloxycarbonyl)
-3-Piperidinyl-methylthioethyl]thiazolium chloride as pale yellow powder 80k (yield 66z)
Obtained.
実施例2
市販品である2−ピペリジメタノール(1,2g、10
++no1)を実施例1と同様に反応させ、目的物質で
あるN−(N’−(ヘキサデシルオキシカルボニル)−
2−ピペリジニル−メチルチオエチル〕チアゾリウムク
ロライドを淡黄色粉末として600■(収率5oz)得
た。Example 2 Commercially available 2-piperidimethanol (1.2 g, 10
++no1) was reacted in the same manner as in Example 1, and the target substance N-(N'-(hexadecyloxycarbonyl)-
600 ml of 2-piperidinyl-methylthioethyl]thiazolium chloride was obtained as a pale yellow powder (yield: 5 oz).
実施例3
水素化リチウムアルミニウム(2,2g、 58smo
ffi )をテトラヒドロフランに懸濁した15分間還
流した。Example 3 Lithium aluminum hydride (2.2g, 58smo
ffi) was suspended in tetrahydrofuran and refluxed for 15 minutes.
4−ピペリジンカルボン酸(5B) (5g、 39s
so j! )を加えた。1時間還流した後、水酸化カ
リウム(20−■Ol)を加えた。不溶勧賞を濾過後、
減圧il!縮し、4−ピペリジンメタノールを油状物質
として2.0g(収率45χ)得た。4-Piperidinecarboxylic acid (5B) (5g, 39s
So j! ) was added. After refluxing for 1 hour, potassium hydroxide (20-■Ol) was added. After filtering the insoluble Kansho,
Decompression! By condensation, 2.0 g (yield: 45x) of 4-piperidine methanol was obtained as an oily substance.
4−ピペリジンメタノール(1,2g、 10saof
fi)を実施例1と同様に反応させ、目的物質であるN
(N’−(ヘキサデシルオキシカルボニル)−4=ピペ
リジニル−メチルチオエチルフチアゾリウムクロライド
を白色束として4.0g(収率93z)得た。4-piperidine methanol (1,2 g, 10 saof
fi) was reacted in the same manner as in Example 1, and the target substance N
4.0 g (yield: 93z) of (N'-(hexadecyloxycarbonyl)-4=piperidinyl-methylthioethyl phthiazolium chloride) was obtained as a white bundle.
実施例4
水素化ナトリウム(0,45g、 11m5+o l
)をヘキサンで洗浄した後、氷冷下N、N−ジメチルホ
ルムアミド10−を加えた。更に、水冷下ジメチルアミ
ノエタノール(0,75g、 8.3wmo j! )
を滴下した後、30分間攪拌した。水冷下実施例1で得
たN−(ヘキサデシルオキシカルボニル)−3−ピペリ
ジニル−メチル−p−トルエンスルフェート(3,0g
、 5.6v++o 1 )をN、N−ジメチルホルム
アミド10ydに溶解して滴下した。50゛Cで8時間
撹拌した後、放冷し、次いで氷水を加えジクロロメタン
で抽出した。ジクロロメタン層を減圧濃縮し、残さをシ
リカゲルクロマトグラフィーに付し、クロロホルム−メ
タノールで溶出しN−(ヘキサデシルオキシカルボニル
)−3−ピペリジニル−メチルジアミノエチルエチルエ
ーテルを淡黄色粉末として1.2g(収率47χ)得た
。Example 4 Sodium hydride (0.45g, 11m5+o l
) was washed with hexane, and then N,N-dimethylformamide 10- was added under ice cooling. Furthermore, dimethylaminoethanol (0.75 g, 8.3 wmo j!) was added under water cooling.
was added dropwise, and the mixture was stirred for 30 minutes. N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-p-toluenesulfate (3.0 g) obtained in Example 1 under water cooling.
, 5.6v++o 1 ) was dissolved in 10 yd of N,N-dimethylformamide and added dropwise. After stirring at 50°C for 8 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol to give 1.2 g of N-(hexadecyloxycarbonyl)-3-piperidinyl-methyldiaminoethyl ethyl ether as a pale yellow powder (yield). A rate of 47χ) was obtained.
IR:(νKBr) cs−’ 1705. ’H−N
MR:δ(CDCj! り0.87(3H,t、 J=
5.9882) 、 1.26 (28H、br) 1
.49”2.04 (4H,m) 。IR: (νKBr) cs-' 1705. 'H-N
MR: δ(CDCj! ri0.87(3H,t, J=
5.9882), 1.26 (28H, br) 1
.. 49”2.04 (4H, m).
2.29(6H,s) 、 2.51 (2H,t、
J=5.86Hz) 、40〜3.70(28,m)
。2.29 (6H, s), 2.51 (2H, t,
J=5.86Hz), 40-3.70 (28, m)
.
3.29 (28、d、 J=5.99Hz) 、 3
.52 (2H,t、 J=5.62Hz) 、 3.
78〜4.27(2H,m)、4.05(2B、t、J
=6.47tlz)。3.29 (28, d, J=5.99Hz), 3
.. 52 (2H, t, J=5.62Hz), 3.
78-4.27 (2H, m), 4.05 (2B, t, J
=6.47tlz).
N−(ヘキサデシルオキシカルボニル)−3ピペリジニ
ル−メチルジアミノエチルエチルエーテル(780■、
1.7m5ojりをエーテル5dに溶解させ、ヨウ化
メチル(48■、 3.4mmoffi)に滴下した。N-(hexadecyloxycarbonyl)-3piperidinyl-methyldiaminoethylethyl ether (780■,
1.7 ml of the solution was dissolved in ether 5d and added dropwise to methyl iodide (48 ml, 3.4 mmoffi).
−晩攪拌後不溶物を濾過しヨウ化〔N−(ヘキサデシル
オキシカルボニル)−3−ピペリジニル−メチルキシ〕
エチルートリメチルアンモニウムを淡黄色粉末として7
80■(収率76z)得た。- After stirring overnight, filter the insoluble matter and iodide [N-(hexadecyloxycarbonyl)-3-piperidinyl-methyloxy]
Ethyltrimethylammonium as pale yellow powder 7
80μ (yield: 76z) was obtained.
実施例5
実施例1で得たN−(ヘキサデシルオキシカル;i:ニ
ル) −3−ピペリジニル−メチル−クロロエチルスル
フィド
アミン<6.5y1mo l )含有トルエン5mに溶
解し、封管中lOO℃−晩反応させた。トルエンを留去
した後、残さをシカゲルクロマトグラフィーに付し、ク
ロロホルム−メタノール−水で溶出し、N− (N’−
(ヘキサデシルオキシカルボニル)−3−ピペリジニ
ル−メチルチオエチル〕 トリメチルアンモニウムクロ
ライドを淡黄色粉末として20■(収率6χ)得た。Example 5 N-(hexadecyloxycal; i: nyl)-3-piperidinyl-methyl-chloroethyl sulfide amine <6.5y1mol) obtained in Example 1 was dissolved in 5m of toluene and heated to 100°C in a sealed tube. - Reacted overnight. After distilling off the toluene, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol-water to give N- (N'-
(Hexadecyloxycarbonyl)-3-piperidinyl-methylthioethyl] 20 ml of trimethylammonium chloride was obtained as a pale yellow powder (yield: 6x).
実施例1〜5で得られた化合物の構造式及び物性値を第
1表に示す。Table 1 shows the structural formulas and physical properties of the compounds obtained in Examples 1 to 5.
実施例6
2−ベンジルオキシメチルモルホリン(1,0g、4.
8ma+of)をメタノール1.2I11を含む2N水
酸化ナトリウム溶液5 d (10++s+o l )
に溶解し、水冷下n−ヘキサデシルクロロホルメート(
1,6g、 4.8mmof)を滴下した。水冷下2時
間、更に室温で1時間攪拌した。IN塩酸でpH3とし
た後、酢酸エチルで抽出した。抽出後を硫酸マグネシウ
ムで乾燥した後、減圧濃縮し、残さをシリカゲルクロマ
トグラフィーにし、N−(ヘキサデシルオキシカルボニ
ル)−2−ベンジルオキシメチルモルホリンを1.9g
(収率72)無色油状とした。Example 6 2-benzyloxymethylmorpholine (1.0 g, 4.
8ma+of) in 2N sodium hydroxide solution containing 1.2I11 methanol 5d (10++s+o l )
Dissolved in n-hexadecyl chloroformate (
1.6 g, 4.8 mmof) was added dropwise. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature. After adjusting the pH to 3 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. The extracted product was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain 1.9 g of N-(hexadecyloxycarbonyl)-2-benzyloxymethylmorpholine.
(Yield: 72) A colorless oil was obtained.
IR:(v neat)cm−’ 1703. ’H−
NMR:δ(CDCl 3)0.88(3H,t) 、
1.26(288,br) 、 2.7(1〜4.0
4 (IIH,w) 、 4.48 (78゜s)、7
.25(5B、s)。IR: (v neat) cm-' 1703. 'H-
NMR: δ(CDCl3)0.88(3H,t),
1.26 (288, br), 2.7 (1~4.0
4 (IIH, w), 4.48 (78°s), 7
.. 25 (5B, s).
N〜(ヘキサデシルオキシカルボニル)−2ベンジルオ
キシメチルモルホリン(120■、2s+molと水酸
化パラジウム炭素(20■)をエタノールに溶解し、水
素置換した。室温で2時間撹拌後、濾過し、ろ液を減圧
濃縮し、N−(ヘキサデシルオキシカルボニル)−2−
モルホリニル−メタノールを100■(収率100%)
白色粉末として得た。N~(hexadecyloxycarbonyl)-2benzyloxymethylmorpholine (120μ, 2s+mol) and palladium hydroxide on carbon (20μ) were dissolved in ethanol and replaced with hydrogen. After stirring at room temperature for 2 hours, it was filtered and the filtrate was was concentrated under reduced pressure to obtain N-(hexadecyloxycarbonyl)-2-
100μ of morpholinyl-methanol (yield 100%)
Obtained as a white powder.
IME(Kbr)cm−’ 3425.1702. ’
H−NMR: δ(CDc 123)0.88(3H,
t)、1.26(28H,br)、2.90〜4.40
(12H,a)。IME (Kbr) cm-' 3425.1702. '
H-NMR: δ (CDc 123) 0.88 (3H,
t), 1.26 (28H, br), 2.90-4.40
(12H, a).
N−(ヘキサデシルオキシカルボニル)−2−モルホリ
ニル−メタノール(10g、2.7mmo l )とト
リエチルアミン<0.4g、4.0s+t*ol )を
ジクロルメタンに溶解した。水冷下撹拌しなから4−塩
化トルエンスルホニル(0,57g、 3.0vsoj
! )をジクロルタン10M1に溶解して滴下した。室
温で一晩撹拌した後、水と飽和食塩水で洗浄した。ジク
ロルメタン層を硫酸マグネシウムで乾燥後、減圧濃縮し
残さをシリカゲルクロマトグラフィーに付し、ヘキサン
−酢酸エチルで溶出しN−(ヘキサデシルオキシカルボ
ニル)−2−モルホリニル−メチル−p−トルエンスル
フェートを白色粉末として640mg(収率44x)得
た。N-(hexadecyloxycarbonyl)-2-morpholinyl-methanol (10 g, 2.7 mmol) and triethylamine <0.4 g, 4.0 s+t*ol) were dissolved in dichloromethane. 4-Toluenesulfonyl chloride (0.57 g, 3.0 vsoj) was stirred under water cooling.
! ) was dissolved in 10M1 dichlorothane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluted with hexane-ethyl acetate to obtain N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-p-toluene sulfate as white. 640 mg (yield 44x) was obtained as a powder.
IRE(Kbr)CI−’ 1702. ’H−NMR
:δ(CDCj! り0.88(31,t) 。IRE(Kbr)CI-' 1702. 'H-NMR
: δ(CDCj! ri 0.88(31,t).
1.26(281,br)、2.42(3H,−)、2
.70−4.20(118,s)、7.25(2H,d
)、7.73((2H,d)。1.26 (281, br), 2.42 (3H, -), 2
.. 70-4.20 (118, s), 7.25 (2H, d
), 7.73 ((2H, d).
水素化ナトリウム(80g、 2.0mmoj! )を
ヘキサンで洗浄した後、N、Nジメチルホルムアミド1
01dに懸濁した。水冷下撹拌しなから2−メルカプト
エタノール(120■、 1.5mmof)を滴下した
後、30分間撹拌した。水冷下、N−(ヘキサデシルオ
キシカルボニル)−2−モルホリニル−メチル−pトル
エンスルフェートをN、Nジメチルホルムアミド10j
dに溶解して滴下した。2時間撹拌した後、放冷し、次
いで氷水を加えジクロルメタンで抽出した。ジクロルメ
タン層を減圧濃縮し、残さをシリカゲルクロマトグラフ
ィーに付し、ヘキサン−酢酸エチルで溶出し〔N−(ヘ
キサデシルオキシカルボニル)−2−モルホリニル−メ
チル]チオエチルアルコールを油状物質として500■
(収率90χ)得た。Sodium hydride (80 g, 2.0 mmoj!) was washed with hexane and then diluted with N,N dimethylformamide 1
01d. After stirring under water cooling, 2-mercaptoethanol (120 ml, 1.5 mmof) was added dropwise, and the mixture was stirred for 30 minutes. Under water cooling, N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-p-toluene sulfate was dissolved in N,N dimethylformamide (10j).
d and added dropwise. After stirring for 2 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate and using [N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl]thioethyl alcohol as an oil for 500 μl.
(yield: 90x).
IR:(νneat)cm−’ 3405,1700.
’H−NMR: δ(CDCl :l)0.88 (
38,t) 、 1.26 (28H、br) 、 2
.50〜4.20 (16H,m) 。IR: (νneat)cm-' 3405,1700.
'H-NMR: δ(CDCl:l)0.88 (
38,t), 1.26 (28H,br), 2
.. 50-4.20 (16H, m).
(N−(ヘキサデシルオキシカルボニル)−2−モルホ
リニル−メチルコチオエチルアルコール(46011g
、 1.1mmof )とトリエチルアミン(200■
。(N-(hexadecyloxycarbonyl)-2-morpholinyl-methylcothioethyl alcohol (46011g)
, 1.1 mmof) and triethylamine (200 mmof)
.
2mmof)をジクロルメタンに溶解した。水冷下撹拌
しながらメタンスルホニルクロライド(230■。2 mmof) was dissolved in dichloromethane. methanesulfonyl chloride (230 μl) while stirring under water cooling.
2.0tstmo l ) WK下した。室温で一晩撹
拌した後、ジクロルメタンを留去し、残さをシリカゲル
クロマトグラフィーでヘキサン−酢酸エチルで溶出し、
N−(ヘキサデシルオキシカルボニル)−2−モルホリ
ニル−メチル−クロロエチル−スルフィドを油状物質と
して3500Ig(収率69z)得た。2.0tstmol) WK was lowered. After stirring overnight at room temperature, dichloromethane was distilled off, and the residue was chromatographed on silica gel, eluting with hexane-ethyl acetate.
3500 Ig (yield 69z) of N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-chloroethyl-sulfide was obtained as an oily substance.
IR:(!I neat)cm−’ 1693. ’)
I−NMR:δ(CDC13)0.88(3H,t)
、 1.26(28H,br) 、2.45〜4.25
(15B、m) 。IR: (!I neat) cm-' 1693. ')
I-NMR: δ (CDC13) 0.88 (3H, t)
, 1.26 (28H, br) , 2.45-4.25
(15B, m).
N−(ヘキサデシルオキシカルボニル)−2−モルホリ
ニル−メチル−クロロエチル−スルフィド(350g
、 0.75mao l )をチアゾール(1,0g、
12B1mo l )を溶解し、封管中100″C−
晩反応させた。チアゾールを留去した後、残さをシリカ
ゲルクロマトグラフィーに付し、クロロホルム−メタノ
ール−水で溶出し、N−(N’−ヘキサデシルオキシカ
ルボニル)−2−モルホリニル−メチルチオエチル〕チ
アゾリウムクロライドを淡黄色粉末として150■(収
率36z)得た。N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-chloroethyl-sulfide (350g
, 0.75 mao l) and thiazole (1.0 g,
12B1 mol) was dissolved in a sealed tube at 100″C-
The reaction was carried out in the evening. After distilling off the thiazole, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol-water to remove N-(N'-hexadecyloxycarbonyl)-2-morpholinyl-methylthioethyl]thiazolium chloride. 150 ml (yield 36 z) was obtained as a yellow powder.
実施例7
水素化ナトリウム(0,34g、 8.5++v+of
)をヘキサンで洗浄した後、水冷下N、Nジメチルホ
ルムアミド10M1を加えた。更に、水冷下ジメチルア
ミノエタノール(0,57g、 6.4gmoffi
)を滴下した後、30分間撹拌した。水冷下N−(ヘキ
サデシルオキシカルボニル)−2−モルホリニル−メチ
ル−p−トルスルフィト(2,3g、 4.3mmo
Il )をN、Nジメチルホルムアミド101dに溶解
して滴下した。50℃で8時間撹拌した後、放冷し、次
いで氷水を加えジクロルメタンで抽出した。ジクロルメ
タン層を減圧濃縮し、残さをシリカゲルクロマトグラフ
ィーに付し、クロロホルム−メタノールで溶出し[N−
(ヘキサデシルオキシカルボニル)−2−モルホリニル
−メチルツージメチルアミノエーテルを油状物質として
200■(収率10り得た。Example 7 Sodium hydride (0.34g, 8.5++v+of
) was washed with hexane, and then 10M1 of N,N dimethylformamide was added under water cooling. Furthermore, dimethylaminoethanol (0.57g, 6.4gmoffi) was added under water cooling.
) was added dropwise, and the mixture was stirred for 30 minutes. N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-p-tolsulfite (2.3 g, 4.3 mmo) under water cooling.
Il) was dissolved in N,N dimethylformamide 101d and added dropwise. After stirring at 50°C for 8 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with chloroform-methanol [N-
(Hexadecyloxycarbonyl)-2-morpholinyl-methyltudimethylaminoether was used as an oily substance to obtain 200 μl (yield: 10).
IR:(y KBr) ell−’ 1702. ’H
−NMR:δ(CDCl 3)0、88(31,t)
、 1.26 (28H,br) 、 2.30 (6
H,s) 、 2.45〜4.25(158,m)。IR: (y KBr) ell-' 1702. 'H
-NMR: δ(CDCl3)0,88(31,t)
, 1.26 (28H,br) , 2.30 (6
H,s), 2.45-4.25 (158, m).
(N−(ヘキサデシルオキシカルボニル)−2−モルホ
リニル〕−ジメチルアミノエーテル(180■、0.4
IllIIIol)をエーテル5111i!に溶解させ
、ヨウ化メチル(131g、 0.8mmof )に滴
下した。−晩撹拌後不溶物を濾過しヨウ化〔N−(ヘキ
サデシルオキシカルボニル)−2−モルホリニル−メチ
ルオキシラエチル−トリメチルアンモニウムを淡黄色粉
末として150■(収率63z)得た。(N-(hexadecyloxycarbonyl)-2-morpholinyl)-dimethylaminoether (180■, 0.4
IllIIIol) to ether 5111i! and added dropwise to methyl iodide (131 g, 0.8 mmof). After stirring overnight, the insoluble matter was filtered to obtain 150 ml of iodized [N-(hexadecyloxycarbonyl)-2-morpholinyl-methyloxylaethyl-trimethylammonium] as a pale yellow powder (yield 63z).
実施例8 2−ベンジル−1,3−ペロパンジオール(32g。Example 8 2-benzyl-1,3-peropanediol (32g).
180vgtao l )を酢酸ビニル(34,6g、
400m+so 1 )に溶解した。リパーゼP (
1,8g)を加え、5°Cで3時間撹拌した0反応溶液
を濾過した後、濾液を減圧濃縮し、残さをシリカゲルク
ロマトグラフィーでジロルメタン:メタノール(70:
1)で溶出させると(S)−1−アセトキシ−2−ベン
ジルオキシ−3−プロパツールが油状物質として35.
3g(収率8B%光学純度91Xee)が得られた。180vgtaol) to vinyl acetate (34.6g,
400m+so 1 ). Lipase P (
After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using dilormethane:methanol (70:
When eluted with 1), (S)-1-acetoxy-2-benzyloxy-3-propatol was obtained as an oily substance at 35.
3 g (yield: 8B%, optical purity: 91Xee) was obtained.
(S)−1−アセトキシ−2−ペンジルオキシー3−プ
ロパツール(20g、 90mmo 1 )とトリエチ
ルアミン(14g、 135mmo j2 )をジロル
メタンに溶解した。(S)-1-acetoxy-2-penzyloxy-3-propatol (20 g, 90 mmol) and triethylamine (14 g, 135 mmol) were dissolved in dilormethane.
水冷下撹拌しなから4−塩化トルエンスルホニル(21
g、 108mmo 1 )をジロルメタンニ溶解LT
滴下した。室温で一晩撹拌した後、水と飽和食塩水で洗
浄した。ジクルメタン層を硫酸マグネシウムで乾燥後、
減圧濃縮し、残さをシリカゲルクロマトグラフィーでヘ
キサン:酢酸エチル(10:1)で溶出させると(R)
−3−アセトキシ−2−ヘンシルオキシ−1−トシル
オキシプロパン33g(収率97χ)が得られた。After stirring under water cooling, 4-toluenesulfonyl chloride (21
g, 108 mmo 1) was dissolved in dilormethane LT.
dripped. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. After drying the diclmethane layer with magnesium sulfate,
After concentration under reduced pressure, the residue was chromatographed on silica gel and eluted with hexane:ethyl acetate (10:1) to give (R).
33 g of -3-acetoxy-2-hensyloxy-1-tosyloxypropane (yield 97x) was obtained.
(R) −3−アセトキシ−2−ヘンシルオキシ1−ト
シルオキシプロパン(33g、 87imo j2 )
を水酸化ナトリウム(3,8g、 96mmo 1 )
のエタノール溶液に溶解した。水冷下、−時間撹拌した
。6N塩酸で中和した後、エタノール溶液を留去し残さ
をジクロルメタン層を硫酸マグネシウムで乾燥後、減圧
濃縮した。残さをイソプロピルエーテルで再結晶すると
(R)−1−ヒドロキシ−2−ベンジルオキシ−3−ト
シルオキシプロパンが、白色粉末として20g (収率
68z)が得られた。(R) -3-acetoxy-2-hensyloxy 1-tosyloxypropane (33g, 87imo j2)
Sodium hydroxide (3.8g, 96mmo 1)
was dissolved in an ethanol solution of The mixture was stirred for - hours under water cooling. After neutralizing with 6N hydrochloric acid, the ethanol solution was distilled off, and the dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to obtain 20 g (yield: 68z) of (R)-1-hydroxy-2-benzyloxy-3-tosyloxypropane as a white powder.
(R)−1−ヒドロキシ−2−ベンジルオキシ3−トシ
ルオキシプロパン(20g、 60mmo I!、)を
エタノールに溶解した。パラジウム炭素(2g)を加え
水素で置換した。室温で一晩撹拌した。反応溶液を濾過
した後、ろ液を減圧濃縮すると(R)−3−)シルトキ
シ−1,2−プロパンジオールが白色粉末として15g
(収率100X)が得られた。(R)-1-Hydroxy-2-benzyloxy-3-tosyloxypropane (20 g, 60 mmol I!,) was dissolved in ethanol. Palladium on carbon (2 g) was added and the mixture was replaced with hydrogen. Stir overnight at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain 15 g of (R)-3-)siltoxy-1,2-propanediol as a white powder.
(Yield 100X) was obtained.
(R)−3−)シルトキシ−1,2−プロパンジオール
(15g、 60mmo l )をメタノール25!I
dlとエーテル12dに溶解した。水冷下、ナトリウム
(1,4g、60mmo l )を−時間かけて滴下し
た。さらに−時間撹拌した後、反応溶液を減圧濃縮した
。残さにエーテルを加え濾過した後、ろ液を減圧濃縮し
た。(R)-3-) Siltoxy-1,2-propanediol (15 g, 60 mmol) in methanol 25. I
dl and ether 12d. Under water cooling, sodium (1.4 g, 60 mmol) was added dropwise over a period of - hours. After stirring for an additional hour, the reaction solution was concentrated under reduced pressure. After adding ether to the residue and filtration, the filtrate was concentrated under reduced pressure.
残さをクロロホルムを加え減圧濃縮すると(R)グリシ
ドールが油状物質として4.4g(収率100Z)が得
られた。The residue was added with chloroform and concentrated under reduced pressure to obtain 4.4 g (yield: 100 Z) of (R) glycidol as an oily substance.
水素化ナトリウム(3,2g、 80nuwo l )
をヘキサンで洗浄した後、テトラヒドロフランに懸濁さ
せた。Sodium hydride (3.2g, 80nuwo l)
After washing with hexane, it was suspended in tetrahydrofuran.
水冷下撹拌しながら、 (R)−グリシドールを(3,
7g。While stirring under water cooling, (R)-glycidol (3,
7g.
60mmo i )を滴下した。直ちにヘンシルブロマ
イド(12,6g、74問ol〉を滴下した。水冷下、
−晩撹拌した後、氷水を加えた。エーテルで抽出し、硫
酸マグネシウムで乾燥後、減圧濃縮し、次いで反応混合
物をシリカゲルクロマトグラフィーに付し、ヘキサン−
酢酸エチル(10:1)で溶出させると(S)3−ベン
ジルオキシ−1,2−エポキシプロパンが油状物質とし
て7g(収率71z)が得られた。60 mmo i) was added dropwise. Immediately, hensyl bromide (12.6 g, 74 ol) was added dropwise. Under water cooling,
- After stirring overnight, ice water was added. After extraction with ether, drying over magnesium sulfate, and concentration under reduced pressure, the reaction mixture was subjected to silica gel chromatography, and hexane-
Elution with ethyl acetate (10:1) gave 7 g (yield 71z) of (S)3-benzyloxy-1,2-epoxypropane as an oil.
2−アミノエチルスルホン酸(30g、 215mmo
i )を70χ水酸化ナトリウム溶液25ad!に溶
解した。50℃で(S) −3−ベンジルオキシ−1,
2−エポキシプロパン(7g、 73v++o l )
をメタノール401dに溶解して滴下した。50℃で一
時間撹拌した後、70χ水酸化ナトリウム溶液40ad
を滴下した。50℃でさらに16時間撹拌した。300
dの水を加えトルエンで抽出した。トルエン層を硫酸マ
グネシウムで乾燥後減圧濃縮し、残差をシリカゲルクロ
マトグラフィーに付し、クロロホルム:メタノール(2
0:1)で溶出させると(S)−モルホリン−2−メタ
ノールが油状物質として3.8g(収率43z)が得ら
れた。2-Aminoethylsulfonic acid (30g, 215mmo
i) with 70χ sodium hydroxide solution 25ad! dissolved in (S)-3-benzyloxy-1, at 50°C
2-Epoxypropane (7g, 73v++ol)
was dissolved in methanol 401d and added dropwise. After stirring for 1 hour at 50°C, 40ad of 70x sodium hydroxide solution was added.
was dripped. The mixture was further stirred at 50°C for 16 hours. 300
Water from step d was added and extracted with toluene. The toluene layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
0:1), 3.8 g (yield 43z) of (S)-morpholine-2-methanol was obtained as an oily substance.
以下実施例6と同様にして(S)−(+) −N 〔N
’−(ヘキサデシルオキシカルボニル)−2−モルホリ
ニル−メチルチオエチル]チアゾリウムクロライドを得
た。Thereafter, in the same manner as in Example 6, (S)-(+)-N [N
'-(hexadecyloxycarbonyl)-2-morpholinyl-methylthioethyl]thiazolium chloride was obtained.
実施例9
(S)−1−アセトキシ−2−ベンジルオキシ−3プロ
パツール
アミン(13g, 100mmo j! )をジクロル
メタンに溶解した。水冷下撹拌しながらメトキシメチル
クロリド(6.5g, 81wmo l )を滴下した
.室温で一晩撹拌した後乾燥後、減圧!縮すると(S)
−1−アセトキシ−2−ベンジルオキシ−3−メトキシ
メチルプロパンが油状物質として18g(収率100z
)得られた。Example 9 (S)-1-acetoxy-2-benzyloxy-3 propazuramine (13 g, 100 mmo j!) was dissolved in dichloromethane. Methoxymethyl chloride (6.5 g, 81 wmol) was added dropwise while stirring under water cooling. After stirring overnight at room temperature and drying, reduce the pressure! When it shrinks (S)
-1-acetoxy-2-benzyloxy-3-methoxymethylpropane as an oily substance (18 g (yield 100z)
) obtained.
(S)−1−アセトキシ−2−ベンジルオキシ−3−メ
トキシメチルプロパン(18g.67mmof)を水酸
化ナトリウム(2.7g, 67++nof)のエタノ
ール溶液に溶解した。水冷下−時間撹拌した, 6N塩
酸で中和した後エタノールを留去し残差をジクロルメタ
ンで抽出した。ジクロルメタン層を硫酸マグネシウムで
乾燥後、減圧濃縮すると(R)−1−ヒドロキシ−2−
ベンジルオキシ−3−メトキシメチルオキシプロパンが
油状勧賞として15g(収率100%)得られた。(S)-1-acetoxy-2-benzyloxy-3-methoxymethylpropane (18 g.67 mmof) was dissolved in an ethanol solution of sodium hydroxide (2.7 g, 67++nof). The mixture was stirred for an hour under water cooling, neutralized with 6N hydrochloric acid, ethanol was distilled off, and the residue was extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure to give (R)-1-hydroxy-2-
15 g (yield: 100%) of benzyloxy-3-methoxymethyloxypropane was obtained as an oily substance.
(R)−1−ヒドロキシ−2−ヘンシルオキシ−3−メ
トキシメチルオキシプロパン(15g、67+s+++
offi)とトリエチルアミン(Log、 100m5
o l )をジクロルメタンに溶解した。水冷下、撹拌
しなから4−塩化トルエンスルホニル(15g、 81
a+mo 1 )をジクロルメタンに溶解して滴下した
。室温で一晩撹拌した後、水と飽和食塩水で洗浄した。(R)-1-Hydroxy-2-hensyloxy-3-methoxymethyloxypropane (15g, 67+s+++
offi) and triethylamine (Log, 100m5
o l) was dissolved in dichloromethane. Under water cooling and stirring, 4-toluenesulfonyl chloride (15 g, 81
a+mo 1 ) was dissolved in dichloromethane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine.
ジクロルメタン層を硫酸マグネシウムで乾燥後、減圧濃
縮し残差をシリカゲルクロマトグラフィーでヘキサン−
酢酸エチル(5:1)で溶出させると(S)−1−)シ
ルオキシ−2−ベンジルオキシ−3−メトキシメチルオ
キシプロパン15g (収率98z)得られた。The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified with hexane by silica gel chromatography.
Elution with ethyl acetate (5:1) gave 15 g (yield 98z) of (S)-1-)yloxy-2-benzyloxy-3-methoxymethyloxypropane.
(S)−1−トシルオキシ−2−ベンジルオキシ3−メ
トキシメチルオキシプロパン(25g、 65*so
l )を6N塩酸で15dを含むメタノール溶液に加え
60℃で8時間撹拌した。2N水酸化ナトリウム溶液で
中和した後、メタノールを留去し、残差をジクロルメタ
ンで抽出した。ジクロルメタン層を水と飽和食塩水で洗
浄し、硫酸マグネシウムで乾燥後、減圧濃縮すると(S
)−1−トシルオキシ−2−ベンジルオキシ−3−プロ
パツールが白色粉末として21g(収率98z)得られ
た。(S)-1-Tosyloxy-2-benzyloxy 3-methoxymethyloxypropane (25g, 65*so
1) was added to a methanol solution containing 15d with 6N hydrochloric acid and stirred at 60°C for 8 hours. After neutralizing with 2N sodium hydroxide solution, methanol was distilled off and the residue was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain (S
21 g (yield: 98z) of -1-tosyloxy-2-benzyloxy-3-propatool was obtained as a white powder.
以下実施例8と同様にしてR−(−)−(N”(ヘキサ
デシルオキシカルボニル)−2−モルホリニル−メチル
チオエチル〕チアゾリウムクロライドを得た。Thereafter, in the same manner as in Example 8, R-(-)-(N"(hexadecyloxycarbonyl)-2-morpholinyl-methylthioethyl)thiazolium chloride was obtained.
実施例10
(S)−(−) −3−モルホリンメタノール(115
)(7001g、 6.0aso l )をメタノール
2−を含む2N水酸化ナトリウム溶液6 dl (12
*so i! )に溶解し、水冷下n−ヘキサデシルク
ロロホルメート(1,8g、6.0sumo l )を
滴下した。水冷下2時間、更に室温で1時間撹拌した。Example 10 (S)-(-)-3-morpholinemethanol (115
) (7001 g, 6.0 asol) in 6 dl (12
*so i! ), and n-hexadecyl chloroformate (1.8 g, 6.0 sumol) was added dropwise under water cooling. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature.
IN塩酸でp)13とした後、酢酸エチルで抽出した
。抽出液を硫酸マグネシウムで乾燥した後、減圧の濃縮
し、残差をシリカゲルクロマトグラフィーに付し、S−
(−)−N−(ヘキサデシルオキシカルボニル)−3−
モルホリニル−メタノールを1.9g (収率81χ)
無色油状として得た。After adjusting to p)13 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. After drying the extract over magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
(-)-N-(hexadecyloxycarbonyl)-3-
1.9g of morpholinyl-methanol (yield 81χ)
Obtained as a colorless oil.
IR:(νneat)c+*−’ 3450.1700
. ’H−NMR:δ(CDCf 、)0.88(3H
,t)、 1.26(28B、br)、2.90〜4.
40(12H,w)。IR:(νneat)c++-' 3450.1700
.. 'H-NMR: δ(CDCf,)0.88(3H
, t), 1.26 (28B, br), 2.90-4.
40 (12H, w).
S−(−)−N−(ヘキサデシルオキシカルボニル)−
3−モルホリニル−メタノール(1,8g、4.7ta
tao I! ) とトリエチルアミン(0,7g、
7.0+wmo l )をジクロルメタンに溶解した
。水冷下撹拌しなから4−塩化トルエンスルホニル(1
,1g、5.6mmof)をジクロルメタン101dに
溶解して滴下した。室温で一晩撹拌した後、水と飽和食
塩水で洗浄した。ジクロルメタン層を硫酸マグネシウム
で乾燥後、減圧濃縮し、残差をシリカゲルクロマトグラ
フィーに付し、ヘキサン−酢酸エチルで溶出し、5(−
)−N−(ヘキサデシルオキシカルボニル)−3−モル
ホリニル−メチル−p−)ルエンスルフェートを白色粉
末として400■(収率16χ)得た。S-(-)-N-(hexadecyloxycarbonyl)-
3-morpholinyl-methanol (1.8g, 4.7ta
Tao I! ) and triethylamine (0.7g,
7.0+wmol) was dissolved in dichloromethane. After stirring under water cooling, 4-toluenesulfonyl chloride (1
, 1 g, 5.6 mmof) was dissolved in 101 d of dichloromethane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate to obtain 5(-
)-N-(hexadecyloxycarbonyl)-3-morpholinyl-methyl-p-)luene sulfate was obtained as a white powder in an amount of 400 μm (yield: 16×).
IRE(νKBr) 3−’ 1705. ’H−NM
R:δ(CDCj!s)0.88(3H,t) 、 1
.26 (28H,br) 、 2.40 (3H,s
) 、 2.80〜4.40(IIH,s)、7.20
(2H,d)、7.68(2H,d)。IRE(νKBr) 3-' 1705. 'H-NM
R: δ (CDCj!s) 0.88 (3H, t), 1
.. 26 (28H,br), 2.40 (3H,s
), 2.80-4.40 (IIH, s), 7.20
(2H, d), 7.68 (2H, d).
水素化ナトリウム(64■、1.6問of)をヘキサン
で洗浄した後、N、N“ジメチルホルムアミドl〇−に
懸濁した。水冷下撹拌しなから2−メルカプトエタノー
ル(9011g、 1.2n+mo jl! )を滴下
した後、30分間撹拌した。水冷下、S−(−)−N−
(ヘキサデシルオキシカルボニル)−3−モルホリニル
−メチル−P−トルエンスルフェート(400■。Sodium hydride (64 cm, 1.6 questions) was washed with hexane and suspended in N,N dimethylformamide l〇-.While stirring under water cooling, 2-mercaptoethanol (9011 g, 1.2 n + mo) was added to the solution. ) was added dropwise and stirred for 30 minutes. Under water cooling, S-(-)-N-
(Hexadecyloxycarbonyl)-3-morpholinyl-methyl-P-toluenesulfate (400 ml.
0.8tamo Il )をN、N’ジメチルホルムア
ミド10−に溶解して滴下した。2時間撹拌した後、放
冷し、次いで氷水を加えジクロルメタンで抽出した。ジ
クロルメタン層を減圧濃縮し、残差をシリカゲルクロマ
トグラフィーに付し、ヘキサン−酢酸エチルで溶出し、
S−(−)−(N−(ヘキサデシルオキシカルボニル)
−3−モルホリニル−メチル)チオエチルアルコールを
油状物質として300■(収率84z)得た。0.8 tamo Il) was dissolved in N,N' dimethylformamide 10- and added dropwise. After stirring for 2 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate.
S-(-)-(N-(hexadecyloxycarbonyl)
-3-morpholinyl-methyl)thioethyl alcohol was obtained as an oily substance in an amount of 300 ml (yield: 84 z).
IR:(νneat)cm−’ 3395.1695.
’H−NMR:δ(CDCj! z)0.88(3B
、 t) 、 1.26(288,br) 、 2.3
0=4.40(16H,s) 。IR: (νneat)cm-' 3395.1695.
'H-NMR: δ(CDCj!z)0.88(3B
, t) , 1.26 (288,br) , 2.3
0=4.40 (16H, s).
S−(−)−(N−(ヘキサデシルオキシカルボニル)
−3−モルホリニル−メチルコチオエチルアルコール(
300M、 0.7s+mof)とトリエチルアミン(
130■、 1.3nuwo I! )をジクロルメタ
ンニ溶解した。水冷下撹拌しながらメタンスルホニルク
ロライド(110■、 1.0mmo l )滴下した
。室温で一晩撹拌した後、ジクロルメタンを留去し、残
差をシリカゲルクロマトグラフィーでヘキサン−酢酸エ
チルで溶出し、S−(−)−N−(ヘキサデシルオキシ
カルボニル)−3−モルホリニル−メチル−クロロエチ
ル−スルフィドを油状′!#J質として150■(収率
48z)得た。S-(-)-(N-(hexadecyloxycarbonyl)
-3-morpholinyl-methylcothioethyl alcohol (
300M, 0.7s+mof) and triethylamine (
130■, 1.3nuwo I! ) was dissolved in dichloromethane. Methanesulfonyl chloride (110 cm, 1.0 mmol) was added dropwise while stirring under water cooling. After stirring overnight at room temperature, dichloromethane was distilled off and the residue was chromatographed on silica gel eluting with hexane-ethyl acetate to give S-(-)-N-(hexadecyloxycarbonyl)-3-morpholinyl-methyl- Chloroethyl sulfide in oil form! #J quality 150 ml (yield 48 z) was obtained.
IR:(νneat)cm−’ 1698. ’H−N
MR:δ(CDCffi ff)0.88(30,t)
、1.26(28H,br)、2.70〜4.20(1
58,m)。IR: (νneat)cm-' 1698. 'H-N
MR: δ(CDCffi ff)0.88(30,t)
, 1.26 (28H, br), 2.70-4.20 (1
58, m).
S−(−)−N−(ヘキサデシルオキシカルボニル)−
3−モルホリニル−メチル−クロロエチルスルフィド(
15011g、 0.3mmojりをチアゾール(1,
0g+ 12smo 1 )に溶解し、封管中100°
C−晩反応させた。チアゾールを留去した後、残差をシ
リカゲルクロマトグラフィーに付し、クロロホルム−メ
タノール−水で溶出し、S−(−)−N−(N’−(ヘ
キサデシルオキシカルボニル)−3−モルホリニル−メ
チルチオエチルフチアゾリウムクロライドを淡黄色粉末
として20■(収率12χ)得た。S-(-)-N-(hexadecyloxycarbonyl)-
3-morpholinyl-methyl-chloroethyl sulfide (
15011 g, 0.3 mmoj of thiazole (1,
0g + 12smo 1 ) and heated at 100° in a sealed tube.
C - Reacted overnight. After distilling off the thiazole, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol-water to give S-(-)-N-(N'-(hexadecyloxycarbonyl)-3-morpholinyl-methylthio 20 ml of ethylphthiazolium chloride was obtained as a pale yellow powder (yield 12x).
実施例11
実施例10と同様に反応させ、目的物質であるR−(+
)−N−(N’−(ヘキサデシルオキシカルボニル)−
3−モルホリニル−メチルチオエチルフチアゾリウムク
ロライドを得た。Example 11 The reaction was carried out in the same manner as in Example 10, and the target substance R-(+
)-N-(N'-(hexadecyloxycarbonyl)-
3-morpholinyl-methylthioethyl phthiazolium chloride was obtained.
実施例6〜11で得られた化合物の構造式及び物性値を
第2表に示す。The structural formulas and physical properties of the compounds obtained in Examples 6 to 11 are shown in Table 2.
/ 実施例12 4−メチルピペラジン−2−メタノール(130■。/ Example 12 4-Methylpiperazine-2-methanol (130μ.
1.0mmoj2)をジクロルメタンに溶解し、水冷下
nヘキサデシルクロロホルメート(300■、 1.0
mmojl! )を滴下した。水冷下2時間、更に室温
で1時間撹拌した。溶媒を減圧濃縮し、残差をシリカゲ
ルクロマトグラフィーに付し、ヘキサデシル 2(ヒド
ロキシメチル)−4−メチルピペラジン−1−カルボキ
シレートを250■(収率63χ)無色油状として得た
。Dissolve 1.0 mmoj2) in dichloromethane and cool with water to dissolve n-hexadecyl chloroformate (300 mm, 1.0
mmojl! ) was added dropwise. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain 250 μl (yield: 63×) of hexadecyl 2(hydroxymethyl)-4-methylpiperazine-1-carboxylate as a colorless oil.
R: (J/ neat)cyr−’ 3230.17
00. ’H−NMR: δ(coc iL :+)
0.88(3H,t)、1.26(28H,br)、2
.9(1〜4.40(128,m)。R: (J/neat)cyr-' 3230.17
00. 'H-NMR: δ(cociL:+)
0.88 (3H, t), 1.26 (28H, br), 2
.. 9 (1-4.40 (128, m).
ヘキサデシル 2−(ヒドロキシメチル)−4メチルビ
ペラジン−1−カルボキシレート(400■、 1.0
mmol)とトリエチルアミン(0,2[、2,0ml
1+o l )をジクロルメタンに溶解した。水冷撹拌
しなから4−塩化トルエンスルホニル(23011g、
1.2mmo l )をジクロルメタン10−に溶解
して滴下した。室温で一晩撹拌した後、水と飽和食塩水
で洗浄した。Hexadecyl 2-(hydroxymethyl)-4methylbiperazine-1-carboxylate (400■, 1.0
mmol) and triethylamine (0,2 [, 2,0 ml
1+ol) was dissolved in dichloromethane. 4-Toluenesulfonyl chloride (23011 g,
1.2 mmol) was dissolved in 10-dichloromethane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine.
ジクロルメタン層を硫酸マグネシウムで乾燥後、(3H
,t) 、 1.26(28H,br) 、 2.20
(3H,s) 、 2.47−4.23(158,m
) 。After drying the dichloromethane layer with magnesium sulfate, (3H
,t), 1.26(28H,br), 2.20
(3H,s), 2.47-4.23(158,m
).
ヘキサデシル 2−(((2−クロロエチル)千オ〕メ
チル〕−4−メチルピペラジン−1−カルボキシレート
(220111g 、 0.48mmo j2 )をチ
アゾール(400g、4.8問o1)に溶解し、封管中
100°C−晩反応させた。チアゾールを留去した後、
残差をシリカゲルクロマトグラフィーに付し、クロロホ
ルムメタノール−水で溶出し、N−(N’−(ヘキサデ
シルオキシカルボニル)−N−メチルピペラジン−2メ
チルチオエチルフチアゾリウム クロライドを淡黄色粉
末として40■(収率15χ)得た。Hexadecyl 2-(((2-chloroethyl)1,000]methyl]-4-methylpiperazine-1-carboxylate (220111 g, 0.48 mmo j2) was dissolved in thiazole (400 g, 4.8 questions o1) and sealed in a tube. The mixture was reacted overnight at 100°C. After distilling off the thiazole,
The residue was subjected to silica gel chromatography, eluted with chloroform methanol and water, and N-(N'-(hexadecyloxycarbonyl)-N-methylpiperazine-2-methylthioethyl phthiazolium chloride was obtained as a pale yellow powder for 40 μm). (Yield 15χ) was obtained.
実施例13
実施例12記載のN−(ヘキサデシルオキシカルボニル
)−N−メチルピペラジン−2−メタノール(1,2g
、3.0simo l )と2−ブロモエチルリン酸ジ
クロリド(860■、 3.6wa+ojl! )をベ
ンゼンに溶解し、水冷下撹拌しながらピリジン(290
■、 3.6+uio iL )を滴下し、更に12時
間撹拌した。水20dを加えた後、1時間還流した。冷
却後、エーテルで抽出した。抽出液を硫酸マグネシウム
で乾燥させ、減圧濃縮することにより油状の残さを得た
。これをチアゾール(2,6g、 30a+mof )
に溶解し、封管中で90°C−晩撹拌した。反応混合物
を減圧濃縮後、残さに炭酸銀(1,2g、 4.5++
uwo iL )とメタノール30dを加え室温で一晩
撹拌した。不溶物質を濾過した後、減圧濃縮し、シリカ
ゲルクロマトグラフィーに付し、クロロホルム−メタノ
ール−水で溶出しN−(ヘキサデシルオキシカルボニル
)−N−メチルピペラジン−2−メチル(チアゾリウム
)エチルホスフェートを淡黄色粉末として170■(収
率102)得た。(Table、11参照)実施例12
.13で得られた化合物の構造式及び物性値を第3表に
示す。Example 13 N-(hexadecyloxycarbonyl)-N-methylpiperazine-2-methanol (1,2 g) described in Example 12
, 3.0simol) and 2-bromoethylphosphoric dichloride (860cm, 3.6wa+ojl!) were dissolved in benzene, and while stirring under water cooling, pyridine (290cm) was dissolved.
3.6+uio iL) was added dropwise, and the mixture was further stirred for 12 hours. After adding 20 d of water, the mixture was refluxed for 1 hour. After cooling, it was extracted with ether. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. Add this to thiazole (2.6g, 30a+mof)
and stirred overnight at 90°C in a sealed tube. After concentrating the reaction mixture under reduced pressure, the residue contained silver carbonate (1.2 g, 4.5++
30 d of methanol were added, and the mixture was stirred at room temperature overnight. After filtering off insoluble materials, the insoluble substances were concentrated under reduced pressure, and subjected to silica gel chromatography, eluting with chloroform-methanol-water to remove N-(hexadecyloxycarbonyl)-N-methylpiperazine-2-methyl(thiazolium)ethyl phosphate. 170 μm (yield: 102) was obtained as a yellow powder. (See Table, 11) Example 12
.. The structural formula and physical properties of the compound obtained in 13 are shown in Table 3.
実施例14
L−(−)−システィン エチル エステルハイドロク
ロライド(123)(1,0g、 5.4mmof )
とジイトプロピルエチルアξン(3,5g、 27sm
oI!、)をジクロルメタンに溶解した。水冷下、撹拌
しながらブロムアセチルプロ柔ド(1,6g、8.1o
nof )を滴下した。室温で一晩撹拌後、水と飽和食
塩水で洗浄した。ジクロルメタン層を硫酸マグネシウム
で乾燥後、減圧濃縮し、残差をシリカゲルクロマトグラ
フィーに付し、クロロホルム−メタノールで溶出し、エ
チル−(S)−(−) −5−オキソチオモルホリン−
3−カルボキシレートを油状物質とし7190mg (
収率19X)得た。Example 14 L-(-)-cysteine ethyl ester hydrochloride (123) (1.0 g, 5.4 mmof)
and diitopropylethylamine (3.5g, 27sm
oI! ) was dissolved in dichloromethane. Bromoacetylpropyrode (1.6g, 8.1o) was stirred under water cooling.
nof) was added dropwise. After stirring overnight at room temperature, the mixture was washed with water and saturated brine. The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluted with chloroform-methanol to give ethyl-(S)-(-)-5-oxothiomorpholine-
7190 mg of 3-carboxylate as an oily substance (
A yield of 19X) was obtained.
MS(s+/e):189(M”)、IR:(νnea
t)as−’ 1738,1660゜’H−NMR:
δ(CDCj! り1.30(31,t、J−9,4
0Hz)、2.92=3、50 (411,m) 、
4.26 (2H,q、 J−7,42Hz) 、 4
.79 (1B、 s) 。MS (s+/e): 189 (M”), IR: (νnea
t) as-'1738,1660°'H-NMR:
δ(CDCj! ri 1.30(31,t, J-9,4
0Hz), 2.92=3,50 (411,m),
4.26 (2H, q, J-7, 42Hz), 4
.. 79 (1B, s).
6.74(18,br)。6.74 (18,br).
エチル−(S)−(−) −5−オキソチオモルホリン
−3−カルボキシレート(1,9g、 10snoj!
、)をテトラヒドロフランに溶解した。氷冷下、Red
−A 1(1,5d、5問of)を滴下した。室温で
一晩撹拌した後、402水酸化カリウム溶液を泡が出な
くなるまで加えた。炭酸カリウムで飽和後、酢酸エチル
で抽出した。抽出液を減圧I!縮し、(S)−(−)−
チオモルホリン−3−メタノールを油状物質として95
0■(収率71z)得た。Ethyl-(S)-(-)-5-oxothiomorpholine-3-carboxylate (1,9 g, 10snoj!
) was dissolved in tetrahydrofuran. Under ice cooling, Red
- A 1 (1,5d, 5 questions) was dropped. After stirring overnight at room temperature, potassium 402 hydroxide solution was added until no more bubbles appeared. After saturated with potassium carbonate, the mixture was extracted with ethyl acetate. Depressurize the extract I! Shrink, (S)-(-)-
Thiomorpholine-3-methanol as oil 95
0■ (yield 71z) was obtained.
MS(m/e):133(M”)、IR:(νneat
)am−’ 3400゜(S)−(−)−チオモルホリ
ン−3−メタノールをメタノールIJII!を含む2N
水酸化ナトリウム溶液3 m (6gmoj! )に溶
解し、水冷下n−Hexadecylchlorofo
rmate(70011g、 2.3mmo l )
を滴下した。水冷下2時間、更に室温で一晩撹拌し
た。 IN塩酸でpH3とした後、酢酸エチルで抽出し
た。抽出液を硫酸マグネシウムで乾燥した後、減圧濃縮
し、残差をシリカゲルクロマトグラフィーに付し、ヘキ
サデシル(S)−(−) −3−(ヒドロキシメチル)
チオモルホリン−4−カルボキシレートを120■(収
率13z)無色油状として得た。MS (m/e): 133 (M”), IR: (νneat
) am-' 3400° (S)-(-)-thiomorpholine-3-methanol to methanol IJII! 2N including
Dissolve n-Hexadecylchlororofo in 3 m (6 g moj!) of sodium hydroxide solution and cool with water.
rmate (70011g, 2.3mmol)
was dripped. The mixture was stirred for 2 hours under water cooling and then overnight at room temperature. After adjusting the pH to 3 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. After drying the extract over magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain hexadecyl (S)-(-)-3-(hydroxymethyl).
Thiomorpholine-4-carboxylate was obtained as a colorless oil in the form of 120 μm (yield 13z).
IR:(y neat)cig−’ 3425.168
0. ’H−NMR: δ(CDCj! 3)0.88
(3H,t) 、 1.26(28H,br) 、
2.16−3.50 (6H,@) 、 3.80〜4
.77(6H,a+)。IR:(y neat)cig-' 3425.168
0. 'H-NMR: δ (CDCj! 3) 0.88
(3H, t), 1.26 (28H, br),
2.16-3.50 (6H, @), 3.80-4
.. 77 (6H, a+).
(S)−(−) −3−(ヒドロキシメチル)チオモル
ホリン−4−カルボキシレート(2,3g、5.1mm
o l )とトリエチルアミン(1,2g、 11a+
a+oiりをジクロルメタンに溶解した。水冷下撹拌し
なから4−塩化トルエンスルホニル(1,6g、8.5
mmo it )をジクロルメタン10−に溶解して滴
下した。室温で一晩撹拌した後、水と飽和食塩水で洗浄
した。ジクロロメタン層を硫酸マグネシウムで乾燥後、
減圧濃縮し、残差をシリカゲルクロマトグラフィーに付
し、ヘキサン−酢酸エチルで溶出し、ヘキサデシル(S
)−(−)−3−(クロロメチル)チオモルホリン4−
カルボキシレートを油状物質として360mg(収率1
5z)得た。(S)-(-)-3-(hydroxymethyl)thiomorpholine-4-carboxylate (2.3g, 5.1mm
o l ) and triethylamine (1.2 g, 11a+
The a+oil mixture was dissolved in dichloromethane. After stirring under water cooling, 4-toluenesulfonyl chloride (1.6 g, 8.5
mmoit) was dissolved in dichloromethane 10- and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. After drying the dichloromethane layer with magnesium sulfate,
It was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluted with hexane-ethyl acetate, and hexadecyl (S
)-(-)-3-(chloromethyl)thiomorpholine 4-
360 mg of carboxylate as oil (yield: 1
5z) Obtained.
IR:(νneat)cm−’ 1702. ’H−N
MR:δ(CDCf :l) 0.88(38、t)
、 1.26 (28H,br) 、 2.20J、6
5 (6H、m) 、 3.65〜4.80(5H,m
)。IR: (νneat)cm-' 1702. 'H-N
MR: δ (CDCf:l) 0.88 (38, t)
, 1.26 (28H, br) , 2.20J, 6
5 (6H, m), 3.65-4.80 (5H, m
).
水素化ナトリウム(40■、1.0 +uaoj! )
をヘキサンで洗浄した後、N、Nジメチルホルムアミド
1〇−に懸濁した。水冷下撹拌しながら2−メルカプト
エタノール(60■、 0.8n+mof )を滴下し
た後、30分間撹拌した。水冷下、ヘキサデシル(S)
(−)−1−(クロロメチル)チオモルホリン4−カル
ホキシレー) (200mg、 0.5mmo I!
)をN、Nジメチルホルムアミド10−に溶解して滴下
した。Sodium hydride (40■, 1.0 +uaoj!)
After washing with hexane, it was suspended in 10-N,N dimethylformamide. 2-Mercaptoethanol (60 ml, 0.8 n+mof) was added dropwise while stirring under water cooling, and the mixture was stirred for 30 minutes. Under water cooling, hexadecyl (S)
(-)-1-(chloromethyl)thiomorpholine 4-carboxyle) (200 mg, 0.5 mmo I!
) was dissolved in 10-N,N dimethylformamide and added dropwise.
2時間撹拌した後、放冷し、次いで氷水を加えジクロル
メタンで抽出した。ジクロルメタン層を減圧濃縮し、残
差をシリカゲルクロマトグラフィーに付し、ヘキサン−
酢酸エチルで?容出し、ヘキサデシル(S)−(−)−
3−C((2−ヒドロキシエチル)チオ〕メメル〕チオ
モルホリン−4−カルボキシレートを油状物質として1
50■(収率65χ)得た。After stirring for 2 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
With ethyl acetate? Discharge, hexadecyl (S)-(-)-
3-C((2-hydroxyethyl)thio]memel]thiomorpholine-4-carboxylate as an oily substance at 1
50μ (yield: 65χ) was obtained.
IR:(νneat)cm−’ 3430,1700.
’H−NMR: δ(CDCl :+)0.88(
3H,t) 、 1.26(28H,br) 、 2.
23〜4.67(16H,m) 。IR: (νneat)cm-' 3430, 1700.
'H-NMR: δ(CDCl:+)0.88(
3H, t), 1.26 (28H, br), 2.
23-4.67 (16H, m).
ヘキサデシル(S)−(−)−3−(((2−ヒドロキ
シエチル)チオ〕メメル)チオモルホリン4−カルボキ
シレート(150■、 0.3111mo l )とト
リエチルアミン(60■、 0.6mmo 42 )を
ジクロルメタンに溶解した。水冷下撹拌しながらメタン
スルホニルクロライド(70■、 0.6mmof )
滴下した。Hexadecyl (S)-(-)-3-((2-hydroxyethyl)thio]memel)thiomorpholine 4-carboxylate (150 µ, 0.3111 mol) and triethylamine (60 µ, 0.6 mmo 42) Dissolved in dichloromethane.Methanesulfonyl chloride (70μ, 0.6mmof) was added while stirring under water cooling.
dripped.
室温で一晩撹拌した後、ジクロルメタンを留去し、残さ
をシリカゲルクロマトグラフィーでヘキサン−酢酸エチ
ルでt容出し、ヘキサデシル(S)−(−)3−(((
2−クロロエチル)チオ〕メチル〕チオモルホリン−4
−カルボキシレートを油状物質として110■(収率7
1χ)得た。After stirring at room temperature overnight, dichloromethane was distilled off, and the residue was chromatographed on silica gel with hexane-ethyl acetate to give hexadecyl (S)-(-)3-(((
2-chloroethyl)thio]methyl]thiomorpholine-4
- Carboxylate as oily substance 110 μ (yield 7
1χ) obtained.
R:(v neat)cub−’ 1700. ’H−
NMR:δ(CDC13)0.88(3H,t)、1.
26(28H,br)、2.47〜4.61(15H,
m)。R: (v neat)cub-' 1700. 'H-
NMR: δ (CDC13) 0.88 (3H, t), 1.
26 (28H, br), 2.47-4.61 (15H,
m).
ヘキサデシル(S)−(−) −3−C((2−クロロ
エチル)チオ〕メチル〕チオモルホリンー4カルボキシ
レート(11011g、0.23m+ao l )をチ
アゾール(1,0g、 12n+a+o l )に溶解
し、封管中100°C−晩反応させた。チアゾールを留
去した後、残さをシリカゲルクロマトグラフィーに付し
、クロロホルム−メタノール−水で溶出し、(S) −
(−) −N〔N”−(ヘキサデシルオキシカルボニル
)−3−チオモルホリンメチルチオエチル〕チアゾリウ
ムクロライドを淡黄色粉末として15g(収率12X)
得た。Hexadecyl (S)-(-)-3-C((2-chloroethyl)thio]methyl]thiomorpholine-4carboxylate (11011 g, 0.23 m+aol) was dissolved in thiazole (1.0 g, 12n+a+o l) and sealed in a tube. After distilling off the thiazole, the residue was subjected to silica gel chromatography, eluted with chloroform-methanol-water, and (S)-
(-) -N [N”-(hexadecyloxycarbonyl)-3-thiomorpholine methylthioethyl] thiazolium chloride as pale yellow powder, 15 g (yield 12X)
Obtained.
実施例14で得られた化合物の構造及び物性値を第4表
に示す。The structure and physical properties of the compound obtained in Example 14 are shown in Table 4.
実施例15
水素化リチウムアルミニウム(1,7g、 46++u
wof )をテトラヒドロフランに懸濁した。■5分間
還流した後、インドール−2−カルボン酸(5g、31
+mol)を加えた。1時間還流した後、水酸化カリウ
ム溶液(16mmo l )を加えた。不溶物質を濾過
後、減圧濃縮し、2−インドリンメタノールを油状物質
とし74.8g (収率1002)得た。Example 15 Lithium aluminum hydride (1.7 g, 46++ u
wof) was suspended in tetrahydrofuran. ■ After refluxing for 5 minutes, indole-2-carboxylic acid (5 g, 31
+mol) was added. After refluxing for 1 hour, potassium hydroxide solution (16 mmol) was added. After filtering out insoluble materials, the mixture was concentrated under reduced pressure to obtain 74.8 g (yield: 1002) of 2-indoline methanol as an oily substance.
2−インドリンメタノール(1,5g、 10問of)
を実施例1と同様に反応させ、目的物質であるNCN’
−(ヘキサデシルオキシカルボニル)−2−インドリニ
ル−メチルチオエチル〕チアゾリウム クロライドを淡
黄色粉末として50■(収率132)得た。2-Indoline methanol (1.5g, 10 questions)
was reacted in the same manner as in Example 1, and the target substance NCN'
-(Hexadecyloxycarbonyl)-2-indolinyl-methylthioethyl]thiazolium chloride was obtained as a pale yellow powder in the form of 50 μl (yield: 132).
実施例例15で得た化合物の構造式及び物性値を第5表
に示す。The structural formula and physical property values of the compound obtained in Example 15 are shown in Table 5.
実施例16
市販品である2−アきノエタノール(1,2g、 2O
n+mo Ilを実施例1と同様に反応させ、目的物質
であるN(N’−(へ牛すデシルオキシ力ルボニル)−
アミノ−2−エチルチオエチル]チアゾリウムクロライ
ドを淡黄色粉末として380mg (収率53z)得た
。Example 16 Commercially available 2-acinoethanol (1.2 g, 2O
n+mo Il was reacted in the same manner as in Example 1 to obtain the target substance N(N'-(hesdecyloxycarbonyl)-
380 mg (yield: 53z) of amino-2-ethylthioethyl]thiazolium chloride was obtained as a pale yellow powder.
実施例例16で得た化合物の構造式及び物性値を第6表
に示す。The structural formula and physical property values of the compound obtained in Example 16 are shown in Table 6.
)
実施例17
N−(N’−(ヘキサデシルオキシカルボニル)2−モ
ルホリニル−メチルチオエチル〕チアゾリウム クロラ
イド5g、繊維素グルコン酸カルシウム(崩壊剤)20
0■、ステアリン酸マグネシウム(潤滑剤)100■及
び結晶セルロース9.7gを常法により混合打錠して1
錠中に50■の活性成分を含有する錠剤を得た。) Example 17 N-(N'-(hexadecyloxycarbonyl)2-morpholinyl-methylthioethyl]thiazolium chloride 5g, cellulose calcium gluconate (disintegrant) 20
0 ■, magnesium stearate (lubricant) 100 ■ and crystalline cellulose 9.7 g were mixed and compressed into tablets using a conventional method.
Tablets were obtained containing 50 μ of active ingredient in the tablet.
本発明の一般式(I)で表わされるピロリジン誘導体及
びその酸付加塩は、PAFに対する拮抗作用及びPAF
様血圧降下作用、ホスホリパーゼ阻害作用、腫瘍細胞に
対する増殖抑制作用を有しているので、血小板凝集阻害
剤、抗喘息剤、抗アレルギー剤、抗炎症剤、血圧降下剤
、抗エンドトキシンショック剤、抗腎炎剤、抗膵炎剤、
抗虚血性脳血管障害剤及び抗腫瘍剤として有用である。The pyrrolidine derivative represented by general formula (I) and its acid addition salt of the present invention have an antagonistic effect on PAF and
It has anti-hypertensive effects, phospholipase inhibitory effects, and anti-proliferative effects on tumor cells, so it is used as a platelet aggregation inhibitor, anti-asthmatic agent, anti-allergic agent, anti-inflammatory agent, anti-hypertensive agent, anti-endotoxic shock agent, and anti-nephritis agent. drugs, anti-pancreatitis drugs,
It is useful as an anti-ischemic cerebrovascular disorder agent and an anti-tumor agent.
これらの作用は実験室での実験により確められており、
例えばPAFに対する拮抗作用は以下に述べるスクリー
ニング系により確認した。These effects have been confirmed through laboratory experiments.
For example, the antagonistic effect on PAF was confirmed by the screening system described below.
AFtfE
雄性ウサギより採血した血液と3.13χクエン酸ナト
リウム水溶液を9 : 1 (v/v)の割合で混合し
、室温で10分間遠心分離(120G) して得られた
多血小板血漿を用いて、P A F 4 Xl0−”
Mによる血小板の凝集をポーン(Born)の凝集計に
よる吸光度法によって測定した(J、 Physiol
、、 162巻、67ページ(1962年〉〕。AFtfE Blood collected from male rabbits and 3.13χ sodium citrate aqueous solution were mixed at a ratio of 9:1 (v/v), and platelet-rich plasma obtained by centrifugation (120G) for 10 minutes at room temperature was used. , P A F 4 Xl0-”
Platelet aggregation by M was measured by absorbance method using a Born aggregometer (J, Physiol
,, Volume 162, Page 67 (1962)].
結果は次表に示した通りで、作用の50%を抑制または
阻害する本発明化合物の濃度■CS。で示した。The results are shown in the table below, where the concentration of the compound of the present invention that suppresses or inhibits 50% of the effect ■CS. It was shown in
以上の結果が示すように本発明の式(I)で表わされる
化合物は、PAF誘発血小板凝集作用を示し、PAFに
対する拮抗作用を有する物質であることがわかった。As shown by the above results, the compound represented by formula (I) of the present invention was found to be a substance that exhibits a PAF-induced platelet aggregation action and has an antagonistic action against PAF.
/
第7表
新規ヘテロ環誘導体のウサギ血液中のPAFPAFに対
する拮抗作用。/ Table 7 Antagonism of novel heterocyclic derivatives against PAFPAF in rabbit blood.
PAF様血圧降下作用。PAF-like blood pressure lowering effect.
誘発血小板凝集作用
ホスホリパーゼ阻害作用並びに腫瘍細胞に対する増殖抑
制作用または分化誘導作用を有しており、医薬品して有
用である。It has an induced platelet aggregation effect, a phospholipase inhibitory effect, and an antiproliferative or differentiation-inducing effect on tumor cells, and is useful as a pharmaceutical.
Claims (1)
ます▼基(Eは炭素数1〜8の直鎖または分岐したアル
キル基を示す。)酸素原子あるいはイオウ原子を示す。 Aはカルボニル基あるいはメチレン基を示し、Bは単結
合、酸素原子、イオウ原子、窒素原子あるいはリン酸基
を示す。Cは単結合あるいは炭素数1〜6のアルキレン
基を示し、Dはアミノ基あるいは式−NHCOR^1、
−NHR^2、−N(R^2)_2または−^■N(R
^2)_3Y^■(式中、R^1は炭素数1〜6のアル
キル基またはフェニル基を示し、R^2は炭素数1〜6
のアルキル基を示し、Y^■は酸の陰イオンを示す、た
だし、複数のR^2が結合している場合にはそれらは同
一であっても異なっていてもよい。)あるいは複素環基
▲数式、化学式、表等があります▼を示す。Rは炭素数
2〜22のアルキル基を示す。 また、環部とAとの結合は単結合でAの配位がα位ある
いはβ位の光学活性体あるいは両配位の混合物であるラ
セミ体を示す。〕 で表わされるヘテロ環誘導体またはその酸付加塩。 (2)請求項1記載のヘテロ環誘導体またはその酸付加
塩を有効成分とする血小板凝集阻害剤。 (3)請求項1記載のヘテロ環誘導体またはその酸付加
塩を有効成分とする抗喘息剤。 (4)請求項1記載のヘテロ環誘導体またはその酸付加
塩を有効成分とする抗アレルギー剤。 (5)請求項1記載のヘテロ環誘導体またはその酸付加
塩を有効成分とする抗炎症剤。 (6)請求項1記載のヘテロ環誘導体またはその酸付加
塩を有効成分とする血圧降下剤。(7)請求項1記載の
ヘテロ環誘導体またはその酸付加塩を有効成分とする抗
エンドトキシンショック剤。 (8)請求項1記載のヘテロ環誘導体またはその酸付加
塩を有効成分とする抗腎炎剤。 (9)請求項1記載のヘテロ環誘導体またはその酸付加
塩を有効成分とする抗膵炎剤。 (10)請求項1記載のヘテロ環誘導体またはその酸付
加塩を有効成分とする抗虚血性脳血管障害剤。 (11)請求項1記載のヘテロ環誘導体またはその酸付
加塩を有効成分とする抗腫瘍剤。[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, ~8 straight-chain or branched alkyl group) represents an oxygen atom or a sulfur atom. A represents a carbonyl group or a methylene group, and B represents a single bond, an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphoric acid group. C represents a single bond or an alkylene group having 1 to 6 carbon atoms, D represents an amino group or the formula -NHCOR^1,
-NHR^2, -N(R^2)_2 or -^■N(R
^2)_3Y^■ (In the formula, R^1 represents an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R^2 represents an alkyl group having 1 to 6 carbon atoms.
represents an alkyl group, and Y^■ represents an acid anion. However, when multiple R^2's are bonded, they may be the same or different. ) or a heterocyclic group ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼. R represents an alkyl group having 2 to 22 carbon atoms. Further, the bond between the ring part and A is a single bond, and an optically active substance in which A is coordinated at the α-position or β-position, or a racemic body which is a mixture of both coordinations is shown. ] A heterocyclic derivative or an acid addition salt thereof. (2) A platelet aggregation inhibitor comprising the heterocyclic derivative according to claim 1 or an acid addition salt thereof as an active ingredient. (3) An anti-asthmatic agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (4) An antiallergic agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (5) An anti-inflammatory agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (6) An antihypertensive agent containing the heterocyclic derivative according to claim 1 or an acid addition salt thereof as an active ingredient. (7) An anti-endotoxin shock agent comprising the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (8) An anti-nephritis agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (9) An anti-pancreatitis agent comprising the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (10) An anti-ischemic cerebrovascular disorder agent comprising the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (11) An antitumor agent comprising the heterocyclic derivative according to claim 1 or an acid addition salt thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3364890A JPH03240779A (en) | 1990-02-16 | 1990-02-16 | New hetero-ring derivative and drug containing thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3364890A JPH03240779A (en) | 1990-02-16 | 1990-02-16 | New hetero-ring derivative and drug containing thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH03240779A true JPH03240779A (en) | 1991-10-28 |
Family
ID=12392270
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3364890A Pending JPH03240779A (en) | 1990-02-16 | 1990-02-16 | New hetero-ring derivative and drug containing thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH03240779A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998032757A1 (en) * | 1997-01-24 | 1998-07-30 | Kyorin Pharmaceutical Co., Ltd. | Pyrroloindole derivatives and intermediates in producing the same |
JP2006225300A (en) * | 2005-02-16 | 2006-08-31 | National Institute Of Advanced Industrial & Technology | New n-sulfenylpyrrole compound and its manufacturing method |
-
1990
- 1990-02-16 JP JP3364890A patent/JPH03240779A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998032757A1 (en) * | 1997-01-24 | 1998-07-30 | Kyorin Pharmaceutical Co., Ltd. | Pyrroloindole derivatives and intermediates in producing the same |
US6080859A (en) * | 1997-01-24 | 2000-06-27 | Kyorin Pharmaceutical Co., Ltd. | Pyrroloindole derivatives and intermediates in producing the same |
JP2006225300A (en) * | 2005-02-16 | 2006-08-31 | National Institute Of Advanced Industrial & Technology | New n-sulfenylpyrrole compound and its manufacturing method |
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