JPS609509B2 - Production method of 6-aminochroman derivative - Google Patents
Production method of 6-aminochroman derivativeInfo
- Publication number
- JPS609509B2 JPS609509B2 JP5475375A JP5475375A JPS609509B2 JP S609509 B2 JPS609509 B2 JP S609509B2 JP 5475375 A JP5475375 A JP 5475375A JP 5475375 A JP5475375 A JP 5475375A JP S609509 B2 JPS609509 B2 JP S609509B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- formulas
- chromanyl
- cholesterol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000004519 manufacturing process Methods 0.000 title claims 2
- GYELWTXNPXFOGQ-UHFFFAOYSA-N 3,4-dihydro-2h-chromen-6-amine Chemical class O1CCCC2=CC(N)=CC=C21 GYELWTXNPXFOGQ-UHFFFAOYSA-N 0.000 title 1
- -1 Ketone compounds Chemical class 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 3
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 22
- 238000012360 testing method Methods 0.000 description 14
- 238000005259 measurement Methods 0.000 description 12
- 235000012000 cholesterol Nutrition 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 244000215068 Acacia senegal Species 0.000 description 5
- 229920000084 Gum arabic Polymers 0.000 description 5
- 239000000205 acacia gum Substances 0.000 description 5
- 235000010489 acacia gum Nutrition 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 101150041968 CDC13 gene Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- WHWDWIHXSPCOKZ-UHFFFAOYSA-N hexahydrofarnesyl acetone Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)=O WHWDWIHXSPCOKZ-UHFFFAOYSA-N 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 238000000449 magic angle spinning nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WHWDWIHXSPCOKZ-SJORKVTESA-N 6,10,14-Trimethyl-2-pentadecanone Natural products CC(C)CCC[C@@H](C)CCC[C@H](C)CCCC(C)=O WHWDWIHXSPCOKZ-SJORKVTESA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 101100537937 Caenorhabditis elegans arc-1 gene Proteins 0.000 description 1
- 240000004528 Catalpa ovata Species 0.000 description 1
- 235000010005 Catalpa ovata Nutrition 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 102000010029 Homer Scaffolding Proteins Human genes 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZUNGGJHBMLMRFJ-UHFFFAOYSA-O ethoxy-hydroxy-oxophosphanium Chemical compound CCO[P+](O)=O ZUNGGJHBMLMRFJ-UHFFFAOYSA-O 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- JPTOCTSNXXKSSN-UHFFFAOYSA-N methylheptenone Chemical compound CCCC=CC(=O)CC JPTOCTSNXXKSSN-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は次の一般式（１）
〔式中Ｒ，、Ｒ２、Ｒ３は水素またはメチル基を、Ｒ４
は水素または低級アルキル基を、ｍ、ｎは０〜３の整数
を表わす。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the following general formula (1) [wherein R,, R2, and R3 are hydrogen or a methyl group, and R4
represents hydrogen or a lower alkyl group, and m and n represent integers of 0 to 3.
またＡ、Ｂは水素原子、あるいはＡ−Ｂ間で結合手を形
成する場合のあることを表わす。〕で表わされる新規な
６ーアミノクロマン化合物の不飽和脂肪酸アミド体の合
成法に関するものである。Further, A and B represent hydrogen atoms or a bond may be formed between A and B. This invention relates to a method for synthesizing an unsaturated fatty acid amide of a novel 6-aminochroman compound represented by the following.
本発明に依る化合物（１）は優れた血中および肝中のコ
レステロール低下作用を有するがそれは次の薬理試験の
結果より明らかである。Compound (1) according to the present invention has an excellent blood and liver cholesterol-lowering effect, which is clear from the results of the following pharmacological tests.
薬理試験 【１｝ 検体化合物：次の化合物を選定した。Pharmacological testing [1} Test compound: The following compound was selected.
Ｎ−（２・２・５・７・８ーベンタメチルークロマニル
−６）−ゲラノイルアミド（以下化合物Ａと称す）Ｎ−
（２・２・５’７・８−ペンタメチル−クロマニル−６
）−フアルネシロイルアミド（以下化合物Ｂと称す）Ｎ
−メチル一Ｎ−（２・２・５・７・８ーベンタメチルー
クロマニル−６）ーフアルネシロィルアミド（以下化合
物Ｃと称す）Ｎ一〔２−（４′・８・１２ートリメチル
ートリデシル）−２−メチルークロマニル−６〕−フア
ルネシロィルアミド（以下化合物Ｄと称す）Ｎ−メチル
−Ｎ一〔２−（４′・８・１２−トリメチルートリデシ
ル）一２・５１７・８−テトラメチルークロマニル−６
〕−フアルネシロイルアミド（以下化合物Ｅと称す）Ｎ
−メチル一Ｎ−〔２−（４′・８・１２−トリメチルー
トリデシル）一２・５・７・８−テトラメチルークロマ
ニル−６〕−フイテノイルアミド（以下化合物Ｆと称す
）剛 使用動物
ウィスター系雄性ラット（体重１４０〜１７０夕）を１
検体化合物につき５匹使用した。N-(2.2.5.7.8-bentamethyl-chromanyl-6)-geranoylamide (hereinafter referred to as compound A) N-
(2,2,5'7,8-pentamethyl-chromanyl-6
)-furnesiroylamide (hereinafter referred to as compound B) N
-Methyl-N-(2,2,5,7,8-bentamethyl-chromanyl-6)-farnesilylamide (hereinafter referred to as compound C)N-[2-(4',8,12 -trimethyl-tridecyl)-2-methyl-chromanyl-6]-farnesilylamide (hereinafter referred to as compound D) decyl)-2,517,8-tetramethyl-chromanyl-6
]-Farnesiroylamide (hereinafter referred to as compound E) N
-Methyl-N-[2-(4',8,12-trimethyl-tridecyl)-2,5,7,8-tetramethyl-chromanyl-6]-phitenoylamide (hereinafter referred to as compound F) Animals used: 1 male Wistar rat (body weight 140-170 mm)
Five animals were used for each test compound.
【３｝ 試験項目
（ｉ）正常飼料投与動物に対する作用
【ィー 投与法、投与量および測定法
検体化合物Ａ〜Ｆを５％水性アラビアゴ
ム溶液に懸濁させ、各々２００の９／ｋ９１日の投与量
で、８日間連続で経経口投与した。[3] Test item (i) Effect on animals administered normal diet [i] Administration method, dosage and measurement method Sample compounds A to F were suspended in a 5% aqueous gum arabic solution, and each was administered at 200 9/k for 91 days. The dose was orally administered for 8 consecutive days.
一方、５％水性アラビアゴム溶液だけを同様に投与して
ブランクテストを行ないコントロールとした。On the other hand, a blank test was conducted by administering only a 5% aqueous gum arabic solution in the same manner as a control.
投与８日目の血中および肝中の総コレステロール量およ
びェステル型コレステロール量を測定した。On the 8th day of administration, the total amount of cholesterol and the amount of ester-type cholesterol in the blood and liver were measured.
‘。‘.
｝ 測定結果結果は次表に示す如くである。} The measurement results are as shown in the table below.
数値は８日間投与後の総コレステロールおよびェステル
型コレステロールの残存量である。The values are the remaining amounts of total cholesterol and ester-type cholesterol after 8 days of administration.
従って数値の小さいもの程、コレステロール低下作用は
優れている（５匹平均値）。Therefore, the lower the value, the better the cholesterol-lowering effect (average value for 5 animals).
表 １
（ｉｉ｝ コレステロール負荷飼料投与動物に対する作
用【ィ）授与法、投与量および測定法
薬学雑誌、９２巻、７号、８７９〜８８５頁（１９７２
王）記載の方法に準じて、使用動物にコレステロール２
重量％、コール酸１重量％を混ぜた飼料を与え、同時に
検体化合物Ａ〜Ｆを５％水性アラビアゴム溶液に懸濁さ
せ、各々２００の９′ｋ９１日の投与量で、５日間連続
で経口投与した。Table 1 (ii) Effects on animals administered with cholesterol-loaded feed (a) Method of administration, dosage and measurement Pharmaceutical Journal, Vol. 92, No. 7, pp. 879-885 (1972
Cholesterol 2 was added to the animals used according to the method described in
At the same time, test compounds A to F were suspended in a 5% aqueous gum arabic solution and administered orally for 5 consecutive days at a dose of 200 9'k91 days each. administered.
一方、５％水性アラビゴム溶液だけを同様に投与してブ
ランクテストを行い、コントロールとした。On the other hand, a blank test was conducted by administering only a 5% aqueous gum arabic solution in the same manner as a control.
投与５日間の血中および肝中の総コレステロール量およ
びェステル型コレステロール量を測定した。The total amount of cholesterol and the amount of ester type cholesterol in the blood and liver were measured for 5 days after administration.
【０ｌ 測定結果 結果は次表に示す如くである。0l measurement result The results are shown in the table below.
数値は５日間投与後の総コレステロールおよびヱステル
型コレステロールの残存量である。The values are the remaining amounts of total cholesterol and ester-type cholesterol after 5 days of administration.
従って数値の小さいもの程、コレステロール低下作用は
優れている（５匹平均値）。Therefore, the lower the value, the better the cholesterol-lowering effect (average value for 5 animals).
表
（ｉｉｉ）急性毒性試験
‘ィー 投与法、没与量
検体化合物Ａ〜Ｆを５％水性アラビアゴ
ム溶液に懸濁させ、各検体化合物毎に５００雌／ｋ９、
２０００雌／ｋ９の投与量で経口投与した。Table (iii) Acute toxicity test Administration method, dose amount Test compounds A to F were suspended in a 5% aqueous gum arabic solution, 500 females/k9 for each test compound,
It was administered orally at a dose of 2000 females/k9.
投与後５００ｗｎド【一・いドＭ＾−Ｍ／ｋｇ投与群に
ついては４口回、１００００雌／ｋｇ投与群については
７日間の観察時間をもうけた。仲 観察結果
いずれの検体化合物でも１００００のｃ／ｋｇの投与量
で、はじめて一過性の下痢が認められたにすぎず、体重
増加も順調であった。After administration, observation time was allowed for 4 times for the 500 wn/kg administration group and 7 days for the 10,000 female/kg administration group. Naka: Observation Results For all test compounds, only transient diarrhea was observed for the first time at a dose of 10,000 c/kg, and weight gain was also normal.
死亡例は認められなかった。No deaths were observed.
以上の結果から、検体化合物の経口急性毒性は極めて低
し、ものと考えられる。From the above results, the oral acute toxicity of the test compound is considered to be extremely low.
また致死量（ＬＤ）は１００００の９／ｋ９（経口）以
上と推定される。｛４’結果この薬理試験より、化合物
Ａ〜Ｆはいずれも優れたコレステロール低下作用を有し
、その毒性（急性毒性）も極めて低いと判明した。Furthermore, the lethal dose (LD) is estimated to be 10,000 9/k9 (oral) or more. {4'Results This pharmacological test revealed that compounds A to F all have excellent cholesterol-lowering effects, and their toxicity (acute toxicity) is also extremely low.
以上の薬理試験の結果より、化合物Ａ〜Ｆで代表される
本発明の化合物（１）は血中コレステロールの増加に起
因する疾患、特に動脈硬化、糖尿病、肝疾患などいわゆ
る成人病の予防および治療Ｐ−（Ｎークロマニルーアセ
トアミド）−アルキルーフェニルホスホネート（次式）
〔式中Ｒ，、Ｒ２、Ｒ３、Ｒ４およびｎは前記の意味を
表わす。From the results of the above pharmacological tests, the compounds (1) of the present invention represented by Compounds A to F are effective for preventing and treating diseases caused by increased blood cholesterol, especially so-called adult diseases such as arteriosclerosis, diabetes, and liver diseases. P-(N-chromani-acetamide)-alkyl-phenylphosphonate (formula below)
[In the formula, R,, R2, R3, R4 and n represent the above meanings.
Ｎｋは低級ァルキルを表わす。〕化合物（Ｄ）と化合物
（囚）から導かれるゥィテッヒ試薬との反応は通常ゥィ
テッヒ反応（前記文献参照）に従って反応させる事によ
り行われる。Nk represents a lower alkyl. ] The reaction between the compound (D) and the Wittig reagent derived from the compound (container) is usually carried out by reacting according to the Wittig reaction (see the above-mentioned literature).
反応に際しては通常ブチルリチウム、ナトリウムアミド
、ナトリウムハイドライド、ナトリウムメチラート、カ
リウムｔ−ブトキサィド、苛性カリ、炭酸ソーダ、トリ
ェチルアミン等のアルカリ試薬を添加する。また反応は
無溶媒でも進行するが、通常ウィテッヒ反応に使用され
る溶媒、たとえはベンゼン、トルエン、キシレン、ヘキ
サン、石油エーテル、リグロィンシクロヘキサン、エチ
ルヱーナル、イソプロピルエーテル、ジオキサン、テト
ラヒドロフラン、酷酸エチルェステル、ジメチルホルム
アミド等を使用する事により反応をより一層円滑に、ま
た後処理もより容易に行う事ができる。出発原料の６ー
ハロアセトアミトークロマン化合物（ｍ）は新規化合物
であるが、例えばトリェチルアミン、ピリジン等を溶媒
として次式に利用価値が大きいと考えられる。During the reaction, an alkaline reagent such as butyllithium, sodium amide, sodium hydride, sodium methylate, potassium t-butoxide, caustic potash, sodium carbonate, triethylamine, etc. is usually added. Although the reaction proceeds without a solvent, the solvents usually used in the Wittig reaction, such as benzene, toluene, xylene, hexane, petroleum ether, ligroin cyclohexane, ethyl endal, isopropyl ether, dioxane, tetrahydrofuran, harsh acid ethyl ester, By using dimethylformamide or the like, the reaction can be carried out even more smoothly and post-treatment can be carried out more easily. Although the starting material 6-haloacetamitochroman compound (m) is a new compound, it is considered to have great utility in the following formula using, for example, triethylamine, pyridine, etc. as a solvent.
本発明は次の一般式（０） 〔式中Ａ、Ｂおよびｍは前記の意味を表わす。The present invention is based on the following general formula (0) [In the formula, A, B and m have the above meanings.
〕で表わされるケトン化合物に、次の一般式（ｍ）〔式
中Ｒ，、Ｒ２、Ｒ３、Ｒ４およびｎは前記の意味を表わ
し、Ｘはハロゲン原子をあらわす。〕で表わされる６−
アミノクロマン化合物のハロアセトアミド体から導かれ
るウィテッヒ試薬を反応させて次の一般式（１）〔式中
Ｒ，、Ｒ２、Ｒ３、Ｒ４、Ａ、Ｂ、ｍ、ｎは前記の意味
を表わす。] The ketone compound represented by the following general formula (m) [wherein R,, R2, R3, R4 and n represent the above-mentioned meanings, and X represents a halogen atom. ] 6-
A Wittig reagent derived from a haloacetamide form of an aminochroman compound is reacted to form the following general formula (1) [wherein R,, R2, R3, R4, A, B, m, and n represent the above-mentioned meanings.
〕で表わされる６ーアミノクロマン化合物の不飽和脂肪
酸アミドを合成する事よりなる。It consists of synthesizing an unsaturated fatty acid amide of a 6-aminochroman compound represented by ].
本発明において化合物（ｍ）から導かれるウィテッヒ試
薬としては化合物（ｍ）を、例えばトリフェニルホスフ
ィン〔（Ｃ６公）３Ｐ〕、フェニルジアルコキシホスフ
イン〔Ｃ６日５（ＡＩｋ○）２Ｐ〕あるいはトリァルキ
ルホスフアィト〔Ｐ（０山ｋ）３〕（但しＮｋは低級ア
ルキル基）等の燐化合物を、ワツズワース等（Ｗａｄｗ
ｏｒｔｈ．ｅｔａｌ）〔ジャーナル・オブ・ジ・アメリ
カン・ケミカル・ソサイアテイ（Ｊ．Ａｍ．Ｃｈｅｍ．
Ｓｏｃ．）第８窃萱１７３３頁（１９６１）〕、ホーナ
ー等（Ｈｏｍｅｒ．ｅｔａｌ）〔ベリヒテ（Ｂｅｒ．）
第９５巻５８１頁（１９６２年）〕、グリーンワールド
等（Ｇｒｅｅｎ肌ｌｄ．ｅｔａｌ）〔ジャーナル・オブ
・ジ・オルガニック・ケミストリ−（Ｊ．仇ｇ．○ｈｅ
ｍ）第２８巻１１２８頁（１９６３年）〕等の方法に従
って調整される次のものを挙げる事ができる。In the present invention, as a Wittig reagent derived from compound (m), compound (m) can be used, for example, as triphenylphosphine [(C6 public) 3P], phenyldialkoxyphosphine [C6 day 5 (AIk○) 2P] or trialkyl Phosphorus compounds such as phosphite [P(0 mountain k)3] (where Nk is a lower alkyl group) are prepared by Wadsworth et al.
orth. etal) [J. Am. Chem.
Soc. ) No. 8 Theft, p. 1733 (1961)], Homer et al. [Ber.
Vol. 95, p. 581 (1962)], Green World et al. [Journal of the Organic Chemistry (J.
m) Vol. 28, p. 1128 (1963)].
Ｐ−（Ｎ一６ークロマニルーアセトアミド）ージアルキ
ルホスホネート（次式）Ｐ−（Ｎ一６ークロマニルーア
セトアミド）−トリフェニルホスホニウム塩（次式）〔
式中Ｒ，、Ｒ２、Ｒ３、Ｒ４およびｎは前記の意味を表
わす。P-(N-6-chromaniluacetamide)-dialkylphosphonate (following formula) P-(N-6-chromaniluacetamido)-triphenylphosphonium salt (following formula) [
In the formula, R,, R2, R3, R4 and n have the above meanings.
〕で表わす６−アミノクロマン化合物にハロアセチルハ
ラィドを反応させる事により容易に得る事ができる。It can be easily obtained by reacting a 6-aminochroman compound represented by the following with a haloacetyl halide.
次に実施例により本発明を説明する。Next, the present invention will be explained with reference to Examples.
実施例 １
Ｎ−（２・２・５・７・８−ペンタメチルークロマニル
−６）−フィテノィルアミドの合成（工程１） ６−ク
ロルアセトアミド−２１２・５・７・８−ペンタメチル
クロマンの合成６ーアミンー２・２・５１７１８−ペン
タメチルークロマン５１９、ピリジン４０夕をベンゼン
１．５れこ溶解して得られた溶液に、瀦洋下、１５〜２
０００でクロルアセチルクロラィド４５夕を滴下した。Example 1 Synthesis of N-(2,2,5,7,8-pentamethyl-chromanyl-6)-phytenolamide (Step 1) 6-chloroacetamide-212,5,7,8-pentamethyl Synthesis of Chroman 6-Amine-2.2.51718-Pentamethyl-Chroman 519 and pyridine 40% were dissolved in 1.5 benzene to obtain a solution.
45 ml of chloracetyl chloride was added dropwise at 0.000 g.
滴下終了後１５〜２０ｏｏに保ちつつ３時間擁梓を継続
した。反応終了後、反応混合物を氷分に分散させ、５％
塩酸、５％重炭酸ソーダ水溶液、水で順次洗浴し、次い
でＥ硝で乾燥したのち減圧濃縮し、茶色板状結晶として
目的物を得た。収量６９タ 融点１５８〜１６００Ｃ元
素分析値 Ｃ，６日２２Ｎ０２ＣＩとしてＣ 日Ｎ理論
値（％） ６４．９６ ７．５０ ４．７４実測値（
％） ６４．９５ ７．５５ ４．７５（工程２）
Ｎ−（２・２・５・７１８−ペンタメチルークロマニル
一６）ーフイテノイルアミドの合成工程１で得た６ーク
ロルアセトアミド−２・２・５・７・８ーベンタメチル
ークロマン５．９夕とトリエチルホスフアィト８．３夕
より得られたＰ一〔Ｎ一（２・２・５・７・８−ペンタ
メチルークロマニル）−アセトアミド）一ジエチルホス
ホネートをベンゼン１００私に溶解させて得られる溶液
に２０００、損枠下、ナトリウムェチラート２．７夕を
加えたのち、６・１０・１４ートリメチルー２−ペンタ
デカノン８．１夕を滴下した。After the completion of dropping, the retention was continued for 3 hours while maintaining the temperature at 15 to 20 oo. After the reaction is completed, the reaction mixture is dispersed in ice and 5%
The mixture was washed successively with hydrochloric acid, a 5% aqueous sodium bicarbonate solution, and water, then dried over E-nitrogen, and concentrated under reduced pressure to obtain the desired product as brown plate-like crystals. Yield 69 ta Melting point 158-1600C Elemental analysis value C, 6 days as 22N02CI C day N theoretical value (%) 64.96 7.50 4.74 Actual value (
%) 64.95 7.55 4.75 (Step 2)
N-(2,2,5,718-pentamethyl-chromanyl-6)-phitenoylamide 6-chloroacetamide-2,2,5,7,8-bentamethyl-chromanyl 5 obtained in synthesis step 1 P-[N-(2.2.5.7.8-pentamethyl-chromanyl)-acetamido)-diethylphosphonate obtained from .9 and triethyl phosphite was dissolved in 100% benzene. To the solution obtained, 2,000 ml of sodium ethylate was added, and then 8.1 ml of 6,10,14-trimethyl-2-pentadecanone was added dropwise.
滴下終了後、２０℃にて蝿梓を８時間継続した。反応終
了後、反応混合物を水に分散したのち、水で洗糠、次い
で三硝で乾燥したのち減圧濃縮した。残澄をｎーヘキサ
ン・エチルエーテル混合溶媒を溶出溶媒とするシリカゲ
ルクロマト操作により精製、溶媒を留去して目的物を淡
黄色油状物質として得た。収量９．３夕 （収率９１％
）
元素分析値Ｃ３４日５７Ｎ０２として
Ｃ 日 Ｎ
理論値（％） ７９．７９ １１．２３ ２．７４
実測値（％） ７９．８１ １１．２２ ２．７５
１Ｒスペクトル測定値（伽‐１）３２６０（しＮＥ）、
１６６０（しＣ＝。After the dropwise addition was completed, fly azusa was continued at 20° C. for 8 hours. After the reaction was completed, the reaction mixture was dispersed in water, washed with water, dried over Sannitro, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of n-hexane and ethyl ether as an eluent, and the solvent was distilled off to obtain the desired product as a pale yellow oil. Yield: 9.3 yen (yield: 91%)
) Elemental analysis value C34th 57N02 C day N Theoretical value (%) 79.79 11.23 2.74
Actual value (%) 79.81 11.22 2.75
1R spectrum measurement value (Ka-1) 3260 (SHNE),
1660(shiC=.
）ＭＡＳスペクトル測定値Ｍ十：５１１
ＮＭＲスペクトル測定値（７：ＣＤＣ１３）Ｎ−Ｈ；２
．８５（ＩＨ）芳香族ＣＨ３：８．９８（ＱＨ）
クロマン３位−ＣＨ２：８．２１（が）
クロマン４位−Ｃ泣：７．４１（２Ｈ）
ＣＨ＝；４．８０（ＩＨ）
実施例 ２
Ｎ−（２・２・５１７・８−ペンタメチルークロマニル
−６）ーゲラノィルアミドの合成６−クロルアセトアミ
ド−２・２・５・７・８ーベンタメチルークロマン７．
４夕とトリエチルホスファィト５．０夕より調製したＰ
−〔Ｎ−（２・２・５・７・８ーベンタメチル−クロマ
ニル）ーアセトアミド〕−ジエチルホスホネートとメチ
ルヘプテノン３．８夕とを実施例１・工程２に従って反
応処理した。) MAS spectrum measurement value M: 511 NMR spectrum measurement value (7: CDC13) N-H; 2
．． 85 (IH) Aromatic CH3: 8.98 (QH) Chroman position 3-CH2: 8.21 (ga) Chroman position 4-C position: 7.41 (2H) CH=;4.80 (IH) Example 2 Synthesis of N-(2.2.517.8-pentamethyl-chromanyl-6)-geranoylamide 6-chloroacetamide-2.2.5.7.8-bentamethyl-chroman7.
P prepared from 4.0 μm and triethyl phosphite 5.0 μm
-[N-(2.2.5.7.8-bentamethyl-chromanyl)-acetamido]-diethylphosphonate and 3.8 hours of methylheptenone were reacted according to Example 1, Step 2.
目的物を淡黄褐色粉状物として目的物を得た。収量８．
４夕 （収率９１％）
融点１００〜１０ぞ○
元素分析値 ０２４日３５Ｎ０２として
Ｃ 日Ｎ
理論値（％） ７８．００ ９．５５ ３．７９実測
値（％） ７８．０４ ９．４８ ３．７６１Ｒスペ
クトル測定値（弧‐１）３２５０（しＮＨ）、１６６０
（しＣ＝。The desired product was obtained as a pale yellowish brown powder. Yield 8.
4 days (yield 91%) Melting point 100-10 ○ Elemental analysis value 024 days C as 35N02 Theoretical value (%) 78.00 9.55 3.79 Actual value (%) 78.04 9.48 3 .761R spectrum measurement value (arc-1) 3250 (shiNH), 1660
(ShiC=.
）ＭＡＳスペクトル測定値Ｍ＋：３６９
ＮＭＲスペクトル測定値（丁：ＣＤＣ１３）Ｎ−Ｈ：３
．３５（ＩＨ）〜ｏｍＣＨ３：７．９２（班）
クロマン−３位ＣＨ２；８．１２（２Ｈ）クロマン‐４
位Ｃ比：７．４０（汎）
ＣＨ＝；４．２２（ＩＨ）、４．８０（ＩＨ）クロマン
−３位Ｃ公；８．１４（２Ｈ）クロマン山４位ＣＨ２：
７．４２（２Ｈ）ＣＨ：；４．２２（ＩＨ）、４．９０
（が）実施例 ３Ｎ−メチル一Ｎ一（２・２・５・７・
８−ペンタメチル−クロマニル−６）−フアルネシロイ
ルアミドの合成６ークロルアセトアミド一２・２・５・
７・８−ペンタメチルクロマン１１．８夕とトリエチル
ホスフアィト８．３夕より調製したＰ−〔Ｎ−（２・２
・５・７・８ーベンタメチルークロマニル）−アセトア
ミド〕一ジェチルホスホネートとゲラニルアセトン９．
７夕とを実施例１・工程２に従って反応処理した。) MAS spectrum measurement value M+: 369 NMR spectrum measurement value (double: CDC13) NH: 3
．． 35 (IH) ~ omCH3: 7.92 (group) Chroman-3 position CH2; 8.12 (2H) Chroman-4
Position C ratio: 7.40 (general) CH =; 4.22 (IH), 4.80 (IH) Chroman - 3rd place C; 8.14 (2H) Chroman mountain 4th place CH2:
7.42 (2H) CH:; 4.22 (IH), 4.90
(but) Example 3N-methyl-N-(2, 2, 5, 7,
Synthesis of 8-pentamethyl-chromanyl-6)-farnesiroylamide 6-chloroacetamide-2.2.5.
P-[N-(2.2
・5,7,8-bentamethyl-chromanyl)-acetamide] monoethylphosphonate and geranyl acetone9.
7 and was subjected to reaction treatment according to Example 1, Step 2.
目的物を淡黄色油状物質として得た。収量１６．８夕
（収率９６％）
元素分析値 ０２９比３Ｎ０２として
Ｃ 日Ｎ
理論値（％） ７９．５８ ９．９０ ３．２０実測
値（％） ７９．５３ ９．８７ ３．２３１Ｒスペ
クトル測定値（肌‐１）３２５０（しＮＨ）、１６６０
（しＣニ。The desired product was obtained as a pale yellow oil. Yield 16.8 evenings
(Yield 96%) Elemental analysis value 029 ratio 3N02 C Day N Theoretical value (%) 79.58 9.90 3.20 Actual value (%) 79.53 9.87 3.231R spectrum measurement value (skin- 1) 3250 (shiNH), 1660
(Shi C Ni.
）ＭＡＧスペクトル測定値Ｍ十：４３７
ＮＭＲスペクトル測定値（ィ：ＣＤＣ１３）Ｎ−Ｈ；３
．２２（ＩＨ）ＮｏｍＣＨ３：７．９４（斑）
船) MAG spectrum measurement value M: 437 NMR spectrum measurement value (i: CDC13) N-H; 3
．． 22 (IH) NomCH3: 7.94 (spot) Ship
Claims (1)
形成する場合のあることを表わす。 またｍは０〜３の整数を表わす。〕で表わされるケトン
化合物に、次の一般式▲数式、化学式、表等があります
▼ 〔式中Ｒ＿１、Ｒ＿２およびＲ＿３は水素またはメチル
基を、Ｒ＿４は水素または低級アルキル基を表わす。 Ｘはハロゲン原子を表わし、ｎは０〜３の整数を表わす
。〕で表わされる６−アミノクロマン化合物のハロアセ
トアミド体からは導かれるウイテツヒ試薬を反応させる
事を特徴とする、次の一般式▲数式、化学式、表等があ
ります▼ 〔式中Ｒ＿１、Ｒ＿２、Ｒ＿３、Ｒ＿４、Ａ、Ｂ、ｍ、
ｎは前記の意味を表わす。 〕で表わされる６−アミノクロマン化合物の不飽和脂肪
酸アミド体の製法。[Claims] 1. The following general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, A and B represent hydrogen atoms or a bond may be formed between A and B. Moreover, m represents an integer of 0 to 3. ] Ketone compounds represented by the following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1, R_2 and R_3 represent hydrogen or a methyl group, and R_4 represents hydrogen or a lower alkyl group. X represents a halogen atom, and n represents an integer of 0 to 3. ] There are the following general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1, R_2, R_3 ,R_4,A,B,m,
n represents the above meaning. ] A method for producing an unsaturated fatty acid amide form of a 6-aminochroman compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5475375A JPS609509B2 (en) | 1975-05-12 | 1975-05-12 | Production method of 6-aminochroman derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5475375A JPS609509B2 (en) | 1975-05-12 | 1975-05-12 | Production method of 6-aminochroman derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS51131878A JPS51131878A (en) | 1976-11-16 |
| JPS609509B2 true JPS609509B2 (en) | 1985-03-11 |
Family
ID=12979517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5475375A Expired JPS609509B2 (en) | 1975-05-12 | 1975-05-12 | Production method of 6-aminochroman derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS609509B2 (en) |
-
1975
- 1975-05-12 JP JP5475375A patent/JPS609509B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS51131878A (en) | 1976-11-16 |
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