JPS6256860B2 - - Google Patents
Info
- Publication number
- JPS6256860B2 JPS6256860B2 JP53047061A JP4706178A JPS6256860B2 JP S6256860 B2 JPS6256860 B2 JP S6256860B2 JP 53047061 A JP53047061 A JP 53047061A JP 4706178 A JP4706178 A JP 4706178A JP S6256860 B2 JPS6256860 B2 JP S6256860B2
- Authority
- JP
- Japan
- Prior art keywords
- serine
- dihydroxyphenyl
- threo
- methyl ester
- acid
- 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
- 239000002253 acid Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- -1 3-(3,4-dihydroxyphenyl)serine methyl ester Chemical compound 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- QXWYKJLNLSIPIN-JAMMHHFISA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid Chemical compound OC(=O)[C@@H](N)C(O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-JAMMHHFISA-N 0.000 description 5
- 238000010531 catalytic reduction reaction Methods 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- QXWYKJLNLSIPIN-JGVFFNPUSA-N droxidopa Chemical compound OC(=O)[C@@H](N)[C@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-JGVFFNPUSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- WTAKTSZELSYVQL-LURJTMIESA-N (2s)-2-(3,4-dihydroxyanilino)-3-hydroxypropanoic acid Chemical class OC[C@@H](C(O)=O)NC1=CC=C(O)C(O)=C1 WTAKTSZELSYVQL-LURJTMIESA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は医薬的価値の極めて高い新規な３−
（３・４−ジヒドロキシフエニル）セリン誘導体
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 3-
The present invention relates to (3,4-dihydroxyphenyl)serine derivatives.
更に詳しくは、本発明は価値ある薬理活性特に
顕著な制癌作用を示す３−（３・４−ジヒドロキ
シフエニル）セリンメチルエステル及びその酸付
加塩に関するものである。 More particularly, the present invention relates to 3-(3,4-dihydroxyphenyl)serine methyl ester and its acid addition salts which exhibit valuable pharmacological activities, particularly significant anticancer activity.
３−（３・４−ジヒドロキシフエニル）セリン
は、DOPSと称せられ、比較的古くよりその合成
がなされていたものであり、また近年にいたつて
３−（３・４−ジヒドロキシフエニル）アラニン
（DOPAと称せられる）との構造上の関連性よ
り、その生理活性ないし薬理作用が注目され始め
てきたものである。 3-(3,4-dihydroxyphenyl)serine is called DOPS and has been synthesized for a relatively long time, and in recent years, 3-(3,4-dihydroxyphenyl)alanine Due to its structural relationship with (referred to as DOPA), its physiological activity or pharmacological action has begun to attract attention.
しかし、その合成が比較的困難であつた為か今
日までの３−（３・４−ジヒドロキシフエニル）
セリン及びその関連化合物に関する合成研究報告
は非常に限られたものである。 However, perhaps because its synthesis was relatively difficult, 3-(3,4-dihydroxyphenyl)
There are very limited synthetic research reports on serine and its related compounds.
一方、その薬理活性に関する研究も、比較的少
なく、例えば同化合物が抗パーキソン剤としての
可能性を有することが述べられている特開昭52−
125630号等が散見されるのみである。 On the other hand, there are relatively few studies on its pharmacological activity, such as JP-A No. 52-2003, which states that the compound has potential as an anti-Parxonal agent.
Only issues such as No. 125630 can be seen here and there.
本発明者等は、かねてより３−（３・４−ジヒ
ドロキシフエニル）セリン及びその関連化合物の
合成研究とその薬理活性についての研究を行つて
きたが、此度３−（３・４−ジヒドロキシフエニ
ル）セリンメチルエステルを合成し、その薬理作
用について検索したところ、当該化合物が顕著な
制癌作用を有することを見出して本発明を完成し
た。 The present inventors have been conducting research on the synthesis of 3-(3,4-dihydroxyphenyl)serine and its related compounds and research on their pharmacological activities. After synthesizing phenyl)serine methyl ester and searching for its pharmacological effects, the present invention was completed by discovering that the compound has a significant anticancer effect.
本発明化合物は毒性も弱く忍容性も良好なので
制癌剤として好ましい性質を有しているものと言
える。本発明化合物は文献未記載の新規化合物で
ある。 The compound of the present invention has low toxicity and good tolerability, so it can be said that it has favorable properties as an anticancer agent. The compound of the present invention is a new compound that has not been described in any literature.
３−（３・４−ジヒドロキシフエニル）セリン
は生体内で代謝を受け、生体内重要物質であるノ
ルエピネフリンすなわち２−ヒドロキシ−２−
（３・４−ジヒドロキシフエニル）エチルアミン
に変換される事が既に知られているが、本発明化
合物の場合においても同様な生体内運命を有する
事が推定される。 3-(3,4-dihydroxyphenyl)serine undergoes metabolism in the body and produces norepinephrine, which is an important substance in the body, i.e. 2-hydroxy-2-
Although it is already known that it is converted to (3,4-dihydroxyphenyl)ethylamine, it is presumed that the compound of the present invention has a similar in vivo fate.
本発明化合物の忍容性の良好な事は、このよう
な事情によるものであろうことが充分に推定され
る。 It is fully assumed that the good tolerability of the compounds of the present invention is due to such circumstances.
本発明化合物は例えば、３−（３・４−ジヒド
ロキシフエニル）セリンを直接メチルエステル化
するか、あるいは式（）
（式中Ｒは水素原子またはベンジルオキシカルボ
ニル基、tert−ブトキシカルボニル基、トリフル
オロアセチル基等のアミノ酸のアミノ基の保護基
として後に緩和な条件で除去しうる通常用いられ
る保護基を示す。）
で示される化合物をメチルエステル化した後、脱
保護基反応に付することにより製造できる。この
場合のメチルエステル化法とはアミノ酸のメチル
エステル化法として通常用いられる方法でよい。
例えば、メタノール中塩酸、硫酸、ｐ−トルエン
スルホン酸等の酸触媒の存在下あるいは塩化チオ
ニルの存在下反応させるという方法をあげること
ができる。又、ジアゾメタン、ジメチル硫酸等の
メチル化剤で処理する方法でもよい。 The compound of the present invention can be obtained by directly methyl esterifying 3-(3,4-dihydroxyphenyl)serine, or by formula () (In the formula, R represents a hydrogen atom or a commonly used protecting group for the amino group of an amino acid, such as a benzyloxycarbonyl group, a tert-butoxycarbonyl group, or a trifluoroacetyl group, which can be removed later under mild conditions.) It can be produced by methyl esterifying the compound represented by and then subjecting it to deprotection reaction. The methyl esterification method in this case may be a method commonly used for methyl esterification of amino acids.
For example, a method may be mentioned in which the reaction is carried out in methanol in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or the like, or in the presence of thionyl chloride. Alternatively, a method of treatment with a methylating agent such as diazomethane or dimethyl sulfate may be used.
式（）で示される化合物を原料として用いた
場合にはエステル化反応後脱保護基反応が必要と
なる。この脱保護基反応としては、緩和な条件で
保護基を除去できる方法として接触還元反応、弱
酸性条件反応、弱塩基性条件反応およびこれらを
組合せた反応を用いることができる。 When a compound represented by formula () is used as a raw material, a deprotection reaction is required after the esterification reaction. As this deprotecting reaction, a catalytic reduction reaction, a reaction under weakly acidic conditions, a reaction under weakly basic conditions, and a reaction in combination thereof can be used as a method capable of removing the protecting group under mild conditions.
上記の如くして製造できる本発明化合物はアミ
ノ酸のエステルであるので、所望に応じ生理的に
無害の各種の無機酸および有機酸たとえば塩酸、
臭化水素酸、酢酸、蓚酸、乳酸、クエン酸、リン
ゴ酸、酒石酸、コハク酸等との酸付加塩を形成す
ることができる。 Since the compounds of the present invention that can be produced as described above are esters of amino acids, various physiologically harmless inorganic and organic acids such as hydrochloric acid, hydrochloric acid,
Acid addition salts can be formed with hydrobromic acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, tartaric acid, succinic acid, etc.
なお、本発明化合物には２個の不斉炭素原子が
存在する為、立体異性体であるスレオ体エリスロ
体及びそれらの光学異性体が存在する。本発明者
等は３−（３・４−ジヒドロキシフエニル）セリ
ン及び関連化合物の合成研究に於て、立体異性体
の分離法並びに光学分割法を既に見出している。
従つて本発明化合物についても所望に応じ異性体
を分離製造することができる。 In addition, since the compound of the present invention has two asymmetric carbon atoms, there exist stereoisomers such as threo isomer, erythro isomer, and optical isomers thereof. The present inventors have already discovered a method for separating stereoisomers and an optical resolution method in their research on the synthesis of 3-(3,4-dihydroxyphenyl)serine and related compounds.
Therefore, isomers of the compounds of the present invention can be separated and produced as desired.
次に実施例をあげ本発明を更に詳細に説明する
が本発明はもちろんこれらによつてなんら限定さ
れるものではない。 Next, the present invention will be explained in more detail with reference to Examples, but the present invention is of course not limited to these in any way.
実施例 １
DL−スレオ−３−（３・４−ジベンジルオキシ
フエニル）セリン・塩酸塩20ｇを無水メタノール
180mlに溶解し、−５〜−10℃に冷却下塩化チオニ
ル28ｇを滴下した。滴下後45〜50℃に加温し、４
時間反応させた後、減圧下濃縮し、エーテルを加
え、結晶を析出させた。これをメタノール／エー
テルより再結晶１、mp149〜150℃であるDL−ス
レオ−３−（３・４−ジベンジルオキシフエニ
ル）セリンメチルエステル・塩酸塩を得た。Example 1 20 g of DL-threo-3-(3,4-dibenzyloxyphenyl) serine hydrochloride was added to anhydrous methanol.
The solution was dissolved in 180 ml, and 28 g of thionyl chloride was added dropwise while cooling at -5 to -10°C. After dropping, warm to 45-50℃,
After reacting for an hour, the mixture was concentrated under reduced pressure, and ether was added to precipitate crystals. This was recrystallized from methanol/ether to obtain DL-threo-3-(3,4-dibenzyloxyphenyl)serine methyl ester hydrochloride having a mp of 149-150°C.
実施例 ２
DL−スレオ−３−（３・４−ジベンジルオキシ
フエニル）セリン・塩酸塩0.80ｇを無水メタノー
ル10mlに加え、冷却下塩酸ガスを通じた後、４時
間還流した。実施例１と同様に処理し0.80ｇの
DL−スレオ−３−（３・４−ジベンジルオキシフ
エニル）セリンメチルエステル・塩酸塩を得た。Example 2 0.80 g of DL-threo-3-(3,4-dibenzyloxyphenyl)serine hydrochloride was added to 10 ml of anhydrous methanol, and after passing hydrochloric acid gas through the mixture while cooling, the mixture was refluxed for 4 hours. Treated in the same manner as in Example 1, 0.80g of
DL-threo-3-(3,4-dibenzyloxyphenyl)serine methyl ester hydrochloride was obtained.
実施例 ３
DL−エリスロ−３−（３・４−ジベンジルオキ
シフエニル）セリン・塩酸塩60ｇ、無水メタノー
ル300mlと塩化チオニル50ｇを用いて実施例１と
同様に反応させて、mp141〜143℃のDL−エリス
ロ−３−（３・４−ジベンジルオキシフエニル）
セリンメチルエステル・塩酸塩を得た。Example 3 A reaction was carried out in the same manner as in Example 1 using 60 g of DL-erythro-3-(3,4-dibenzyloxyphenyl) serine hydrochloride, 300 ml of anhydrous methanol, and 50 g of thionyl chloride, and the reaction temperature was mp141-143°C. DL-erythro-3-(3,4-dibenzyloxyphenyl)
Serine methyl ester hydrochloride was obtained.
実施例 ４
DL−スレオ−３−（３・４−ジベンジルオキシ
フエニル）セリンメチルエステル・塩酸塩6.1ｇ
をメタノール90mlに溶解した後、５％パラジウム
−炭素0.2ｇを加え接触還元した。水素を吸わな
くなつてから、不溶物を去次に溶媒を留去しイ
ソプロピルアルコールより結晶化した。これをイ
ソプロピルアルコールより再結晶して、mp147〜
149℃のDL−スレオ−３−（３・４−ジヒドロキ
シフエニル）セリンメチルエステル・塩酸塩を得
た。Example 4 6.1 g of DL-threo-3-(3,4-dibenzyloxyphenyl)serine methyl ester hydrochloride
After dissolving in 90 ml of methanol, 0.2 g of 5% palladium-carbon was added for catalytic reduction. After no longer absorbing hydrogen, insoluble matter was removed, the solvent was distilled off, and crystallization was performed from isopropyl alcohol. This was recrystallized from isopropyl alcohol and mp147~
DL-threo-3-(3,4-dihydroxyphenyl)serine methyl ester hydrochloride at 149°C was obtained.
実施例 ５
DL−エリスロ−３−（３・４−ジベンジルオキ
シフエニル）セリンメチルエステル・塩酸塩5.46
ｇ、メタノール70mlと５％パラジウム−炭素0.3
ｇを用い実施例４と同様に接触還元を行い、
mp141〜143℃のDL−エリスロ−３−（３・４−
ジヒドロキシフエニル）セリンメチルエステル塩
酸塩を得た。Example 5 DL-erythro-3-(3,4-dibenzyloxyphenyl)serine methyl ester hydrochloride 5.46
g, methanol 70ml and 5% palladium-carbon 0.3
Catalytic reduction was carried out in the same manner as in Example 4 using g.
DL-Erythro-3-(3・4-
Dihydroxyphenyl)serine methyl ester hydrochloride was obtained.
実施例 ６
Ｌ−スレオ−３−（３・４−ジベンジルオキシ
フエニル）−Ｎ−カルボベンズオキシ−セリン2.8
ｇを酢酸エチル20mlに溶解し、氷冷却下撹拌しな
がら、常法により調製したジアゾメタンのエーテ
ル溶液を滴下した。ジアゾメタンの黄色の色がも
はや消失しなくなつたら滴下をやめ、溶媒を濃縮
した。石油エーテルを加え結晶化してmp113〜
116℃、〔α〕２０ Ｄ−20.5゜（Ｃ＝1.0、CHCl3）であ
る
Ｌ−スレオ−３−（３・４−ジベンジルオキシフ
エニル）−Ｎ−カルボベンズオキシ−セリンメチ
ルエステル2.7ｇを得た。Example 6 L-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine 2.8
g was dissolved in 20 ml of ethyl acetate, and while stirring under ice cooling, an ether solution of diazomethane prepared by a conventional method was added dropwise. When the yellow color of diazomethane no longer disappeared, the dropwise addition was stopped and the solvent was concentrated. Add petroleum ether and crystallize mp113~
116°C, 2.7 g of L-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine methyl ester, [α] 20 D -20.5° (C = 1.0, CHCl 3 ) I got it.
これをメタノール75mlに溶解し、濃塩酸0.4ml
と５％パラジウム−炭素0.4ｇを加え水素添加し
た。接触還元反応後、不溶物を除き溶媒を留去し
てイソプロピルアルコールで結晶化した。これを
イソプロピルアルコールで再結晶し、mp148〜
149℃、〔α〕２０ Ｄ−6.7゜（Ｃ＝1.06、MeOH）のＬ
−スレオ−３−（３・４−ジヒドロキシフエニ
ル）セリンメチルエステル・塩酸塩を得た。 Dissolve this in 75ml of methanol and 0.4ml of concentrated hydrochloric acid.
and 0.4 g of 5% palladium-carbon were added and hydrogenated. After the catalytic reduction reaction, insoluble materials were removed, the solvent was distilled off, and the mixture was crystallized from isopropyl alcohol. This was recrystallized with isopropyl alcohol and mp148~
149℃, [α] 20 D -6.7゜(C=1.06, MeOH) L
-threo-3-(3,4-dihydroxyphenyl)serine methyl ester hydrochloride was obtained.
実施例 ７
Ｄ−スレオ−３−（３・４−ジベンジルオキシ
フエニル）−Ｎ−カルボベンズオキシ−セリン4.3
ｇを酢酸エチル25mlに溶解し実施例６と同様にジ
アゾメタンのエーテル溶液で処理し、mp113〜
115℃、〔α〕２０ Ｄ＋24.5°（Ｃ＝1.1、CHCl3）であ
る
Ｄ−スレオ−３−（３・４−ジベンジルオキシフ
エニル）−Ｎ−カルボベンズオキシ−セリン4.0ｇ
を得た。Example 7 D-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine 4.3
g was dissolved in 25 ml of ethyl acetate, treated with an ether solution of diazomethane in the same manner as in Example 6, and mp113~
4.0 g of D-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine at 115°C, [α] 20 D +24.5° (C = 1.1, CHCl 3 )
I got it.
これをメタノール110mlに溶解し、濃塩酸0.7
ml、５％パラジウム−炭素0.6ｇを加えて、実施
例６と同様に接触還元を行つて、mp149〜150
℃、〔α〕２０ Ｄ＋7.6゜（Ｃ＝1.03、MeOH）のＤ−ス
レオ−３−（３・４−ジヒドロキシフエニル）セ
リンメチルエステル・塩酸塩を得た。 Dissolve this in 110ml of methanol and add 0.7ml of concentrated hydrochloric acid.
ml, 0.6 g of 5% palladium-carbon was added, and catalytic reduction was carried out in the same manner as in Example 6, resulting in mp149-150.
C, [α] 20 D +7.6° (C=1.03, MeOH) D-threo-3-(3,4-dihydroxyphenyl)serine methyl ester hydrochloride was obtained.
実験例 １
ICR系雄性マウス（１群６匹）に一匹当たりザ
ルコーマ180 106個をそけい部筋肉内に移植し
た。24時間目よりスレオ−３−（３・４−ジヒド
ロキシフエニル）セリンメチルエステル塩酸塩
528mg／Kg／dayをマウスの腹腔内に５回隔日投
与した。投与開始後14日目にマウスを屠殺し腫瘍
を取り出し腫瘍の重量を食塩水投与の対照群の腫
瘍の重量と比較した。スレオ−３−（３・４−ジ
ヒドロキシフエニル）セリンメチルエステル塩酸
塩投与群は対照群に比べ45％の腫瘍増殖抑制が認
められた。Experimental Example 1 180 10 6 Sarcomas were implanted into the groin muscles of ICR male mice (6 mice per group). Threo-3-(3,4-dihydroxyphenyl)serine methyl ester hydrochloride from 24 hours onwards
528 mg/Kg/day was intraperitoneally administered to mice 5 times every other day. On the 14th day after the start of administration, the mice were sacrificed, the tumors were removed, and the weights of the tumors were compared with those of the saline-administered control group. Tumor growth was inhibited by 45% in the threo-3-(3,4-dihydroxyphenyl)serine methyl ester hydrochloride administration group compared to the control group.
Claims (1)
ンメチルエステル及びその酸付加塩。1 3-(3,4-dihydroxyphenyl)serine methyl ester and its acid addition salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4706178A JPS54138537A (en) | 1978-04-19 | 1978-04-19 | Novel 3-(3,4-dihydroxy-phenyl) serine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4706178A JPS54138537A (en) | 1978-04-19 | 1978-04-19 | Novel 3-(3,4-dihydroxy-phenyl) serine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS54138537A JPS54138537A (en) | 1979-10-27 |
| JPS6256860B2 true JPS6256860B2 (en) | 1987-11-27 |
Family
ID=12764630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4706178A Granted JPS54138537A (en) | 1978-04-19 | 1978-04-19 | Novel 3-(3,4-dihydroxy-phenyl) serine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS54138537A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5288898A (en) * | 1985-09-30 | 1994-02-22 | Zaidan Hojim Biseibutsu Kagaku Kenkyu Kai | N-methylphenylserine alkyl ester derivatives and uses thereof |
-
1978
- 1978-04-19 JP JP4706178A patent/JPS54138537A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54138537A (en) | 1979-10-27 |
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