JPS6127393B2 - - Google Patents
Info
- Publication number
- JPS6127393B2 JPS6127393B2 JP59262387A JP26238784A JPS6127393B2 JP S6127393 B2 JPS6127393 B2 JP S6127393B2 JP 59262387 A JP59262387 A JP 59262387A JP 26238784 A JP26238784 A JP 26238784A JP S6127393 B2 JPS6127393 B2 JP S6127393B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- acid
- compound
- oxo
- residue
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 229920000137 polyphosphoric acid Polymers 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 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
- 241000699670 Mus sp. Species 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- UBKQRASXZMLQRJ-UHFFFAOYSA-N 2-phenylsulfanylethanamine Chemical compound NCCSC1=CC=CC=C1 UBKQRASXZMLQRJ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- IMLAIXAZMVDRGA-UHFFFAOYSA-N 2-phenoxyethanamine Chemical compound NCCOC1=CC=CC=C1 IMLAIXAZMVDRGA-UHFFFAOYSA-N 0.000 description 1
- -1 3-piperidone compound Chemical group 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 230000000881 depressing effect Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、次の一般式〔〕で表わされる８−
オキソ−３−アザエリスリナン誘導体およびその
酸付加塩に関する。
ただし、Ｙは−OCH2−、又は−SCH2−を表
わし、R1、R2、R3は水素を表わし、R4は水素、
低級アルキル、
The present invention provides 8-
The present invention relates to oxo-3-azaerythrinane derivatives and acid addition salts thereof. However, Y represents -OCH2- or -SCH2- , R1 , R2 , R3 represent hydrogen, R4 represents hydrogen,
lower alkyl,
【式】（R5、R6
は同一又は異なつて水素又は低級アルキルを表わ
す。）、[Formula] (R 5 and R 6 are the same or different and represent hydrogen or lower alkyl),
【式】【formula】
【式】（ｍは１又は２を表わ す。）又は[Formula] (m represents 1 or 2 vinegar. ) or
【式】を表わ
す。
本発明者らは種々のアザエリスリナン誘導体を
合成しその薬理作用を検討中、本発明化合物が強
力なる作用を有すること見い出し本発明を完成し
た。
本発明化合物は文献末載の新規化合物であつ
て、中枢神経抑制作用、特に強い鎮痛作用を有
し、医薬品として有用である。本発明化合物は
種々の方法によつて製造することができるが、Represents [formula]. The present inventors synthesized various azaerythrinane derivatives and while studying their pharmacological effects, discovered that the compound of the present invention had a strong effect and completed the present invention. The compound of the present invention is a novel compound described in the literature, has a central nervous system depressing effect, particularly a strong analgesic effect, and is useful as a pharmaceutical. The compounds of the present invention can be produced by various methods, but
【式】
一般式〔〕（式中、R7は抵級アルキル、又は抵
級アラルキル、R8は低級アルキルを表わす。）で
示される化合物と一般式〔〕（式中R1、R2、
R3、Ｙは前記と同じ）で示される化合物とを不
活性な有機溶媒中で加熱縮合し、縮合物を単離す
るか又は単離することなく、酸性条件下で加熱し
て閉環せしめることにより得ることができる。
加熱縮合に使用する不活性な有機溶媒として
は、ベンゼン、トルエン、キシレン、DMF、ジ
オキサン、セロソルブ、ジクライム等の高沸点溶
媒を使用し、水分除去器を付して加熱還流するの
が好ましい。
次に酸性条件下での閉環反応は硫酸、臭化水素
酸、塩酸、リン酸等の鉱酸類あるいはギ酸、ｐ−
トルエンスルホン酸、トリクロル酢酸、トリフル
オロ酢酸等の有機酸類か又はポリリン酸
（PPA）、ポリホス・フエートエステル（PPE）、
五酸化リン、酸性イオン交換樹脂等を単独又は水
溶液か有機溶媒中で加熱することにより行なわれ
る。反応温度は30〜250℃の温度範囲内で、好ま
しくは80〜160℃で行うのがよく、反応時間は30
分から数時間を要して閉環反応が達成される。
一般式〔〕中のR4がR7以外の置換基につい
ては前記閉環反応により合成した一般式〔〕の
化合物、例えば、R4＝ベンジル体について脱ベ
ンジル化を行い、得られるR4＝Ｈ体に所望の置
換基を導入すればよい。脱ベンジル化は一般的な
水素化分解による方法、又はクロロホルメート類
との反応により脱ベンジル化し、次いで加水分解
してR4＝Ｈ体を得る方法、さらにアルキルハラ
イド類を反応せしてめ四級塩とした後脱ベンジル
化してアルキル基を導入する方法等が用いられ
る。
一般式〔〕の化合物（ただしR4＝アルキ
ル）はR4＝Ｈ体から一般的なアルキル化法によ
つても容易に得ることができる。たとえば、脱酸
剤の存在下にアルキルハライド類を反応せしめる
か、アルデヒド類を用い還元的にアルキル化する
方法等である。アラルキル化やアリール化も同様
にして行える。
〔〕式中R1、R2、R3が水酸基の化合物は対
応するメトキシ基の脱メチル化によつても得るこ
とができる。脱メチル化は一般的な方法、たとえ
ば臭化水素酸中で加熱すればほぼ定量的に脱メチ
ル化できる。一般式〔〕のR4が臭化水素酸で
変化を受ける場合は、他の脱メチル化法、たとえ
ばピリジン塩酸塩を用いる方法により行うか又は
R4＝Ｈ体について脱メチル化した後所望の置換
基を導入する方法が用いられる。フエノール性水
酸基を有する〔〕（R4＝Ｈ）のＮ位のアルキル
化は同時に起るＯ−アルキル化をさけるため、脱
酸剤を使用するときは炭酸塩を用いるのが望まし
い。
原料に使用した一般式〔〕のピペリドン誘導
体は下記に示す経路により得られる。すなわち、
一般式〔〕（式中７は前記と同じ。）で示される
３−ピペリドン化合物の４位を式Ｘ−（CH2）2−
Ｚで表される化合物〔〕（式中Ｘはハロゲン、
Ｚはエトキシカルボニル又はニトリル基を示す）
又は式CH2＝CH−Ｚで表わされる化合物〔〕
（式中Ｚは前と同一の意味を示す。）と反応せしめ
て〔〕とし、〔〕を加水分解および脱炭酸し
た後エステル化して中間体〔〕を収率よく得る
ことができる。但し、〔〕は比較的不安定な物
質で製造後なるべく早く使用することが望まし
い。以上のようにして得た化合物〔〕は塩酸あ
るいは生理学的に許容し得る酸によつて結晶性酸
付加塩に変えることができる。
本発明化合物の薬理作用は以下のように確認さ
れた。
Kostar等の方法〔Fed.Proc.、18412（1959）
を参照〕に準じてdd系雄性マウス（体重25〜32
ｇ）１群６匹として用い、0.6％酢酸を10ml/Kg腹
腔内投与した際に生じるWrithing数を測定し、
対照群に対する抑制を指標とした。また、体重23
〜30ｇのdd系雄性マウスを用い、一群４匹とし
て各被検薬物投与（i.p.）後24時間における死亡
率より、Weil氏法によつてLD50値を算出した。
これらの結果を表１に示す。[Formula] A compound represented by the general formula [] (in the formula, R 7 represents lower alkyl or lower aralkyl, and R 8 represents lower alkyl) and the general formula [] (in the formula, R 1 , R 2 ,
R 3 , Y is the same as above) is heated and condensed in an inert organic solvent, and the condensate is isolated or without isolation, heated under acidic conditions to cause ring closure. It can be obtained by As the inert organic solvent used in the thermal condensation, it is preferable to use a high boiling point solvent such as benzene, toluene, xylene, DMF, dioxane, cellosolve, diclime, etc., and heat it to reflux with a water remover attached. Next, the ring-closing reaction under acidic conditions is carried out using mineral acids such as sulfuric acid, hydrobromic acid, hydrochloric acid, phosphoric acid, formic acid, p-
Organic acids such as toluenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, or polyphosphoric acid (PPA), polyphosphate ester (PPE),
This is carried out by heating phosphorus pentoxide, acidic ion exchange resin, etc. alone or in an aqueous solution or an organic solvent. The reaction temperature is within the temperature range of 30~250℃, preferably 80~160℃, and the reaction time is 30~250℃.
The ring closure reaction takes minutes to several hours to accomplish. For substituents in which R 4 in the general formula [] is other than R 7 , the compound of the general formula [] synthesized by the ring-closing reaction, for example, the R 4 = benzylic form is debenzylated, and the resulting R 4 = H A desired substituent may be introduced into the body. Debenzylation can be carried out by a general hydrogenolysis method, by debenzylation by reaction with chloroformates, and then by hydrolysis to obtain the R 4 =H form, or by further reaction with alkyl halides. A method is used in which a quaternary salt is formed and then debenzylated to introduce an alkyl group. The compound of the general formula [] (where R 4 =alkyl) can be easily obtained from the R 4 =H form by a general alkylation method. For example, methods include reacting alkyl halides in the presence of a deoxidizing agent, or reductively alkylating using aldehydes. Aralkylation and arylation can be performed in the same manner. A compound in which R 1 , R 2 and R 3 are hydroxyl groups can also be obtained by demethylating the corresponding methoxy group. Demethylation can be carried out almost quantitatively by a general method, for example, by heating in hydrobromic acid. When R 4 in the general formula [] undergoes a change with hydrobromic acid, it can be carried out by other demethylation methods, such as a method using pyridine hydrochloride, or
A method is used in which the R 4 =H form is demethylated and then a desired substituent is introduced. When using a deoxidizing agent, it is preferable to use a carbonate in order to avoid simultaneous O-alkylation during alkylation at the N position of [] (R 4 =H) having a phenolic hydroxyl group. The piperidone derivative of the general formula [] used as a raw material can be obtained by the route shown below. That is, The 4-position of the 3-piperidone compound represented by the general formula [] (in the formula, 7 is the same as above) is replaced by the formula X-(CH 2 ) 2 -
Compound represented by Z [ ] (wherein X is halogen,
Z represents ethoxycarbonyl or nitrile group)
Or a compound represented by the formula CH 2 =CH-Z []
(In the formula, Z has the same meaning as before) to give [], and after hydrolyzing and decarboxylating [], it is esterified to obtain the intermediate [] in good yield. However, [ ] is a relatively unstable substance, and it is desirable to use it as soon as possible after production. The compound [] obtained as described above can be converted into a crystalline acid addition salt with hydrochloric acid or a physiologically acceptable acid. The pharmacological action of the compound of the present invention was confirmed as follows. The method of Kostar et al. [Fed. Proc., 18 412 (1959)
DD male mice (body weight 25-32
g) Using 6 animals per group, measuring the number of writings produced when 10 ml/Kg of 0.6% acetic acid was intraperitoneally administered,
The inhibition relative to the control group was used as an index. Also, weight 23
The LD 50 value was calculated by Weil's method from the mortality rate 24 hours after administration (ip) of each test drug using ~30 g DD male mice in a group of 4 mice.
These results are shown in Table 1.
【表】
これらの結果により、本発明化合物の優れた薬
理作用が明白である。
以下に本発明化合物の１部を例示する。[Table] These results clearly demonstrate the excellent pharmacological action of the compounds of the present invention. A part of the compounds of the present invention are illustrated below.
【表】
実施例 １
３−ベンジル−８−オキソ−３−アザ−11a−
オキサ−Ｃ−ホモエリスリナン（化合物番号
６）
エチル（１−ベンジル−３−ピペリドン−４−
イル）アセテート2.75ｇとβ−フエノキシエチル
アミン1.4ｇをトルエン30mlに溶解し、水分除去
器を付したコルベン中で約20時間加熱還流する。
反応液を濃縮して残留物にポリリン酸（PPA）
30ｇを加え、約130℃の油浴上で３時間加熱撹拌
する。冷後、反応液を150mlの氷水中に注ぎ、炭
酸カリウムで中和する。遊離する油状物をクロロ
ホルムで抽出し、抽出液を水洗し、硫酸マグネシ
ウムで乾燥した後、クロロホルムを減圧下に留去
する。残留物にエーテルを加えて下溶物を濾去
し、エーテル溶液を濃縮して3.8ｇの残留物を得
る。これを塩酸塩として結晶化し、濾取し粗結晶
3.0ｇ（収率77％）を得た。エタノールから再結
晶して融点262℃（dec.）の結晶2.8ｇを得た。
実施例 ２
３−ベンジル−８−オキソ−３−アザ−11a−
チア−Ｃ−ホモエリスリナン（化合物番号７）
エチル（１−ベンジル−３−ピペリドン−４−
イル）アセテート2.75ｇとβ−チオフエノキシエ
チルアミン1.5ｇをトルエン30mlに溶解し、実施
例１と同様に反応させ、反応液を濃縮して残留物
にポリリン酸（PPA）30ｇを加え、110〜120℃
の油浴上で４時間加熱撹拌する。実施例１と同様
に処理して得たクロロホルム抽出物2.8ｇをカラ
ムクロマトグラフイー（シリカゲル80ｇ、酢酸エ
チルで溶出）で精製して抽状物1.7ｇを得る。こ
れを塩酸塩として結晶化し、エタノールから再結
晶して融点265〜267℃（dec.）の結晶1.5ｇ（収
率37.5％）を得た。
実施例 ３
８−オキソ−３−アザ−11a−オキサ−Ｃ−ホ
モエリスリナン（化合物番号18）
３−ベンジル−８−オキソ−３−アザ−11a−
オキサ−Ｃ−ホモエリスリナン塩酸塩14.1ｇを50
％含水エタノール100mlに溶解し、10％、パラジ
ウム−炭素4.5ｇを触媒として常温常圧下で接触
還元する。還元後触媒を濾去し、濾液を減圧下に
濃縮する。残渣を結晶化し、濾取してエタノール
から再結晶する。
塩酸塩得量10.3ｇ（収率93％）。融点168〜169
℃（dec.）。無色プリズム晶。
塩基（エーテルから再結晶）融点94〜95℃。
実施例 ４
３−メチル−８−オキソ−３−アザ−11a−オ
キサ−Ｃ−ホモエリスリナン（化合物番号26）
８−オキソ−３−アザ−11a−オキサ−Ｃ−ホ
モエリスリナン2.6ｇとパラホルムアルデヒド
0.45ｇの混合物にギ酸２mlを加え、110℃の油浴
上で３時間加熱する。冷後、残留物に氷水15mlを
加え、炭酸カリウムで中和する。遊離する油状物
をクロロホルムで抽出し、抽出液を水洗し、硫酸
マグネシウムで乾燥してからクロロホルムを減圧
下に留去する。残留物を結晶化して濾取し、2.3
ｇ（収率85％）の粗結晶を得た。酢酸エチルから
再結晶する。融点152.5〜154℃。
塩酸塩：融点315℃（dec.）。無色針状晶（エタ
ノールから再結晶）。
実施例 ５
３−アリル−８−オキソ−３−アザ−11a−オ
キサ−Ｃ−ホモエリスリナン（化合物番号27）
８−オキソ−３−アザ−11a−オキサ−Ｃ−ホ
モエリスリナン2.0ｇをＮ・Ｎ−ジメチルホルム
アミド20mlに溶解し、炭酸カリウム2.0ｇを加
え、室温で撹拌下、アリルブロマイド0.98ｇを滴
下して16時間撹拌する。反応液を減圧下に濃縮
し、残留物に酢酸エチルを加えて抽出する。抽出
液を水洗後、10％塩酸水溶液で酸可溶部を抽出す
る。酸性液を炭酸カリウムで中和し、遊離物をク
ロロホルムで抽出する。抽出液を水洗し、硫酸マ
グネシウムで乾燥した後、クロロホルムを留去す
る。残留物にエーテルを加えて、不溶物を濾去す
る。エーテル溶液を放置すると結晶が析出する。
これを濾取して、融点131.5〜132.5℃の結晶2.15
ｇ（収率93％）を得た。
塩酸塩：融点260℃（dec.）。無色針状晶（エタ
ノールから再結晶）。[Table] Example 1 3-benzyl-8-oxo-3-aza-11a-
Oxa-C-homoerythrinane (compound number 6) Ethyl (1-benzyl-3-piperidone-4-
2.75 g of acetate and 1.4 g of β-phenoxyethylamine were dissolved in 30 ml of toluene and heated under reflux for about 20 hours in a Kolben equipped with a water remover.
Concentrate the reaction solution and the residue contains polyphosphoric acid (PPA)
Add 30g and heat and stir on an oil bath at about 130°C for 3 hours. After cooling, pour the reaction solution into 150 ml of ice water and neutralize with potassium carbonate. The liberated oil is extracted with chloroform, the extract is washed with water, dried over magnesium sulfate, and the chloroform is distilled off under reduced pressure. Ether was added to the residue, the lower solution was filtered off, and the ether solution was concentrated to obtain 3.8 g of residue. This is crystallized as a hydrochloride, and the crude crystals are collected by filtration.
3.0 g (yield 77%) was obtained. Recrystallization from ethanol gave 2.8 g of crystals with a melting point of 262°C (dec.). Example 2 3-benzyl-8-oxo-3-aza-11a-
Thia-C-homoerythrinane (compound number 7) Ethyl (1-benzyl-3-piperidone-4-
2.75 g of β-thiophenoxyethylamine and 1.5 g of β-thiophenoxyethylamine were dissolved in 30 ml of toluene and reacted in the same manner as in Example 1. The reaction solution was concentrated, and 30 g of polyphosphoric acid (PPA) was added to the residue. ~120℃
Heat and stir on an oil bath for 4 hours. 2.8 g of the chloroform extract obtained in the same manner as in Example 1 is purified by column chromatography (80 g of silica gel, eluted with ethyl acetate) to obtain 1.7 g of the extract. This was crystallized as a hydrochloride and recrystallized from ethanol to obtain 1.5 g of crystals (yield: 37.5%) with a melting point of 265-267°C (dec.). Example 3 8-oxo-3-aza-11a-oxa-C-homoerythrinane (compound number 18) 3-benzyl-8-oxo-3-aza-11a-
Oxa-C-homoerythrinan hydrochloride 14.1g 50
Dissolve in 100 ml of 10% aqueous ethanol and catalytically reduce the mixture at room temperature and pressure using 4.5 g of 10% palladium-carbon as a catalyst. After reduction, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is crystallized, filtered off and recrystallized from ethanol. 10.3 g of hydrochloride was obtained (yield 93%). Melting point 168-169
°C (dec.). Colorless prismatic crystal. Base (recrystallized from ether) melting point 94-95°C. Example 4 3-Methyl-8-oxo-3-aza-11a-oxa-C-homoerythrinane (Compound No. 26) 2.6 g of 8-oxo-3-aza-11a-oxa-C-homoerythrinane and paraformaldehyde
Add 2 ml of formic acid to 0.45 g of the mixture and heat on an oil bath at 110° C. for 3 hours. After cooling, add 15 ml of ice water to the residue and neutralize with potassium carbonate. The liberated oil is extracted with chloroform, the extract is washed with water, dried over magnesium sulfate and the chloroform is distilled off under reduced pressure. The residue was crystallized and collected by filtration, 2.3
g (yield: 85%) of crude crystals were obtained. Recrystallize from ethyl acetate. Melting point 152.5-154℃. Hydrochloride: Melting point 315℃ (dec.). Colorless needles (recrystallized from ethanol). Example 5 3-allyl-8-oxo-3-aza-11a-oxa-C-homoerythrinane (compound number 27) 2.0 g of 8-oxo-3-aza-11a-oxa-C-homoerythrinane was dissolved in N.N-dimethyl Dissolve in 20 ml of formamide, add 2.0 g of potassium carbonate, and while stirring at room temperature, add 0.98 g of allyl bromide dropwise and stir for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. After washing the extract with water, extract the acid-soluble portion with a 10% aqueous hydrochloric acid solution. Neutralize the acidic solution with potassium carbonate and extract the free product with chloroform. After washing the extract with water and drying with magnesium sulfate, chloroform is distilled off. Ether is added to the residue and insoluble matter is filtered off. If the ether solution is allowed to stand, crystals will precipitate.
Filter this and collect 2.15% crystals with a melting point of 131.5-132.5℃.
g (yield 93%) was obtained. Hydrochloride: Melting point 260℃ (dec.). Colorless needles (recrystallized from ethanol).
Claims (1)
３−アザエリスリナン誘導体およびその酸付加
塩。 ただし、Ｙは−OCH2−、又は−SCH2−を表
わし、R1、R2、R3は水素を表わし、R4は水素、
低級アルキル、【式】（R5、R6 は同一又は異なつた水素又は低級アルキルを表わ
す。）、【式】 【式】（ｍは１又は２を表わ す。）又は【式】を表わ す。[Claims] 1. 8-oxo- represented by the following general formula []
3-azaerythrinane derivatives and acid addition salts thereof. However, Y represents -OCH2- or -SCH2- , R1 , R2 , R3 represent hydrogen, R4 represents hydrogen,
Lower alkyl, [Formula] (R 5 and R 6 represent the same or different hydrogen or lower alkyl), [Formula] [Formula] (m represents 1 or 2), or [Formula].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59262387A JPS60185785A (en) | 1984-12-11 | 1984-12-11 | 3-azaerythrinan derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59262387A JPS60185785A (en) | 1984-12-11 | 1984-12-11 | 3-azaerythrinan derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP55018329A Division JPS6019913B2 (en) | 1980-02-15 | 1980-02-15 | 3-azaerythrinane derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60185785A JPS60185785A (en) | 1985-09-21 |
| JPS6127393B2 true JPS6127393B2 (en) | 1986-06-25 |
Family
ID=17375049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59262387A Granted JPS60185785A (en) | 1984-12-11 | 1984-12-11 | 3-azaerythrinan derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60185785A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11273592B2 (en) | 2011-08-26 | 2022-03-15 | Dow Global Technologies Llc | Bioriented polyethylene film |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0504517A (en) * | 2005-10-20 | 2007-09-25 | Univ Estadual Paulista Julio D | use, in the modulation of cholinergic and / or serotonergic and / or gabaergic systems of vertebrates, of a standardized crude plant extractor, pharmaceutical composition for the treatment of disorders associated with cholinergic and / or serotonergic and / or gabaergic system dysfunction, and production of medicament for the modulation of cholinergic and / or serotonergic and / or gabaergic systems of vertebrates |
-
1984
- 1984-12-11 JP JP59262387A patent/JPS60185785A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11273592B2 (en) | 2011-08-26 | 2022-03-15 | Dow Global Technologies Llc | Bioriented polyethylene film |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60185785A (en) | 1985-09-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HU185133B (en) | Process for producing 1-hydroxy-octahydro-benzo-bracket-c-bracket closed-quinolines and derivatives | |
| NO803453L (en) | PROCEDURE FOR THE PREPARATION OF PIPERIDYLBENZIMIDAZOLONE DERIVATIVES | |
| JPS6123790B2 (en) | ||
| US2852520A (en) | Trialkoxybenzoyloxyalkyl derivatives related to norharman | |
| JPS6127393B2 (en) | ||
| US3437662A (en) | Polyhydroisoquinoline antiviral agents | |
| US6576764B2 (en) | Synthesis and crystallization of piperazine ring-containing compounds | |
| EP0518414B1 (en) | Thioxanthenone antitumor agents | |
| US4507308A (en) | Analgesically or anti-inflammatory effective 4-quinolyl anthranilic acid derivatives | |
| IE41462B1 (en) | Piperidyl-methylenedioxybenzene derivatives | |
| US4806560A (en) | Imidazo[4,5-b]pyridin-2-one derivatives | |
| US4302458A (en) | Phthalidyl-isoquinoline derivatives | |
| US4276296A (en) | Substituted benzopyrano[3,4-c]pyridines, compositions and use thereof | |
| EP0143333B1 (en) | [Bis(hydroxymethyl)-methyl]-isoquinoline derivatives, process for preparing them and pharmaceutical compositions containing them | |
| JPH0121828B2 (en) | ||
| EP0018077A2 (en) | Phenylmorphans, processes for their preparation and pharmaceutical compositions containing them | |
| JPS6124395B2 (en) | ||
| US4048321A (en) | Disubstituted azabicycloalkanes | |
| US3476755A (en) | 8,13-diazasteroids | |
| US3127405A (en) | I-phenylalkyl | |
| US4537895A (en) | Isoquinoline derivatives | |
| US4041173A (en) | 2-Carboxy-(7-,8- and 9-substituted)-5-oxo-5H-dibenzo (a,d) cycloheptenes and the corresponding 10,11-dihydro compounds | |
| JPS6058919B2 (en) | Phthalidyl-isoquinoline derivatives, their production methods and pharmaceuticals containing them | |
| US3631035A (en) | 2-vinyl-1 4-dihydroquinazoline derivatives | |
| JPH0676401B2 (en) | Quinoline derivative and medicament containing the same |