KR800000814B1 - Process for preparing morphorinones - Google Patents
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- KR800000814B1 KR800000814B1 KR7501365A KR750001365A KR800000814B1 KR 800000814 B1 KR800000814 B1 KR 800000814B1 KR 7501365 A KR7501365 A KR 7501365A KR 750001365 A KR750001365 A KR 750001365A KR 800000814 B1 KR800000814 B1 KR 800000814B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
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Abstract
Description
본 발명은 일반식(I)으로 표시되는 신규 몰포리논 유도체의 제법에 관한 것이다.The present invention relates to a method for producing a novel morpholinone derivative represented by general formula (I).
(상기 식중)(In the above meal)
Z는 산소 또는 유황원자를 표시하며, X는 수소원자, 할로겐원자, 저급알킬기, 카복실기, 저급 알콕시기, 저급알콕시카보닐기 또는 카바모일기를 표시한다. Y는, Z가 유황원자일 경우에는 수소원자, 할로겐원자 또는 저급알킬기를 표시하고, Z가 산소원자인 경우에는 수소원자, 할로겐원자, 저급 알킬기, 저급알콕시기, 수산기, 아랄킬옥시기, 카복실기, 저급알콕시 카보닐기 또는 시아노기를 표시한다.)Z represents an oxygen or sulfur atom and X represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a carbamoyl group. Y represents a hydrogen atom, a halogen atom or a lower alkyl group when Z is a sulfur atom, and a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, an aralkyloxy group or a carboxyl group when Z is an oxygen atom. , Lower alkoxy carbonyl group or cyano group.)
본 발명자들은 혈액중의 트리글리세라이드 및 콜레스테롤 저하작용을 가지고 동맥 경화의 예방 및 치료제로서 유용한 화합물의 탐색에 노력을 기울여 오던 중, 상기 신규 화합물이 유효함을 발견하여 본 발명을 완성하였다. 즉, 일반식(I)으로 표시되는 이 몰포리논 유도체는 다음 일반식The present inventors have completed the present invention by discovering that the novel compound is effective while trying to search for a compound which has a triglyceride and cholesterol lowering effect in the blood and is useful as an agent for preventing and treating atherosclerosis. That is, this morpholinin derivative represented by general formula (I) has the following general formula
(단, Y, Z는 상기와 동일)(Y, Z are the same as above)
의 에폭사이드류와 일반식Epoxides and general formula
(단, X는 상기와 동일하고, R1은 수소원자 또는 저급알킬기를 표시함)(Where X is the same as above and R 1 represents a hydrogen atom or a lower alkyl group)
으로 표시되는 페닐그리신 유도체를 직접적으로, 또는 예를들면 벤젠, 톨루엔, 키실렌, N, N-디메틸포름아미드, 디옥산, 초산등의 유기용매의 존재하에 80-180℃의 온도로 3-24시간 반응시키는 것에 의하여 얻어진다. 이 반응은, 예를들면 염산, 황산, 초산등의 산 촉매에 의하여 촉진된다.The phenylglycine derivatives represented by the formula 3 are directly or at a temperature of 80-180 ° C. in the presence of organic solvents such as benzene, toluene, xylene, N, N-dimethylformamide, dioxane and acetic acid, for example. It is obtained by making it react for 24 hours. This reaction is promoted by acid catalysts, such as hydrochloric acid, sulfuric acid, and acetic acid, for example.
[II]와 [III]의 반응에 있어서의 생성물은, 공지의 화합물[V] (Khimicheskie Sredstva Zashchity Rastenii 1970, 256)에 [VI]을 작용시켰을 때의 생성물[I]과 일치하였다. [V]와 [VI]과의 반응으로 [VII]이 생성되는 것은 생각될 수 없으므로, [II]와 [III]의 반응에 있어서, 입체 장해가 적은 말단의 탄소에서 SN2반응이 일어난 것으로 결론된다. 또한 일반적으로 페닐글리시딜에테르류와 아닐린류와의 반응은, 입체장해가 적은 말단탄소에서 일어나는 것이 알려져 있다. (Chemical Review 59 P737(1959)).The product in reaction of [II] and [III] was consistent with the product [I] when [VI] was made to react with known compound [V] (Khimicheskie Sredstva Zashchity Rastenii 1970, 256). It is unthinkable that the reaction of [V] and [VI] produces [VII], therefore, in the reaction of [II] and [III], it is concluded that the SN 2 reaction occurred at the terminal carbon with little steric hindrance. do. In general, it is known that the reaction between phenylglycidyl ethers and anilines occurs at terminal carbons with little steric hindrance. (Chemical Review 59 P737 (1959)).
(식중 A는 염소 또는 취소를 표시하고, X, Y, Z는 상기와 동일하다.(Wherein A represents chlorine or cancellation, and X, Y and Z are the same as above).
이렇게 하여서 얻어진 몰포리논 유도체(I)는 완전히 신규한 물질로서 현저한 지질(脂質)저하 작용을 가진다. 그 혈중 지질 저하 활성을 제1표에 표시한다.The morpholinone derivative (I) thus obtained is a completely novel substance and has a significant lipid lowering action. The blood lipid lowering activity is shown in the 1st table | surface.
[제1표][Table 1]
정상 혈중 지질 함량 생쥐(8주령 숫생쥐)에게 100mg/kg /일을 3.5일 경구 투여한 후의 혈청 지질의% 저하율.Percent reduction in serum lipids after oral administration of 100 mg / kg / day to normal blood lipid content mice (8 week old male mice) for 3.5 days.
(주) 화합물명(숫자)은 제2표중의 그것과 대응한다.Note: The compound name (number) corresponds to that in the second table.
제1표에 기재한 값은, 각각의 화합물을 100mg/kg/일의 투여량으로 3.5일 처리한 후의 혈청 콜레스테롤 및 트리글리세라이드의 농도 변화를 표시한 것이다. 이들 화합물은, 각 10마리씩으로 된 생쥐 집단에 대하여 1일 2회 식도 소식자를 사용하여 경구적으로 투여하였다.The values shown in Table 1 indicate the change in the concentrations of serum cholesterol and triglycerides after 3.5 days of treatment with each compound at a dose of 100 mg / kg / day. These compounds were administered orally using esophageal mediators twice a day to a group of 10 mice each.
이어서 일반적으로 최종 투여 4시간후에 채혈하여, 혈청중의 콜레스테롤 농도를 래빈 및 잭크의 방법, 또 트리글리세라이드 농도를 캐스라 및 레데라의 방법에 의하여 자동 분석기로 측정하였다. 제1표에 기재된 여러 예에 있어서, 처리균의% 저하율은 미처리 대조균 (플라세보균)에 대한 것이며, 플라세보균의 값을 100으로 표시하고 있어, 이 결과에서도 명백한 바와 같이, 화합물 2 및 화합물 87은 클로피브레이트보다 강한 트리글리세라이드 저하 작용을 나타냈다.Blood was then collected, usually 4 hours after the last dose, and the cholesterol concentration in serum was measured by an automated analyzer by Lavin and Jack's method, and triglyceride concentration by Casra and Redera's method. In the various examples described in Table 1, the% reduction rate of the treated bacteria is for untreated control bacteria (placebo bacteria), and the value of placebo bacteria is expressed as 100, and as is clear from these results, Compound 2 and Compound 87 Has a stronger triglyceride lowering effect than clofibrate.
다음에 실시예에 대하여 본 발명을 상세히 설명하지만, 본 발명은 이 실시예에만 한정되는 것은 아니다.Next, although an Example demonstrates this invention in detail, this invention is not limited only to this Example.
[실시예 1]Example 1
4-(m-클로로페닐)-6-(P-클로로페녹시메틸)-2-몰포리논의 제법.Preparation of 4- (m-chlorophenyl) -6- (P-chlorophenoxymethyl) -2-morpholinone.
N-(m-클로로페닐)글리신 에틸에스테르 5.3g(0.025몰)과 P-클로로페닐글리시딜에테르 4.6g(0.025몰)을 180℃에서 24시간 가열후 냉각하고, 에탄올로부터 결정화하면 5.0g의 결정을 얻는다. 모액을 감압 농축하여 잔사를 10ml의 초산중에서 6시간 환류한 후, 초산을 감압하에 유거하고, 에탄올에서 결정화하면 다시 1.5g의 결정이 얻어진다. 양자를 에탄올-벤젠에서 재결정하여 융점 128-129℃의 결정 5.0g(수율 57%)을 얻는다.5.3 g (0.025 mol) of N- (m-chlorophenyl) glycine ethyl ester and 4.6 g (0.025 mol) of P-chlorophenyl glycidyl ether were heated at 180 ° C. for 24 hours, cooled, and crystallized from ethanol. Get a decision. The mother liquor was concentrated under reduced pressure, and the residue was refluxed in 10 ml of acetic acid for 6 hours, and then acetic acid was distilled off under reduced pressure, and crystallized in ethanol to obtain 1.5 g of crystals. Both were recrystallized in ethanol-benzene to obtain 5.0 g (yield 57%) of crystals having a melting point of 128-129 ° C.
원소분석치:C17H15ClNO3 Elemental Analysis Value: C 17 H 15 ClNO 3
이하 동일한 조작에 의하여 일군의 화합물[I]을 제조할 수 있었다. 그들을 제2표에 일괄적으로 표시하였다. 또한 실시예 1의 방법으로 제조한 물질은, 화합물 번호 28로서 표시 되어 있다.Hereinafter, a group of compound [I] could be manufactured by the same operation. They are indicated collectively in the second table. In addition, the substance manufactured by the method of Example 1 is represented by compound number 28.
[제2표][Table 2]
Claims (1)
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Application Number | Priority Date | Filing Date | Title |
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KR7501365A KR800000814B1 (en) | 1975-06-20 | 1975-06-20 | Process for preparing morphorinones |
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KR7501365A KR800000814B1 (en) | 1975-06-20 | 1975-06-20 | Process for preparing morphorinones |
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KR800000814B1 true KR800000814B1 (en) | 1980-08-21 |
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1975
- 1975-06-20 KR KR7501365A patent/KR800000814B1/en active
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