KR100425881B1 - New morphinan derivatives - Google Patents

New morphinan derivatives Download PDF

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KR100425881B1
KR100425881B1 KR10-2001-0013173A KR20010013173A KR100425881B1 KR 100425881 B1 KR100425881 B1 KR 100425881B1 KR 20010013173 A KR20010013173 A KR 20010013173A KR 100425881 B1 KR100425881 B1 KR 100425881B1
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formula
represented
cyclopropylmethyl
following formula
effect
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KR20010044661A (en
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김형춘
주왕기
이필호
고광호
최신건
신은주
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고광호
이필호
신은주
주왕기
김형춘
최신건
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/28—Morphinans

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Abstract

본 발명은 하기 화학식 1로 표현되는 신규한 몰피난 유도체 및 이의 제조방법에 관한 것으로, 몰피난의 3- 및 17-번 탄소 위치에 치환체를 변화시킴으로서 무시할 수 있을 정도의 향정신성 효과를 가지며 우수한 항경련 효과와 신경보호효과를 갖는 신규한 몰피난 유도체를 용이하게 얻을 수 있었다.The present invention relates to a novel morphinan derivative represented by the following formula (1) and a method for preparing the same, having a negligible psychotropic effect by changing substituents at the 3- and 17-carbon positions of morphinan and having excellent anticonvulsability. Novel morphinan derivatives having an effect and a neuroprotective effect could be easily obtained.

화학식 1Formula 1

상기 화학식 1에서, 탄소수는 19∼21개, R은 시클로프로필메틸 또는 알릴기, R'는 R이 시클로프로필메틸일 경우 메틸, R이 알릴기일 경우에는 수소이다.In Formula 1, the carbon number is 19 to 21, R is a cyclopropylmethyl or allyl group, R 'is methyl when R is cyclopropylmethyl, hydrogen when R is an allyl group.

Description

신규한 몰피난 유도체{New morphinan derivatives}New morphinan derivatives

본 발명은 항경련제로서 유용한 하기 화학식 1로 표현되는 신규한 몰피난 유도체 및 이의 제조방법에 관한 것으로, 좀 더 구체적으로는 무시할 수 있을 정도의 향정신성 효과만을 가지며 우수한 항경련 효과를 갖는 것으로 몰피난의 3- 및 17-번 탄소 위치에 치환체를 변화시킨 것을 특징으로 하는 신규한 몰피난 유도체 및 이의 제조방법에 관한 것이다.The present invention relates to a novel morphinan derivative represented by the following Chemical Formula 1 useful as an anticonvulsant agent and a method for preparing the same, and more specifically, to a negligible psychotropic effect and having an excellent anticonvulsant effect. The present invention relates to novel morphinan derivatives characterized by changing substituents at the 3- and 17-carbon positions and to methods for their preparation.

화학식 1Formula 1

상기 화학식 1에서, 탄소수는 19∼21개, R은 시클로프로필메틸 또는 알릴기, R'는 R이 시클로프로필메틸일 경우 메틸, R이 알릴기일 경우에는 수소이다.In Formula 1, the carbon number is 19 to 21, R is a cyclopropylmethyl or allyl group, R 'is methyl when R is cyclopropylmethyl, hydrogen when R is an allyl group.

덱스트로메트로판(3-메톡시-17-메틸몰피난, DM)은 거의 40년 동안 진해제로서 광범위하게 사용되어 온 비마약성 몰피난 유도체이다. 최근에 덱스트로메트로판은 항경련 및 신경 보호 특성으로 인하여 주목을 받고 있으며, 간질을 포함한 신경계 장애에 대한 많은 임상 실험에서 고무적인 실험 결과가 도출되고 있다.Dextrose metropan (3-methoxy-17-methylmorphinan, DM) is a nondrug morphinan derivative that has been used extensively as an antitussive for nearly 40 years. Recently, dextrometropan has attracted attention due to its anticonvulsant and neuroprotective properties, and inspiring experimental results have been derived from many clinical trials of neurological disorders including epilepsy.

그러나, 어린이에 유독하고 많은 양의 덱스트로메트로판 투여와 관련된 정신병 유발성의 반응에 관한 일련의 보고는 이의 대사산물에 기인한 것이며, 청년기에 남용 가능성이 그 원인으로 파악되고 있다.However, a series of reports of psychotic-induced reactions involving toxic and high doses of dextrometropan in children are due to their metabolites and the potential for abuse in adolescents is attributed.

한편, 본 발명자 등은 덱스트로메트로판 자체가 향정신성 행동 패턴을 나타내며, 설치류에 있어서 덱스트로메트로판이 코카인의 행동패턴을 나타낼 가능성이 있다라는 것을 확인하였다. 뿐만 아니라, 만성적인 덱스트로메트로판 투여는 펜시클리딘(pencyclidine : PCP)에 의하여 유발되는 면역억제효과와 유사한 세포면역반응을 교란하는 것을 확인하였다.On the other hand, the present inventors have confirmed that dextrometron plate itself exhibits psychoactive behavior patterns, and that in rodents, dextrometron plate may exhibit ***e behavior patterns. In addition, chronic dextrometropan administration has been shown to disrupt cellular immune responses similar to the immunosuppressive effects induced by pencyclidine (PCP).

즉, 덱스트로메트로판은 부작용이 많이 발생하는 문제점이 있었다.In other words, dextrometophan had a problem that a lot of side effects occur.

따라서, 본 발명의 목적은 무시할 수 있을 정도의 향정신성 효과를 가지며 우수한 항경련 효과와 신경보호효과를 갖는 신규한 몰피난 유도체를 제공하는 데 있다.Accordingly, it is an object of the present invention to provide a novel morphinan derivative having a negligible psychotropic effect and an excellent anticonvulsant effect and neuroprotective effect.

본 발명의 다른 목적은 상기 목적의 신규한 몰피난 유도체의 용이한 제조방법을 제공하는 데 있다.Another object of the present invention is to provide an easy method for preparing a novel morphinan derivative for this purpose.

상술한 목적 뿐만 아니라 용이하게 표출될 수 있는 다른 목적들을 달성하기 위하여 본 발명에서는 몰피난의 3- 및 17-번 탄소 위치에 치환기를 변화시킴으로서무시할 수 있을 정도의 향정신성 효과를 가지며 우수한 항경련 효과와 신경보호효과를 갖는 신규한 몰피난 유도체를 용이하게 얻을 수 있었다.In order to achieve the above-mentioned object as well as other objects that can be easily expressed, the present invention has a psychotropic effect which is negligible by changing substituents at the 3- and 17-carbon positions of the morphinan, and has excellent anticonvulsive effect and Novel morphinan derivatives having a neuroprotective effect could be easily obtained.

본 발명을 좀 더 상세히 설명하면 다음과 같다.The present invention is described in more detail as follows.

본 발명에 따른 신규한 몰피난 유도체는 하기 화학식 1로 표현되는 것을 특징으로 한다.The novel morphinan derivative according to the present invention is characterized by the following formula (1).

화학식 1Formula 1

상기 화학식 1에서, 탄소수는 19∼21개, R은 시클로프로필메틸 또는 알릴기, R'는 R이 시클로프로필메틸일 경우 메틸, R이 알릴기일 경우에는 수소이다.In Formula 1, the carbon number is 19 to 21, R is a cyclopropylmethyl or allyl group, R 'is methyl when R is cyclopropylmethyl, hydrogen when R is an allyl group.

또한, 본 발명의 신규한 몰피난 유도체는 하기 화학식 2로 표현되는 덱스트로메트로판의 브롬화수소염을Ο-탈메틸화하여 하기 화학식 3으로 표현되는 덱스트로르판(Dextrorphan : DX)을 얻은 다음, 덱스트로르판을 수소화나트륨(NaH) 존재하에서 시클로프로필메틸 브로마이드 또는 알릴 브로마이드와 반응시켜 각각 하기 화학식 4로 표현되는 3-시클로프로필메톡시-17-메틸몰피난과 3-알릴옥시-17-메틸몰피난을 얻은 후, 3-알릴옥시-17-메틸몰피난을 1-클로로에틸 클로로포르메이트로 반응시켜 하기 화학식 5로 표현되는 3-알릴옥시몰피난을 얻는 방법에 의하여 제조된다.Further, to the novel mole evacuation derivative of the present invention the brominated Flame of dextromethorphan Metro plate represented by the formula 2 Ο - to the demethylation dextromethorphan reupan represented by the following general formula (3): obtained (Dextrorphan DX), then index Reacting tropane with cyclopropylmethyl bromide or allyl bromide in the presence of sodium hydride (NaH), 3-cyclopropylmethoxy-17-methylmorphinan and 3-allyloxy-17-methylmorphinan represented by the following formula (4) After obtaining, 3-allyloxy-17-methylmorphinane was reacted with 1-chloroethyl chloroformate to prepare 3-allyloxymorphinane represented by the following formula (5).

덱스트로메트로판의 브롬화수소염은 특별히 한정되는 것은 아니지만, 본 발명에서는 47%의 브롬화수소를 갖는 것을 사용하였으며,Ο-탈메틸화는 본 발명이 속하는 기술 분야에서 통상적으로 사용되는 방법을 사용하였고, 덱스트로메트로판의 브롬화수소염의Ο-탈메틸화에 의한 덱스트로르판의 수득은 정량적인 수율로 얻어졌다.Hydrogen bromide salt of dextrometophan is not particularly limited, but in the present invention, the one having 47% hydrogen bromide was used, Ο -demethylation used a method commonly used in the art to which the present invention belongs, The yield of dextropan by O -demethylation of the hydrogen bromide of dextrometropan was obtained in quantitative yield.

덱스트로르판으로부터의 3-시클로프로필메톡시-17-메틸몰피난과 3-알릴옥시-17-메틸몰피난 수득은 각각 94%와 98%로 얻을 수 있었다.3-cyclopropylmethoxy-17-methylmorphinan and 3-allyloxy-17-methylmorphinan obtained from dextropan were 94% and 98%, respectively.

본 발명에 의한 몰피난 유도체는 무시할 수 있을 정도의 향정신성 효과를 가지며 우수한 항경련 효과와 신경보호효과를 갖는 유용한 것이다.The morphinan derivative according to the present invention has a negligible psychotropic effect and is useful for having an excellent anticonvulsant effect and a neuroprotective effect.

다음의 실시예 및 비교예는 본 발명을 좀 더 상세히 설명하는 것이지만 본 발명의 범주를 한정하는 것은 아니다.The following examples and comparative examples further illustrate the invention but do not limit the scope of the invention.

실시예 1Example 1

상기 화학식 2로 표현되는 것으로 47%의 브롬화수소를 갖는 덱스트로메트로판의 브롬화수소염을 통상적인 방법에 의하여Ο-탈메틸화하여 상기 화학식 3으로표현되는 덱스트로르판(Dextrorphan : DX)을 정량적인 수율로 얻은 다음, 덱스트로르판을 수소화나트륨(NaH) 존재하에서 시클로프로필메틸 브로마이드와 반응시켜 상기 화학식 4로 표현되는 3-시클로프로필메톡시-17-메틸몰피난을 94%의 수율로 얻었다.Of the: (DX Dextrorphan) Quantitative dextromethorphan reupan by demethylation, which is represented by the formula (3) - that Ο by bromide Hydrogen Flame of dextromethorphan Metro plate having a hydrogen bromide 47% in the conventional method are represented by the general formula (2) After obtaining in yield, dextrorphan was reacted with cyclopropylmethyl bromide in the presence of sodium hydride (NaH) to give 3-cyclopropylmethoxy-17-methylmorphinane represented by Formula 4 in 94% yield.

실시예 2Example 2

시클로프로필메틸 브로마이드 대신에 알릴 브로마이드를 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응시켜 3-알릴옥시-17-메틸몰피난을 98%의 수율로 얻은 다음, 3-알릴옥시-17-메틸몰피난을 1-클로로에틸 클로로포르메이트로 반응시켜 상기 화학식 5로 표현되는 3-알릴옥시몰피난을 얻었다.The reaction was carried out in the same manner as in Example 1, except that allyl bromide was used instead of cyclopropylmethyl bromide to give 3-allyloxy-17-methylmorphinan in 98% yield, followed by 3-allyloxy-17-methyl The morphinan was reacted with 1-chloroethyl chloroformate to obtain 3-allyloxymorphinan represented by the formula (5).

비교예 1Comparative Example 1

상기 화학식 2로 표현되는 것으로 47%의 브롬화수소를 갖는 덱스트로메트로판의 브롬화수소염을 수산화암모늄(NH4OH) 수용액으로부터 추출에 의하여 유리염으로 변환시킨 다음, 1,2-디클로로에탄에 결정성 유리염을 용해한 용액에 탄산칼륨과 1-클로로에틸 클로로포름에이트를 0℃에서 첨가한 후, 질소분위기하에서 6시간 동안 환류하여 하기 화학식 6으로 표현되는 3-메톡시몰피난을 얻었다.The hydrogen bromide salt of dextrose metropane having 47% hydrogen bromide as represented by Chemical Formula 2 was converted into a free salt by extraction from an aqueous solution of ammonium hydroxide (NH 4 OH), and then crystallized in 1,2-dichloroethane. Potassium carbonate and 1-chloroethyl chloroformate were added to the solution in which the free free salt was dissolved at 0 ° C., and refluxed for 6 hours under a nitrogen atmosphere to obtain 3-methoxymorphinan represented by the following formula (6).

비교예 2Comparative Example 2

비교예 1에서 얻은 3-메톡시몰피난을 47%의 브롬화수소와 반응시켜 하기 화학식 7로 표현되는 3-하이드록시몰피난을 70%의 수율로 얻었다.3-methoxymorphinan obtained in Comparative Example 1 was reacted with 47% of hydrogen bromide to obtain 3-hydroxymorphinan represented by the following Chemical Formula 7 in a yield of 70%.

실험예 1Experimental Example 1

실시예 1 및 2에서 얻은 3-시클로프로필메톡시-17-메틸몰피난과 3-알릴옥시몰피난, 덱스트로메토르판, 덱스트로르판, 비교예 1 및 2에서 얻은 3-메톡시몰피난과 3-하이드록시몰피난에 대한 항경련 효과와 신경보호 효과를 평가하기 위하여 동물실험을 행하였다.3-cyclopropylmethoxy-17-methylmorphinane and 3-allyloxymorphinane obtained in Examples 1 and 2, dextromethorphan, dextrone, 3-methoxymorphinan obtained in Comparative Examples 1 and 2 Animal experiments were conducted to evaluate the anticonvulsant and neuroprotective effects on and 3-hydroxymorphinan.

즉, 카인산(kainic acid)에 의하여 유발된 증세에 대한 상기 화합물들의 항경련 효과(신경보호 효과)를 평가하였으며, 정신병 유발 정도를 특징화하는 운동패턴(locomotor patterns(circling behaviors))이 실험되어졌다. 활성화 단백질(AP)-1 DNA 결합능의 세기가 항경련 효과를 생화학적으로 증명하기 위하여 쥐해마(rat hippocamus)에서 실험되어졌다.In other words, the anticonvulsant effect (neuroprotective effect) of the compounds on the symptoms caused by kainic acid was evaluated, and locomotor patterns (circling behaviors) characterizing the degree of psychosis incidence were tested. lost. The strength of activating protein (AP) -1 DNA binding capacity was tested in rat hippocamus to biochemically demonstrate anticonvulsant effects.

체계적인 카인산 투여에 의하여 발생되는 증세가 사람의 측두엽간질 증세와 거의 유사하기 때문에 본 발명에서는 카인산을 신경독(neurotoxin)으로 사용하였다.In the present invention, the cacaic acid was used as a neurotoxin because the symptom generated by systematic phosphate administration was almost similar to that of human temporal lobe epilepsy.

실험 결과를 하기의 표 1 내지 표 3에 기재하였다.The experimental results are shown in Tables 1 to 3 below.

쥐에 있어서 몰피난에 의한 급성독성Acute Toxicity by Morphine Evacuation in Rats 구 분division 급성독성 LD50(mg/kg) p.o.Acute toxicity LD50 (mg / kg) p.o. 급성독성 LD50(mg/kg) i.p.Acute Toxicity LD50 (mg / kg) i.p. 실시예 1의 화합물Compound of Example 1 〉150〉 150 〉85〉 85 실시예 2의 화합물Compound of Example 2 〉150〉 150 〉85〉 85 덱스트로메토르판Dextromethorphan 〉150〉 150 〉80〉 80 덱스트로르판Dextrorphan 〉150〉 150 〉80〉 80 비교예 1의 화합물Compound of Comparative Example 1 〉150〉 150 〉80〉 80 비교예 2의 화합물Compound of Comparative Example 2 〉150〉 150 〉80〉 80

쥐에 있어서 몰피난에 의한 선회행동Turning Behavior by Morphine Evacuation in Rats 구 분division 투여량(mg/kg, i.p.)Dose (mg / kg, i.p.) NN 선회행동(절대회전각 ±S.E./3분)Turning behavior (absolute rotation angle ± S.E. / 3 minutes) 실시예 1의 화합물Compound of Example 1 20402040 88 152 ±13f 200 ±19a,f 152 ± 13f 200 ± 19a, f 실시예 2의 화합물Compound of Example 2 20402040 88 162 ±13f 192 ±12a,f 162 ± 13f 192 ± 12a, f 덱스트로메트로판Dextrose Metropan 20402040 88 190 ±18a 250 ±24b 190 ± 18a 250 ± 24b 덱스트로르판Dextrorphan 20402040 88 310 ±24c,d 392 ±26c,d 310 ± 24CD 392 ± 26CD 비교예 1의 화합물Compound of Comparative Example 1 20402040 88 194 ±19a,e 242 ±22b,c 194 ± 19a, e 242 ± 22b, c 비교예 2의 화합물Compound of Comparative Example 2 20402040 88 178 ±12e 240 ±23a,e 178 ± 12e 240 ± 23a, e 대 조 군Control 식 염 수Saline 1212 130 ±12130 ± 12 펜시클리딘(PCP)Penciclidine (PCP) 55 88 421 ±21c 421 ± 21 c

* 선회행동(한계활동(marginal activity))은 약물 주사 30분 후에 자동화 비디오트레킹 시스템(automated videotracking system)을 사용하여 실험하였다.Rotational behavior (marginal activity) was tested 30 minutes after drug injection using an automated videotracking system.

* N은 쥐의 수.* N is the number of rats.

* a는 p＜0.05 대 식염수.a is p <0.05 vs. saline.

* b는 p＜0.01 대 식염수.b is p <0.01 versus saline.

* c는 p＜0.001 대 식염수.c is p <0.001 versus saline.

* d는 p＜0.05 대 상응하는 덱스트로메토르판 투여량.d is p <0.05 vs. corresponding dextromethorphan dose.

* e는 p＜0.05 대 상응하는 덱스트로르판 투여량.* e is p <0.05 vs. corresponding dextropane dose.

* f는 p＜0.01 대 상응하는 덱스트로르판 투여량.f is p <0.01 vs. corresponding dextrone plate dose.

* a, b, c, d, e, f는 윌리엄스-윌코손 멀티플 랭크 섬 테스트 (Williams -wilcoxon multiple rank sum test)* a, b, c, d, e and f are the Williams-wilcoxon multiple rank sum test

쥐에 있어서 몰피난에 의한 항경련(신경 보호) 효과.Anticonvulsant (neuroprotective) effect by morphinan in rats. 구 분division 투여량(mg/kg, i.p.)Dose (mg / kg, i.p.) KA(10mg/kg, i.p.)KA (10 mg / kg, i.p.) 발병빈도Incidence 4시간 후의해마의 AP-1 DNA 결합활성(밀도단위)AP-1 DNA Binding Activity (Density Unit) of Hippocampus After 4 Hours 4일 후의 해마의 AP-1 DNA 결합활성(밀도단위)AP-1 DNA Binding Activity (Density Units) of Hippocampus After 4 Days 사망율(48시간후)Mortality rate after 48 hours 실시예 1의 화합물Compound of Example 1 20402040 ++++ 1.8 ±0.2b,d1.1 ±0.1c,d 1.8 ± 0.2 b, d 1.1 ± 0.1 c, d 14.6 ±1.0b10.2 ±1.2c 14.6 ± 1.0 b 10.2 ± 1.2 c 9.2 ±0.7c6.4 ±0.4c 9.2 ± 0.7 c 6.4 ± 0.4 c 2/15c2/15c 2/15 c 2/15 c 실시예 2의 화합물Compound of Example 2 20402040 ++++ 1.7 ±0.1b,d1.2 ±0.1c,d 1.7 ± 0.1 b, d 1.2 ± 0.1 c, d 14.8 ±0.9b10.2 ±1.1c 14.8 ± 0.9 b 10.2 ± 1.1 c 8.7 ±0.9c5.1 ±0.2c 8.7 ± 0.9 c 5.1 ± 0.2 c 1/15c1/15c 1/15 c 1/15 c 덱스트로메토르판Dextromethorphan 20402040 ++++ 1.9 ±0.2b1.2 ±0.1c 1.9 ± 0.2 b 1.2 ± 0.1 c 15.4 ±1.2b10.2 ±1.2c 15.4 ± 1.2 b 10.2 ± 1.2 c 10.2 ±1.4b6.2 ±0.8c 10.2 ± 1.4 b 6.2 ± 0.8 c 2/15c1/15c 2/15 c 1/15 c 덱스트로르판Dextrorphan 20402040 ++++ 2.6 ±0.2b1.7 ±0.2b 2.6 ± 0.2 b 1.7 ± 0.2 b 19.2 ±1.6b13.3 ±1.2c 19.2 ± 1.6 b 13.3 ± 1.2 c 14.3 ±1.2b11.3 ±1.0b 14.3 ± 1.2 b 11.3 ± 1.0 b 3/15c2/15c 3/15 c 2/15 c 비교예 1의 화합물Compound of Comparative Example 1 20402040 ++++ 2.5 ±0.2b2.0 ±0.1b 2.5 ± 0.2 b 2.0 ± 0.1 b 17.2 ±1.4b15.2 ±1.2b 17.2 ± 1.4 b 15.2 ± 1.2 b 13.2 ±0.9b10.1 ±1.1b 13.2 ± 0.9 b 10.1 ± 1.1 b 2/15c2/15c 2/15 c 2/15 c 비교예 2의 화합물Compound of Comparative Example 2 20402040 ++++ 1.9 ±0.2b1.5 ±0.1b 1.9 ± 0.2 b 1.5 ± 0.1 b 16.4 ±2.0b12.3 ±1.4c 16.4 ± 2.0 b 12.3 ± 1.4 c 12.5 ±1.2b8.2 ±0.6c 12.5 ± 1.2 b 8.2 ± 0.6 c 2/15c2/15c 2/15 c 2/15 c 대 조 군Control --- -(식염수)+(KA만)-(Saline) + (KA only) 0.0 ±0.04.2 ±0.4a 0.0 ± 0.04.2 ± 0.4 a 1.0 ±0.229.9 ±2.1a 1.0 ± 0.229.9 ± 2.1a 2.0 ±0.118.1 ±2.0a 2.0 ± 0.118.1 ± 2.0 a 0/10c7/15a 0/10 c 7/15 a

* 각각의 값은 평균 ±15마리 쥐(발병빈도에 있어서)와 4마리 쥐(AP-1 DNA 결합활성에 있어서)의 S.E.이다.* The values are S.E. in the mean ± 15 rats (onset) and 4 rats (on AP-1 DNA binding activity).

* KA는 카인산임.* KA is caric acid.

* 발병정도는 자동화 비디오트레킹 시스템(automated videotracking system)하에서 KA 주입후 4시간 동안 기록되었다.The incidence was recorded for 4 hours after KA infusion under an automated videotracking system.

* AP-1 DNA 결합 활성은 KA 주입후 4시간 및 4일에 측정되었다.* AP-1 DNA binding activity was measured 4 hours and 4 days after KA injection.

* AP-1 DNA 결합 활성은 윌리엄스-윌코손 멀티플 랭크 섬 테스트 (Williams- wilcoxon multiple rank sum test)를 사용하여 계산되었다.* AP-1 DNA binding activity was calculated using the Williams-wilcoxon multiple rank sum test.

* 사망율의 통계는 치-스퀘어 테스트(Chi-square test)를 사용하여 계산되었다.* Statistics of mortality were calculated using the Chi-square test .

* a는 p＜0.05 대 식염수.a is p <0.05 vs. saline.

* b는 p＜0.05 대 KA만.* b is only p <0.05 vs KA.

* c는 p＜0.01 대 KA만.* c is only p <0.01 vs. KA.

* d는 p＜0.05 대 상응하는 덱스트로르판 투여량.d is p <0.05 vs. corresponding dextrone plate dose.

상기와 같이 본 발명에서는 몰피난의 3- 및 17-번 탄소 위치에 치환체를 변화시켜 무시할 수 있을 정도의 향정신성 효과를 가지며 우수한 항경련 효과와 신경보호효과를 갖는 신규한 몰피난 유도체를 용이하게 얻을 수 있었다.As described above, in the present invention, a novel morphinane derivative having an antipsychotic effect and a superior anticonvulsant effect and a neuroprotective effect is easily obtained by changing substituents at the carbon positions of 3- and 17-numbers of morphinan. Could.

Claims (2)

항경련제로서 유용한 하기 화학식 1로 표현되는 신규한 몰피난 유도체.Novel morphinan derivative represented by the following formula (1) useful as an anticonvulsant. 화학식 1Formula 1 상기 화학식 1에서, 탄소수는 19∼21개, R은 시클로프로필메틸 또는 알릴기, R'는 R이 시클로프로필메틸일 경우 메틸, R이 알릴기일 경우에는 수소이다.In Formula 1, the carbon number is 19 to 21, R is a cyclopropylmethyl or allyl group, R 'is methyl when R is cyclopropylmethyl, hydrogen when R is an allyl group. 하기 화학식 2로 표현되는 덱스트로메트로판의 브롬화수소염을 Ο-탈메틸화하여 하기 화학식 3으로 표현되는 덱스트로르판(Dextrorphan : DX)을 얻은 다음, 덱스트로르판을 수소화나트륨(NaH) 존재하에서 시클로프로필메틸 브로마이드 또는 알릴 브로마이드와 반응시켜 각각 하기 화학식 4로 표현되는 3-시클로프로필메톡시-17-메틸몰피난과 3-알릴옥시-17-메틸몰피난을 얻은 후, 3-알릴옥시-17-메틸몰피난을 1-클로로에틸 클로로포르메이트로 반응시켜 하기 화학식 5로 표현되는 3-알릴옥시몰피난을 얻는 것을 특징으로 하는 몰피난 유도체의 제조방법.Hydrogen bromide salt of dextrose metropane represented by the following formula (2) was O-demethylated to obtain dextrorphan (Dextrorphan: DX) represented by the following formula (3), and then the dextropan was cyclodeposited in the presence of sodium hydride (NaH). Reaction with propylmethyl bromide or allyl bromide to obtain 3-cyclopropylmethoxy-17-methylmorphinan and 3-allyloxy-17-methylmorphinan represented by the following formula (4), respectively, followed by 3-allyloxy-17- A method for producing a morphinan derivative, characterized by reacting methylmorphinan with 1-chloroethyl chloroformate to obtain 3-allyloxymolfinan represented by the following formula (5). 화학식 2Formula 2 화학식 3Formula 3 화학식 4Formula 4 화학식 5Formula 5
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4247697A (en) * 1979-09-10 1981-01-27 Hoffmann-La Roche Inc. 3-Phenoxy morphinans and their derivatives
JPS6089474A (en) * 1983-10-20 1985-05-20 Toyo Pharma- Kk Morphinan derivative, production thereof and antitumor agent containing said compound
US5258386A (en) * 1991-06-05 1993-11-02 The United States Of America As Represented By The Secretary Of The Army (+)-3-substituted-N alkylmorphinans, synthesis and use as anticonvulsant and neuroprotective agents
JPH06316564A (en) * 1993-01-06 1994-11-15 F Hoffmann La Roche Ag O-aryl ether of morphanan
KR950011413A (en) * 1993-10-12 1995-05-15 로날 샤삐라 Substituted 1-niphthyl-3-pyrazolecarboxamide active against neurotensin. Preparation thereof and pharmaceutical composition containing same
KR960008234A (en) * 1994-08-26 1996-03-22 정몽원 Beverage chiller

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4247697A (en) * 1979-09-10 1981-01-27 Hoffmann-La Roche Inc. 3-Phenoxy morphinans and their derivatives
JPS6089474A (en) * 1983-10-20 1985-05-20 Toyo Pharma- Kk Morphinan derivative, production thereof and antitumor agent containing said compound
US5258386A (en) * 1991-06-05 1993-11-02 The United States Of America As Represented By The Secretary Of The Army (+)-3-substituted-N alkylmorphinans, synthesis and use as anticonvulsant and neuroprotective agents
JPH06316564A (en) * 1993-01-06 1994-11-15 F Hoffmann La Roche Ag O-aryl ether of morphanan
KR950011413A (en) * 1993-10-12 1995-05-15 로날 샤삐라 Substituted 1-niphthyl-3-pyrazolecarboxamide active against neurotensin. Preparation thereof and pharmaceutical composition containing same
KR960008234A (en) * 1994-08-26 1996-03-22 정몽원 Beverage chiller

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