KR800001249B1 - Process for preparing substituted n-(1-(3,4-methylenedioxphenyl)-propyl(2))-n'-substituted phenyl piperazines - Google Patents

Process for preparing substituted n-(1-(3,4-methylenedioxphenyl)-propyl(2))-n'-substituted phenyl piperazines Download PDF

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KR800001249B1
KR800001249B1 KR7501843A KR750001843A KR800001249B1 KR 800001249 B1 KR800001249 B1 KR 800001249B1 KR 7501843 A KR7501843 A KR 7501843A KR 750001843 A KR750001843 A KR 750001843A KR 800001249 B1 KR800001249 B1 KR 800001249B1
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propyl
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methylenedioxyphenyl
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오토 렌트 에른스트
멘트루프 안톤
스크롬 쿠르트
프뢸케 빌헬름
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닥터, 오토휭케, 기젤라 벨안
씨 에취 베링거죤
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

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Abstract

Title compd. (I; R1 = Cl, Me; R2 = H, Cl, MeO) and its acid addition salt, useful as CNS suppressant was prepd. by introducing 1-(3,4-methylenedioxypheny1)propy1-(2) group into II. Thus, the mixt. of 29.0g(0.14mol)(2-methy1-4-methoxy) phenylpiperazine, 41.5g 1-(3,4-methylenedioxypheny1)-propanol(2)-methansulfonate and 44g potash in 250ml xylene was refluxed, vacuum distd., and recrystallized to give N-[1-(3,4-methylenedioxypheny1)propy1(2) -N'-(2-methy1-4-methoxypheny1)piperazine(m.p. 256-259≰C).

Description

치환된 N-[1-(3,4-메틸렌디옥시페닐)-프로필(2)]-N-치환된 페닐피페라진의 제조방법Process for preparing substituted N- [1- (3,4-methylenedioxyphenyl) -propyl (2)]-N-substituted phenylpiperazine

본 발명은 중추억제제 및 혈중지방농도 감소제로서 유용한 구조식(I)의 1-페닐-프로필(2)-피페라진의 라세미체 또는 광학적 활성체 및 이들의 산부가염의 제조방법에 관한 것이다.The present invention relates to a racemate or optically active substance of 1-phenyl-propyl (2) -piperazine of structural formula (I) useful as a central inhibitor and a blood fat reducing agent, and a method for preparing acid addition salts thereof.

Figure kpo00001
Figure kpo00001

여기서 R1이 염소일 때, R2는 수소 또는 염소이고 R1이 메틸일 때 R2는 메톡시이다.Wherein when R 1 is chlorine, R 2 is hydrogen or chlorine and when R 1 is methyl R 2 is methoxy.

중추 억제작용을 가진 구조식(II)의 화합물 및 그의 산부가염에 대해서는 독일공개특허 명세서 제1670144호에 이미 알려진 바 있다.Compounds of formula (II) having a central inhibitory activity and acid addition salts thereof are already known from German Patent Publication No. 1670144.

Figure kpo00002
Figure kpo00002

여기서 Ar는 서로 아넬화된(annelled) 두개의 환을 가지고 있는 방향족기이며, R1과 R2는 수소, 할로겐, CF3기 또는 탄소수 1 내지 4의 알킬이나 알콕시를 나타낸다.Ar is an aromatic group having two rings annelled with each other, and R 1 and R 2 represent hydrogen, halogen, CF 3 group or alkyl or alkoxy having 1 to 4 carbon atoms.

상기 구조식(I)의 화합물은 독일공개특허명세서 제1670144호에 기술되어 있지 않으며 이들의 산부가염은 중추억제 작용의에 혈중의 지방농도 및 플레스테린 농도를 감소시키는 탁월한 작용이 있음이 발견되었다. 따라서 본 화합물은 혈중 지방농도를 감소시키는 제제로도 사용될 수 있다. 또한 본 화합물은 독일공개특허 명세서 제2136929호의 화합물보다 우수하다.The compounds of formula (I) are not described in German Patent Publication No. 1670144 and it has been found that their acid addition salts have an excellent effect of reducing blood fat and fosterin concentrations due to their central inhibitory action. Therefore, the present compound can also be used as an agent for reducing blood fat concentration. In addition, the present compound is superior to the compound of German Patent Application No. 2136929.

1일 용량은 25 내지 75mg, 바람직하기로는 40 내지 60mg이며, 따라서 1일에 1 내지 5회 투여시의 1회 용량량은 5 내지 75mg이다.The daily dose is 25 to 75 mg, preferably 40 to 60 mg, and thus the single dose amount is 5 to 75 mg when administered 1 to 5 times per day.

구조식(I) 화합물의 독성은 매우 낮으므로 치료에 극히 바람직한 안전지수를 갖는다.The toxicity of the compounds of formula (I) is very low and therefore has a very good safety index for treatment.

관상동맥혈전증의 예방에는 구조식(I)의 화합물을 관학장제, 예를들면 디피리다몰(-2,6-비스(디에탄올아미노)-4,8-디피페리디노-[5,4-d]-피리미딘)과 혼합하여 1일 50 내지 150mg(1회용량 10 내지 150mg)을 사용한다.Prevention of coronary thrombosis includes the use of a compound of formula (I) as an intestinal agent, e.g., dipyridamole (-2,6-bis (diethanolamino) -4,8-dipiperidino- [5,4-d] -Pyrimidine) and 50 to 150 mg (daily dose 10 to 150 mg) is used.

본 발명의 활성성분은 공지의 방법으로 통상의 제형, 즉 정제나 제피정, 에멀젼, 산제, 캅셀제, 혹은 서방출형으로 제조한다. 이를 위해서는 통상의 약학적 부형제를 사용하여 통상의 방법으로 제조한다. 예를들면 정제는 활성성분을 탄산칼슘이나 인산칼슘, 락토즈와 같은 불활성 희석제와 옥수수전분이나 알긴산과 같은 붕해제, 전분이나 젤라틴과 같은 결합제, 마그네슘 스테아레이트나 활석과 같은 활제 및/또는 카복시폴리메틸렌, 카복시메틸셀루로즈, 셀루로즈아세테이트 프탈레이트 또는 폴리비닐 아세테이트와 같은 서방출 보조제와 혼합하여 제조한다.The active ingredient of the present invention is prepared by a known method in a conventional formulation, that is, tablets, tablets, emulsions, powders, capsules, or sustained release. To this end it is prepared by conventional methods using conventional pharmaceutical excipients. For example, tablets may contain the active ingredient as an inert diluent such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc, and / or carboxypolymethylene And a slow release aid such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate.

또한 정제를 몇 개의 층으로 할수도 있다. 또한 정제제조와 유사한 방법으로 제조한 핵정을 정제의 제피에 통상적으로 사용되는 시약, 예를들면 폴리비닐피리돈이나 쉘락, 아라비아고무활석, 이산화티탄, 설탕등으로 제피하여 제피정을 만든다.The tablets can also be in several layers. In addition, the core tablet prepared by the method similar to tablet preparation is coated with a reagent commonly used for coating tablets, for example, polyvinylpyridone or shellac, gum arabic, titanium dioxide, sugar, etc. to make a tablet tablet.

서방출형 제제를 얻기 위해서나 또는 배합 불가를 피하기 위해서 핵정을 여러층으로 해도 좋다. 제피도 서방출을 위해서 여러층으로 할수 있다. 여기에서 사용되는 부형제는 정제에서 사용된 것과 같다.In order to obtain a sustained release formulation or to avoid impossibility of mixing, the core tablet may be formed in multiple layers. Zephyr can also be layered for slow release. Excipients used herein are the same as used in tablets.

각 활성성분의 쥬스나 활성성분 복합제의 쥬스는 부가적으로 삭카린이나 사이클라메트, 글리세린, 설탕과 같은 감미료와 미각을 돋구어주는 바닐린이나 오렌지 추출물과 같은 향료를 함유시킬 수 있으며 또한 현탁액 보조제나 나트륨 카복시메틸 셀루로즈와 같은 증량제, 지방알콜과 에틸렌디옥사이드의 축합 생성물과 같은 습윤제, P-하이드록시벤조에이트와 같은 방부제등을 함유시킬 수 있다.Juice of each active ingredient or juice of the active ingredient combination may additionally contain sweeteners such as saccharin, cyclammet, glycerin, sugar and flavoring agents such as vanillin or orange extract which enhance the taste, and also suspension aid or sodium Extenders such as carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols and ethylene dioxide, preservatives such as P-hydroxybenzoate, and the like.

각 활성성분이나 활성성분 복합제를 함유하는 캅셀제는 활성성분을 락토즈나 솔비톨같은 담체와 혼합하여 젤라틴 캅셀에 충진시켜 제조한다.Capsules containing each active ingredient or active ingredient combination are prepared by mixing the active ingredient with a carrier such as lactose or sorbitol and filling it into a gelatin capsule.

적합한 좌제는 각 활성성분, 또는 활성성분 복합제를 중성지방, 폴리에틸렌글리콜이나 그 유도체와 같은 통상의 담체에 섞어 제조한다.Suitable suppositories are prepared by mixing each active ingredient, or active ingredient combination, with a conventional carrier such as triglycerides, polyethylene glycols or derivatives thereof.

본 발명의 신규화합물은 다음과 같은 방법으로 제조한다.The novel compounds of the present invention are prepared by the following method.

a) 1-(3,4-메틸렌디옥시페닐)프로필-(2)기를 구조식(III)의 피페라진 화합물에 도입시킨다.a) A 1- (3,4-methylenedioxyphenyl) propyl- (2) group is introduced into the piperazine compound of formula (III).

Figure kpo00003
Figure kpo00003

여기서 R1, R2는 전술한 바와같으며, 도입반응은 구조식(III)의 화합물을 친전자성 1-(3,4-메틸렌디옥시페닐)프로필(2)유도체, 예를들면 1-(3,4-메틸렌디옥시페닐)프로필(2)-클로라이드, -브로마이드, -메실레이트, 혹은 -토실레이트와 산결합체 존재하에 반응시키거나 구조식(III)의 화합물을 1-(3,4-메틸렌디옥시페닐)프로판온(2)와, 촉매적으로 활성화된 수소나 금속하이드라이드(예, 리튬알루미늄 하이드라이드, 붕수소화나트륨)과 같은 환원제 존재하에 반응시켜 수행한다.Wherein R 1 , R 2 are as described above, and the incorporation reaction allows the compound of formula III to be electrophilic 1- (3,4-methylenedioxyphenyl) propyl (2) derivative, for example 1- ( 3,4-methylenedioxyphenyl) propyl (2) -chloride, -bromide, -mesylate, or -tosylate in the presence of an acid bond or reacting the compound of formula (III) with 1- (3,4-methylene It is carried out by reacting dioxyphenyl) propanone (2) with a reducing agent such as catalytically activated hydrogen or metal hydride (e.g. lithium aluminum hydride, sodium borohydride).

b) 또는, 구조식(IV)의 할로겐함유 화합물은 촉매적으로 활성화된 수소로 처리하거나b) Or, the halogen-containing compound of formula IV may be treated with catalytically activated hydrogen or

Figure kpo00004
Figure kpo00004

여기서 R1, R2는 전술한 바와같고, Hal은 염소, 브롬, 요오드, 바람직하기로는 염소를 나타낸다.Wherein R 1 , R 2 are as described above and Hal represents chlorine, bromine, iodine, preferably chlorine.

c) 구조식(V)의 화합물과 구조식(VI)의 화합물을 반응시키거나c) reacting a compound of formula (V) with a compound of formula (VI)

Figure kpo00005
Figure kpo00005

여기서 Q는

Figure kpo00006
기 또는
Figure kpo00007
기이며 X는 음이온 상태로 쉽게 제거될 수 있는 기로, 할로겐원자나 알킬, 또는 아릴설포닐옥시기이며 Q1은 Q와 같은 의미를 가지나 모든 경우 Q1과 Q는 서로 다른 것을 나타낸다.Where Q is
Figure kpo00006
Flag or
Figure kpo00007
X is a group which can be easily removed in an anionic state, halogen atom, alkyl, or arylsulfonyloxy group, Q 1 has the same meaning as Q, but in all cases Q 1 and Q are different.

d) 구조식(VII)의 2중 2급디아민을 구조식(VIII)의 화합물과 반응시키거나d) reacting the secondary secondary diamine of formula (VII) with a compound of formula (VIII), or

Figure kpo00008
Figure kpo00008

Figure kpo00009
Figure kpo00009

여기서 R1, R2, X는 전술한 바와같다.Where R 1 , R 2 , and X are as described above.

e) 구조식(IX)의 화합물을 LiAlH4와 같은 금속하이드라이드로 환원시키거나e) reducing the compound of formula IX to a metal hydride such as LiAlH 4 , or

Figure kpo00010
Figure kpo00010

여기서 R1, R2는 전술한 바와같고, A는 -COCH2, -CO-CO- 또는 CH2-CO기이다.Wherein R 1 , R 2 are as defined above and A is a -COCH 2 , -CO-CO- or CH 2 -CO group.

f) 구조식(X)의 화합물을 구조식(XI)의 화합물과 반응시켜 제조한다.f) prepared by reacting a compound of formula (X) with a compound of formula (XI).

Figure kpo00011
Figure kpo00011

Figure kpo00012
Figure kpo00012

여기서 X는 전술한 바와같고 염소나 브롬이 바람직하다. 이 반응은 산결합제 존재하에 약간 가온시키며 하는 것이 좋다.X is as described above and chlorine or bromine is preferred. This reaction is preferably warmed slightly in the presence of an acid binder.

a) 내지 f) 제법의 출발물질중 일부는 기지의 것이며 알려지지 않은 화합물들은 통상의 화학문헌, 예를들면 Houben-weyl의 제1판 및 제2판에 기술된 방법으로 제조할 수 있다.Some of the starting materials of the a) to f) preparations are known and unknown compounds can be prepared by the methods described in conventional chemical literature, such as the first and second editions of Houben-weyl.

구조식(III)의 화합물은 예를들면 J.Am.Chem.Soc. 76, P1853(1954) 및 J.Med.Chem. 8, P332(1965)에 기술된 방법에 따라 제조할 수 있다. 1-(3,4-메틸렌디옥시페닐)프로필(2)클로라이드, -브로마이드, -토실레이트 및 -메실레이트와 같은 친전자성의 1-(3,4-메틸렌디옥시페닐)프로필92)-유도체는 1-(3,4-메틸렌디옥시페닐)프로판올(2)(실시예 1참조)을 에스테르화하여 얻을 수 있으며 Org.Shnth.Coll Vol P573의 방법에 의해서는 1-(3,4-메틸렌디옥시페닐)프로판온(2)를 얻는다.Compounds of formula (III) are described, for example, in J. Am. Chem. Soc. 76, P1853 (1954) and J. Med. Chem. 8, P332 (1965). Electrophilic 1- (3,4-methylenedioxyphenyl) propyl92) -derivatives such as 1- (3,4-methylenedioxyphenyl) propyl (2) chloride, -bromide, -tosylate and -mesylate Can be obtained by esterifying 1- (3,4-methylenedioxyphenyl) propanol (2) (see Example 1) and by the method of Org.Shnth.Coll Vol P573 1- (3,4-methylene Dioxyphenyl) propanone (2) is obtained.

구조식(IV)의 화합물은 일본특허 제23 412/64호의 방법에 따라 얻을 수 있는데, 1-(3,4-메틸렌디옥시페닐)-1-브로모프로판온(2)와 N-(치환페닐)-피페라진을 반응시켜 상응하는 N-[1-(3,4-메틸렌디옥시페닐)]-N′-(치환페닐)-피페라진을 얻고 통상의 방법, 예를들면 J. Chem. Soc. (런던)1963 P 1385의 방법에 따라 PCl5로, 또는 독일특허 공개 명세서 제1212973호에 따라 SOCl2로 할로겐화하여 N-[1-(3,4-메틸렌디옥시페닐) 1-하이드록시프로필(2)]-N′-(치환페닐)피페라진을 얻을 수 있다.Compounds of formula (IV) can be obtained according to the method of Japanese Patent No. 23 412/64, wherein 1- (3,4-methylenedioxyphenyl) -1-bromopropanone (2) and N- (substitutedphenyl) ) -Piperazine is reacted to give the corresponding N- [1- (3,4-methylenedioxyphenyl)]-N '-(substitutedphenyl) -piperazine and conventional methods such as J. Chem. Soc. (London) N- [1- (3,4-methylenedioxyphenyl) 1-hydroxypropyl by halogenation with PCl 5 according to the method of 1963 P 1385 or with SOCl 2 according to German Patent Publication No. 1212973. 2)]-N '-(substituted phenyl) piperazine.

구조식(V)의 비스(β-할로에틸)아민류는 그 상응하는 아민 Q-NH2(Q는 전술한 바와같음)와 에틸렌옥사이드, 또는 할로에탄올과 반응시키고 이렇게하여 얻어진 비스(β-하이드록시에틸)아민류를 SOCl2나 PCl5로 처리하여 얻을 수 있다.Bis (β-haloethyl) amines of formula (V) are reacted with the corresponding amine Q-NH 2 (Q is as described above) with ethylene oxide or haloethanol and thus obtained bis (β-hydroxyethyl Amines can be obtained by treatment with SOCl 2 or PCl 5 .

구조식(VI)와 (VII)의 출발물질은 독일특허공보 제1212973호에 따라 제조할 수 있으며, 구조식(VIII)과 (XI)는 상응하는 글리콜을 할로겐 부가시키거나 상응하는 알칸의 수소를 할로겐으로 치환시켜 제조할 수 있다.Starting materials of the formulas (VI) and (VII) can be prepared according to German Patent Publication No. 1212973, wherein the formulas (VIII) and (XI) can be halogenated to the corresponding glycol or hydrogen to the halogen of the corresponding alkane. It can be prepared by substitution.

구조식(IX)의 출발물질은 예를들면 J.Med.Chem. P 154-158(1964)의 방법에 따라 제조할 수 있으며 구조식(X)의 화합물은 본 출원의 제법(a)에 따라 3,4-메틸렌디옥시페닐 유도체 대신에 3,4-디하이드록시페닐프로필(2) 유도체와 구조식(III)의 화합물을 반응시켜 제조할 수 있다.Starting materials of formula (IX) are described, for example, in J. Med. Chem. It may be prepared according to the method of P 154-158 (1964), and the compound of formula (X) is substituted with 3,4-dihydroxyphenyl instead of 3,4-methylenedioxyphenyl derivative according to the preparation method (a) of the present application. It can be prepared by reacting a propyl (2) derivative with a compound of formula (III).

구조식(I) 화합물은 -CH(CH3)기에 부젠탄소를 가지고 있어 광학적 대장체와 라세미체가 존재하게 된다. 광학적 활성화합물은 이미 -CH(CH3)기로 구성되어 있는 광학적 활성 출발물질로부터 a) 내지 f) 제법에 따라 제조하든지, 라세미체를 광학적으로 활성이 있는 산 예를들면 디벤조일-D-타타르산이나 브로모 캄포선폰산으로 부분입체이성 염을 만들어 분별 침전시키거나 분별결정시켜 분리해낸다.The compound of formula (I) has a butene carbon in the —CH (CH 3 ) group so that an optically large and racemate is present. The optically active compounds are prepared according to the processes a) to f) from optically active starting materials already composed of -CH (CH 3 ) groups, or the racemates can be produced by optically active acids such as dibenzoyl-D-tartar. Diastereomeric salts are prepared with acid or bromo camphorsulfonic acid and fractionated precipitated or fractionated to separate.

본 발명에 따른 물질은 적합한 산과 반응하여 생리적으로 가능한 산 부가염으로 전환될 수 있다.The substances according to the invention can be converted into physiologically possible acid addition salts by reaction with a suitable acid.

적합한 산의 예를들면 염산, 브롬산, 황산, 메탄설폰산, 석신산, 타타르산 등이 있다.Examples of suitable acids are hydrochloric acid, bromic acid, sulfuric acid, methanesulfonic acid, succinic acid, tartaric acid and the like.

다음의 실시예는 본 발명을 설명하는 것이며 본 발명의 범위가 여기에 국한되는 것은 아니다.The following examples illustrate the invention and are not intended to limit the scope thereof.

A. 제조 실시예A. Manufacturing Example

[실시예 1]Example 1

[N-[1-(3,4-메틸렌디옥시페닐)프로필(2)]-N′-(2-메틸--4-메톡시페닐)피페라진][N- [1- (3,4-methylenedioxyphenyl) propyl (2)]-N '-(2-methyl-4-methoxyphenyl) piperazine]

(2-메틸-4-메톡시)페닐피페라진 29.0g(0.14몰)을 1-(3,4-메틸렌디옥시페닐)-프로판올(2)-메탄설포네이트(페놀과 메실클로라이드의 에스테르화에 의해 생성) 41.5g 및 포타시(Potash) 44g과 함께 크실렌 250ml중에서 7시간동안 환류시키고 용매를 진공 증류시킨다. 잔유물을 수성메탄올성 염산으로 재결정화하면 융점 256 내지 259℃의 상기 표제 화합물의 염산염이 얻어진다.29.0 g (0.14 mol) of (2-methyl-4-methoxy) phenylpiperazine was added to the esterification of 1- (3,4-methylenedioxyphenyl) -propanol (2) -methanesulfonate (phenol and mesyl chloride). By refluxing in 250 ml of xylene with 41.5 g and 44 g of Potash for 7 hours and distilling off the solvent in vacuo. Recrystallization of the residue with aqueous methanolic hydrochloric acid gives the hydrochloride of the title compound at a melting point of 256 to 259 ° C.

[실시예 2]Example 2

[N-[1-(3,4-메틸렌디옥시페닐)프로필(2)]-N′-(2-클로로페닐)피페라진][N- [1- (3,4-methylenedioxyphenyl) propyl (2)]-N '-(2-chlorophenyl) piperazine]

2-클로로페닐피페라진 27.5g(0.14몰)을 1-(3,4-메틸렌디옥시페닐)-프로판올(2)-메탈설포네이트 41.5g 및 포타시 44g과 함께 크실렌 250ml중에서 7시간동안 환류시킨다. 실시예 1과 같은 조작을 계속하면 융점 248℃의 상기 표제 화합물의 염산염이 얻어진다.27.5 g (0.14 mol) of 2-chlorophenylpiperazine are refluxed for 7 hours in 250 ml of xylene with 41.5 g of 1- (3,4-methylenedioxyphenyl) -propanol (2) -metalsulfonate and 44 g of potash. . The same operation as in Example 1 was carried out to obtain the hydrochloride of the title compound at a melting point of 248 ° C.

[실시예 3]Example 3

[N-[1-(3,4-메틸렌디옥시페닐)프로필(2)]-N′-(2,4-디클로로페닐)피페라진][N- [1- (3,4-methylenedioxyphenyl) propyl (2)]-N '-(2,4-dichlorophenyl) piperazine]

2,4-디클로로페닐피페라진 32.5g(0.14몰)을 1-(3,4-메틸렌디옥시페닐)-프로판올(2)-메탄설포네이트 41.5g(0.16몰) 및 포타시 44g과 함께 크실렌 250ml중에서 7시간동안 환류시킨다. 실시예 1과 같은 조작을 계속하면 융점 259 내지 263℃의 상기 표제화합물의 염산염이 얻어진다.250 ml of xylene with 32.5 g (0.14 mole) of 2,4-dichlorophenylpiperazine and 41.5 g (0.16 mole) of 1- (3,4-methylenedioxyphenyl) -propanol (2) -methanesulfonate and 44 g of potash Reflux for 7 hours. The same operation as in Example 1 was continued to obtain hydrochloride of the title compound at melting point 259 to 263 占 폚.

B. 조성의 실시예B. Examples of Composition

[실시예 1(정제)]Example 1 (Tablet)

Figure kpo00013
Figure kpo00013

[제법][quite]

활성성분을 일부의 부형제와 혼합하여 전분수용액으로 잘 반죽하고 통상의 방법으로 체를 통하여 제립한다. 이 과립을 나머지 부형제와 섞어 250mg 정제로 티정한다. 상기에 지정한 활성성분 대신에 같은량의 N-[1-(3′,4′-메틸렌디옥시페닐)-프로필(2)]-N-′2,4-디클로로페닐피페라진을 사용할수도 있다.The active ingredient is mixed with some excipients, kneaded well with starch solution, and granulated through a sieve in a conventional manner. This granule is mixed with the remaining excipients and tableted into 250 mg tablets. The same amount of N- [1- (3 ', 4'-methylenedioxyphenyl) -propyl (2)]-N-'2,4-dichlorophenylpiperazine may be used instead of the active ingredient specified above.

[실시예 2(정피정제)]Example 2 (finish tablet)

Figure kpo00014
Figure kpo00014

[제법][quite]

활성성분을 부형제 일부와 혼합하여 전분수용액으로 잘 반죽하고 통상의 방법으로 체를 통하여 재립한다. 이 과립을 나머지 부형제와 섞어 380mg 핵정으로 타정한후 활석, 설탕 및 아라비아고무로 제피한다.The active ingredient is mixed with a part of the excipient, kneaded well with a starch solution and re-sieved through a sieve in a conventional manner. The granules are mixed with the remaining excipients and compressed into 380 mg core tablets, followed by talc, sugar and gum arabic.

[실시예 3(건조-충진 캅셀제)]Example 3 (made of dry-filled capsule)

다음에 기술된 조성물을 함유하는, 경구투여에 적합한 젤라틴 캅셀은 건조한산제를 캅셀에 충진, 밀봉하여 통상의 방법으로 제조한다.Gelatin capsules suitable for oral administration containing the composition described below are prepared in a conventional manner by filling and sealing the dry powder into the capsules.

Figure kpo00015
Figure kpo00015

Claims (1)

구조식(III)의 피페라진 화합물에 1-(3,4-메틸렌디옥시페닐)프로필-(2)기를 도입시켜 다음 구조식(I)의 화합물 및 이들의 산부가염을 제조하는 방법.A process for preparing the compound of formula (I) and acid addition salts thereof by introducing a 1- (3,4-methylenedioxyphenyl) propyl- (2) group into the piperazine compound of formula (III).
Figure kpo00016
Figure kpo00016
 상기 구조식에서 R1이 염소일 때, R2는 수소 또는 염소이고, R1이 메틸일 때 R2는 메톡시기를 나타낸다.When R 1 is chlorine in the above formula, R 2 is hydrogen or chlorine, and when R 1 is methyl, R 2 represents a methoxy group.
KR7501843A 1975-08-20 1975-08-20 Process for preparing substituted n-(1-(3,4-methylenedioxphenyl)-propyl(2))-n'-substituted phenyl piperazines KR800001249B1 (en)

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