JPS58194861A - Novel piperidine derivative and its preparation - Google Patents
Novel piperidine derivative and its preparationInfo
- Publication number
- JPS58194861A JPS58194861A JP7650882A JP7650882A JPS58194861A JP S58194861 A JPS58194861 A JP S58194861A JP 7650882 A JP7650882 A JP 7650882A JP 7650882 A JP7650882 A JP 7650882A JP S58194861 A JPS58194861 A JP S58194861A
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- Japan
- Prior art keywords
- acid
- formula
- amidino
- group
- compound
- Prior art date
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Abstract
Description
【発明の詳細な説明】
本発明は医薬として有用な次の一般式（１）（式中、Ｒ
１は水素原子またはアルコキシ基を、Ｒ２は二重結合を
有する基、を示す）で表わされる新規ピペリジン誘導体
およびその酸付加塩ならびにその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention describes the following general formula (1) (wherein R
1 represents a hydrogen atom or an alkoxy group, R2 represents a group having a double bond), an acid addition salt thereof, and a method for producing the same.
本発明者らは数多くのピペリジン系化合物を合成し、そ
の薬理作用を検討していたところ、上記一般式（Ｉ）で
表わされる新規化合物が優れた血小板凝集抑制作用を有
し、医薬として有用であることを見い出し、本発明を完
成した。The present inventors synthesized a number of piperidine-based compounds and investigated their pharmacological effects, and found that a new compound represented by the above general formula (I) has an excellent platelet aggregation inhibiting effect and is useful as a medicine. They discovered something and completed the present invention.
従って、本発明の目的は一般式（１）で表わされる医薬
として有用な新規化合物を提供することにある。Therefore, an object of the present invention is to provide a novel compound represented by general formula (1) that is useful as a medicine.
他の目的は、一般式（Ｉ）で表わされる化合物を製造す
るだめの方法を提供することにある。Another object is to provide an alternative method for producing the compound represented by general formula (I).
一般式（１）の新規ピペリジン誘導体のＲ１で表トキシ
基、エトギシ基、プロポキシ基、ブトキシ基などがあげ
られる。また、Ｒ２で表わされる基としては、ビニル基
、アリル基、ブテニル基、フェニルビニル基、ベンゾイ
ルビニル基、シンナモイル基、カルボキシビニル基、ベ
ンジルオキシカルボニルビニル基、ジフェニルメチルオ
キシカルボニルビニル基などがあげられる。Examples of R1 in the novel piperidine derivative of general formula (1) include a toxoxy group, an ethyloxy group, a propoxy group, and a butoxy group. Examples of the group represented by R2 include a vinyl group, an allyl group, a butenyl group, a phenylvinyl group, a benzoylvinyl group, a cinnamoyl group, a carboxyvinyl group, a benzyloxycarbonylvinyl group, and a diphenylmethyloxycarbonylvinyl group. .
一般式（１）の本発明化合物の酸付加塩としては、塩酸
、臭化水素酸、硫酸、リン酸、酢酸、乳酸、マレイン酸
、フマル酸、酒石酸、クエン酸、メタンスルホンＷｌ、
ｐ −）ルエンスルホン酸などとの酸付加塩があげられ
る。Examples of acid addition salts of the compound of the present invention of general formula (1) include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfone Wl,
Examples include acid addition salts with p-)luenesulfonic acid and the like.
本発明の一般式（１）の新規ピペリジン誘導体およびそ
の酸付加塩は次の如くして製造される〇
（式中、Ｒ１およびＲ２は前記と同じ）すなわち、式（
ｎ）で表わされる１−アミジノ−４−ピペリジンプロピ
オン酸またはその反応性誘導体に一般式（至）で表わさ
れるフェノール類を反応させることによシ、一般式（Ｉ
）で表わされる新規ピペリジン誘導体が製造される。The novel piperidine derivatives of general formula (1) and acid addition salts thereof of the present invention are produced as follows (wherein R1 and R2 are the same as above), that is, the formula (
By reacting 1-amidino-4-piperidinepropionic acid represented by n) or a reactive derivative thereof with a phenol represented by general formula (I),
) A new piperidine derivative is produced.
ただし、一般式（１）中のＲ２にカルボキシル基を含有
する化合物が目的化合物である場合には、原料である一
般式（至）のフェノール類トシて、ジフェニルメチル基
などによジカルボキシル基が保護された化合物を用いて
、式（Ｉｔ）の化合物と反応させてカルボキシル基が保
護された形の一般式（Ｉ）の化合物を得た後に、当該保
護基を蟻酸あるいはトリフルオロ酢酸にて脱離せしめる
ことにより製造される。However, if the target compound is a compound containing a carboxyl group in R2 in general formula (1), the dicarboxyl group may be removed by diphenylmethyl group, etc. After the protected compound is reacted with a compound of formula (It) to obtain a compound of general formula (I) with a protected carboxyl group, the protecting group is removed with formic acid or trifluoroacetic acid. Manufactured by separating.
式（ＩＩ）の化合物の反応性誘導体としては、酸クロラ
イド、酸ブロマイドなどの酸ハライド、クロル炭酸エチ
ルエステル、クロル炭酸ブチルエステルなどの混合酸無
水物や活性エステルなどがあげられる。これらの反応性
誘導体と一般式（至）のフェノール類との反応は、−１
０℃〜室温で［１５〜５時間攪拌することにょシ行なわ
れる。反応溶媒としては、ジメチルホルムアミド、ジク
ロルメタン、ジクロルエタン、クロロホルム、アセトニ
トリルなどがあげられ、トリエチルアミン、ジメチルア
ニリンなどの三級アミンの存在下に行なうことが好まし
い。Examples of reactive derivatives of the compound of formula (II) include acid halides such as acid chloride and acid bromide, mixed acid anhydrides and active esters such as ethyl chlorocarbonate and butyl chlorocarbonate. The reaction between these reactive derivatives and the phenols of the general formula (to) is -1
Stirring is carried out for 15 to 5 hours at 0°C to room temperature. Examples of the reaction solvent include dimethylformamide, dichloromethane, dichloroethane, chloroform, and acetonitrile, and the reaction is preferably carried out in the presence of a tertiary amine such as triethylamine and dimethylaniline.
式（Ｉｌ）の化合物またはその塩と一般式（至）の化合
物の反応は、ジシクロヘキシルカルボジイミドなどのカ
ルボジイミド類を縮合剤として用いて、室温にて５時間
〜５日間攪拌するのが好ましい。反応溶媒としては、ジ
メチルポルムアミド、ジメチルアセトアミド、ピリジン
、トルエン、キシレン、−ジメチルスルホキシドなどあ
るいはこれらの混合物が好ましい。The reaction between the compound of formula (Il) or a salt thereof and the compound of general formula (-) is preferably carried out using a carbodiimide such as dicyclohexylcarbodiimide as a condensing agent and stirring at room temperature for 5 hours to 5 days. Preferred reaction solvents include dimethylpolamide, dimethylacetamide, pyridine, toluene, xylene, -dimethylsulfoxide, and mixtures thereof.
また、以上の縮合反応により得られた一般式（夏）の化
合物のカルボキシル基の保護基であるジフェニルメチル
基の脱離反応は、蟻酸あるいはトリフルオロ酢酸の存在
下に０〜１゜０℃の温度で数時間攪拌することによシ容
易に行なわれる。In addition, the elimination reaction of the diphenylmethyl group, which is a protective group for the carboxyl group of the compound of the general formula (Natsu) obtained by the above condensation reaction, is carried out at 0 to 1°C in the presence of formic acid or trifluoroacetic acid. This is easily accomplished by stirring at room temperature for several hours.
一般式（１）の新規ピペリジン誘導体の酸付加塩を得る
には、原料である式（Ｉｔ）の化合物を酸付加塩の形で
用い、目的物もその塩の形で得るのが好ましい。In order to obtain the acid addition salt of the novel piperidine derivative of general formula (1), it is preferable to use the compound of formula (It) as a starting material in the form of an acid addition salt and to obtain the target product in the form of the salt.
なお、原料である式（ＩＩ）の１−アミジノ−４−ピペ
リジンプロピオン酸は、４−ピペリジンプロピオン酸に
０−メチルイソ尿素またはＳ−メチルイソチオ尿素を室
温にて５〜２０時間反応させることによ）容易に得られ
る。Note that the raw material 1-amidino-4-piperidinepropionic acid of formula (II) can be obtained by reacting 4-piperidinepropionic acid with 0-methylisourea or S-methylisothiourea at room temperature for 5 to 20 hours). easily obtained.
以上の如くして得られる一般式（１）の本発明化合物は
、血小板凝集抑制作用を有し、種々の血栓性疾患の治療
剤として有用である。The compound of the present invention represented by the general formula (1) obtained as described above has a platelet aggregation inhibiting effect and is useful as a therapeutic agent for various thrombotic diseases.
血小板凝集抑制作用はウサギ血小板を用いて次の如く試
験した。すなわち、ウサギの頚動脈よシ常法によシ採血
し、Ｐｌａｔｅｌｅｔ ｒｉｃｈｐｌａｓｍａ （Ｐ
ＲＰ ）およびＰｌａｔｅｌｅｔ ｐｏｏｒｐｌａｓ
ｍａ （Ｐ Ｐ Ｐ ）を得た。ＰＲＰはＰＰＰで希
釈して血小板数が２０〜３０×１０４／ｃ ｕｍｍ の
血小板浮遊液を得た。この血小板浮遊液４５０１１ｔに
被験化合物を加え、３７℃１分間攪拌後、コラーゲンま
たはアラキドン酸２５瀕を添加して、血小板凝集の経過
を透過度の変化としてアブレボメータにより記録した○
凝集率はＥｍｍｏｎｓ らの方法（：ｃ＋ａｎｃｅｔ
。The platelet aggregation inhibitory effect was tested using rabbit platelets as follows. Specifically, blood was collected from the carotid artery of a rabbit using a conventional method, and platelet rich plasma (P
RP) and Platelet poorplas
ma (P P P ) was obtained. PRP was diluted with PPP to obtain a platelet suspension having a platelet count of 20 to 30 x 104/cumm. The test compound was added to 45011t of this platelet suspension, and after stirring for 1 minute at 37°C, collagen or arachidonic acid was added for 25 minutes, and the progress of platelet aggregation was recorded as a change in permeability using an abbrevometer.
The aggregation rate was determined by the method of Emmons et al. (:c+ancet
.
１ニア１〜７７）に準拠して評価した。結果を表１に示
す。1-77). The results are shown in Table 1.
表１゜
一：効果なし
＋： ２５〜５０チ抑制
廿：５１〜７５％抑制
丑Ｆ： ７６〜１００チ抑制
アラキドン酸濃度：６ｍＭ
コラーゲン濃度 ＝ １０μな−
Ａ：１−アミジノ−４−ピペリジンプロピオン酸４１−
アリール−２＋−メトキシフェニルエステル［ｆｌｍ
Ｂ：アスピリン
表１の如く、本発明化合物は、アラキドン酸またはコラ
ーゲンにより惹起される血小板凝集を強く阻害し、血栓
性疾患治療剤として有用である。Table 1: No effect +: 25-50 inhibition: 51-75% inhibition F: 76-100 inhibition Arachidonic acid concentration: 6mM Collagen concentration = 10μ A: 1-amidino-4-piperidine propion Acid 41-
Aryl-2+-methoxyphenyl ester [flm B: Aspirin As shown in Table 1, the compounds of the present invention strongly inhibit platelet aggregation induced by arachidonic acid or collagen, and are useful as therapeutic agents for thrombotic diseases.
次に実施例をあげて本発明の詳細な説明するが、もとよ
シ本発明はこれにより限定されるものではない。EXAMPLES Next, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.
実施例１
１−アミジノ−４−ピペリジンプロピオン酸４１−アリ
ル−２′−メトキシフェニルエステル塩酸塩：
１−アミジノ−４−ピペリジンプロピオン酸塩酸塩′！
ｈ、Ｏｓｌ＋およびオイゲノール２．１２を無水ピリ９
フ３０ｍｔ中に溶解し、これにジシクロへキシルカルボ
ジイミド２．６ｆを添加し、２夜攪拌後さらにジシクロ
へキシルカルボジイミドＣＬ４ｆを追加し続いて一夜室
温で攪拌した。析出した結晶を炉別し、溶媒を減圧留去
した。残渣に酢酸エチルを加え、冷所に２日間放置して
析出した結晶をｐ取した。これ全酢酸エチル、エーテル
にて洗浄後、風乾し喪。これに水５０−を加え、室温で
１時間攪拌し、不溶分を沖取し、エーテルにて洗浄後、
風乾して、融点８３〜８６℃の無色結晶として１−アミ
ジノ−４〜ビベリジンプロビオン酸４１−アリル−２′
−メトキシフェニルエステル塩酸塩１．４ ｔ （収率
２９チ）を得九〇五３６（２Ｈ，ａ、 Ｐｈ−０旦２−
）＆８０（５Ｈ，８，Ｐｈ−０−０旦３）４．９２〜５
．２４ （２Ｈ，ｍ、 ＝ＯＯ２０５，７２〜６．１６
（ＩＨ，ｍ、 −Ｃ旦＝）１、．６４〜７．０４（５Ｈ
，ｍ、芳香族水素）実施例２
１−アミジノ−４−ピペリジンプロピオン酸２１− （
β−フェニルカルボニルエチニル）フェニルエステルｔ
Ｊｌ酸塩：
１−アミジノ−４−ビベリジンプロビオンＷｌ塩ｔｌ［
［５ｙ 、 ２−ヒドロキシカルコン４．８２、ジシ
クロへキシルカルボジイミド４．４ｔおよび無水ピリジ
ン３０−の混合物を室温で４６時間攪拌した。不溶物を
ν別後、減圧下に溶媒を留去し、得られた橙色油状物を
酢酸エチルで洗浄し、ガム状物とした。これを水に溶か
し、次いで析出した固形物に水とエーテルを加えて攪拌
し、−夜冷所に放置した。Example 1 1-amidino-4-piperidinepropionic acid 41-allyl-2'-methoxyphenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid hydrochloride'!
h, Osl+ and eugenol 2.12 in anhydrous Pyri 9
2.6f of dicyclohexylcarbodiimide was added thereto, and after stirring for 2 nights, 4f of dicyclohexylcarbodiimide was further added, followed by stirring overnight at room temperature. The precipitated crystals were separated in a furnace, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was left in a cold place for 2 days, and the precipitated crystals were collected. After washing with total ethyl acetate and ether, air dry. Add 50% of water to this, stir at room temperature for 1 hour, remove insoluble matter, wash with ether,
Air-dried to give 41-allyl-2' 1-amidino-4-viveridineprobionic acid as colorless crystals with a melting point of 83-86°C.
-Methoxyphenyl ester hydrochloride 1.4 t (yield: 29 cm) was obtained.
)&80(5H,8,Ph-0-0dan3)4.92~5
．． 24 (2H, m, =OO205,72~6.16
(IH, m, -Cdan=)1,. 64-7.04 (5H
, m, aromatic hydrogen) Example 2 1-amidino-4-piperidinepropionic acid 21- (
β-phenylcarbonylethynyl) phenyl ester t
Jl salt: 1-amidino-4-biveridineprobion Wl salt tl [
[5y, A mixture of 4.82 t of 2-hydroxychalcone, 4.4 t of dicyclohexylcarbodiimide and 30 t of anhydrous pyridine was stirred at room temperature for 46 hours. After removing insoluble matter, the solvent was distilled off under reduced pressure, and the resulting orange oil was washed with ethyl acetate to give a gum-like product. This was dissolved in water, then water and ether were added to the precipitated solid, stirred, and left in a cool place overnight.
得られた固形物を、水およびエーテルで数回洗浄して、
融点約８５℃の黄色針状晶として１−アミジノ−４−ピ
ペリジンプロピオン酸２１− （β−フェニルカルボニ
ルエチニル）フェニルエステル塩酸塩３２（収率３２．
ｓ ％ ）を得た。The resulting solid was washed several times with water and ether and
1-amidino-4-piperidinepropionic acid 21-(β-phenylcarbonylethynyl)phenyl ester hydrochloride 32 as yellow needles with a melting point of about 85°C (yield 32.
s %) was obtained.
＆５〜ａＯ（１１Ｈ，ｍ、 −０Ｈ＝ＯＲ−。&5~aO(11H,m, -0H=OR-.
芳香族水素）
実施例３
１−アミジノ−４−ピペリジンプロピオン酸２′−シン
ナモイルフヱニルエステル塩酸塩：
１−アミジノ−４−ピペリジンプロピオン酸塩酸塩５９
ｖ２’−ヒドロキシカルコン４．８１１ ジシクロへキ
シルカルボジイミド４．４ｆおよび無水ピリジン３０−
の混合物を室温で４６時間攪拌した。不溶物をＦ別後、
減圧下１１−
に溶媒を留去して得られた黄色油状物を酢酸エチルで洗
浄した。得られたガム状物を水に溶かし、析出した固形
物に水およびエーテルを加えて攪拌し、−夜冷所に放置
した。得られた固形物を水およびエーテルで数回洗浄し
て融点１０３〜１０５℃の白色粉末として１−アミジノ
−４−ピペリジンプロピオンｌ１２２’−シンナモイル
フエニルエステル！酸！１．８２（収率１９４慢）を得
喪。Aromatic hydrogen) Example 3 1-amidino-4-piperidinepropionic acid 2'-cinnamoylphenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid hydrochloride 59
v2'-hydroxychalcone 4.811 dicyclohexylcarbodiimide 4.4f and anhydrous pyridine 30-
The mixture was stirred at room temperature for 46 hours. After separating the insoluble matter by F,
The solvent was distilled off under reduced pressure at 11°C, and the resulting yellow oil was washed with ethyl acetate. The resulting gum was dissolved in water, water and ether were added to the precipitated solid, stirred, and left in a cool place overnight. The resulting solid was washed several times with water and ether to give a white powder with a melting point of 103-105° C. 1-amidino-4-piperidinepropion l122'-cinnamoyl phenyl ester! acid! 1.82 (yield 194%) was obtained.
６．６〜７．６（１１Ｈ，ｍ、 −０Ｈ＝ＯＨ−。6.6-7.6 (11H, m, -0H=OH-.
芳香族水素）
実施例４
１−アミジノ−４−ピペリジンプロピオンＩＩ ４’
−（β−ジフェニルメチルオキシカルボニル）エチニル
フェニルエステル！酸［：ｐ−ヒドロキシ桂皮酸および
ジフェニルジアゾメタンよυ製したｐ−ヒドロキシ桂皮
酸ジフェニルメチルエステル９．９ｆ’ｌｌｋヒｌＪ１
２−
ジン７０−に溶解し、これに１−アミジノ−４−ピペリ
ジンプロピオン酸塩酸塩＆４２およびジシクロへキシル
カルボジイミド５．６ｔを添加し、室温で６日間攪拌後
４５℃に昇温して一夜攪拌し、ここでジシクロへキシル
カルボジイミド１．４２を追加し、さらに−夜４５℃に
で攪拌し友。放冷後、析出した結晶を戸数し、冷ピリジ
ンで数回洗浄後、酢酸エチル、エーテルで洗浄し、風乾
した。得られた結晶を１００−のジクロルメタン中で攪
拌し、不溶分を炉別して溶媒を減圧留去し、エーテルを
加えた。析出した結晶を戸取し、酢酸エチル、エーテル
で洗浄し、風乾して融点１３５〜１３８℃の無色結晶と
して、１−アミジノ−４−ピペリジンプロピオン酸４１
− （β−ジフェニルメチルオキシカルボニル）エテニ
ルフェニルエステタ塩酸塩Ｌａｔ（収率４３チ）を得た
。Aromatic hydrogen) Example 4 1-amidino-4-piperidine propion II 4'
-(β-diphenylmethyloxycarbonyl)ethynyl phenyl ester! Acid [: p-hydroxycinnamic acid diphenyl methyl ester prepared from p-hydroxycinnamic acid and diphenyldiazomethane 9.9f'llkHilJ1
2-Dissolved in Zine 70-, 1-amidino-4-piperidine propionic hydrochloride &42 and 5.6 t of dicyclohexylcarbodiimide were added thereto, and after stirring at room temperature for 6 days, the temperature was raised to 45°C and stirred overnight. Then, 1.42 g of dicyclohexylcarbodiimide was added, and the mixture was further stirred at 45°C overnight. After cooling, the precipitated crystals were separated, washed several times with cold pyridine, then washed with ethyl acetate and ether, and air-dried. The obtained crystals were stirred in 100% dichloromethane, insoluble matter was filtered out, the solvent was distilled off under reduced pressure, and ether was added. The precipitated crystals were collected, washed with ethyl acetate and ether, and air-dried to give 1-amidino-4-piperidinepropionic acid 41 as colorless crystals with a melting point of 135-138°C.
- (β-diphenylmethyloxycarbonyl)ethenyl phenyl esteta hydrochloride Lat (yield: 43 cm) was obtained.
６．４６（ＩＨ，（１，１６Ｈ２，＝Ｏ旦−ｃｏ）＆９
６（ＩＨ，ｓ −０−０旦二）
６．８０〜７．７０ （１４Ｈ，ｍ、芳香族水素→７．
６７（１Ｈ，ｄ、１６Ｈｚ、−０旦＝）実施例５
１−アミシノー４−ビペリジンプロビオン酸４’−（β
−カルボキシ）エチニルフェニルエステル塩酸塩：
１−アミジノ−４−ピペリジンプロピオン酸４’−（β
−ジフェニルメチルオキシカルボニル）エチニルフェニ
ルエステルｔＪ［［２，６りを蟻酸５０−に溶解し、４
０℃にて２時間攪拌した。溶媒を減圧留去し、今後、残
渣にエーテルを加え、析出した結晶ｔＦ取し、エーテル
にて数回洗浄して、融点２４９〜２５０℃の無色結晶と
して１−アミジノ−４−ピペリジンプロピオン酸４１（
β−カルボキシ）エチニルフェニルエステルｔＪ［ｆｆ
１１．７ｆ（収率９．ｉ％）を得た。6.46(IH, (1,16H2,=Odan-co) &9
6 (IH, s -0-0 dan 2) 6.80-7.70 (14H, m, aromatic hydrogen → 7.
67 (1H, d, 16Hz, -0 temps =) Example 5 1-amicino 4-biperidineprobionic acid 4'-(β
-Carboxy)ethynyl phenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid 4'-(β
-diphenylmethyloxycarbonyl)ethynyl phenyl ester tJ [[2,6] was dissolved in formic acid 50-,
The mixture was stirred at 0°C for 2 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals tF were collected and washed several times with ether to give 1-amidino-4-piperidinepropionic acid 41 as colorless crystals with a melting point of 249-250°C. (
β-carboxy)ethynyl phenyl ester tJ[ff
11.7f (yield 9.i%) was obtained.
＆４５（Ｉ Ｈ，ａ、 、ｒ ＝ １６Ｈｚ、 ＝ａＨ
Ｏｏ ）７．６８（ＩＨ，（１，Ｊ＝１６Ｈ２，−０旦
＝）７、０−４〜７．ａ ２ （４ｎ、 ｍ、芳香族水
素）実施例６
１−アミジノ−４−ピペリジンプロピオン酸２′−メト
キシ−４１−（β−ジフェニルメチルオキシカルボニル
）エチニルフェニルエステル塩酸塩：
１−アミジノ−４−ピペリジンプロピオン酸塩酸塩６ｆ
１４−ヒドロキシ−３−メトキシ桂皮酸ジフェニルメチ
ルエステル１ｏｆジシクロへキシルカルボジイミド５．
６ｆおよび無水ジメチルホルムアミド５ｏ−の混合物を
室温で６６時間攪拌した。更１／Ｃ６０’Ｃで１時間攪
拌し、不溶物を炉別後、溶媒を留去して得られた淡黄色
油状ｉを酢酸エチル、エーテルで処理して固形物を得た
。これを水に溶かし、析出した粉末をアセトン、エーテ
ルで洗浄した。更にメタノルルーエーテルよシ再１５−
結晶して、融点１１８〜１２０’Ｃの白色粉末として１
−アミジノ−４−ピペリジンプロピオン酸２′−メトキ
シ−、ｓｌ −（β−ジフェニルメチルオキシカルボニ
ル）エチニルフェニルエステル塩酸塩２．８？（収率１
９．４ ％ ）を得た〇
五６１（３Ｈ，ｓ、 −００Ｈ３）
６．５０ （Ｉ Ｈ，ｄ、 Ｊ＝２７Ｈｚ、 ＝＝Ｏ旦
−ｃｏ）＆７５（ＩＨ，８，−０−ＯＲ：）
６．９４〜７．５０（１３Ｈ，ｍ、芳香族水素）７．５
４（ＩＨ，（１，Ｊ＝２７Ｈｚ、 −０Ｆｌ＝り実施例
７
１−アミジノ−４−ピペリジンプロピオン酸２１−メト
キシ−４１−（β−カルボキシ）エチニルフェニルエス
テル［酸［：
１−アミジノ−４−ピペリジンプロピオン酸２′−メト
キシ−４１−（β−ジフェニルメチルオキシカルボニル
）エチニルフェニル塩酸１６−
塩１６ｔ、蟻酸３０−の溶液を５０℃にて１時間攪拌し
た。反応液を濃縮し、今後十分量のエーテルを加え、−
夜冷所に放置した。析出した結晶をエーテルにて洗浄後
、風乾して融点１９８〜２００℃の白色粉末として１−
アミジノ−４−ピペリジンプロピオン酸２１−メトキシ
−４１−（β−カルボキシ）エチニルフェニルエステル
塩酸塩１．１２を得た。&45(I H,a, , r = 16Hz, =aH
Oo) 7.68 (IH, (1, J=16H2, -0 degrees=)7,0-4~7.a2 (4n, m, aromatic hydrogen) Example 6 1-amidino-4-piperidine propion Acid 2'-methoxy-41-(β-diphenylmethyloxycarbonyl)ethynylphenyl ester hydrochloride: 1-amidino-4-piperidinepropionate hydrochloride 6f
14-Hydroxy-3-methoxycinnamic acid diphenylmethyl ester 1 of dicyclohexylcarbodiimide5.
A mixture of 6f and anhydrous dimethylformamide 5o- was stirred at room temperature for 66 hours. The mixture was further stirred at 1/C60'C for 1 hour, and after the insoluble matter was filtered out, the solvent was distilled off, and the resulting pale yellow oil was treated with ethyl acetate and ether to obtain a solid. This was dissolved in water, and the precipitated powder was washed with acetone and ether. Further crystallization with methanol-ether gives 1 as a white powder with a melting point of 118-120'C.
-amidino-4-piperidinepropionic acid 2'-methoxy-, sl -(β-diphenylmethyloxycarbonyl)ethynyl phenyl ester hydrochloride 2.8? (yield 1
9.4%) was obtained. ) 6.94-7.50 (13H, m, aromatic hydrogen) 7.5
4(IH, (1,J=27Hz, -0Fl=ri) Example 7 1-amidino-4-piperidinepropionic acid 21-methoxy-41-(β-carboxy)ethynyl phenyl ester [acid [: 1-amidino-4 A solution of 16 t of -piperidinepropionic acid 2'-methoxy-41-(β-diphenylmethyloxycarbonyl)ethynyl phenyl hydrochloride 16- salt and 30- of formic acid was stirred at 50°C for 1 hour.The reaction solution was concentrated and Add amount of ether, −
I left it in a cool place at night. The precipitated crystals were washed with ether and air-dried to form a white powder with a melting point of 198-200°C.
1.12 of amidino-4-piperidinepropionic acid 21-methoxy-41-(β-carboxy)ethynyl phenyl ester hydrochloride was obtained.
３８１ （５Ｈ，ｓ、 −００旦３）
６．４７（１Ｈ，ａ、Ｊ＝１６ｎｚ、＝Ｑ旦Ｃ０）７．
７８（ＩＨ，ｄ、、Ｔ＝１６Ｈｚ、 −０旦＝）ａ１５
〜ａ５０（５Ｈ，ｍ、芳香族水素）以 上381 (5H, s, -00dan3) 6.47 (1H,a, J=16nz, =QdanC0)7.
78 (IH, d,, T=16Hz, -0dan=) a15
~a50 (5H, m, aromatic hydrogen) or more
Claims (2)
二重結合を有する基を示す）で表わされる新規ピペリジ
ン誘導体およびその酸付加塩。(1) A novel piperidine derivative represented by the general formula C (in which R1 represents a hydrogen atom or an alkoxy group and R2 represents a group having a double bond) and an acid addition salt thereof.
またはその反応性誘導体に一般式 （式中、Ｒ１は水素原子またはアルコキシ基を、Ｒ２は
二重結合を有する基を示す）で表わされるフェノール類
を反応させることを特徴とする一般式 （式中、Ｒ１およびＲ２は前記と同じ）で表わされる新
規ピペリジン誘導体またはその酸付加塩の製造法。(2) Adding phenols represented by the general formula (wherein R1 represents a hydrogen atom or an alkoxy group, and R2 represents a group having a double bond) to 1-amidino-4-piperidinepropionic acid or its reactive derivative. A method for producing a novel piperidine derivative represented by the general formula (wherein R1 and R2 are the same as above) or an acid addition salt thereof, which is characterized by causing a reaction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7650882A JPS58194861A (en) | 1982-05-10 | 1982-05-10 | Novel piperidine derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7650882A JPS58194861A (en) | 1982-05-10 | 1982-05-10 | Novel piperidine derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58194861A true JPS58194861A (en) | 1983-11-12 |
| JPH021831B2 JPH021831B2 (en) | 1990-01-12 |
Family
ID=13607185
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7650882A Granted JPS58194861A (en) | 1982-05-10 | 1982-05-10 | Novel piperidine derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58194861A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260307A (en) * | 1990-07-05 | 1993-11-09 | Hofmann-La Roche Inc. | Guanidine derivatives compositions and use |
| US5792769A (en) * | 1995-09-29 | 1998-08-11 | 3-Dimensional Pharmaceuticals, Inc. | Guanidino protease inhibitors |
| US6034127A (en) * | 1995-12-29 | 2000-03-07 | 3-Dimensional Pharmaceuticals, Inc. | Amidino protease inhibitors |
-
1982
- 1982-05-10 JP JP7650882A patent/JPS58194861A/en active Granted
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260307A (en) * | 1990-07-05 | 1993-11-09 | Hofmann-La Roche Inc. | Guanidine derivatives compositions and use |
| US5393760A (en) * | 1990-07-05 | 1995-02-28 | Hoffmann-La Roche Inc. | Guanidine derivatives |
| US5583133A (en) * | 1990-07-05 | 1996-12-10 | Hoffmann-La Roche Inc. | Guanidine derivatives |
| US5595999A (en) * | 1990-07-05 | 1997-01-21 | Hoffmann-La Roche Inc. | Guanidine derivatives |
| US5763436A (en) * | 1990-07-05 | 1998-06-09 | Hoffmann-La Roche Inc. | Guanidine derivatives |
| US5792769A (en) * | 1995-09-29 | 1998-08-11 | 3-Dimensional Pharmaceuticals, Inc. | Guanidino protease inhibitors |
| US6034127A (en) * | 1995-12-29 | 2000-03-07 | 3-Dimensional Pharmaceuticals, Inc. | Amidino protease inhibitors |
| US6133315A (en) * | 1995-12-29 | 2000-10-17 | 3-Dimensional Pharmaceuticals, Inc. | Amidino protease inhibitors |
| US6225302B1 (en) | 1995-12-29 | 2001-05-01 | 3-Dimensional Pharmaceuticals, Inc. | Amidino protease inhibitors |
| US6281206B1 (en) | 1995-12-29 | 2001-08-28 | 3-Dimensional Pharmaceuticals, Inc. | Amidino protease inhibitors |
| US6414020B2 (en) | 1995-12-29 | 2002-07-02 | 3- Dimensional Pharmaceuticals, Inc. | Amidino protease inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH021831B2 (en) | 1990-01-12 |
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