N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide | 59825-55-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide
• 英文别名: N-[1-(2-phenoxy-ethyl)-piperidin-4-yl]-N-phenyl-propionamide；Phenoxyethyl-norfentanyl；N-[1-(2-phenoxyethyl)piperidin-4-yl]-N-phenylpropanamide
• CAS: 59825-55-7
• 化学式: C₂₂H₂₈N₂O₂
• 分子量: 352.477
• InChiKey: KOMXSJAJYURFRZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-苯胺-1-苯甲基哌啶 在 palladium 10% on activated carbon 、 四丁基溴化铵 、 氢气 、 potassium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 溶剂黄146 、 1,2-二氯乙烷 、 乙腈 为溶剂， 生成 N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide
  参考文献：
  名称：

  N-（1-苯乙基-4-哌啶基）丙酰苯胺（芬太尼）及其1-取代类似物在瑞士白化病小鼠中的合成及比较生物功效

  摘要：

  芬太尼[ N-（1-苯乙基-4-哌啶基）丙酰苯胺]是一种流行的麻醉镇痛剂，在世界范围内都在临床上使用。然而，由于剂量过量和狭窄的治疗指数，芬太尼及其几种类似物已在人类中引起滥用和死亡。本研究报告了芬太尼及其四个类似物，即N-（1-丙基-4-哌啶基）丙酰苯胺（1），N-（1-（2-苯氧基乙基）-4-哌啶基）的合成和比较生物功效。丙酰苯胺（2），N-（1-（3-（苯氧丙基）-4-哌啶基）丙酰苯胺（3）和N-（1-（2-氰基乙基）-4-哌啶基）丙酰苯胺（4），其中芬太尼的苯乙基链被不同的官能团取代，即烷基，醚基和腈基。通过三种不同的途径确定化合物的中值致死剂量（LD 50），发现所有类似物比芬太尼更安全。通过对中枢神经系统，周围神经系统和自主神经系统自发活动的观察评估，发现所有类似物均与芬太尼相似。此外，所有类似物的神经毒性作用均被盐酸纳洛酮（阿片类药物拮抗剂）逆转，证实它们的作用是通过阿片样物

  DOI：

  10.1007/s00044-012-0390-6

文献信息

• Arylethers and pharmaceutical compositions
  申请人：Science Union et Cie

  公开号：US04027028A1

  公开（公告）日：1977-05-31

  This invention relates to amino piperidines bearing on the endocyclic nitrogen atom an aryloxy alkyl side chain and the acid addition salts thereof. This invention also relates to processes for making the same. The compounds of this invention have therapeutical utility namely in the cardiovascular field. They may be used in the form of pharmaceutical compositions. DESCRIPTION OF THE PRIOR ART The prior art may be illustrated with the following references French drug Patents Nos. 2429 M; 2430 M; 2431 M; Belgian Patent No. 615,350. SUMMARY OF THE INVENTION This invention relates to new 4-amino piperidines and more particularly to N-aralkoxy 4-phenylamino piperidines. The aryl and phenyl nuclei may be unsubstituted or substituted by one or several substituents. This invention also provides processes for producing such compounds. Namely they may be produced by condensing an aryloxy alkyl halide with a 4-phenylamino piperidine. This invention also relates to pharmaceutical compositions including as active ingredient at least one 4-phenylamino N-aryloxy alkyl piperidine or an acid addition salt thereof in admixture with an inert carrier. This invention further relates to a method for treating hypertension in hypertensive humans or animals. DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to novel arylethers, to the processes for their preparation and to pharmaceutical compositions incorporating them as active ingredient. More particularly the present invention provides aryloxy lower alkyl piperidines of the general formula I: ##STR1## in which R.sub.2 is a hydrogen or a lower alkyl radical R.sub.3 is the acyl residue of an organic alkylcarboxylic acid having up to 10 carbon atoms. R.sub.4 is a phenyl radical selected from the group consisting of unsubstituted phenyl and a substituted phenyl radical of the formula ##STR2## WHEREIN R.sub.1 is a radical selected from the group consisting of halogen, lower alkoxy and lower alkylene dioxy AND Q IS AN INTEGER OF 1 TO 3 WITH THE PROVISO THAT WHEN R.sub.1 is a lower alkylene dioxy, Q IS 1 OR 2, X is an alkylene radical selected from the group consisting of ##STR3## in which R is a lower alkyl radical N IS 1 OR 2 AND Ar is an aromatic homo-or hetero cyclic radical selected from the group consisting of (a) a phenyl radical of the general formula ##STR4## IN WHICH X.sub.1 is a radical selected from the group consisting of halogen atom, lower alkyl, lower alkenyloxy, lower alkynyloxy, lower alkylthio, carboxyl, lower alkoxy carbonyl, lower alkenyl, lower alkylene-dioxy, nitro, amino, lower alkylamino, di(lower alkyl) amino, lower acylamino, sulfamido, lower alkylamino sulfonyl, di(lower alkylamino) sulfonyl, lower alkyl sulfonyl, aminocarbonyl, cyano and trifluoromethyl m is zero or an integer from 1 to 5 with the proviso that when X.sub.1 is a lower alkylene dioxy m is 1 or 2 (b) a bicyclic radical of the general formula ##STR5## in which (1) Z and A together form an ethylidene radical, B and D together form an ethylidene radical and p is 1 (2) Z is an imino radical-- NH-- , A and B together form an ethylidene radical, D is a methylene radical and p is zero, 1 or 2 (3) Z is a sulphur atom, A and B together form an ethylene or an ethylidene radical, D is a methylene radical and p is zero or an integer from 1 to 3 The invention also provides acid addition salts of the compounds of the general formula I Due to their basic character, mineral or organic acids may be added to the compounds of general formula I. Such acids are preferably therapeutically compatible mineral or organic acids and there are mentioned as example of preferred salts, those with hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, fumaric acid, methylsulphonic acid, isethionic acid, glucose-1 phosphoric acid and hydrochloric acid. Among the compounds of general formula I they are presently preferred the aryloxy lower alkyl piperidines of the general formula I'. ##STR6## in which R is a hydrogen atom or a lower alkyl radical, n is an integer from 2 to 4, R.sub.2 is a hydrogen atom or a lower alkyl radical, R.sub.3 is the acyl radical of an alkane carboxylic acid having up to 10 carbon atoms, R.sub.4 is a phenyl radical, and Ar is (a) a phenyl radical of the general formula ##STR7## in which X is a substituent selected from halogen atoms and lower alkyl, lower alkenyloxy, lower alkynyloxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, nitro, amino, lower alkyl amino, di (lower alkyl) amino, lower acylamino, sulfamido, lower alkylaminosulfonyl, (di lower alkyl amino) sulfonyl, lower alkylsulfonyl, amino carbonyl, cyano and trifluoromethyl radicals, and m is zero or an integer from 1 to 5, or (b) a homo -or heterobicyclic radical of general formula ##STR8## in which (i) Z and A together form an ethylidene radical, B and D together form an ethylidene radical and p is 1; or (ii) Z is an imino radical-- NH-- , A and B together form an ethylidene radical, D is a methylene radical and p is zero, 1 or 2; or (iii) Z is a sulphur atom, A and B together form an ethylene radical or an ethylidene radical, D is a methylene radical and p is zero or an integer from 1 to 3, and the acid addition salts thereof. The term "lower alkyl" is used herein to designate a hydrocarbyl group having from 1 to 6 carbon atoms in a straight or branched chain and which may be substituted by a hydroxyl, lower alkoxy or dilower alkyl amino group. Examples of such lower alkyl groups are methyl, ethyl, isopropyl, sec butyl, neo-pentyl, tert.butyl, n-hexyl, hydroxyethyl and diethylaminoethyl groups. The term "halogen" is used herein to designate preferably fluorine or chlorine atoms. It may be, also, bromine or iodine The term "lower alkenyl" is used herein to designate a hydrocarbyl group with one or more olefinic double bonds and having from 2 to 10 carbon atoms in a straight or branched chain. Examples of such alkenyl groups are allyl, methallyl, isopentenyl, dimethyl allyl, butenyl and triallyl methyl group. The term "lower alkynyl" is used herein to designate a hydrocarbyl group having a triple bond and having from 2 to 6 carbon atoms, for example, the ethynyl, propynl-yl, propyn-2-yl and methyl-1 but-2-ynyl groups. Preferred acyl radicals are especially those derived from lower alkanoic acids, for example acetic acid, butyric acid, isovalerianic acid, caproic acid, diethylamino acetic acid, pimelic acid, succinic acid, .beta.-ethoxy-acetic acid and (di n-propyl) acetic acid. The term "lower alkoxy" is used therein to designate a lower alkyloxy radical having from 1 to 6 carbon atoms and which may be substituted in the alkyl chain by a hydroxy, a, acyloxy or a dilower alkylamino radical. The term "lower alkylene dioxy" is intended to designate a methylene dioxy radical, an ethylene dioxy or a propylene dioxy radical. When X is substituted with at least a lower alkyl radical, the carbon atom which bears this substituent is asymmetric; such compounds of general formula I may be resolved into their stereoisomers and the compounds of the present invention can therefore be in racemic or optically-active forms. In addition, when R.sub.2 is a lower alkyl radical, a new center of symmetry is created and the diastereoisomers may be resolved. The amino side chain in the piperidine ring also produces an asymmetric carbon atom. The corresponding diastereoisomers may be separated by resolution by chemical or physical methods. The compounds of the present invention possess interesting pharmacological properties, especially anti-hypertensive properties. Their pharmacological properties are distinct from those of 4-aminopiperidines previously described in the literature (Brevets speciaux de Medicament N.degree. 2429 M, 2430 M and 2431 M) as having potent analgesic and neuroleptic properties. The compounds of the general formula I are devoid of any significant analgesic properties. The compounds of the present invention may therefore be used for therapeutic use in human or veterinary medicine, as drugs for treating hypertension without risk of noxious side-effects. Due to their interesting pharmacological properties the following compounds may particularly be cited: -N-( 2,6 dichlorophenoxy) ethyl 4-(N'-phenyl N' -propionylamino) piperidine -N-( 2,6-dimethyl phenoxyethyl) 4-(N'-phenyl N'-propionylamino) piperidine -N-( 2,6-dimethoxy phenoxyethyl) 4-(N'-phenyl N'propionylamino) piperidine -N-( 2,6-dimethyl phenoxypropyl) 4-(N'-phenyl N'propionylamino) piperidine -N-(.alpha. -naphtoxyethyl) 4-(N'-phenyl N'propionylamino) piperidine -N-[ 2-(2,6-dimethyl phenoxy) propyl]4-N'-phenyl N'-propionylamino) piperidine -N-( 2,6-dimethyl phenoxyethyl) 4-[N'phenyl N'(dipropyl acetylamino)] piperidine -N-( 2,6-dimethyl phenoxyethyl) 4-[N'(3,4-methylene dioxyphenyl) N'propionylamino] piperidine -cis dl N-(2,6 dimethyl phenoxyethyl) 3-methyl 4-(N'-phenyl N'-propionylamino) piperidine For therapeutic use, they can be administered in the form of pharmaceutical compositions including a compound of general formula I as active ingredient and one or more non-toxic inert pharmaceutical carriers suitable for oral, parenteral, sublingual or rectal administration. More specifically, the pharmaceutical compositions may be in the form of ampuls, phials, multidose flasks, autoinjectable syringes, tablets, coated tablets, capsules, powders, granules, syrups, sublingual tablets and suppositories. The useful posology will vary depending on the therapeutic use, the age and the weight of the patient and the seriousness of the illness. It may range from 1 to 250 mg per unit dosage and the administration may be repeated one to four times a day. The present invention also provides a process for producing compounds of general formula I which comprises reacting a 4-aminopiperidine of general formula III ##STR9## in which R.sub.2, R.sub.3 and R.sub.4 have meanings given above with an ester of an aryloxy alkanol of the general formula II ar-- O-- (X).sub.n -- Y (II) in which Ar-- , X, n have the same meanings given above, and Y is a halogen atom or the acyl residue of an alkylsulphonic acid or an arylsulphonic acid, to obtain a compound of general formula I which may, if desired, be salified by addition of a mineral or organic acid or resolved into its optical isomers or diastereoisomers. According to the present invention, the above-described condensation is preferably carried out in an inert solvent in the presence or absence of a basic agent. Preferably the solvent is a polar solvent, such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide or acetonitrile. The solvent may also be a halogenated solvent such as methylene chloride or dichloroethane, an aromatic hydrocarbon such as benzene or toluene, or a cycloalkane such as cyclohexane. Preferred esters are those which are derived from readily cleaved acids such as methanesulphonic acid, ethanesulphonic acid, benzenesulfonic acid or p-toluenesulphonic acid. Among the halides, chlorides and bromides are especially referred. When a bromide is used, it is especially suitable to carry out the condensation in the presence of an alkali metal iodide, in the presence of a dilower alkyl ketone such as acetone or methylisobutyl ketone. The basic agent may be a trilower alkylamine such as triethylamine, a dilower alkyl arylamine such as dimethylamino aniline or a pyridine base such as pyridine, collidine or lutidine. The basic agent may also be an excess of aminopiperidine of general formula III or the solvent when it is a disubstituted lower alkylamide or a phosphoramide. The present invention also provides a process for producing compounds of general formula I which comprises submitting a compound of general formula IV ##STR10## in which n, Ar, R.sub.2, R.sub.3 and R.sub.4 have the meanings given above, and X' is a radical selected from the group consisting of -- CH.sub.2 -- CHOH, -- CHOH-- CH.sub.2 --, -- CO-- CH.sub.2 -- and CH.sub.2 -- CO-- to the action of a reducing agent and recovering the desired compound of general formula I Preferably the reducing agent is hydrogen in the presence of a catalyst such as platinum or palladium. The reducing agent is hydrazine in the presence of potassium hydroxide when an oxo group is present in the alkylene chain. According to another aspect of the invention, there is provided a process for producing a compound of general formula I which comprises condensing compound of general formula II ar-- O-- (X).sub.n -- Y (II) in which Ar, X, Y and n have the above-given definitions with a 4-aminopyridine of the formula VI ##STR11## in which R.sub.2, R.sub.3 and R.sub.4 have the meanings give above, to produce a 4-amino pyridinium salt of the formula VII ##STR12## on which the substituents are defined as above specified and reducing the latter by catalytic hydrogenation or by means of mixed alkali metal hydride to an amino piperidine of formula I. The catalyst may be based on a metal of the platinium family such as platinum, palladium, iridium or rhodium. The mixed metal hydride may be an alkali metal borohydride or an alkali metal aluminohydride. A compound of general formula I may also be produced according to the invention by condensing an aryloxy radical of general formula VIII ar-- O-- (X).sub.n -- OH (VIII) in which Ar, X and n have the above-specified meanings with an aminopiperidine of general formula II ##STR13## in which R.sub.2, R.sub.3 and R.sub.4 have the meanings given above, in the presence of a hydrogenation catalyst to produce the desired compound of formula I. More specifically the hydrogenation catalyst is RANEY nickel and, preferably RANEY nickel WR. The compounds of general formula I may further be produced according to the invention by submitting an aryloxy alkylpiperidine of the formula V ##STR14## in which Ar, X, n, R.sub.2 and R.sub.4 are defined as above to the action of an acylating agent derived from an alkane carboxylic acid having up to 10 carbon atoms and recovering the desired compound of formula I. The acylating agent is preferably a halide of the alkane carboxylic acid or the alkane carboxylic acid in the presence of a dehydrating agent such as a dialkyl-or a dicycloalkyl carbodiimide. The compounds of general formula I may also be produced according to the invention by submitting an aminopiperidine of general formula II ##STR15## in which R.sub.2, R.sub.3 and R.sub.4 have the meanings given above to the action of an alkylene difunctional derivative of the formula IX y-- (x).sub.n -- OH (IX) in which R, n and Y have the meanings given above to obtain an (aminopiperidino) alkanol of the formula X ##STR16## treating the latter with an acylating agent derived from a hydrohalic acid, to produce a halide of the formula XI ##STR17## in which Hal is a halogen atom, and reacting the halide with a phenol of the formula XII ar-- OH (XII) in which Ar has the meaning given above to produce a compound of general formula I. Preferably the acylating agent derived from a hydrohalic acid is phosphorous tribromide, phosphorous sxychloride, a sulphuric or sulphonyl halide, such as thionyl chloride or sulphuryl chloride, an aryl sulphonyl halide such as benzene sulphonyl chloride or p-toluene-sulphonyl chloride or a metallic halide such as vanadium chloride. The optically-active reagent which may be used for resolving the compounds of formula I is preferably an optically-active organic acid such as an optically-active carboxylic acid, for example d-tartaric acid, 1-ketogulonic acid, 1-ascorbic acid, 1-menthyloxyacetic acid, abietic acid, d-N,N-diemthyl tartramic acid, an optically-active sulphonic acid for example d-camphosulphonic acid or an optically-active phosphoric acid such as d-glucose-1-phosphoric acid or d-glucose-1,6-diphosphoric acid. The starting materials of general formula III and the starting materials of general formula VIII may be obtained according to the processes described in U.S. Patent No. 3,131,218 and in J. Med. Chem. 6 (1963) 63. The starting materials of general formula II may be obtained according to known processes, for example that disclosed in German Patent No. 1,470,357. The following Examples illustrate the invention. The temperatures are expressed in degrees Centigrade.

  本发明涉及带有内环氮原子上的芳氧基烷基侧链的氨基哌啶及其酸加成盐。本发明还涉及制备这些化合物的方法。本发明中的化合物在心血管领域具有治疗功效，可用于制备药物组合物。先前的技术可以通过以下参考文献进行说明：法国药品专利号2429 M、2430 M、2431 M；比利时专利号615,350。本发明涉及新的4-氨基哌啶，尤其是N-芳基氧基4-苯基氨基哌啶。芳基和苯基核可能未经取代或经过一个或多个取代基取代。本发明还提供制备这些化合物的方法。具体而言，它们可以通过将芳氧基烷基卤化物与4-苯基氨基哌啶缩合而制得。本发明还涉及包括至少一种4-苯基氨基N-芳氧基烷基哌啶或其酸加成盐作为活性成分与惰性载体混合的药物组合物。本发明还涉及一种治疗高血压的方法。
• US4027028A
  申请人：——

  公开号：US4027028A

  公开（公告）日：1977-05-31
• Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice
  作者：Pradeep Kumar Gupta、Shiv Kumar Yadav、Yangchen Doma Bhutia、Poonam Singh、Pooja Rao、Niranjan Laxman Gujar、Kumaran Ganesan、Rahul Bhattacharya

  DOI：10.1007/s00044-012-0390-6

  日期：2013.8

  routes and all the analogs were found to be safer than fentanyl. Observational assessment on spontaneous activities of the central nervous system, peripheral nervous system, and autonomic nervous system revealed that all the analogs were similar to fentanyl. Further, the neurotoxic effects of all the analogs were reversed by naloxone hydrochloride (opioid antagonist), confirming that their effects were mediated

  芬太尼[ N-（1-苯乙基-4-哌啶基）丙酰苯胺]是一种流行的麻醉镇痛剂，在世界范围内都在临床上使用。然而，由于剂量过量和狭窄的治疗指数，芬太尼及其几种类似物已在人类中引起滥用和死亡。本研究报告了芬太尼及其四个类似物，即N-（1-丙基-4-哌啶基）丙酰苯胺（1），N-（1-（2-苯氧基乙基）-4-哌啶基）的合成和比较生物功效。丙酰苯胺（2），N-（1-（3-（苯氧丙基）-4-哌啶基）丙酰苯胺（3）和N-（1-（2-氰基乙基）-4-哌啶基）丙酰苯胺（4），其中芬太尼的苯乙基链被不同的官能团取代，即烷基，醚基和腈基。通过三种不同的途径确定化合物的中值致死剂量（LD 50），发现所有类似物比芬太尼更安全。通过对中枢神经系统，周围神经系统和自主神经系统自发活动的观察评估，发现所有类似物均与芬太尼相似。此外，所有类似物的神经毒性作用均被盐酸纳洛酮（阿片类药物拮抗剂）逆转，证实它们的作用是通过阿片样物