WO2005030722A1 - Derive d'amide de n-(4-piperidinyle) n-substitue - Google Patents

Derive d'amide de n-(4-piperidinyle) n-substitue Download PDF

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WO2005030722A1
WO2005030722A1 PCT/JP2004/014562 JP2004014562W WO2005030722A1 WO 2005030722 A1 WO2005030722 A1 WO 2005030722A1 JP 2004014562 W JP2004014562 W JP 2004014562W WO 2005030722 A1 WO2005030722 A1 WO 2005030722A1
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group
carbon atoms
alkyl
methyl
piperidine
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PCT/JP2004/014562
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English (en)
Japanese (ja)
Inventor
Toshihiro Takahashi
Tsuyoshi Endo
Syogo Sakuma
Nobutaka Mochiduki
Tomio Yamakawa
Kiichi Shika
Toru Kawasaki
Toshiyasu Imai
Kenji Hirate
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Nippon Chemiphar Co., Ltd.
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Priority to JP2005514305A priority Critical patent/JPWO2005030722A1/ja
Publication of WO2005030722A1 publication Critical patent/WO2005030722A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to an N-substituted mono-N- (4-piperidyl) amide derivative or a salt thereof, and an analgesic containing the same as an active ingredient.
  • Patent Document 1 Japanese Patent Application Laid-Open No. Sho 53-149980 (hereinafter referred to as Patent Document 2), Japanese Patent Application Laid-Open No. 2-292922 (hereinafter referred to as Patent Document 3).
  • Patent Document 2 Japanese Patent Application Laid-Open No. Sho 53-149980
  • Patent Document 3 Japanese Patent Application Laid-Open No. 2-292922
  • Patent Document 4 Japanese Patent Application Laid-Open No. 2-300167 (hereinafter referred to as Patent Document 4) or Zhongguo Yaoke Daxue Xu ebao 1993, 24, p2 57-263 (hereinafter referred to as Non-Patent Document 4). Many compounds have been reported, and they are known to have analgesic and anesthetic effects.
  • Patent Document 1 describes the following equation (A)
  • Patent Document 4 describes the following equation (B)
  • N-substituted-N- (4-piberidyl) amide derivative represented by the following formula is described as a drug having analgesic activity.
  • Non-Patent Document 1 describes the following equation (C),
  • Funtanyl a representative compound of N-substituted mono-N- (4-piperidinyl) amide derivatives, has been clinically used as an anesthetic aid and analgesic.
  • the analgesic action of these N-substituted-N- (4-piperidinyl) amide derivatives is considered to be a monoreceptor agonist which is thought to be due to an agonist action on the mu-receptor, one of the opioid receptors.
  • morphine is well known in addition to ⁇ -substituted 1- (4-piperidinyl) amide derivatives such as fentanyl.
  • these drugs have side effects such as dependence, bradycardia, respiratory depression, and gastrointestinal motility suppression, and there is a need to provide new analgesics with reduced side effects. .
  • the 1-substituted 1- (4-piperidinyl) amide derivative of the compound of the present invention has a structure in which the 1-position of piperidine is substituted with an alkyl group, and the terminal carbon atom of the alkyl group has a phenyl group and a carbamoyl group. Are combined.
  • the terminal carbon atom is substituted only with a fuel group in the above formula ( ⁇ ), and is substituted only with a methoxycarbonyl group in the formula ( ⁇ ).
  • the above formula ( In C) the terminal carbon atom is substituted by a phenyl group and a carboxyl group (or an ethoxycarbonyl group), and therefore, the compound of the present invention and these compounds are structurally distinct from each other.
  • the portion corresponding to NR 5 R 6 (amine) of the compound of the present invention is an amino acid residue. Disclosure of the invention
  • An object of the present invention is to provide a novel N-substituted mono-N- (4-piberidur) amide derivative having an analgesic action or a salt thereof. That is, the present invention relates to a compound represented by the following general formula (I) or a salt thereof.
  • R 1 is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having a 3 to 7 membered ring, an alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, or Or a 6-membered heterocyclic group,
  • R is a substituent or a group or atom selected from a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom.
  • R 3 represents a hydrogen atom, a fuel group, an alkoxycarbonyl group having 2 to 8 carbon atoms, or a methyl group which is tt-substituted by an alkoxy group having 1 to 6 carbon atoms,
  • R 4 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, nitro Represents a group which may have 1 to 3 groups or atoms selected from a group, a cyano group, or an amino group,
  • R 5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group (the alkyl portion has 1 to 6 carbon atoms, and the aryl group has 6 to 10 carbon atoms),
  • R 6 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a fluor group, a 5- or 6-membered heterocyclic group, an aralkyl group (the alkyl portion has 1 to 6 carbon atoms, and the aryl portion has 6 to 10) or a heterocyclic alkyl group (the alkyl portion has 1 to 6 carbon atoms, and the heterocyclic ring is a 5- or 6-membered ring, which may be condensed with a benzene ring.).
  • the C1 to C6 anoalkyl group is a halogen atom, a 3- to 7-membered cycloalkyl group, a C1 to C6 anorecoxy group, an amino group, an alkylamino group (the alkyl moiety has 1 to 6 carbon atoms).
  • dialkylamino group (each alkyl moiety has 1 to 6 carbon atoms), 2 to 6 carbon atoms asinoleamino group, rubamoyl group, alkyl rubamoyl group (alkyl moiety has 1 to 6 carbon atoms), dialkyl It may have 1 to 5 groups or atoms as substituents selected from carbamoyl (each alkyl portion has 1 to 6 carbon atoms), a hydroxyl group, a nitro group, or a cyano group.
  • the phenyl group, the heterocyclic group, the aryl part of the aralkyl group and the heterocyclic part of the heterocyclic alkyl include a halogen atom, Alkyl group with 1 to 6 carbon atoms, alkoxy group with 1 to 6 carbon atoms, alkyl group with 1 to 6 carbon atoms substituted with halogen atom, amino group, alkyl amino group (alkyl group with 1 to 6 carbon atoms) , Dialkylamino group (each alkyl moiety has 1 to 6 carbon atoms), C2 to C6 acylamino group, carbamoyl group, alkarylcarbamoyl group (ananolecyl moiety has 1 to 6 carbon atoms), dialkylcarbamoyl (Each alkyl moiety has 1 to 6 carbon atoms), and has 1 to 5 groups or
  • R 6 are the heterocyclic (ring members for 5-7 membered ring together with the nitrogen atom to which R 5 and R 5 and R 6 are attached, further in addition to the nitrogen atom to which R 5 and R 6 are attached
  • the heterocyclic ring may be an alkyl group having 1 to 6 carbon atoms or an aralkyl group (the alkyl portion may have 1 to 6 carbon atoms).
  • the aryl portion may have 6 to 10 carbon atoms or may be substituted with an acyl group having 2 to 6 carbon atoms. ) May be formed,
  • R 7 represents a hydrogen atom or a methyl group
  • the present invention also relates to an analgesic containing the compound represented by the general formula (I) or a salt thereof as an active ingredient.
  • R 1 is an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or a pentyl group.
  • a 3- to 7-membered cycloalkyl group preferably a cyclopropyl group
  • a cyclopropyl group such as a cyclopropyl group, a cyclopentyl group, or a cyclohexyl group, a methoxy group, an ethoxy group.
  • butyl group, i-butyl group, t-butyl group, or alkyl group having 1 to 6 carbon atoms such as A tyl group or a methoxymethyl group, preferably a methoxymethyl group) or a 5- or 6-membered heterocyclic group such as a furyl group, a thiazolyl group or a chel group (preferably a furyl group or A phenyl group.
  • R 2 is a 5- or 6-membered heterocyclic group such as a phenyl group, a pyridyl group, a pyrazyl group, a pyrimidyl group, or a pyrazole group which may have 1 to 3 substituents;
  • a pyridyl group or a pyrazyl group Preferably, a pyridyl group or a pyrazyl group.
  • Examples of preferred substituents for the phenyl group and the heterocyclic group include halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an i-peptizole.
  • Group, t-butyl group, or pentyl group Alkoxy groups having 1 to 6 carbon atoms, such as alkyl groups, methoxy groups, ethoxy groups, propyloxy groups, isopropyloxy groups, butyloxy groups, i-l-butyloxy groups, t-l-butyloxy groups, and pentyloxy groups.
  • R 3 represents a hydrogen atom, a phenyl group, a methoxycarbol group or an ethoxycarbol group, or a C2 to C8 ethoxy group, or a methoxy, ethoxy, propyloxy, or isopropyloxy group; And a methynole group (such as a methoxymethyl group) substituted with an alkoxy group having 1 to 6 carbon atoms such as butyloxy, butyloxy, i-butyloxy, t_butyloxy, or pentyloxy. Represents a methoxycarbonyl group or a methoxymethyl group.
  • R 4 is a fuel group which may have 1 to 3 substituents.
  • Examples of such a substituent include a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or a pentyl group C1-6 such as alkyl, methoxy, ethoxy, propynoleoxy, isopropyloxy, butyloxy, i-butyloxy, t-butyloxy, or pentyloxy groups having 1 to 6 carbon atoms
  • C 1 -C 6 anolequinole group such as butyl group or pentyl group (triphneoleolomethinole group, chloromethinole group, 2-chloro Butyl group, 2-Buromoechiru group, or a 2-Furuoroechiru group), a nitro group, shea Anomoto, or include an amino group.
  • R 5 is a hydrogen atom, a methyl group, Echiru group, a propyl group, an isopropyl group, butyl - group, i- heptyl group, t one-heptyl group, or an Al killed or benzyl group having 1 to 6 carbon atoms such as pentyl (The alkyl portion has 1 to 6 carbon atoms and the aryl portion has 6 to 10 carbon atoms), more preferably a hydrogen atom, a methyl group or an ethyl group.
  • R 6 is a hydrogen atom, or a methyl group, an ethyl group, a propyl group, an isopropyl group, an butyl group, an i-butyl group, a t-butyl group, a benzyl group, which may have 1 to 5 substituents; 5- or 6-membered heterocyclic groups such as alkyl groups having 1 to 6 carbon atoms such as hexyl group, phenyl group, furyl group, chel group, pyrrolinole group, pyridyl group or tetrahydropyrael, and benzyl group Aralkyl groups such as phenethyl group, 3-phenylpropyl group or 2-naphthylethyl group (the alkyl moiety has 1 to 6 carbon atoms, and the aryl moiety has 6 to 10 carbon atoms), or 2- (2- Pyridyl) ethyl group, (3-Chenyl)
  • examples of the substituent which may be possessed by the ⁇ / alkyl group having 1 to 6 carbon atoms include halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom, and 3 to 7 atoms such as a cyclopropyl group.
  • cycloalkynole methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, i-butyloxy, t-butyloxy C1 to C6 alkoxy groups such as a pentyloxy group, an amino group, an alkylamino group such as a methylamino group (the alkyl moiety has 1 to 6 carbon atoms), a dialkylamino group such as a dimethylamino group (each alkyl The moiety has 1 to 6 carbon atoms, such as an acetylamino group, an alkyl canolebamoyl group having 2 to 6 carbon atoms such as an acylamino group, a carbamoyl group, and an N-methylcarbamoyl group (the carbon number of the alkyl moiety is 1 to 6).
  • N, N-dimethylcarbamoyl group and the like a dialkyl group such as a rubamoyl group (each alkyl portion has 1 to 6 carbon atoms), a hydroxyl group, a nitro group, or a cyano group.
  • a dialkyl group such as a rubamoyl group (each alkyl portion has 1 to 6 carbon atoms), a hydroxyl group, a nitro group, or a cyano group.
  • it has a fuel group, a heterocyclic group, an aryl moiety of an aralkyl group and a heterocyclic moiety of a heterocyclic alkyl (including a benzene ring when the heterocycle is condensed with a benzene ring).
  • substituents which may be substituted include a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, a methynole group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group or a pentyl group C1-C6 alkyl, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, i-butynoleoxy, t-butyloxy, and pentoxy groups, etc.
  • a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom
  • methynole group such as a fluorine atom, a chlorine atom or a bromine atom
  • methynole group such as a fluorine atom, a chlorine atom or
  • alkoxy groups 1 to 3 fluorine atoms, methyl groups, ethyl groups, C1 to C6 phenols such as phenyl, isopropyl, petit / le, i-butyl, t-butyl, or pentyl (trifluoromethyl, chloromethyl, 2-chloro) Alkyl group such as ethyl group, 2-bromoethyl group or 2-fluoroethyl group), amino group, methylamino group (the alkyl moiety has 1 to 6 carbon atoms), dimethylamino group, etc.
  • the number is from 1 to 6>, an alkylamino group such as an acetylamino group having 2 to 6 carbon atoms, an alkylamino group such as N-methylcarbamoyl, an N-methylcarbamoyl group, and an N-methylcarbamoyl group.
  • Dialkyl carbamoyl groups such as dimethylcarbamoyl group (each alkyl moiety has 1 to 6 carbon atoms), hydroxyl group, hydroxymethyl group, nitro group, Shiano group Kyona are.
  • the R 6 is, R.
  • R 5 and piperidine with the nitrogen atom to which R 6 is attached It may form a 5- to 7-membered complex ring such as a ring, morpholine ring, thiomoleforin ring or piperazine ring.
  • the heterocyclic ring may be an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl / le group, a pentyl group, or a benzyl group.
  • Alkyl moiety has 1 to 6 carbon atoms
  • aryl moiety has 6 to 10 carbon atoms
  • R 7 is a hydrogen atom or a methyl / le group.
  • n 1 or 2, and preferably 1.
  • R 3 is a methyl group substituted with an alkoxy group having 2 to 8 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. Or a salt thereof.
  • the compound of the present invention is a compound represented by the above general formula (I) wherein R 7 is a methyl group and R 3 is a hydrogen atom or an alkoxycarbonyl group having 2 to 8 carbon atoms. Its salts are preferred.
  • R 2 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a carbon atom substituted with a halogen atom as a substituent.
  • R 2 is a halogen atom as a substituent, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon, or have been 1 to carbon atoms substituted by a halogen atom
  • the heterocyclic group of R 2 is a group selected from a pyridyl group, a virazinyl group, a pyrimidyl group, and a pyrazole group, and the substituent of the heterocyclic ring is a halogen atom,
  • the above is a group or atom selected from 1 to 6 alkyl groups
  • the compound represented by the general formula (I), the compound represented by the above (1) or (2) or a salt thereof is preferable.
  • R 6 is an aralkyl group (the alkyl moiety has 1 to 6 carbon atoms, and the aryl moiety
  • alkyl moiety has 1 to 6 carbon atoms, and the aryl moiety
  • the compound represented by any of (5) or a salt thereof is preferred.
  • the T-reel part of the aralkyl group and the heterocyclic part of the heterocyclic alkyl are a halogen atom, an alkynole having 1 to 6 carbon atoms.
  • an alkoxy group having 1 to 6 carbon atoms an alkyl group having 1 to 6 carbon atoms replaced by a halogen atom, an amino group, an alkylamino group (the alkyl portion has 1 to 6 carbon atoms), a dialkylamino group ( Each alkyl moiety has 1 to 6 carbon atoms), C2 to C6 asinoleamino, rubamoyl, alkyl rubamoyl
  • Alkyl moiety has 1 to 6 carbon atoms
  • dialkyl rubamoyl each alkyl moiety has 1 to 6 carbon atoms
  • hydroxy group hydroxymethyl group
  • nitro group or cyano group It may have 1 to 5 groups.
  • the compound of the present invention is preferably a compound represented by the above general formula (I) wherein m is 1, a compound represented by any of the above (1) to (6), or a salt thereof.
  • the compounds of the present invention represented by the above general formula (I) may have diastereomers, optical isomers, and the like. These isomers are also included in the present invention.
  • the compound of the present invention also includes pharmaceutically acceptable salts such as salts with inorganic acids such as hydrochloric acid or sulfuric acid, and salts with organic acids such as oxalic acid, citric acid or tartaric acid.
  • pharmaceutically acceptable salts such as salts with inorganic acids such as hydrochloric acid or sulfuric acid
  • organic acids such as oxalic acid, citric acid or tartaric acid.
  • R 8 represents a benzyl group or an alkyl group having 1 to 6 carbon atoms (branchable), and Z is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group, or a tosyloxy group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and m are the same as above.
  • the starting material (a) is prepared by a known method (PGH V an D ae 1 eeta 1., Arzneu m. I Forschh.
  • the starting material (a) is reacted with the ⁇ -unsaturated ester (b) in a solvent that does not participate in the reaction such as aceto-tolyl at room temperature to 80 ° C. by the Michae 1 reaction.
  • a solvent that does not participate in the reaction such as aceto-tolyl at room temperature to 80 ° C. by the Michae 1 reaction.
  • the starting material (d) In a solvent that does not participate in the reaction of aceto-tolyl, 4-methyl-2-pentanone, N, N-dimethylformamide, etc., in the presence of a base such as sodium carbonate, carbonated carbonate or triethylamine, the starting material (
  • the reaction temperature is between room temperature and 150 ° C.
  • Z is a chlorine atom or a bromine atom in the compound represented by the general formula (c)
  • Deprotection (_R 8 ) is performed by catalytic reduction using a catalyst such as palladium-carbon in a solvent such as methanol or ethanol when R 8 is a benzyl group, and when R 8 is a t-butyl group. Is carried out by an acid treatment with trifluoroacetic acid or the like.
  • R 8 is an alkyl group having 1 to 6 carbon atoms other than a t-butyl group
  • dimethyl hydroxide is used in a mixed solvent of water and an organic solvent miscible with water, such as methanol, ethanol, and tetrahydrofuran.
  • Deprotection (1 R 8 ) is carried out by the action of a strong base such as sodium hydroxide, potassium hydroxide or the like.
  • the reaction temperature in this case is 0 to 60 ° C.
  • the deprotection (one R 8) may be applied conventional acid hydrolysis with hydrochloric acid or the like.
  • the reaction temperature in this case is 20 to 120 ° C. 4)
  • Third step
  • the condensation reaction between the compound of formula (e) and the amine (f) can be carried out in a solvent that does not participate in the reaction such as dichloromethane, N, N-dimethylformamide, etc. in a solvent such as 1-hydroxybenzotriazole or N-hydroxysuccinyl.
  • the reaction temperature is between 0 and 60 ° C.
  • compound (d) which is an intermediate raw material of the compound of the present invention, can also be produced by the following method B.
  • the starting material (h) is a known method (Z—X. Wangeta 1, J. Med. Chem., 1995, 38, 3652, etc.) and the like. It can be synthesized by a method.
  • the compound of general formula (i) can be synthesized by reacting the starting material (h) with the compound represented by general formula (b) or (c) in the same manner as in the first step of the above-mentioned method A. .
  • the acylation reaction of the general formula (i) is carried out by the general formula (j) in the presence of a base such as triethylamine or N-methylmorpholine in a solvent which does not participate in the reaction such as dichloromethane, chloroform and toluene. It is carried out by reacting the acid chloride represented. The reaction temperature ranges from room temperature to the reflux temperature of the solvent.
  • the acylation reaction of the general formula (i) is carried out using an acid anhydride represented by the general formula (k) in the presence or absence of a solvent that does not participate in the reaction, such as toluene. It can be performed at a temperature of ⁇ 150 ° C. Representative examples of the thus-obtained compounds of the present invention are shown below. Representative compounds of the present invention
  • R 2 phenyl group (substituent is Y)
  • R 3 methoxycarboyl group
  • R 4 phenol group (substituent is W)
  • R 2 is a fuunyl group (substituent is Y)
  • R 3 is a methoxycarbonyl group
  • R 4 is a phenyl group
  • R 7 is ⁇ .
  • R 2 a phenyl group (substituent is Y)
  • R 4 a phenyl group
  • R 6 (CH 2 ) n—R 9
  • a compound of the present invention represented by the following formula.
  • peripheral and central (systemic) ⁇ -obideoid receptor antagonists were evaluated for the analgesic effect of the diacid writhing test, and the results described in Examples 1, 11, 31, 31 and 46 below were obtained.
  • the analgesic effect of the compound of the present invention was found to be peripheral. (Table 16)
  • the compound of the present invention represented by the above general formula (I) has an excellent analgesic action and is therefore useful as an analgesic.
  • drugs that selectively act on peripheral w-receptors are expected to be analgesics without side effects (dependence, etc.) based on central action.
  • the compound of the present invention can be administered to humans orally or parenterally.
  • composition it can be manufactured in the form of tablets, capsules, powders, injections, suppositories, or transdermals in the technical field of formulation.
  • the dose of the compound of the present invention is about 0.0 lmg to 100 mg per day in the case of an oral preparation, and about 0.001 mg to 100 mg in the case of injection (j in the case of j). However, it can be increased or decreased depending on age, symptoms, etc.
  • the title compound was obtained as a diastereomer mixture in the same manner as in Reference Example 1 (2) using cis-3-methyl-41- (phenylamino) piperidine and 2-phenyl benzyl penate.
  • Ci S obtained above 3-[3-Methyl-41- (phenylamino) piperidine-1-inole] — Benzyl 2-phenylpropionate (1.16 g, 2.71 mm o 1)
  • Propionyl chloride (0.30 mL, 3.44 mmol) was added dropwise to a solution of triethylamine (0.53 mL) in dichloromethane (12 mL) under ice-cooling. After stirring at room temperature for 6 days, an aqueous layer of sodium bicarbonate was added to the reaction mixture to separate the organic layer, which was washed with saturated saline and dried over anhydrous sodium sulfate.
  • the title compound was obtained as a diastereomer mixture in the same manner as in Reference Example 1 (2) using trans--3-methyl-41- (phenylamino) piperidine and 2-benzylpropenoate benzyl.
  • the title compound was obtained in the same manner as in Reference Example 8 (4) using 4-amino-1,1-benzinolepiperidine-141-methyl methyl canoleponate and octamorphine virazine.
  • Example 1 [4-Methoxycarbol-41 (phenylpropionylamino) piperidin-11-yl] Using 2-phenylpropionic acid and 28% aqueous ammonia, Example 1 (1) The title compound was obtained in the same manner.
  • Example 1 (2) Using 1- (2-methylcarbamoyl-2-phenylethyl) -4- (phenylpropionylamino) piperidine obtained in the above manner, the same procedure as in Example 1 (2) was carried out using methyl 4-butyrate and oxalic acid. The title compound was obtained as a white powder.
  • Example 1 (1) using 3- (4-methoxyphenyl) -4- (phenylpropionylamino) piperidin-11-yl-2-phenylpropionic acid and N-ethylmethylamine. ) To give the title compound.
  • Example 1 Using 1- [2- (ethylmethylcarbamoyl) -12-phenylethyl] -14- (phenylpropio-lamino) piperidine obtained from the above, there was obtained Example 1 ( The title compound was obtained as white crystals in the same manner as in 2). Mp: 173-176 ° C
  • Example 1 Using the obtained 11- [2- (benzylmethylcarbamoyl) -12-phenyl-2-ene] —41- (pheninolepropio-luamino) piperidine-14-methyl ribonate and oxalic acid The title compound was obtained as white crystals in the same manner as in 1 (2).
  • Example 1 (1) using 4-phenylpropionic acid and phenethylamine, and using 4-methoxyphenylepionate 4- (phen- / repropioni / reamino) piperidine-1 // The title compound was obtained in the same manner.
  • the title compound was converted to white crystals in the same manner as in Example 1 (2) using propionic acid amide and oxalic acid. I got it.
  • Example 1 (1) using 4- [4-methoxycarbonyl-2-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and ⁇ ⁇ ⁇ -methyl-3-phenylpropylamine ) To give the title compound.
  • Example 3 [4-Methoxycarbinyl 4- (phenylpropionylamino) piperidine-11-yl]
  • Example 1 using 2-phenylpropionic acid and morpholine
  • Example 1 3- [4-Methoxycarbonyl 4- (phenylpropionylamino) piperidin-11-yl] -12-Phenylpropionic acid and D-darcosamine hydrochloride were used as in Example 1 (1). Similarly, the title compound was obtained as a white powder.
  • IR (cm— 1 , KBr): 3350, 2950, 1720, 1680, 1660, 1550, 1550, 1450, 1 3 8 0, 1 2 6 0, 1 2 4 0, 1 2 2 0, 1 1 5 0, 6 9 0.
  • IR (cm— 1 , KBr): 3400, 1740, 1720, 1680, 1660, 1640, 1540, 1490, 1 4 5 0, 1 3 8 0, 1 2 3 0, 1 2 0 0, 7 0 0.
  • Diastereomer A and diastereomer B of enylpropionic acid amide were each converted to oxalate in the same manner as in Example 1 (2) to give the title compounds, respectively, as white powders.
  • Diastereomer A (crystallized from ethyl acetate)
  • Diastereomer B (crystallized from mother liquor after precipitation of diastereomer A)
  • Example 3 8 1-C 2-"2-(4-hydroxy 1 H-indone 1-3-yl) ethyl canole Bamoinole] 1-2-feninole ethinole] 1-4 1 (Feninole propio-lamino) pyridine (4) Methyl rubonate oxalate
  • the binding experiment to the ⁇ -Opioid receptor was performed using a membrane sample (RECEPT) of the human ⁇ opioid receptor (GenBank Accession NO. L2511) expressed in CHO-K1 cells by gene transfer. OR BIOL OGY IN C.). [ 3 H] DAMG O was used as the radioligand.
  • the binding ratio in the presence of each concentration of the test substance to the specific binding of [ 3 H] DAMGO was calculated, and the IC 5 was determined by GraphPad Prism. The value was determined.
  • mice ICR male mice were used as 8 to 10 mice per group. Thirty minutes after the subcutaneous administration of the test substance, a 0.6% aqueous acetic acid solution (0.1 mLZlOg body weight) was intraperitoneally administered. Thereafter, the number of risings occurring in 20 minutes was counted. ED 5 based on the suppression rate for the number of expression in the control group. The value was calculated.
  • ICR male mice were used as 8 to 10 mice per group.
  • the test substance was administered subcutaneously.
  • Twenty minutes later, a 0.6% acetic acid aqueous solution was intraperitoneally administered (0.1 mL / l Og body weight), and the number of writhing developed in the following 20 minutes was counted. Rising inhibition rate and NARO in test substance alone group
  • the inhibition rates of the groups treated with dexamethasone or naloxone hydrochloride were compared.
  • Example numbers indicate the compounds obtained in the above-mentioned synthesis examples, and oxalate was used in all cases except for Example 23 (Tables 15 and 16 are the same).
  • the analgesic effect of oral peramide used as another comparative drug was almost completely antagonized by the peripheral antagonist. From the above results, it was confirmed that the analgesic effect of fentanyl was not attributable to peripheral / X-obioid receptors but was to be expressed via central ⁇ -obioid receptors. In addition, it was confirmed that the analgesic effect of oral peramide was expressed via a peripheral ⁇ -year-old poid receptor.

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Abstract

La présente invention concerne un composé représenté par la formule générale (I) représentée ci-dessous, ou un sel de celui-ci. L'invention concerne aussi un analgésique contenant un composé de ce type ou un sel de celui-ci, en tant que principe actif. Dans la formule (I): R1 représente un groupe alkyle comprenant de 1 à 6 atomes de carbone ou analogue; R2 représente un groupe phényle ou analogue; R3 représente un atome d'hydrogène, un groupe alcoxycarbonyle comprenant de 2 à 8 atomes de carbone, un groupe méthyle substitué par un groupe alcoxy comprenant de 1 à 6 atomes de carbone ou analogue; R4 représente un groupe phényle qui peut comprendre un substituant; R5 représente un atome d'hydrogène, un groupe alkyle comprenant de 1 à 6 atomes de carbone ou un groupe aralkyle; R6 représente un atome d'hydrogène, un groupe alkyle comprenant de 1 à 6 atomes de carbone, qui peut comprendre un substituant, un groupe phényle, un groupe hétérocyclique à 5 ou 6 éléments, un groupe aralkyle, un groupe alkyle hétérocyclique ou analogue; R7 représente un atome d'hydrogène ou un groupe méthyle; m vaut 1 ou 2.
PCT/JP2004/014562 2003-09-29 2004-09-28 Derive d'amide de n-(4-piperidinyle) n-substitue WO2005030722A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030931A1 (fr) * 2004-09-14 2006-03-23 Nippon Chemiphar Co., Ltd. Derive d’amide n-(4-piperidinyl) n-substitue
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10766925B2 (en) * 2016-04-11 2020-09-08 Arizona Board Of Regents On Behalf Of The University Of Arizona Opioid receptor modulators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60248670A (ja) * 1984-04-09 1985-12-09 ビ−オ−シ−　インコ−ポレ−テツド Ｎ−アリ−ル−ｎ−（４−ピペリジニル）アミドならびにかかる化合物を用いる薬剤組成物および方法
JPH02300167A (ja) * 1989-02-15 1990-12-12 Glaxo Inc 鎮痛剤として用いられるｎ―フエニル―ｎ―（４―ピペリジニル）アミド
WO2003082819A1 (fr) * 2002-04-01 2003-10-09 Nippon Chemiphar Co.,Ltd. Derive de n-phenyl-n-(4-piperidinyl)amide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60248670A (ja) * 1984-04-09 1985-12-09 ビ−オ−シ−　インコ−ポレ−テツド Ｎ−アリ−ル−ｎ−（４−ピペリジニル）アミドならびにかかる化合物を用いる薬剤組成物および方法
JPH02300167A (ja) * 1989-02-15 1990-12-12 Glaxo Inc 鎮痛剤として用いられるｎ―フエニル―ｎ―（４―ピペリジニル）アミド
WO2003082819A1 (fr) * 2002-04-01 2003-10-09 Nippon Chemiphar Co.,Ltd. Derive de n-phenyl-n-(4-piperidinyl)amide

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030931A1 (fr) * 2004-09-14 2006-03-23 Nippon Chemiphar Co., Ltd. Derive d’amide n-(4-piperidinyl) n-substitue
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
US11498896B2 (en) 2014-12-19 2022-11-15 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10766925B2 (en) * 2016-04-11 2020-09-08 Arizona Board Of Regents On Behalf Of The University Of Arizona Opioid receptor modulators

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