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WO2005030721A1 - Derive de piperidine - Google Patents

Derive de piperidine Download PDF

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Publication number
WO2005030721A1
WO2005030721A1 PCT/JP2004/014563 JP2004014563W WO2005030721A1 WO 2005030721 A1 WO2005030721 A1 WO 2005030721A1 JP 2004014563 W JP2004014563 W JP 2004014563W WO 2005030721 A1 WO2005030721 A1 WO 2005030721A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
group
alkyl group
salt
piperidine derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2004/014563
Other languages
English (en)
Japanese (ja)
Inventor
Tomio Yamakawa
Shinichi Yoshida
Kaoru Hara
Heinojo Yamasaka
Kazushiro Yamaguchi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Chemiphar Co Ltd
Original Assignee
Nippon Chemiphar Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Chemiphar Co Ltd filed Critical Nippon Chemiphar Co Ltd
Publication of WO2005030721A1 publication Critical patent/WO2005030721A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D211/54—Sulfur atoms
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to piperidine derivatives having an antioxidant effect.
  • antioxidants represented by natural phenols such as tocopherols, flavonoids, and gallic acids, and heptylhydroxytoluene (BHT).
  • Amines also have an antioxidant effect, and various amino acids, p-phenylenediamine and the like are known to have an antioxidant effect.
  • these compounds having an antioxidant effect are used not only as additives for a drug substance containing a drug substance that is easily oxidized, but also for diseases related to oxidative stress, for example, dementia, inflammation, ischemic disease, carcinogenesis. It is considered as a potential therapeutic or prophylactic drug.
  • Patent Document 2 is antioxidant Based on the finding that BHT or BHA having antimicrobial activity has an antiviral effect, bis (dialkylphenol) mercaptonore (or mercaptal) is provided as an antiviral agent. 5-g-t-ptyl-4-hydroxyphene-mercaptol has an antiviral effect but has strong cytotoxicity and is mentioned as an unfavorable example. Note that Patent Document 2 does not disclose specific data indicating that this compound has an antioxidant effect.
  • Patent Document 3 A patent application has been filed with respect to 4-buty-noray 4-hydroxydreno-1,4-hydroxy-1, trans-1,6-dimethylbiperidine (WO 03/997788, hereinafter referred to as Patent Document 3).
  • Patent Document 3 The compound described in Patent Literature 3 has 3,5-di-t-peti / le4-hydroxyhydrinolethio and a hydroxyl group at the 4-position of piperidine, but the compound of the present invention has a 3,5-diene It has two t-butyryl 4-hydroxy phenols. Disclosure of the invention
  • An object of the present invention is to provide a piperidine derivative having phenols and amines in the same molecule and having an antioxidant action.
  • aralkyl group having 1 to 8 carbon atoms an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an aralkyl group (the carbon number of the aryl group is 6 to 1 0 represents an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms;
  • R 2 is a hydrogen atom, an aralkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an aralkyl group (the aryl group has 6 to 10 carbon atoms; The alkyl moiety has 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, or an alkyl group having 2 to 8 carbon atoms.
  • R 3 ⁇ Pi 1 4 are the same or different and may be alkyl groups having 1 to 8 carbon atoms, a 3 to 8-membered cycloalkyl group, 1 of 3 halogen atoms carbon atoms is substituted with 1-8 Alkyl group, alkyl group having 1 to 8 carbon atoms, aralkyl group substituted with alkoxy group having 1 to 8 carbon atoms (aryl moiety has 6 to 10 carbon atoms, and alkyl moiety has 1 to 4 carbon atoms) Or an aryl group having 6 to 10 carbon atoms. )
  • the present invention also relates to an antioxidant containing the piperidine derivative represented by the above general formula (I) or a salt thereof as an active ingredient.
  • the alkyl group having a carbon number 1-8 of to R 4 Mechinore group, Echiru group, propyl group, i - propyl group, heptyl group, i one heptyl Group, t-butyl group, pentyl group or hexyl group.
  • alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R 1 to R 4 include methyl substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom.
  • methyl substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom.
  • Ararukiru group to R 4 (the number of carbon atoms of Arinore portion is 6-1 0, the number of carbon atoms in the alkyl moiety content is 1-4) as the benzyl group or the like is phenethyl group.
  • Examples of the aryl group having 6 to 10 carbon atoms of R 4 to R 4 include a phenyl group and a naphthyl group.
  • Examples of the anorecoxy group / reponyl group having 2 to 8 carbon atoms for R 2 include a methoxy group / repoxy group or an ethoxycarbyl group.
  • Examples of the alkylcarbon group having 2 to 8 carbon atoms for R 2 include an acetyl group and a propionyl group.
  • Examples of the 3- to 8-membered cyclic alkyl group of R 3 and R 4 include a cyclic pentyl group and a cyclic hexyl group.
  • Examples of the C 1-8 alkyl group substituted with a C 1-8 alkyl group of R 3 and R 4 include a methoxy group, an ethoxy group, a propyloxy group, an i-propyloxy group and a butyloxy group.
  • the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein is a C 1-8 alkyl group represented by the above general formula (I) Piperidine derivatives or salts thereof are preferred.
  • the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein is a C 1 to C 3 alkyl group represented by the above general formula (I) Piperidine derivatives or salts thereof are preferred.
  • the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein R 3 and R 4 are an alkyl group having 1 to 8 carbon atoms.
  • the piperidine derivative represented by I), the piperidine derivative according to the above (1) or (2), or a salt thereof is preferable.
  • the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), wherein R 3 and R 4 are both t-butyl groups.
  • the piperidine derivative of the present invention is a piperidine derivative represented by the above general formula (I), and represented by the above general formula (I) wherein R 2 is a hydrogen atom.
  • the piperidine derivative, or the piperidine derivative according to any one of the above (1) to (4), or a salt thereof is preferred.
  • the salt of the piperidine derivative represented by the above general formula (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic acid such as hydrochloric acid or sulfuric acid, or a salt of citric acid or tartaric acid. And salts with organic acids.
  • the 2- and 6-positions of the piperidine ring have a trans configuration.
  • a method for synthesizing the piperidine derivative represented by the above general formula (I) will be described. For example, trans-1,6-dimethyl-4,4-bis-[(3,5-di-t-butyl-4-hi) [Droxy) phenylsulfael] piperidine can be obtained by the following synthetic scheme.
  • 2,6-dimethyl-4-oxopiperidine-13,5-dicarboxylic acid ester was obtained from 1,3-diacetone carboxylate, acetoaldehyde and ammonia, and then hydrolyzed and decarboxylated to obtain 2,2-dimethyl-4-oxopiperidine.
  • this is combined with 2,6-zyt-butynol 4-mercaptophenol in an organic solvent such as porcine orifice, and boron trifluoride dimethyl ether.
  • an acid catalyst such as a complex
  • a mixture of a trans form and a cis form is obtained. Further, the trans-form can be separated from this mixture by gel chromatography.
  • the raw material trans 2,6-dimethyl-14-oxopiperidine can be obtained, for example, by the following synthesis route.
  • Tables 1 to 12 show examples of typical compounds of the present invention thus obtained.
  • the antioxidant action of the compound of the present invention was confirmed by measuring the lipid peroxidation inhibitory action of rat liver microsomes. (References)
  • the compound of the present invention since the compound of the present invention has an excellent antioxidant activity, it can be used as an additive for a preparation containing a drug substance that is easily oxidized. It is also expected to be a therapeutic or prophylactic agent for diseases related to oxidative stress, such as dementia, inflammation, ischemic disease, and carcinogenesis.
  • the compound of the present invention can also be used as an antioxidant added for the purpose of maintaining the quality of foods, an antioxidant for plastics for preventing deterioration of plastics due to oxygen in the air, and the like.
  • an appropriate administration method such as general oral administration or parenteral administration.
  • composition it can be produced in the form of tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by a usual method in the technical field of formulation.
  • excipients include lactose, D-mannitol, crystalline cellulose, glucose, etc.
  • disintegrants include starch, carboxymethylcellulose calcium (CMC-C a), and lubricants.
  • CMC-C a carboxymethylcellulose calcium
  • binders include hydroxypropyl cellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).
  • the dose of the compound of the present invention is usually about 0.1 mg / day to 100 mg / day in an injection for adults. mg, orally administered lmg to 2000mg per day, but can be increased or decreased depending on age, symptoms, etc.
  • Example 1 Example 1
  • the reaction was performed in 1 mL of a reaction solution containing the following reagents.
  • Ascorbic acid 100 jumo1 / L
  • the peroxidation reaction was started by adding ascorbic acid and incubated at 37 ° C for 2 hours. Peroxides were measured by the thiobarbituric acid (TBA) method. That is, the reaction solution is 0, After heating at 100 ° C for 15 minutes in the presence of 1% (W / V) and 0.5 mL of 2.8% (W / V) trichloroacetic acid, the chromogen was extracted with butanol. The absorbance of the organic layer at 532 nm was measured.
  • Example 1 The compound of the present invention described in Example 1 at 100 ⁇ 1 ZL concentration almost completely inhibited the lipid peroxidation of rat liver microsomes stimulated with ascorbic acid in the presence of iron ions.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de pipéridine représenté par la formule générale (I) représentée ci-dessous, ou un sel de celui-ci. L'invention a également pour objet un antioxydant contenant un composé de ce type ou un sel de celui-ci comme principe actif. Dans la formule (I): R1 représente un groupe alkyle comprenant de 1 à 8 atomes de carbone ou analogue; R2 représente un atome d'hydrogène, un groupe alkyle comprenant de 1 à 8 atomes de carbone, un groupe alkylcarbonyle comprenant de 2 à 8 atomes de carbone ou analogue; et R3 et R4 peuvent être identiques ou différents et représentent des groupes alkyle comprenant de 1 à 8 atomes de carbone ou analogue.
PCT/JP2004/014563 2003-09-30 2004-09-28 Derive de piperidine Ceased WO2005030721A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003-341433 2003-09-30
JP2003341433 2003-09-30

Publications (1)

Publication Number Publication Date
WO2005030721A1 true WO2005030721A1 (fr) 2005-04-07

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ID=34386224

Family Applications (1)

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PCT/JP2004/014563 Ceased WO2005030721A1 (fr) 2003-09-30 2004-09-28 Derive de piperidine

Country Status (1)

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WO (1) WO2005030721A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
WO2012135669A1 (fr) * 2011-04-01 2012-10-04 Weingarten M David Composés contenant un cycle azoté pour le traitement de troubles inflammatoires

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001124A1 (fr) * 1989-07-14 1991-02-07 Biodor U.S. Holding Nouveaux agents antiviraux
US5126356A (en) * 1989-12-12 1992-06-30 Adir Et Compagnie Piperidine compounds
WO2003099788A1 (fr) * 2002-05-28 2003-12-04 Nippon Chemiphar Co., Ltd. Derives de piperidine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001124A1 (fr) * 1989-07-14 1991-02-07 Biodor U.S. Holding Nouveaux agents antiviraux
US5126356A (en) * 1989-12-12 1992-06-30 Adir Et Compagnie Piperidine compounds
WO2003099788A1 (fr) * 2002-05-28 2003-12-04 Nippon Chemiphar Co., Ltd. Derives de piperidine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
WO2012135669A1 (fr) * 2011-04-01 2012-10-04 Weingarten M David Composés contenant un cycle azoté pour le traitement de troubles inflammatoires

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