WO1997006142A1 - Derives de pyridylmethylphenyl et leur procede de production - Google Patents

Derives de pyridylmethylphenyl et leur procede de production Download PDF

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Publication number
WO1997006142A1
WO1997006142A1 PCT/JP1996/002245 JP9602245W WO9706142A1 WO 1997006142 A1 WO1997006142 A1 WO 1997006142A1 JP 9602245 W JP9602245 W JP 9602245W WO 9706142 A1 WO9706142 A1 WO 9706142A1
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Prior art keywords
general formula
alkyl group
compound
group
same meanings
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PCT/JP1996/002245
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English (en)
Japanese (ja)
Inventor
Nobuo Mochizuki
Akiyoshi Ueda
Tatsumi Suzuki
Masami Hatano
Seiichi Uchida
Nobuhiro Umeda
Hirokazu Yamada
Original Assignee
Nippon Soda 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.)
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Publication date
Application filed by Nippon Soda Co., Ltd. filed Critical Nippon Soda Co., Ltd.
Priority to AU66692/96A priority Critical patent/AU6669296A/en
Publication of WO1997006142A1 publication Critical patent/WO1997006142A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms

Definitions

  • the present invention relates to pyridylmethylfuninyl derivatives useful as antihyperlipidemic agents.
  • the present invention has the general formula (I)
  • X is ⁇ —r 1 (r 1 represents a hydrogen atom or a C 6 alkyl group.), ⁇ ,
  • R is an alkyl group, a halogen atom, d-6 an alkoxy group, human Dorokishi group or C 00 r 2 a (r 2 may indicate to a hydrogen atom or a C 6 alkyl group.), m represents 0, 1, 2 or 3. Or a pharmaceutically acceptable salt thereof, and a method for producing the compound.
  • X is N—r 1 (r 1 is a hydrogen atom or a linear or branched carbon such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.)
  • r 1 is a hydrogen atom or a linear or branched carbon such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.
  • 0, S, SO, S 0, CH represents a CH (CH) or NHS 0 2
  • S 0 2 is more preferable arbitrariness.
  • n represents 0 or an integer of 1 to 9 and an integer of 0 to 9, with 2 to 4 being more preferred.
  • R represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, halogen atom such as fluorine, chlorine, bromine, methoxy, C ⁇ 6 alkoxy group such as ethoxy, propoxy, isopropoxy group, hydroxy group or C 0 r 2 (where r 2 is a hydrogen atom or a linear group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.) Or a branched alkyl group having 1 to 6 carbon atoms.) And m represents 0, 1, 2, or 3. When there are a plurality of Rs, Rs may be the same or different, and R may be substituted at any position on the benzene ring.
  • Examples of the pharmaceutically acceptable salts include salts of compounds represented by the general formula [I] with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and acetic acid, propionic acid, lactic acid, succinic acid, and sake. Salts of organic acids such as lithic acid, cunic acid, benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid can be mentioned.
  • the compound of the present invention can be produced by the following production method.
  • R ′ is a d- 6 alkyl group, a halogen atom, a C alkoxy group or C 0 r 2 (r 2 is a hydrogen atom or a C ⁇ 6 alkyl group. Represents.)
  • Water such as carbonates such as calcium carbonate, alkoxides such as potassium butoxide, sodium hydroxide, and hydroxylating water in an inert solvent such as water, DMS O, and DMF.
  • bases such as oxides and hydrides such as sodium hydride, from 30 ° C to the boiling point of the solvent used, preferably from room temperature to mild heating conditions, for 30 minutes to several 10 hours It is done.
  • X is N- r 1 (r 1 is a hydrogen atom or a C e alkyl group), 0, S, S 0 , S 0 2, or NH S 0 2 compounds are prepared in the following manner be able to.
  • A represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group
  • X ′ represents N—r 1 (r 1 represents a hydrogen atom or a C ⁇ 6 alkyl group) , 0, S, SO, shows the S 0 or NHS 0 2, R, m and n are as defined above.
  • This reaction is carried out in an organic solvent such as acetone, acetonitril, N, N-dimethylsulfoxide (DMS0), N, N-dimethylformamide (DMF), carbonated lime, etc.
  • Organic solvent such as acetone, acetonitril, N, N-dimethylsulfoxide (DMS0), N, N-dimethylformamide (DMF), carbonated lime, etc.
  • Bases such as carbonates, alkoxides such as potassium t-butoxide, hydroxides such as sodium hydroxide and potassium hydroxide, and hydrides such as sodium hydride.
  • the reaction is carried out in the presence at a temperature of from 120 ° C. to the boiling point of the solvent to be used, preferably from room temperature to mild heating, for 30 minutes to several 10 hours.
  • X is N—r 1 and r 1 is a hydrogen atom
  • the reaction proceeds as it is, but one of the hydrogen atoms is protected with a formyl group or the like to prevent side reactions, and after the reaction, Protecting is better.
  • a compound in which X or X ′ is so or so 2 can be produced by oxidizing the corresponding thioether with an oxidizing agent such as hydrogen peroxide or m-chloroperbenzoic acid.
  • a compound in which X is NH 2 SO 2 can also be produced by the following reaction.
  • the amides represented by the formula [VI] are reacted with the sulfonyl halide represented by the formula [VII].
  • the reaction is carried out in an inert solvent such as DMF, DMSO, chloroform, methylene chloride, preferably triethylamine, 1,8-diazabicyclo [5,4,0] -ende-7-ene (DBU)
  • DBU 1,8-diazabicyclo [5,4,0] -ende-7-ene
  • the reaction is carried out in a temperature range from ⁇ 20 to the boiling point of the solvent used for 30 minutes to several 10 hours.
  • the compound in which R is COO r 3 is hydrolyzed in water or an alcohol such as ethanol, using an alkali such as sodium hydroxide or an acid such as hydrochloric acid or sulfuric acid. Thereby, the corresponding C 00 H form is obtained.
  • a compound in which R is a hydroxy group is produced by protecting the hydroxy group with a benzyl group, synthesizing according to the above 1 to 3, and hydrogenating using a palladium carbon catalyst. Can also.
  • the starting compound can be produced, for example, according to the following reaction formula.
  • Ha 1 or Ha 1 ′ represents a halogen atom
  • r 4 represents a hydrogen atom or a methyl group.
  • X ′ R, m and n have the same meanings as described above.
  • the administration can be carried out in any mode that is acceptable for the mode of administration of a drug having utility.
  • oral, nasal, parenteral, topical, transdermal or rectal, solid, semi-solid, lyophilized powder or liquid dosage forms, such as tablets, suppositories, pills, soft and hard capsules, Powders, liquids, suspensions, aerosols and the like can be formulated preferably in an accurate dose, and can be administered in a suitable dosage form which can be easily administered.
  • the compositions contain a conventional pharmaceutical carrier or excipient and a compound of formula (I) alone or as one active ingredient, but may also contain other pharmaceutical or pharmaceutical ingredients. , A carrier, an adjuvant, and the like.
  • the composition preferably contains 5 to 75% by weight of one or more compounds of the general formula [I] or a pharmaceutically acceptable salt thereof, with the balance being suitable pharmaceutically acceptable salts. Excipient.
  • composition for oral administration comprises one or more compounds of the general formula [I] or a pharmaceutically acceptable salt thereof, and any commonly used excipients, such as pharmaceutical It is formed by adding butanol, lactose, starch, gelatinized starch, magnesium stearate, saccharin sodium, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, etc. You.
  • Such compositions are used in the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, suppositories, and the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like, a disintegrant such as croscarmellose sodium or a derivative thereof may be used. It may contain a body, a lubricant such as magnesium stearate, and a binder such as starch, arabiapym, polyvinylpyrrolidone, gelatin, a cellulose ether derivative and the like.
  • a compound of the general formula [I] or a pharmaceutically acceptable salt thereof is dispersed in 0.5% to 50% to form a formulation.
  • the liquid composition that can be administered as a medicament comprises one or more compounds of the general formula [I] or a pharmaceutically acceptable salt thereof in an amount of 0.5% to 50% and an optional medicament adjuvant.
  • the solution is prepared by dissolving or dispersing the solution in a carrier such as water, saline solution, aqueous solution of dextran, glycerol, ethanol, etc., to form a solution or suspension. be able to.
  • the pharmaceutical composition of the present invention may optionally contain a small amount of an auxiliary substance such as a wetting agent or emulsifier, a pH buffer, an antioxidant, such as citric acid, sorbitan monolaurate, or triethanolamine. Alternatively, butylated hydroxytoluene and the like can be added.
  • an auxiliary substance such as a wetting agent or emulsifier, a pH buffer, an antioxidant, such as citric acid, sorbitan monolaurate, or triethanolamine.
  • an antioxidant such as citric acid, sorbitan monolaurate, or triethanolamine.
  • butylated hydroxytoluene and the like can be added.
  • compounds of general formula (I) or a pharmaceutically acceptable salt thereof will have a therapeutic efficacy that will vary depending on the individual and the pathological condition characterized by the hypercholesterolemia being treated. Administered in amounts. Usually, a therapeutically effective daily dose will be about 0.14 mg to about 14.3 mg / day of the compound of formula (I) per kg body weight, preferably about 0.7 mg / kg body weight. mg to about 10 mg / day, most preferably about 4 mg / kg to about 7.2 mg / kg / day. For example, when administered to a human weighing 70 kg, the dose range of the compound of the general formula [I] or a pharmaceutically acceptable salt thereof is preferably about 10 mg to about 1.0 g per day. About 50 mg to about 700 mg per day, most preferably about 100 to about 500 mg per day. Next, it is shown that the compound of the present invention has excellent pharmacological activity.
  • a 2% cholestyramine supplemented feed is added to an SD female rat (body weight: 110 to 130 g). Feeding for ⁇ 10 days increased cholesterol biosynthetic activity. After exsanguination and death at midnight, the liver was removed and 0.1 M phosphate buffer (pH 7.4) containing 2 volumes of 15 mM nicotineamide and 2 mM magnesium chloride was added. Then, it was homogenized with a loose-fitting Teflon homogenizer. The supernatant obtained by centrifugation at 1200 xg for 30 minutes was further centrifuged at 15000 xg for 90 minutes to obtain a microsomal fraction and supernatant. divided.
  • the obtained supernatant was used as a 40% to 80% ammonium sulfate precipitation fraction (soluble fraction).
  • the soluble fraction and the microsome fraction were prepared with 0.1 M phosphate buffer (pH 7.4) to give 1 ml / g liver and 1 ml / 3 g liver, respectively.
  • the enzyme solution having a mixing ratio of 16: 1 was used in the test described below.
  • Cholesterol biosynthesis activity was measured according to the method described in Biochimicaeta 1., Biophysica Acta 486, 70-81 (1977).
  • the enzyme solution prepared in (1) 50-0.1 M phosphate buffer (pH 7.4), 1 mM ATP, 5 mM glucose-1-1 monophosphate, 6 mM glutathione, 6 mM magnesium chloride, 0. 0 4 mM Koenzaimu A, 0. 2 5 mM NAD, 0. 2 5 mM NADP, 1 mM 2- 14 C- acid Na Application Benefits um (1 1 1 MB q.
  • mice 7 to 9-week-old male Crj mice were used. The mice were fed a diet supplemented with 2% cholestyramine for 7 to 10 days in an environment where the lighting was reversed day and night (7 am to 7 pm, dark).
  • the test drug (10 mg Z kg) was dissolved or suspended in distilled water or a 1% aqueous solution of polyoxyethylene hardened castor oil and orally administered at 10:30 am. One hour after the administration of the test drug, the mice were intraperitoneally administered 14 C sodium monoacetate to 5 Ci / 0.5 mlZ mice.
  • the target drug is an imidazolyl phenyl derivative announced at the 115th Annual Meeting of the Pharmaceutical Society of Japan.
  • the present invention relates to a pyridylmethyl phenyl derivative represented by the general formula [I] and a method for producing the same.
  • the compound of the present invention is an antihyperlipidemic drug having excellent activity and safety. Useful.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés, ou certains de leurs sels médicalement admis, représentés par la formule générale (I) et convenant particulièrement comme hypolipémiants. Dans cette formule, X représente N-r1 (r1, représentant hydrogène ou alkyle C¿1?-C6), O, S, SO, SO2, CH2, CH(CH3) ou NHSO2, n représente 0 ou un entier valant de 1 à 9, R représente un alkyle C1-C6, halogéno, alcoxy C1-C6, hydroxy ou COOr?2 (r2¿,représentant hydrogène ou alkyle C¿1?-C6), et m représente 0, 1, 2 ou 3.
PCT/JP1996/002245 1995-08-10 1996-08-08 Derives de pyridylmethylphenyl et leur procede de production WO1997006142A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66692/96A AU6669296A (en) 1995-08-10 1996-08-08 Pyridylmethylphenyl derivatives and process for production thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP22579095 1995-08-10
JP7/225790 1995-08-10
JP19706496 1996-07-08
JP8/197064 1996-07-08

Publications (1)

Publication Number Publication Date
WO1997006142A1 true WO1997006142A1 (fr) 1997-02-20

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WO (1) WO1997006142A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62174040A (ja) * 1985-09-13 1987-07-30 Sankyo Co Ltd ３”−ヒドロキシ−ｍｌ−２３６ｂ誘導体およびその製造法
JPH03184940A (ja) * 1989-08-31 1991-08-12 Merck & Co Inc ７―置換ＨＭＧ―ＣｏＡ還元酵素阻害剤
JPH04112868A (ja) * 1990-09-03 1992-04-14 Otsuka Pharmaceut Co Ltd 置換ヘテロ環を有するフェニルカルボン酸誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62174040A (ja) * 1985-09-13 1987-07-30 Sankyo Co Ltd ３”−ヒドロキシ−ｍｌ−２３６ｂ誘導体およびその製造法
JPH03184940A (ja) * 1989-08-31 1991-08-12 Merck & Co Inc ７―置換ＨＭＧ―ＣｏＡ還元酵素阻害剤
JPH04112868A (ja) * 1990-09-03 1992-04-14 Otsuka Pharmaceut Co Ltd 置換ヘテロ環を有するフェニルカルボン酸誘導体

Also Published As

Publication number Publication date
AU6669296A (en) 1997-03-05

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