WO1994018167A1 - Derive de dibenzylamine substitue - Google Patents

Derive de dibenzylamine substitue Download PDF

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Publication number
WO1994018167A1
WO1994018167A1 PCT/JP1994/000132 JP9400132W WO9418167A1 WO 1994018167 A1 WO1994018167 A1 WO 1994018167A1 JP 9400132 W JP9400132 W JP 9400132W WO 9418167 A1 WO9418167 A1 WO 9418167A1
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WO
WIPO (PCT)
Prior art keywords
substituted
group
salt
derivative
lower alkyl
Prior art date
Application number
PCT/JP1994/000132
Other languages
English (en)
Japanese (ja)
Inventor
Tetsuya Maeda
Kiyoshi Inoguchi
Jun Nakano
Taiji Asano
Tadashi Arika
Original Assignee
Kaken Pharmaceutical 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 Kaken Pharmaceutical Co., Ltd. filed Critical Kaken Pharmaceutical Co., Ltd.
Publication of WO1994018167A1 publication Critical patent/WO1994018167A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms

Definitions

  • the present invention relates to a novel substituted dibenzylamine derivative, and more particularly to a substituted dibenzilamin derivative which is useful in the fields of prevention and treatment of hyperlipidemia, hypercholesterolemia, arteriosclerosis, and the like. It relates to a benzylamine derivative and a salt thereof.
  • Increased blood lipids promote lipid deposition in the intima of the blood vessels, and in particular, increased cholesterol in the blood promotes atherosclerosis, atherosclerosis, coronary and brain! ) It is considered to be a major factor causing an increase in vascular diseases. At present, reduction of blood cholesterol to normal levels is considered to be the most effective means for preventing and treating arterial stiffness.
  • a reductase inhibitor represented by bravastatin inhibits the early stages of the cholesterol biosynthesis system Therefore, it has the disadvantage of suppressing the production of important physiological metabolites other than cholesterol, such as dolichol and ubiquinone.
  • an inhibitor of an enzyme that plays a role in the late stage of the cholesterol biosynthesis system has side effects such as cataract, which is considered to be caused by accumulation of desmosterol.
  • squalene epoxidase inhibitors which suppress the middle stage of cholesterol biosynthesis, are expected to solve the above problems.
  • the main object of the present invention is to find a compound that specifically inhibits squalene epoxidase in mammals, and to predict hyperlipidemia, hypercholesterolemia, and arteriosclerosis.
  • the purpose is to provide a compound having excellent activity as a preventive or therapeutic agent.
  • the present inventors have already developed butenafine, a compound that specifically and potently inhibits fungal sclarene epoxidase (Maeda et al., Pharmaceutical Journal, Vol. 11, pp. 126 ( 1991)), which is used as an antifungal agent, (2) It had little effect on mammalian squalene epoxidase.
  • the present inventors have performed the conversion of the naphthalen portion of butenafin, and as a result, have extremely excellent cholesterol biosynthesis inhibition, which selectively inhibits mammalian epoxidase.
  • the present inventors have found compounds having activity and have led to the present invention.
  • the invention is general
  • R ′ represents a lower alkyl group or a lower alkenyl group
  • R 2 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group
  • R 3 represents 1-4 heteroatoms.
  • a salt thereof or a hyperlipidemia containing the derivative as an active ingredient;
  • the present invention relates to an agent for preventing or treating hypercholesterolemia or arteriosclerosis, and a method for treating hyperlipidemia, hypercholesterolemia or arteriosclerosis using the derivative.
  • examples of the lower alkyl group represented by R ′ and R 2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Shi click b blanking port building group, .pi.-butyl group, tert- heptyl group and the like, is a lower alkenyl group represented by R ', for example, ⁇ Li group, click b chill - etc., represented by R 2
  • Examples of the lower alkoxy group include methoxy, ethoxy, and the like.
  • Hetero atoms in R 3 include a nitrogen atom, an acid purple atom, and a sulfur atom.
  • Examples of a ⁇ line include, for example, phenyl, biaryl group, furyl S, and oxalate.
  • the substituted dibenzyldiamine derivative of the present invention can be converted into an acid addition salt, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts, or organic acid salts with acetic acid, maleic acid, citric acid, oxalic acid, linoleic acid, methansulphonic acid, p-transylsulfonate, etc. Is raised.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the compound of the present invention can be obtained, for example, by any of the following production methods A, B, C and D.
  • R′R 2 and R 3 in each formula have the same meaning as described above, and Z represents a halogen atom or an organic sulfonoxy group.
  • a solvent that does not affect the reaction in any case is used.
  • ether solvents such as ethyl ether, tetrahydrofuran, dioxane, etc.
  • aromatic hydrocarbons such as benzene, toluene, etc.
  • Alcohol solvents such as propanol
  • Various solvents such as halogenated hydrocarbon solvents such as dichloromethane and chloroform are used, and a single solvent or a mixture of these solvents can be used. .
  • the reaction conditions used may be a force that causes the respective compounds to react in approximately equimolar amounts, either from a small excess to 5 times the molar amount, and the reaction temperature may be adjusted.
  • reaction temperatures may be adjusted.
  • reaction times are usually from 5 minutes to 5 days, preferably from 1 hour to 24 hours. is there.
  • alkylation reactions are preferably carried out in the presence of a base.
  • the base used include alkali metal hydrides such as sodium hydride and lithium hydride, and water.
  • Alkali metal hydroxides such as sodium oxide and hydroxylating power, alkaline metal carbonates such as sodium carbonate and potassium carbonate, triethylamine and the like.
  • Organic amines such as pyridine are exemplified.
  • the compound of the present invention obtained in the above step may be isolated and purified by appropriately combining, for example, electrochromatography, solvent extraction, precipitation, and recrystallization. I can do it.
  • Examples of the halogen atom represented by Z include a chlorine atom, a bromine atom, and an iodine atom, and the organic sulfonyloxy group includes a methansulfonyloxy group. And p-toluenesulfonyl-ox group.
  • the compound represented by the general formula [I] of the present invention has a function of inhibiting squalene dipoxidase in mammals and thereby suppressing cholesterol biosynthesis. It is a useful compound for the prevention and treatment of hyperlipidemia, hypercholesterol D-leukemia, and arteriosclerosis.
  • NMR scan Bae click DOO Le is heavy click B port E Lum (CDC 1 3) or d 6 - dimethyl Chi pulse Ruhoki Shi de (DMS 0 - d 6) solution in Te preparative ra Ji Le Shi Using a run (TMS) as an internal standard, a JM-EX270 type spectrum meter (270 MHz, manufactured by JEOL Ltd.) Measured and ⁇ values are given in ppm.
  • the compound of the present invention has excellent cholesterol biosynthesis inhibitory activity.
  • Various diseases caused by excess cholesterol for example, hyperlipidemia, high cholesterol A compound that is effective for the prevention and treatment of blood bleeding or arteriosclerosis.
  • the dosage and frequency of administration depend on the patient's sex, age, weight, and symptoms. In general, oral administration is performed on a platform, from 0.01 to 200 1 3 1 ⁇ per adult per day, divided into 1 to several times, and in the case of parenteral administration, 0.00 It is preferable to administer 1 to 2 mkg in 1 to several divided doses.

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

Abstract

L'invention concerne un dérivé de dibenzylamine substituté représenté par la formule générale (I), ou un sel de celui-ci, et un médicament ainsi qu'un procédé de prévention et de traitement de l'hyperlipémie, de l'hypercholestérolémie ou de l'artériosclérose à l'aide dudit dérivé. Dans ladite formule R1 représente alkyle inférieur ou alcényle inférieur, R2 représente hydrogène, alkyle inférieur ou alcoxy inférieur et R3 représente phényle ou thiényle chacun substitué par un groupe hétérocyclique comportant un à quatre hétéroatomes.
PCT/JP1994/000132 1993-02-01 1994-01-31 Derive de dibenzylamine substitue WO1994018167A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP3616093 1993-02-01
JP5/36160 1993-02-01

Publications (1)

Publication Number Publication Date
WO1994018167A1 true WO1994018167A1 (fr) 1994-08-18

Family

ID=12462021

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/000132 WO1994018167A1 (fr) 1993-02-01 1994-01-31 Derive de dibenzylamine substitue

Country Status (1)

Country Link
WO (1) WO1994018167A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001253A2 (fr) * 1994-07-01 1996-01-18 Warner-Lambert Company Inhibiteurs de pla2 et leur utilisation pour l'inhibition de l'absorption intestinale du cholesterol
US5783593A (en) * 1993-11-04 1998-07-21 Abbott Laboratories Inhibitors of squalene synthetase and protein farnesyltransferase
JP2016536333A (ja) * 2013-09-04 2016-11-24 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 免疫調節剤として有用な化合物
WO2023286713A1 (fr) * 2021-07-14 2023-01-19 日本曹達株式会社 Nouveau polymère, composition de résine contenant celui-ci et corps moulé de celui-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAKUGAKU ZASSHI, Vol. 111(2), p. 126-137 (1991). *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5783593A (en) * 1993-11-04 1998-07-21 Abbott Laboratories Inhibitors of squalene synthetase and protein farnesyltransferase
WO1996001253A2 (fr) * 1994-07-01 1996-01-18 Warner-Lambert Company Inhibiteurs de pla2 et leur utilisation pour l'inhibition de l'absorption intestinale du cholesterol
WO1996001253A3 (fr) * 1994-07-01 1996-07-18 Warner Lambert Co Inhibiteurs de pla2 et leur utilisation pour l'inhibition de l'absorption intestinale du cholesterol
US5968963A (en) * 1994-07-01 1999-10-19 Warner-Lambert Company PLA2 inhibitors and their use for inhibition of intestinal cholesterol absorption
JP2016536333A (ja) * 2013-09-04 2016-11-24 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 免疫調節剤として有用な化合物
WO2023286713A1 (fr) * 2021-07-14 2023-01-19 日本曹達株式会社 Nouveau polymère, composition de résine contenant celui-ci et corps moulé de celui-ci
TWI822177B (zh) * 2021-07-14 2023-11-11 日商日本曹達股份有限公司 新穎聚合物及包含其之樹脂組合物與其成形體

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