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WO1993012069A1 - Nouveau derive d'alcool amine ou son sel - Google Patents

Nouveau derive d'alcool amine ou son sel Download PDF

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Publication number
WO1993012069A1
WO1993012069A1 PCT/JP1992/001629 JP9201629W WO9312069A1 WO 1993012069 A1 WO1993012069 A1 WO 1993012069A1 JP 9201629 W JP9201629 W JP 9201629W WO 9312069 A1 WO9312069 A1 WO 9312069A1
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WO
WIPO (PCT)
Prior art keywords
group
dimethyl
formula
ynyl
pharmaceutically acceptable
Prior art date
Application number
PCT/JP1992/001629
Other languages
English (en)
Japanese (ja)
Inventor
Koyo Matsuda
Hironori Harada
Ryuji Tsuzuki
Koichiro Morihira
Noriki Ito
Hirotoshi Kakuta
Yuichi Iizumi
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Publication of WO1993012069A1 publication Critical patent/WO1993012069A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • 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
    • C07D207/34—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 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
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    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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    • 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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
    • C—CHEMISTRY; METALLURGY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D333/26—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 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
    • C07D333/30—Hetero atoms other than halogen
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel amino alcohol derivative having a squalene epoxidase inhibitory activity, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutical composition containing them, and a method for producing them.
  • Mortality due to ischemic heart disease caused by coronary atherosclerosis is the second highest in Japan after cancer, and is increasing further due to the aging of the population and westernization of diet.
  • Increased blood cholesterol is regarded as a major risk factor for arteriosclerosis, a degenerative disease of the arteries.
  • An increase in blood cholesterol first causes the deposition of lipids in the intima of the large blood vessels, which increase in extent and extent with age, and eventually lead to ischemic heart disease such as myocardial infarction and angina. It presents with clinical symptoms such as cerebral arteriosclerosis such as infarction or aneurysm. Therefore, suppressing the increase in blood cholesterol and lowering it to a normal value is considered to be extremely effective in treating or preventing the above-mentioned various diseases caused by arteriosclerosis.
  • squalene / epoxidase inhibitors which target squalene / epoxidase, an enzyme located in the middle stage of the cholesterol synthesis system, may inhibit the synthesis of other metabolites or the accumulation of harmful substances in the body. It is expected to provide a safer and more safe anticholesterol agent.
  • squalene epoxidase is a rate-limiting enzyme, and it is thought that cholesterol can be reduced more efficiently by selectively inhibiting squalene epoxidase.
  • European Patent Application Publication No. 448,078 discloses various compounds in a wide range of disclosures as compounds having squalene epoxidase inhibitory activity. It is clearly different in structure in that it has a chain.
  • the present inventors have created various compounds and proceeded with screening, and as a result, the phenol derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has been obtained by the known method.
  • the present inventors have found that they have an excellent anticholesterol activity based on squalene-epoxidase inhibitory activity as compared with the compounds, and have completed the present invention.
  • R 1 hydrogen atom, lower alkyl group, lower alkanoyl group or aralkyl group
  • R 2 a lower alkyl group or a formula optionally substituted with a hydroxyl group
  • R 6 ⁇ f — a group represented by
  • Ring B benzene ring or hetero atom consisting of N, 0 or S 1 to
  • R 3 hydrogen atom, lower alkyl group, lower alkenyl group, lower alkanol group, lower alkoxycarbonyl group or aryl group
  • R 4 lower alkyl group
  • n an integer from 0 to 3.
  • an object of the present invention is to provide an amino alcohol derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable hydrate thereof, and a pharmaceutically acceptable salt thereof. It is to provide a solvate or a stereoisomer thereof.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above derivative, or a salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • Still another object of the present invention is to provide a method for producing the above-mentioned derivative, a salt thereof or a stereoisomer thereof.
  • the “lower alkyl group” specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutynole group, a sec-butynole group, a tert-butynole group, a pentisole (aminol) Group, isopentyl group, neopentizole group, tert-pentyl Group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl Group, 1.2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group,
  • alkyl group means a linear or branched one having 1 to 10 carbon atoms.
  • a heptyl group examples include 5-methylhexyl, octyl, 6-methylheptyl, nonyl, 7-methyloctyl, decyl, and 8-methylnonyl.
  • the “lower alkoxy group” includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy (amyloxy) group, an isopentyl group.
  • Examples include a xy group, a tert-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, an 11-ethylpropoxy group, and a hexyloxyl group.
  • “Lower alkoxycarbonyl group” includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group , Pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, etc. Examples include a group formed by esterification with a single linear or branched alcohol and a carboxy group.
  • lower alkanol group examples include straight or branched ones having 1 to 6 carbon atoms, and specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl. Group, isovaleryl group, bivaloyl group, hexanoyl group and the like.
  • lower alkyl group optionally substituted with a hydroxyl group means that any hydrogen atom of the above “lower alkyl group” may be substituted with a hydroxyl group.
  • hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl For example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
  • the “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-probenyl group, an isopropenyl group, a 1-butenyl group. 1,2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylaryl group, 1-methyl-1-propenyl group, 1-methylaryl group, 1,1-dimethylvinyl group, 1-pentenyl group , 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group,
  • aryl group specifically, a phenyl group, a naphthyl group and the like can be exemplified.
  • the “aralkyl group” means a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted by the above “aryl group”.
  • an aryl group is exemplified by a phenyl group or a naphthyl group, Specifically, benzyl, phenyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 1-methyl-2-phenylethyl, 4-phenylbutyl, 3-phenyl Nylbutyl group, 2-Phenylbutyl group, 1-Phenylbutyl group, 2-Methyl-3-Phenylpropyl group, 2-Methyl-2-Phenylpropyl group, 2-Methyl-1-Phenylpropyl group, 1-Methyl-3-Phenylpropyl group, 1 1-methyl-2-phenylpropyl group, 1-methyl-1-phenylpropy
  • aryloxy group a carbocyclic aryloxy group is preferable, and specific examples thereof include a phenoxy group, a naphthyloxy group, an anthroxy group and a phenanthroxy group.
  • heteroatoms consisting of N, 0 or S
  • the “5- or 6-membered heterocyclic group” include, for example, a furyl group, a chenyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a piperyl group, a pyridyl group, a pyrimidinyl group.
  • a virazinyl group and particularly preferred are a phenyl group and a phenyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the compound (I) of the present invention has a double bond and contains an asymmetric carbon atom. Accordingly, the compounds of the present invention include various isomers such as geometric isomers (cis, trans isomers, etc.), tautomers (keto, enol isomers, etc.), optical isomers (optically active, racemic, diastereomer, etc.) It is to be understood that the term stereoisomers in the present description and claims includes mixtures of isomers.
  • the compound (I) of the present invention may form an acid addition salt.
  • salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, and malonic acid. Acids, succinic acid, fumaric acid, maleic acid, lactic acid, lingic acid, tartaric acid, citric acid, organic acids such as methanesulfonic acid and ethanesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid. And acid addition salts thereof.
  • the present invention further includes various hydrates, solvates and polymorphs of the compound (I) of the present invention.
  • the compound of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of the substituent.
  • the typical production method is shown below.
  • the compound represented by the general formula (la) is an amine derivative represented by the general formula (II) And an epoxy compound represented by the general formula (III).
  • reaction proceeds without solvent, it is preferable to carry out the reaction in an organic solvent that does not participate in the reaction.
  • organic solvents not involved in the reaction include alcohols such as methanol, ethanol, and isopropanol, ethers, tetrahydrofuran, ethyl acetate, dimethylformamide, dichloromethane, toluene, and hexane.
  • the compounds (II) and (III) are subjected to the reaction in substantially equimolar amounts or one of them in a slight excess.
  • the reaction temperature usually from room temperature to heating, preferably to reflux temperature.
  • the reaction time is appropriately set in consideration of various reactions.
  • R 1 , R 2 , R 3 , R 4 and n have the above-mentioned meanings, X 1 represents a halogen atom or an organic sulfonic acid residue, R 8 is a lower alkyl group, a lower alkyl group, Means an alkanol, aralkyl or hydroxyl protecting group.
  • the compound (I) of the present invention is obtained by reacting the amine derivative ( ⁇ ) with a halide or sulfonate represented by the general formula (IV), and when R 8 is a protecting group for a hydroxyl group, the protecting group is then removed. It can be manufactured by
  • the halogen atom includes an iodine atom, a bromine atom and a chlorine atom
  • the organic sulfonic acid residue includes an alkanesulfonic acid residue such as a methanesulfonic acid residue and an ethanesulfonic acid residue
  • An aromatic sulfonic acid residue such as a ruenesulfonic acid residue (for example, p-toluenesulfonyloxy group) and a benzenesulfonic acid residue, etc., and a trialkylsilyl group, a methoxymethyl group
  • An easily removable protecting group such as a methoxetoxymethyl group is used.
  • the reaction using a halide as the starting compound (IV) can be carried out without solvent or in an organic solvent such as benzene, toluene, xylene, dimethylformamide, acetonitrile, dichloromethane, dichloroethane, methanol, ethanol, etc., which does not participate in the reaction. It is advantageous to carry out the reaction using (IV) and the compound (II) in an equimolar to slightly excess molar amount at room temperature or under heating, or by heating to reflux.
  • an organic solvent such as benzene, toluene, xylene, dimethylformamide, acetonitrile, dichloromethane, dichloroethane, methanol, ethanol, etc.
  • secondary or tertiary bases such as pyridine, picolin, N, N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, dimethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, and sodium hydrogencarbonate are used.
  • inorganic bases such as potassium carbonate, sodium carbonate, and sodium hydrogencarbonate are used.
  • Ra is a hydrogen atom
  • a method of introducing a protecting group into the amino group and causing the reaction to suppress side reactions, and then removing the protecting group after the reaction can be adopted.
  • a protecting group include a toluenesulfonyl group, an acetyl group, a phenacylsulfonyl group, a trifluoromethanesulfonyl group, and a bisbenzenesulfonyl group. Removal of the protecting group can be easily achieved by conventional hydrolysis.
  • the compound (IV) and an equimolar to slightly excessive molar amount of the compound (II) are converted into an organic solvent inert to the reaction, such as ether, methanol, ethanol, or the like. It is advantageous to carry out in toluene, tetrahydrofuran, etc. under cooling or at room temperature.
  • the reaction time is appropriately set in consideration of various reaction conditions. This reaction may be carried out using a halide in the presence of an organic or inorganic base as in the case of the reaction.
  • Removal of the protecting group for the hydroxyl group can be carried out according to a conventional method.
  • Trialkylsilyl groups can be easily removed by contact with water, and methoxymethyl groups and the like can be easily removed by hydrolysis under acid or basic conditions. can do
  • R 2 , R 3 , R 4 and n have the above-mentioned meanings, and means a hydrogen atom or an alkali metal.
  • lithium, sodium, potassium, etc. are used as the alkali metal. No.
  • the compound represented by (lb) in the compound of the present invention can be produced by reacting the epoxy compound represented by the general formula (V) with a phenol or a metal phenolate of the general formula (VI).
  • the reaction proceeds in the absence of a solvent but usually does not take part in the reaction.
  • a solvent for example, in compounds such as ether, tetrahydrofuran, ethyldiethyl, dimethylformamide, dichloromethane, toluene and hexane, compounds (V) and (VI) It is advantageous to carry out the reaction generally at room temperature or under heating, with each being almost equimolar or one in a slight excess.
  • phenol when ⁇ is a hydrogen atom
  • the reaction is carried out in the presence of a base, such as butyllithium, sodium hydroxide, potassium hydroxide, hydrogen hydride.
  • Bases such as sodium, metallic sodium, and carbonated lime are preferred. 4th manufacturing method
  • R 1 , R 2 , R 3 , R 4 , R 8 , n and M have the above-mentioned meanings, and X 2 represents a halogen atom.
  • the compound (I) of the present invention can also be produced by reacting a halide represented by the general formula (VII) with phenol or phenol (VI) and, if necessary, removing a protecting group.
  • the reaction is almost the same as in the third production method.
  • One of D 1 and ⁇ 1 is the formula ⁇ ⁇ or the formula
  • the organic sulfonic acid residue, R 9 is collected by the group D 1 is represented by the formula -NH
  • R 1 is a halogen atom or an organic sulfonic acid residue
  • a gen atom or an organic sulfonic acid residue, and E 1 is a group represented by the formula
  • R 4 represents a group represented by each.
  • the compound (I) of the present invention comprises a benzylamine derivative represented by the general formula ⁇ ) or a benzyl halide or benzyl sulfonate derivative, (6,6-Dimethyl-2-heptene-14-yl) monohalide or sulfonate represented by the general formula (IX), or lower alkyl halide or sulfonate, or N- (6,6-dimethyl-2-heptene) 144-1) It can also be produced by reacting with 1N-lower alkylamine and, if necessary, removing the protecting group.
  • the reaction can be carried out in almost the same manner as in the second production method.
  • the compound (I) of the present invention comprises a benzaldehyde represented by the general formula (X): It can also be produced by reductive condensation in which an amine represented by (XI) is reacted in the presence of a reducing agent.
  • the reaction is carried out by reacting compound (X) with compound (XI) in the presence of a reducing agent in an organic solvent inert to the reaction, for example, an organic solvent such as tetrahydrofuran, methanol, ethanol, or acetonitrile, or water or a mixed solvent thereof.
  • a reducing agent for example, an organic solvent such as tetrahydrofuran, methanol, ethanol, or acetonitrile, or water or a mixed solvent thereof.
  • hydrides such as sodium borohydride and sodium cyanoborohydride are preferably used.
  • an acid catalyst such as hydrochloric acid or acetic acid may be used. If there are other groups that are susceptible to reduction, they can be selected as desired by selecting reaction conditions.
  • R 2 , R °, R 4 , n and X 2 have the above-mentioned meanings, and R 11 represents a lower alkyl group or an aralkyl group.
  • the compound represented by the general formula (Id) is an ether for reacting the alcohol or alcoholate represented by the general formula (Ic) with the halide or sulfonate represented by the general formula (XI I). It can be manufactured by a chemical method.
  • the reaction can be carried out in substantially the same manner as in the fourth production method. 8th manufacturing method
  • R 2 , R 3 , R 4 and n have the above-mentioned meaning, and R 12 means a -c 5 lower alkyl group.
  • the compound (Ie) of the present compound (I) wherein R 1 is a lower alkanoyl group is obtained by reacting the compound (la) or a reactive derivative thereof with the carboxylic acid represented by the general formula (XIII) or a reactive derivative thereof. It can be produced by esterification.
  • the reaction can be carried out by a conventional method.
  • a reactive derivative of the compound (la) halide persulfonate in which an OH group is replaced by halogen is used.
  • a reactive derivative of the compound (XIII) an acid halide is used. And acid anhydrides and metal salts of acids.
  • the reaction using the alcohol of the compound (la) as the alcohol component is carried out in the following manner: (i) in the presence of a free acid of the compound (II) and a desiccant, an esterification accelerator or a condensing agent, or a Dean-Stark apparatus. Azeotropic dehydration, or in the presence of an acid catalyst, or (ii) Compound (XIII) It is preferable to carry out the reaction in the presence of an acid halide or an acid anhydride, which is a reactive derivative of the above, and a base or an acid.
  • the former reaction is carried out in an organic solvent inert to the reaction, such as benzene, toluene, kishen, dichloromethane, dichloroethane, chlorophonolem or carbon tetrachloride, at room temperature or under heating, and as a drying agent, anhydrous magnesium sulfate or molecular sieve is used.
  • An esterification accelerator such as an aluminum chloride mixed resin, a condensing agent such as dicyclohexyl carbodiimide, and an acid catalyst such as sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and benzenesulfonic acid.
  • trimethylamine, triethylamine, dimethylaniline, pyridine, tetramethylurea, metal, and the like are used in a solvent inert to the reaction such as ether, terolahydrofuran, dioxane, ⁇ ethyl acid, and acetate nitrile.
  • a base such as magnesium
  • a base catalyst such as sulfuric acid, p-toluenesulfonic acid, zinc chloride, sodium nitrate, pyridine, 4-dimethylaminoviridine or 4-pyrrolidinopyridine, and at room temperature or under heating
  • a base such as magnesium
  • a base catalyst such as sulfuric acid, p-toluenesulfonic acid, zinc chloride, sodium nitrate, pyridine, 4-dimethylaminoviridine or 4-pyrrolidinopyridine
  • reaction using halide persulfonate which is a reactive derivative of compound (la), as the alcohol component is performed using methanol (ethanol), acetone, dimethylformamide, ethyl peroxyate, using compound (II) or a salt thereof.
  • a base such as sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, at room temperature or under heating It is preferable to carry out.
  • the compound (I) of the present invention a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable hydrate, a solvate or a stereoisomer thereof has excellent squalene / epoxidase inhibitory activity. And have an excellent inhibitory effect on cholesterol biosynthesis in vivo based on this activity. Was confirmed. Furthermore, since it is effective in a system using human-derived cultured cells, it is effective for humans and warm-blooded animals caused by the action of cholesterol, especially ischemic diseases such as arteriosclerosis, myocardial infarction and angina in humans. It is useful for the prevention and treatment of cerebral arteriosclerosis such as heart disease and cerebral infarction or aneurysm. In addition, the compound of the present invention selectively inhibits squalene epoxidase, which is an enzyme located at the middle stage of the cholesterol biosynthesis system. Has no side effects.
  • Rat Squalene Epoxidase is a Journal of Biological
  • the liver is removed and homogenized with 0.1 MT ris-HC1 buffer (pH 7.5) containing 1 mM EDTA, and lOOOxg. Centrifuged for 0 minutes. The supernatant was further centrifuged at 1,500,000 X g for 1 hour, and the obtained microsomes were suspended in the same buffer so as to have a protein concentration of 50 mg / m 1. The mixture was stirred and solubilized in the presence of X-100.
  • the squalene epoxidase inhibitory activity was measured according to the method described in Journal Biological Chemistry, Vol. 245, p. 1670 (1970).
  • the unsaponifiable substance was extracted with petroleum ether, concentrated to dryness, and dissolved in a small amount of black-mouthed form. Of these, 1/4 of the total petroleum ether extract was measured with a liquid scintillation counter, and 12 were spotted on pre-coated Silicagel TLC, and ethyl benzene monoacetate (99.5: 0.5) was used. It was developed in. The position of the generated 3 H-squalene-1,2,3-epoxide in TLC was identified by ergosterol acid as a marker, and the TLC 3 H-squalene-1,2,3-epoxide was cut off and immersed in a toluene scintillator.
  • Rats (SD, 5-week-old, male) were bred for 9 days in an environment where the lighting was reversed day and night (8:00 am to 8:00 pm, dark), and chow and water were allowed ad libitum.
  • the test drug (dissolved in 0.5% methylcellulose aqueous solution containing 0.8% ethanol and 0.8% cremophor) has a volume of 1m1 and a body weight of 100g, 3mg / kg or 1OmgZkg at 10:00 am. Oral administration.
  • the control group received the same volume of the solvent used.
  • 14 C-sodium acetate was intraperitoneally administered at a 40 / z C i rate. Two hours later, blood was collected from the abdominal vein under ether anesthesia, and serum was separated by centrifugation.
  • ED50 value concentration per rat body weight
  • Hep-G2 Human Hepatoma
  • 1 0 c ⁇ dish After culturing the Human Hepatoma (Hep-G2) cells at 1 0 c ⁇ dish until a monolayer, replace the culture lml, 1 0 1 14 G Add sodium acetate and 1 ⁇ 1 dimethyl sulfoxide solution of the test agent, and incubate for 6 hours at 37 in 5% carbon dioxide mixed air. After completion of the culture, remove the medium by suction, cool on ice, and wash with Dulbecco's buffered saline. The cells obtained are scraped with a rubber policeman and collected by centrifugation. After lysing the collected cells with 0.3N sodium hydroxide (4001), use 2001 of them for extraction, and use the other sample for protein determination.
  • 0.3N sodium hydroxide (4001)
  • the TLC strip is immersed in a toluene scintillator, and the radioactivity is measured using a liquid scintillation counter. The results are corrected for the amount of protein measured by the method described in Journal of Biological 'Chemistry (LBiol. Chem.), Vol. 193, p. 265 (1951). The concentration (IC5 () value) at which the compound of the present invention inhibited cholesterol biosynthesis by 50% in Hep-G2 cultured cells was determined.
  • the compound of the present invention exhibited a significantly stronger activity in inhibiting cholesterol biosynthesis in rats than the control compound.
  • the compound of the present invention also exhibited a significantly stronger activity in inhibiting cholesterol biosynthesis in cultured cells (H-mark G2) than the control compound.
  • the compound of the present invention strongly inhibits squalene epoxidase, especially squalene epoxidase derived from human cancer cells, and inhibits cholesterol biosynthesis even in comparison with the control compound. It is useful for the prevention or treatment of various diseases caused by the action of, for example, arteriosclerosis and other myocardial infarction, ischemic heart disease such as angina, cerebral arteriosclerosis such as cerebral infarction, or aneurysm. Is expected.
  • composition containing one or more of the compounds represented by general formula (I), pharmaceutically acceptable hydrates thereof, etc. as active ingredients Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, tablets, powders, fine granules, granules, tablets, powders, etc. It is prepared as an ointment or patch, and is administered orally (including sublingual administration) or parenterally (including indirect administration).
  • the clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the patient's symptoms, weight, age, sex, etc., and is usually 10 to 500 mg orally per adult per day. Is 100 to 500 mg, parenterally 1 to; lOO mg, preferably 10 to: L 0 O mg. Dosing once or several times. Since the dose varies under various conditions, a smaller dose than the above range may be sufficient.
  • the one or more active substances may include at least one inert diluent, such as lactose, mannitol, glucose, hydroquinol propyl cellulose, microcrystalline cellulose, starch. , Polyvinylpyrrolidone and magnesium aluminate metasilicate.
  • the composition may be formulated according to the usual practice with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamate.
  • a solubilizing agent such as acid or aspartic acid may be contained. Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate, if necessary.
  • a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as purified water. Contains ethanol. This composition may contain solubilizing or solubilizing agents, wetting agents, suspending agents such as suspending agents, sweeteners, flavoring agents, fragrances, and preservatives in addition to the inert diluent. .
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
  • Such compositions may further comprise tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. It may contain additives.
  • Example 6 The compound 5 Og, lactose 407 g, and constarch IOOOg of the compound 9 were uniformly mixed using a fluidized granulation coating apparatus (Okawara Seisakusho). To this, 200 g of a 10% aqueous solution of hydroxypropylcellulose was sprayed for granulation. After drying, pass through a 20-mesh sieve, add 20 g of calcium ruboxymethylcellulose and 3 g of magnesium stearate, and use a rotary tableting machine (Hata Iron Works) to insert a 7 mm x 8.4 Ii mortar and punch. Used to make 120 mg tablets per tablet. BEST MODE FOR CARRYING OUT THE INVENTION
  • the starting compounds of the present invention also include novel substances, and their production methods are shown in Reference Examples.
  • Example 33 the following compound of Example 33 was synthesized.
  • Example 5 2 In the same manner as in Example 1, the following compound of Example 52 was synthesized. Example 5 2
  • optical purity was determined in the same manner as in Example 65 using HP LC analysis. 87% e e.
  • optical purity was determined in the same manner as in Example 70 using HP LC analysis. 84% e e.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé répondant à la formule générale (I), une composition pharmaceutique contenant ledit composé, et un procédé de production de ce composé. Dans ladite formule (I), R1 représente hydrogène, alkyle inférieur, alcanoyle inférieur ou aralkyle; R2 représente alkyle inférieur éventuellement hydroxylé ou bien (a) ou le cycle B est un cycle benzène ou un hétérocycle à 5 ou 6 chaînons portant 1 à 3 hétéroatomes sélectionnés parmi N, O et S; R3 représente hydrogène, alkyle inférieur, alcényle inférieur, alcanoyle inférieur, alcoxycarbonyle inférieur ou aryle; R4 représente alkyle inférieur; R?5, R6 et R7¿ peuvent être identiques ou différents et représentent chacun hydrogène, halogène, alkyle, alcoxy inférieur, aryloxy ou cyano, à condition que deux groupes adjacents sélectionnés parmi R?5, R6 et R7¿ puissent être combinés pour représenter -(CH¿2?)4, -(CH2)3-, -CH=CH-CH-CH- ou (b); et n est un nombre entier pouvant valoir de 0 à 3. Ce composé (I) présente une activité d'inhibition de la squalène époxydase et est utilisé dans la prévention et le traitement de diverses maladies dues au cholestérol telles que l'artériosclérose.
PCT/JP1992/001629 1991-12-16 1992-12-15 Nouveau derive d'alcool amine ou son sel WO1993012069A1 (fr)

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JP35347291 1991-12-16
JP3/353472 1991-12-16
JP28661092 1992-10-01
JP4/286610 1992-10-01
CN93106653A CN1105354A (zh) 1991-12-16 1993-06-09 新型氨基醇衍生物及其盐

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994018191A1 (fr) * 1993-02-05 1994-08-18 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amine
WO1998008838A1 (fr) * 1996-08-27 1998-03-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'amines substitues
WO2007062314A2 (fr) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Inhibiteurs de cetp heterocycliques
WO2008070496A2 (fr) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company Inhibiteurs d'amino cetp étendus
WO2011145022A1 (fr) 2010-05-21 2011-11-24 Pfizer Inc. 2-phénylbenzoylamides
EP2392567A1 (fr) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Derives de benzothiazine et leurs utilisation comme modulateurs de lxr
WO2012120414A2 (fr) 2011-03-04 2012-09-13 Pfizer Inc. Peptides de type edn3 et utilisations associées
WO2014170786A1 (fr) 2013-04-17 2014-10-23 Pfizer Inc. Dérivés de n-pipéridin-3-ylbenzamide dans le traitement des maladies cardiovasculaires
WO2016055901A1 (fr) 2014-10-08 2016-04-14 Pfizer Inc. Composés d'amide substitué
WO2020150473A2 (fr) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Inhibiteurs de pcsk9 et leurs procédés d'utilisation

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JPS4842869B1 (fr) * 1968-07-18 1973-12-14
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CHEMICAL ABSTRACTS, Vol. 85, No. 13, SMITH L.H., "Beta-Adrenergic Blocking Agents. 13. (3-Amino-2-Hydroxypropoxy) Benzamides", Abstract No. 87094k; & J. MED. CHEM., 19 (9), (1976), 1119-23. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994018191A1 (fr) * 1993-02-05 1994-08-18 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amine
WO1998008838A1 (fr) * 1996-08-27 1998-03-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'amines substitues
EP2392567A1 (fr) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Derives de benzothiazine et leurs utilisation comme modulateurs de lxr
WO2007062314A2 (fr) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Inhibiteurs de cetp heterocycliques
WO2008070496A2 (fr) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company Inhibiteurs d'amino cetp étendus
WO2011145022A1 (fr) 2010-05-21 2011-11-24 Pfizer Inc. 2-phénylbenzoylamides
WO2012120414A2 (fr) 2011-03-04 2012-09-13 Pfizer Inc. Peptides de type edn3 et utilisations associées
WO2014170786A1 (fr) 2013-04-17 2014-10-23 Pfizer Inc. Dérivés de n-pipéridin-3-ylbenzamide dans le traitement des maladies cardiovasculaires
WO2016055901A1 (fr) 2014-10-08 2016-04-14 Pfizer Inc. Composés d'amide substitué
WO2020150473A2 (fr) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Inhibiteurs de pcsk9 et leurs procédés d'utilisation
EP4470609A2 (fr) 2019-01-18 2024-12-04 Astrazeneca AB Inhibiteurs de pcsk9 et leurs procédés d'utilisation

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