Classifications

• • 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
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
  • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
  • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
  • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

• the present invention relates to a preventive or therapeutic agent for fatty liver.
• R 1 and R 2 are each independently a hydrogen atom or a lower alkyl group
• R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a lower alkyl group or A lower alkoxy group
• R 7 and R 8 are each independently a hydrogen atom, halogen atom, lower alkyl group, lower lower alkyl group, hydroxy lower alkyl group, cycloalkyl group, heterocycloalkyl group, lower alkoxy group, di (lower Alkyl) amino group, cyclic amino group, di (lower alkyl) amino lower alkyl group, aryl group, aryloxy group, aralkyloxy group, heteroaryl group, cyano group, hydroxyl group, lower acyl group, lower alkylsulfanyl group, lower alkyl group When R 7 and R 8 are adjacent to each other, a sulfonyl group, a carboxy group, a lower alkoxy carbo group or an aralkyloxy carboxy group, or when R 7 and R 8 are adjacent to each other, O— (CH) — O, O — (CH) — or one (CH) —
• n an integer of 1 to 3
• n an integer of 2 to 4
• p represents an integer of 3 to 5;
• R 9 is C (0) —R 1C) , —A′-C ⁇ -R 10 , —0—A 2 —C (0) —R 1C) or a tetrazo mononole 5—inole group,
• R 1 ′′ represents a hydroxyl group, a lower alkoxy group, an aralkyloxy group, or —NRUR 1 2 ;
• R 11 and R 12 are each independently a force representing a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group or a lower alkoxy carbo lower alkyl group, or R 11 and R 12 forces Together with the nitrogen atom to form a cyclic amine,
• a 1 is a lower alkylene group or a lower alkylene group
• a 2 is a lower ananolylene group
• Non-Patent Document 1 Abnormal fat in the liver, including general fatty liver, nonalcoholic steatohepatitis (NASH), hypertrophic fatty liver, diabetic fatty liver, alcoholic fatty liver or toxic fatty liver
• NASH nonalcoholic steatohepatitis
• the number of patients presenting with an increasing number of diseases is increasing year by year, and nonalcoholic steatohepatitis (NASH) is especially regarded as a problem as a serious medical condition! / Speak (see Non-Patent Document 1 or 2) ).
• abnormal fat accumulation in the liver causes inflammation of the liver and liver fibrosis (cirrhosis) or shifts to serious diseases such as liver cancer (Non-Patent Documents 1 to 4). It is extremely important to inhibit this fat accumulation.
• Fat accumulation in the liver is thought to be caused by various factors, including changes in lifestyles in recent years, that are caused by abnormalities in energy metabolism in the liver. Are not uniform (see Non-Patent Document 5).
• dietary therapy, exercise therapy, drug therapy, etc. are being tried as methods for improving fat accumulation in the liver. These methods are not always satisfactory because they are difficult to control and continuously perform. In many cases, the therapeutic effect is not obtained.
• polyphosphatidylcholine is only covered by insurance for fatty liver. As described above, a sufficient treatment method has not yet been established for fat accumulation in the liver, and development of a drug that is more effective for fat accumulation is desired.
• clofibrate a therapeutic agent for hyperlipidemia
• microsomal triglyceride transfer protein inhibitor which is a therapeutic agent for hyperlipidemia, has also been reported to induce fat accumulation in the liver, although it decreases blood neutral fat and cholesterol. 2 or 3, see non-patent document 8 or 9).
• these drugs for treating hyperlipidemia there is no correlation between the amount of neutral fat and cholesterol in the blood and liver, and it has also been observed that it induces fatty liver.
• the aminoamino derivative represented by the above general formula (I) of the present invention is a novel compound, and there has been only one reported example of its usefulness as an agent for preventing or treating fatty liver. It ’s sad.
• Patent Document 1 JP-A-8-119860
• Patent Document 2 Japanese Patent Laid-Open No. 2002-220345
• Patent Document 3 International Publication No. 03Z075232 Pamphlet
• Non-Patent Document 1 Hiromasa Ishii, “Ayumi of Medicine”, 2003, No. 206, No. 5, p. 323— 3 25
• Non-Patent Document 2 Naoki Tanaka, 1 other, “Liver”, 2002, No. 43, No. 12, p. 539- 54 9
• Non-Patent Document 3 Kazuhiko Koike, “Ayumi of Medicine”, No. 206, No. 5, p. 385-388
• Non-Patent Document 4 Kotaro Uchimura, 3 others, “Clinical and Research”, 2003, 80 Tsuji, No. 3, p. 5
• Non-Patent Document 5 Kenichiro Iwamura, “Liver”, 1971, No. 12, No. 12, p. 659—669
• Non-Patent Document 6 Kenichiro Iwamura, “Latest Medicine”, 1978, No. 33, No. 3 No., p. 524— 531
• Non-Patent Document 7 A. Beringer and 3 others, "Deutsche Medizinische Wienschrift", 196 7th, 92nd, No., p. 2388-2392
• Non-Patent Document 8 Ken Ohashi, ". Annu a l review endocrine, metabolic 2000", Chugai medicine, Inc. publication, p 17- 23
• Non-Patent Document 9 Shinichi Osuka, “Internal Medicine”, 2002, 89th, No. 5, p. 875-881 Disclosure of Invention
• the present invention is to provide a pharmaceutical composition useful as an agent for preventing or treating fatty liver.
• R 1 and IT are each independently a hydrogen atom or a lower alkyl group
• R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a lower alkyl group or a lower group.
• R 7 and R 8 are each independently a hydrogen atom, halogen atom, lower alkyl group, lower lower alkyl group, hydroxy lower alkyl group, cycloalkyl group, heterocycloalkyl group, lower alkoxy group, di (lower (Alkyl) amino group, cyclic amino group, di (lower alkyl) amino lower alkyl group, aryl group, aryloxy group, aralkyloxy group, A card representing a teloaryl group, a cyano group, a hydroxyl group, a lower acyl group, a lower alkylsulfanyl group, a lower alkylsulfonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, or R 7 and R 8 are If adjacent, they combine to form one O— (CH) — O, one O— (CH) —, or one (CH) —
• n an integer of 1 to 3
• n an integer of 2 to 4
• p represents an integer of 3 to 5;
• R 9 is C (0) —R 1C) , —A′-C ⁇ -R 10 , —0—A 2 —C (0) —R 1C) or a tetrazo mononole 5—inole group,
• R 1C represents a hydroxyl group, a lower alkoxy group, an aralkyloxy group, or —NRUR 1 2 ;
• R 11 and R 12 are each independently a force representing a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group or a lower alkoxy carbo lower alkyl group, or R 11 and R 12 forces Together with the nitrogen atom to form a cyclic amine,
• a 1 is a lower alkylene group or a lower alkylene group
• a 2 is a lower ananolylene group
• halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.
• the "lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, sec butyl group, tert butyl group, pentyl group, isopentyl group, neopentyl group, tert pentyl group, 1 methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, etc. It is done.
• the lower alkyl group in R 1 R 2 , R 3 , R 4 , R 5 and R 6 is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably Is a methyl group.
• the lower alkyl group in RR 8 and R 9 is preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group, an ethyl group, a propyl group, or an isopropinole group.
• halo lower alkyl group means a lower alkyl group substituted with 1 to 3 of the same or different halogen atoms, and includes, for example, a trifluoromethyl group, a 2-chloroethyl group, 2 — Fluoroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichlorodiethyl group and the like are preferable, and trifluoromethyl group is preferable.
• “Hydroxy lower alkyl group” means a lower alkyl group substituted with a hydroxyl group, and examples thereof include a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, and a 3-hydroxypropyl group. Group, 4-hydroxybutyl group and the like, and is preferably a hydroxymethyl group.
• the "cycloalkyl group” means a saturated cyclic hydrocarbon group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
• a cyclopentyl group or a cyclohexyl group is preferred.
• Heterocycloalkyl group means a 3 to 7-membered saturated heterocyclic group containing an oxygen atom or a sulfur atom in the ring, and includes, for example, a tetrahydrofuryl group, a tetrahydrocenyl group, a tetrahydrobila- And the like.
• the "lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group. Group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.
• the lower alkoxy group in R 3 , R 4 , R 5 and R 6 is preferably an alkoxy group having 1 to 4 carbon atoms, and more preferably a methoxy group.
• the lower alkoxy group in RR 8 and R 9 is preferably an alkoxy group having 1 to 4 carbon atoms, and more preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.
• the lower alkoxy group at R 1 ° is preferably an alkoxy group having 1 to 4 carbon atoms, and more preferably an ethoxy group, a propoxy group, an isopropoxy group or a butoxy group.
• the “di (lower alkyl) amino group” means an amino group disubstituted with a lower alkyl group, and examples thereof include a dimethylamino group and a jetylamino group.
• the “di (lower alkyl) amino lower alkyl group” means a lower alkyl group substituted with a di (lower alkyl) amino group, and examples thereof include a dimethylaminomethyl group.
• “Lower acyl group” means a group represented by (lower alkyl) —CO 2, and includes, for example, an acetyl group, a propionyl group, a petityl group, an isoptyryl group, a bivaloyl group, a valeryl group, an isovaleryl group, and the like. And is preferably a acetyl group.
• the "lower alkylsulfur group” means a group represented by (lower alkyl) -S-, for example, a methylsulfur group, an ethylsulfur group, a propylsulfur group, Examples thereof include an isopropylsulfur group, a butylsulfuric group, a pentylsulfuric group, a hexylsulfuric group, and the like, and a methylsulfuric group or an ethylsulfuric group is preferable.
• “Lower alkylsulfol group” means a group represented by (lower alkyl) -SO-
• Examples thereof include a methanesulfol group, an ethanesulfol group, a propanesulfol group, a butanesulfol group, a pentanesulfol group, and a hexanesulfol group, preferably a methanesulfol group. is there.
• the "lower alkoxy carbo group” means a group represented by (lower alkoxy) CO 2, for example, a methoxy carbo ol group, an ethoxy carbo ol group, a propoxy carbo ol group, an iso Propoxycarbon group, butoxycarbon group, isobutoxycarbol group, sec butoxycarbon group, tert butoxycarbol group, pentyloxycarbon group, hexyloxycarbon group, etc. And preferably a methoxy carbo yl group, an ethoxy carbo ol group, a propoxy carbo ol group, an isopropoxy carbo ol group or a butoxy carbonyl group.
• aryl group is an unsubstituted or group of the following groups: a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group, a carboxy group, and a lower alkoxycarbonyl group independently. This means an aromatic hydrocarbon group having 6 to 14 carbon atoms, which is substituted with 1 to 3 selected groups.
• Aryloxy group means a group represented by (aryl) O, for example, a phenoxy group, a 2 fluorophenoxy group, a 3 fluorophenoxy group, a 4 fluorophenoxy group, 2 Chlorophenoxy group, 4 Chlorophenoxy group, 3, 5 Dichlorophenoxy group, 4-Methylphenoxy group, 4 Trifluoromethylphenoxy group, 2-Methoxyphenoxy group, 4-Methoxyphenoxy group Group, 2 hydroxyphenoxy group, 4 carboxyphenoxy group, 4 methoxycarbophenoxy group, naphthyloxy group, anthryloxy group, phenanthryloxy group, etc., preferably phenoxy group, 4-fluorophenoxy group , 4-chlorophenoxy group, 4-methylphenoxy group or 4-methoxyphenoxy group.
• the "aralkyloxy group” means a lower alkoxy group substituted with an aryl group.
• Examples thereof include a benzyloxy group, a 4-carboxybenzyloxy group, and a 4-methoxycarbolpendioxy group, and a benzyloxy group is preferable.
• the "aralkyloxycarbonyl group” means a group represented by (aralkyloxy) CO 2, for example, a benzyloxycarbonyl group, a phenoxycarbonyl group, 3 Examples thereof include a phenylpropylcarbonyl group, and a benzyloxycarbonyl group is preferred.
• the "heteroaryl group” includes 1 to 5 carbon atoms and 1 to 4 heteroatoms independently selected from the group power of nitrogen atom, oxygen atom and sulfur nuclear power. Or a 6-membered aromatic heterocyclic group, provided that these rings do not contain adjacent oxygen and Z or sulfur atoms.
• Specific examples of the heteroaryl group include, for example, pyrrolyl, furyl, chenyl, imidazolyl, pyrazolyl, 1, 2, 4 triazolyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, pyridyl, birazinyl Group, pyrimidyl group and the like.
• aromatic heterocyclic groups All positional isomers of these aromatic heterocyclic groups are conceivable (for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.). Further, these aromatic heterocycles are independently selected from the group force including a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group, a carboxy group, and a lower alkoxy carbo group as necessary. It can be substituted with 1 to 3 groups.
• Preferred heteroaryl groups are imidazolyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl or pyrimidyl groups.
• the "carboxy lower alkyl group” means a lower alkyl group substituted with a carboxy group.
• a carboxymethyl group for example, a 2-carboxyethyl group, a 1 carboxyethyl group, a 3-carboxypropyl group, 4 Examples thereof include a carboxybutyl group, and a carboxymethyl group is preferred.
• the "lower alkoxycarbonyl lower alkyl group” means a lower alkyl group substituted with a lower alkoxycarbonyl group, and examples thereof include a methoxycarboromethyl group, an ethoxycarboromethyl group, a propoxycarboromethyl group, Propoxycarbonyl methyl group, butoxycarboromethyl group, 2- (ethoxycarbol) ethyl group, 1 (ethoxycarboxyl) ethyl group, 3- (ethoxycarbol) propyl group, 4 (ethoxycarbo- And butyl group, and the like, and preferably a methoxycarboromethyl group, an ethoxycarboromethyl group, a propoxycarboromethyl group, an isopropoxycarboromethyl group, or a butoxycarbonylmethyl group.
• Cyclic amine or cyclic amino group means a 5- to 7-membered saturated cyclic amino group that may contain an oxygen atom in the ring, and examples thereof include a pyrrolidyl group, a piperidyl group, and a morpholinyl group. It is done.
• the “lower alkylene group” means a linear or branched divalent saturated hydrocarbon chain having 1 to 4 carbon atoms, such as —CH 1, —CH 2 CH 1, —CH 2 ( CH) 1, -CH CH C
• the biphenyl bond is a phenyl ring to which R 3 , R 4 , R 5 or is bonded, and R 7 , R 8 or R 9 is bonded. Represents the bond between the ring and the ring.
• the present invention relates to a compound in which each asymmetric carbon atom is in the R configuration, S configuration And compounds of any combination thereof. Further, those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures are included in the scope of the present invention.
• the present invention includes any of the cis isomer, trans isomer, and mixtures thereof.
• the compound represented by the general formula (I) of the present invention includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
• the compound represented by the general formula (I) of the present invention can exist in the form of a salt.
• Such salts include addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfone.
• Acid propionic acid, succinic acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and other addition salts with organic acids, sodium salts, Examples thereof include salts with inorganic bases such as potassium salts and calcium salts, and salts with organic bases such as triethylamine, piperidine, morpholine, lysine and ethylenediamine.
• prodrug means a compound that is converted into a compound represented by the general formula (I) in a living body, and such a prodrug is also within the scope of the present invention.
• Various forms of prodrugs are well known in the art.
• the compound represented by the general formula (I) of the present invention has a carboxy group, as a prodrug, a hydrogen atom of the carboxy group and the following group: a lower alkyl group (for example, methyl Group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, etc.); lower acyloxymethyl group (for example, bivalyloxymethyl group, etc.); 1- (lower acyloxy) ethyl group ( For example, 1- (bivaloyloxy) ethyl group); 1- (lower alkoxycarbonyloxy) ethyl group (eg 1- (tert-butoxycarbonyloxy) ethyl group); or 3-phthalidyl group (for example, tert-butoxycarboxoxymethyl group); And esters formed by substitution with groups.
• a lower alkyl group for example, methyl Group, ethyl group, propyl group, is
• the compound represented by the general formula (I) of the present invention has a hydroxyl group, as a prodrug, a hydrogen atom of the hydroxyl group and the following group: a lower acyl group (for example, an acetyl group, Propiol group, ptylyl group, isoptylyl group, bivaloyl group, etc.); lower alkoxy group (for example, methoxycarbol group, ethoxycarbol group, propoxycarbol group, isopropoxycarbonyl group, tert-butoxycarboxyl group); succinoyl group; lower acyloxymethyl group (for example, bivalyloxymethyl group); 1— (lower acyloxy) ethyl group (for example, 1- (bivalyloxy)) Or a compound formed by substitution with a lower alkoxycarboxoxymethyl group (eg, tert butoxycarboxoxymethyl group). It is.
• a lower acyl group for example, an acety
• a carbonyl group for example, a methoxycarbol group, an ethoxycarbonyl group, a propoxycarb group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, etc.
• prodrug compounds are synthesized according to a method known per se, for example, TWGreen and PGH .Wuts, [Protective uroups in Organic Synthesis J d
• R 1 and R 2 are each independently preferably a hydrogen atom or C lower alkyl
• a group more preferably a hydrogen atom
• R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, preferably a hydrogen atom, a halogen atom.
• R 3 , R 4 , R 5 and R 6 are hydrogen atoms
• R 7 and R 8 are each independently preferably a hydrogen atom, a halogen atom, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group, an aryloxy group, a lower alkylsulfanyl group, a hydroxyl group or a lower acyl. More preferably a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, an aryloxy group, a hydroxyl group or a lower acyl group;
• R 9 is preferably —C (O) —R 10 or —OCH 2 C (O) —R 10 ;
• R 1C is preferably a hydroxyl group or a lower alkoxy group.
• a preferred embodiment of the present invention is a compound of the general formula (II):
• a prophylactic or therapeutic agent for fatty liver comprising the amino alcohol derivative represented by: or a pharmacologically acceptable salt thereof as an active ingredient;
• R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;
• R 7 and R 8 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower lower alkyl group, a cycloalkyl group, a lower alkoxy group, an aryloxy group, a lower alkylsulfur group, a hydroxyl group, or a lower group. Is an acyl group;
• R 9 is C (O) —R 10 or one OCH C (O) —R 10 ;
• R 1G is a hydroxyl group, a lower alkoxy group or an aralkyloxy group
• R 3 , R 4 , R 5 and R 6 is a halogen atom, a lower alkyl group or a lower alkoxy group.
• R 3 , R 4 , R 5 and R 6 is a halogen atom, a lower alkyl group or a lower alkoxy group.
• R 7 is preferably a hydrogen atom
• R 8 is preferably a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, an aryloxy group, a hydroxyl group or a lower acyl group, and more preferably a lower alkyl group, a cycloalkyl group, A lower alkoxy group, an aryloxy group, a hydroxyl group or a lower acyl group, still more preferably a lower alkyl group, a lower alkoxy group, an aryloxy group or a lower acyl group;
• R 4 is preferably a hydrogen atom, a halogen atom or a lower alkyl group
• R 5 is preferably a halogen atom or a lower alkyl group. More preferably, R 4 and R 5 are each independently a lower alkyl group
• R 4 and R 6 are hydrogen atoms
• R 3 is preferably a halogen atom or a lower alkyl group
• R 5 is preferably a hydrogen atom, a halogen atom or a lower alkyl group. It is.
• Another preferred embodiment of the present invention is a compound represented by the general formula (III):
• a prophylactic or therapeutic agent for fatty liver comprising as an active ingredient an amino alcohol derivative represented by the formula or a pharmacologically acceptable salt thereof;
• R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;
• R 7 and R 8 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower lower alkyl group, a cycloalkyl group, a lower alkoxy group, an aryloxy group, a lower alkylsulfur group, a hydroxyl group, or a lower group. Is an acyl group;
• R 9 is C (O) —R 10 or one OCH C (O) —R 10 ;
• R 1U is a hydroxyl group, a lower alkoxy group or an aralkyloxy group; provided that at least one of R 3 , R 4 , R 5 and R 6 is a halogen atom, a lower alkyl group or a lower alkoxy group.
• R 3 and R 6 are preferably hydrogen atoms
• R 4 is preferably a hydrogen atom or a lower alkyl group
• R 5 is preferably a lower alkyl group
• R 7 is preferably a hydrogen atom
• R 8 is preferably a halogen atom or a lower alkyl group.
• Yet another preferred embodiment of the present invention is a compound of the general formula (IV):
• R 7 and R 8 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group or an aryloxy group;
• R 9 is C (O) —R 10 or one OCH C (O) —R 10 ;
• R 1C> is a hydroxyl group, a lower alkoxy group or an aralkyloxy group.
• R 7 is preferably a hydrogen atom
• R 8 is preferably a halogen atom, a lower alkyl group, a halo lower alkyl group, a cycloalkyl group, a lower alkoxy group or an aryloxy group, more preferably a lower alkyl group, a halo lower alkyl group or an aryloxy group.
• Specific examples of preferred embodiments of the present invention include prevention or prevention of fatty liver containing as an active ingredient a selected compound or a lower alkyl ester thereof, or a pharmacologically acceptable salt thereof.
• amino alcohol derivative represented by the general formula (I) of the present invention can be produced by the methods shown in Schemes 1 to 5.
• R 8 and R 9 are as defined above, and Y 1 represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfo-oxy group, or a ⁇ -toluene sulfo-oxy group)
• the amino alcohol derivative (X) and the alkylating agent (XI) in an inert solvent eg, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide, acetonitrile, etc.
• an inert solvent eg, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide, acetonitrile, etc.
• a base eg, ⁇ , ⁇ diisopropylethylamine, triethylamine, etc.
• the compound represented by the general formula (I) can be obtained by reacting in the absence.
• the compound (I) having a carboxylic acid ester group in R 7 , R 8 , and R 9 is prepared by hydrolysis using an aqueous alkali solution in an appropriate solvent (eg, ethanol) as necessary. Can be converted to carboxylic acid.
• compound (I) having a carboxyl group in R 9 can be obtained by using a condensing agent (eg diphenylphosphoryl azide, cyanophosphoric acid) in an inert solvent (eg tetrahydrofuran, methylene chloride, N, N dimethylformamide, etc.).
• a condensing agent eg diphenylphosphoryl azide, cyanophosphoric acid
• an inert solvent eg tetrahydrofuran, methylene chloride, N, N dimethylformamide, etc.
• R 9 and Y 1 are as defined above, R 3 ° is a force representing a hydrogen atom or a lower alkyl group, or two R 3G are — C (CH) C (CH)
• Y 2 represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfo-loxy group
• the compound represented by the general formula (XIII) is obtained by reacting the amino alcohol derivative (X) with the alkylating agent (XII) in the same manner as in Step 1-1.
• Compound (I) is obtained by reacting this compound (XIII) and boronic acid derivative (XIV) in an inert solvent in the presence of a palladium catalyst and a base.
• a palladium catalyst examples include N, N-dimethylformamide, 1,4-dioxane, toluene, and the like.
• the noradium catalyst examples include tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), and the like.
• the base include cesium fluoride and sodium carbonate.
• this reaction can be carried out by adding a ligand such as bis (diphenylphosphino) phenol, if necessary.
• Steps 2-3 and 2-4 Compound (I) can also be obtained by the following reaction. That is, the compound represented by the general formula (XVI) is obtained by reacting the amino alcohol derivative (X) and the alkylating agent (XV) in the same manner as in Step 1-1. Compound (I) is obtained by reacting compound (XVI) and compound (XVII) in the same manner as in Step 2-2.
• Compound (XVI) reacts compound (XIII) with bis (pinacolato) diboron in an inert solvent (eg, N, N-dimethylformamide, 1,4-dioxane, etc.) in the presence of a palladium catalyst and a base.
• a palladium catalyst include dichlorobis (triphenylphosphine) palladium (II).
• the base include potassium acetate.
• this reaction can be carried out by adding a ligand such as bis (diphenylphosphino) pheocene if necessary.
• the compound represented by the general formula (la) is obtained by reacting the amino alcohol derivative (X) and the aldehyde derivative (XVIII) in an appropriate solvent in the presence of a reducing agent.
• Solvents that can be used in this reductive amination reaction include, for example, ethers such as tetrahydrofuran and 1,4-dioxane, halogenated carbons such as methylene chloride, organic power rubonic acids such as acetic acid, hydrocarbons such as toluene, Examples include alcohols such as methanol and ethanol, and acetonitrile. If necessary, combine two or more of these solvents. Can be used.
• the reducing agent include NaBH, NaBH CN, NaBH (
• this reaction can be carried out by adding an acid such as acetic acid, ⁇ -toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, if necessary.
• an acid such as acetic acid, ⁇ -toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, if necessary.
• this reaction is carried out by using a catalytic amount of a metal catalyst (for example, 5-10% palladium carbon, Raney nickel, platinum oxide, non-radium black, 10% platinum Etc.) in the presence of hydrogen.
• a metal catalyst for example, 5-10% palladium carbon, Raney nickel, platinum oxide, non-radium black, 10% platinum Etc.
• This reductive amination reaction is carried out by selecting an appropriate reduction condition depending on the type of substituent in compound (XVIII).
• the compound (la) can also be obtained by the following reaction.
• the compound represented by the general formula (XXII) is obtained by reacting the amino alcohol derivative (X) and the aldehyde (XXI) in the same manner as in Step 3-1.
• This compound (XXII) can also be obtained by reacting compound (XX) with bis (pinacolato) diboron in the same manner as in Step 2-5.
• Compound (la) is obtained by reacting compound (XXII) and compound (XVII) in the same manner as in Step 2-2.
• Step 5-1 By reacting the amino alcohol derivative (X) with the carboxylic acid derivative ( ⁇ ) in an inert solvent (eg, tetrahydrofuran, methylene chloride, N, N dimethylformamide, etc.) in the presence of a condensing agent ( An amide derivative represented by XXIV) is obtained.
• an inert solvent eg, tetrahydrofuran, methylene chloride, N, N dimethylformamide, etc.
• condensing agent An amide derivative represented by XXIV
• condensing agents include diphenylphosphoryl azide, cyanoethyl hexylate, 1,3 dicyclohexylcarbodiimide, 1 [3 (dimethylamino) propyl] 3 ethylcarbodiimide hydrochloride, and benzotriazol.
• rhoyloxytris (dimethylamino) phospho-hexafluorophosphate for example, rhoyloxytris (dimethylamino) phospho-hexafluorophosphate.
• this reaction can be carried out by adding an activator such as N-hydroxysuccinimide or 1-hydroxybenzotriazole, if necessary.
• the amide derivative (XXIV) is obtained by converting the carboxylic acid derivative (XXIII) into an active ester (for example, 4-trophenyl ester, 2,5-dioxapyrrolidine ester, etc.) based on a conventional method. It can also be obtained by reacting with an amino alcohol derivative (X).
• an active ester for example, 4-trophenyl ester, 2,5-dioxapyrrolidine ester, etc.
• This compound (XXIV) is reacted with a reducing agent such as diborane, borane'tetrahydrofuran complex, borane'dimethylsulfide complex, borane'pyridine complex, sodium borohydride Z acetic acid in an inert solvent (eg tetrahydrofuran).
• a reducing agent such as diborane, borane'tetrahydrofuran complex, borane'dimethylsulfide complex, borane'pyridine complex, sodium borohydride Z acetic acid in an inert solvent (eg tetrahydrofuran).
• the compound (la) can also be obtained by the following reaction. That is, the compound represented by the general formula (XXVI) is obtained by reacting the amino alcohol derivative (X) and the carboxylic acid (XXV) in the same manner as in Step 5-1. By reducing this compound (XXVI) in the same manner as in Step 5-2, a compound represented by the general formula (XXII) can be obtained. This compound (XXII) can also be obtained by reacting compound (XX) in the same manner as in Step 2-5. Compound (la) is obtained by reacting Compound (XXII) and Compound (XVII) in the same manner as in Step 2-2. [0079] Among the starting materials used in Scheme 1 or 2, alkylating agents (XI), (XII)
• a compound represented by the general formula (XII) is obtained.
• the azodicarboxylic acid dialkyl ester used in this reaction include jetyl azodicarboxylate, diisopropyl azodicarboxylate, and the like.
• a compound represented by the general formula (XXVIII) is obtained by reacting a phenol derivative (XXVII) and a boronic acid derivative (XIV) in the same manner as in Step 2-2.
• This compound (XX VIII) can also be obtained by reacting phenol derivative (XXIX) and compound (XVII) in the same manner as in Step 2-2.
• This compound (XXVIII) and alcohol derivatives (XXX) Can be reacted in the same manner as in Step 6-1 to obtain the compound represented by the general formula (XI).
• the compound represented by the general formula (XV) is obtained by reacting the phenol derivative (XXIX) and the alcohol derivative (XXX) in the same manner as in Step 6-1.
• R 3 , R 4 , R 5 , R 6 , R 9 , R 3 , Y 1 and ⁇ 2 are as defined above, R 2 ° represents a lower alkyl group, and X 1 represents a chlorine atom or a bromine atom)
• This compound (XXXII) can also be obtained by the following reaction. That is, phenol derivative (XXVII) and compound (XXXI) are present in an inert solvent (eg, N, N-dimethylformamide, acetonitrile) in the presence of a base (eg, potassium carbonate, cesium carbonate, etc.).
• a base eg, potassium carbonate, cesium carbonate, etc.
• the phenoxyacetate is obtained by reacting below.
• This phenoxyacetic acid ester is used with an appropriate reducing agent (borane 'tetrahydrofuran complex, borane' dimethylsulfide complex, borane 'pyridin complex, sodium borohydride, etc.) in an inert solvent (eg tetrahydrofuran). Reduction (compound (XXXII)) is obtained.
• This compound (XXXII) can be converted to a sulfol halide in an inert solvent (eg, methylene chloride, chloroform, etc.) in the presence of a halogenating reagent or a base (eg, N, N-diisopropylethylamine).
• a halogenating reagent e.g, N, N-diisopropylethylamine
• the compound represented by the general formula (Xlla) is obtained by reacting with.
• a halogenating reagent include chlorothionyl, phosphorus tribromide, triphenylphosphine Z carbon tetrabromide, and the like.
• the sulfonyl chloride include methanesulfuryl chloride, p-toluenesulfuryl chloride, and the like.
• Compound (XXXIII) can also be obtained by reacting compound (XXXII) and boronic acid derivative (XIV) in the same manner as in Step 2-2. Furthermore, this compound (XXXIII) can also be obtained by reacting compound (XXXIV) and compound (XVII) in the same manner as in Step 2-2. Can do.
• aldehyde derivatives (XVIII), (XIX) and (XXI) can be produced by the method shown in Scheme 8 or 9.
• An aldehyde derivative represented by the general formula (XIX) can be obtained by acidifying an alcohol derivative ( ⁇ ) with an appropriate oxidizing agent in an inert solvent (eg, methylene chloride).
• an inert solvent eg, methylene chloride
• oxidizing agents include oxalyl chloride, Z dimethyl sulfoxide, or 1,1,1 triacetoxy 1,1-dihydro-1,2-benzodoxol.
• a base sodium hydride, carbonated rhodium, cesium carbonate, etc.
• the acetal derivative (XXXVI) is hydrolyzed with an acid according to a conventional method to obtain an aldehyde derivative represented by the general formula (XIX).
• the compound represented by the general formula (XXXVII) is obtained by reacting the compound (xxvm) with the alkylating agent (XXXV) in the same manner as in Step 9-1.
• This compound (XXXVII) is hydrolyzed in the same manner as in step 92 to induce the aldehyde derivative represented by the general formula (XVIII).
• a conductor is obtained.
• Compound (XXXVII) can also be obtained by reacting compound (XXXVI) and boronic acid derivative (XIV) in the same manner as in Step 2-2. Furthermore, this compound (XXXVII) can also be obtained by reacting compound (XXXVIII) and compound (XVII) in the same manner as in Step 2-2.
• the boronic acid derivative (XIV) used in Schemes 2, 4 and 5 can be synthesized using a commercially available reagent or according to a conventional method.
• the compounds (XlVa) and (XlVb) in which R 9 is a lower alkoxy group and a carboxy group are represented by the scheme
• R 7 , R 8 and R 2 ° are as defined above, Y 3 represents a chlorine atom, a bromine atom or an iodine atom, and Bn represents a benzyl group)
• the allylic halide derivative (XXXIX) is lithiated based on a conventional method and reacted with carbon dioxide to obtain a benzoic acid derivative represented by the general formula (LX).
• This compound (LX) can also be obtained by the following reaction. That is, After introducing a formyl group, such as tert-butyl alcohol, 2-methyl-2-butene, etc., into a suitable oxidant (eg, chlorous acid) Benzoic acid derivatives (LX) can be obtained by acidification using sodium or the like.
• a formyl group such as tert-butyl alcohol, 2-methyl-2-butene, etc.
• benzoic acid derivatives (LX) can be obtained by acidification using sodium or the like.
• this compound (LX) is subjected to esterification and debenzylation according to a conventional method to obtain a benzoic acid ester derivative represented by the general formula (LXII).
• the compound represented by the general formula (XlVa) is obtained by reacting in the same manner as 2-5.
• the boronic acid ester derivative (XlVa) can also be obtained by reacting the halogenated benzoic acid derivative (XVIIa) with bis (pinacolato) diboron in the same manner.
• This compound (XlVa) is hydrolyzed with an aqueous alkaline solution according to a conventional method to obtain a boronic acid derivative represented by the general formula (XlVb).
• the compound (XXXIV) can also be obtained by the following reaction. That is, the compound represented by the general formula (LXVI) is obtained by reacting compound (XXXII) with bis (pinacolato) diboron in the same manner as in Step 2-5. Compound (XXXIV) is obtained by hydrolyzing this compound (LXVI) as necessary.
• a compound represented by the general formula (LXVIII) is obtained by reacting a phenol derivative (LXVII) with a halogenating agent in an appropriate solvent.
• a solvent that can be used for the halogenation reaction include inorganic acids such as sulfuric acid, organic carboxylic acids such as acetic acid, and halogenated hydrocarbons such as salt and methylene.
• the halogenating agent include bromine, N-chlorosuccinimide, N-bromosuccinimide, hydrobromic acid Z-dimethyl sulfoxide, and the like.
• a compound represented by the general formula (XVIIb) is obtained.
• the solvent that can be used in this reaction include N, N-dimethylformamide, dimethyl sulfoxide and the like.
• the phosphine ligand include triphenylphosphine and 1,3-bis (diphenylphosphino) propane.
• the noradium catalyst include palladium acetate.
• the base include triethylamine.
• the amino alcohol derivative represented by the formula (X) used in the above scheme is capable of optically resolving a commercially available enantiomeric mixture according to a conventional method, a method described in the literature (for example, rj. Med. Chem., 1977, 20-7, p.978-981).
• the compound represented by the general formula (I) of the present invention and the intermediate used for producing the compound are isolated and purified as necessary by those skilled in the art. By performing operations such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, it can be isolated and purified.
• the compound of the present invention thus produced has an action of reducing the content of fat in the liver, and is useful as an agent for preventing or treating fatty liver.
• fatty liver refers to a disease in which fat such as triglyceride accumulates abnormally in the liver, and the ratio of the amount of fat to normal cells in the liver and the liver weight increase abnormally, It is a disease in which the size of the liver is abnormally increased, and includes a progressive type in which the amount of accumulated fat further increases. Furthermore, it includes those that shift to other diseases due to fat accumulation and those that accompany inflammation. Specifically, in addition to general fatty liver, non-alcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), hypertrophic fatty liver, alcoholic fatty liver, toxic fatty liver, diabetes Fatty liver, acute pregnant fatty liver, and the like.
• NAFL non-alcoholic fatty liver
• NASH nonalcoholic steatohepatitis
• hypertrophic fatty liver alcoholic fatty liver
• alcoholic fatty liver toxic fatty liver
• diabetes Fatty liver acute pregnant fatty liver, and the like.
• the preventive or therapeutic effect of the liver can be confirmed, for example, by a test using CD (SD) -IGS rats that develop fatty liver by administration of a high fat diet (CE-2).
• SD CD
• CE-2 high fat diet
• the aminoamino derivative represented by the above general formula (I) is orally administered to rats, symptoms such as increase in the amount of fat accumulated in the rat liver are observed when the compound is not administered. It was confirmed that it was significantly suppressed as compared with the case.
• the above results indicate that the pharmaceutical composition containing the amino alcohol derivative represented by the general formula (I) as an active ingredient prevents fatty liver, which is considered to be caused by fat accumulation in the liver. This proves that it is extremely effective as a therapeutic agent.
• the compound represented by the general formula (I), which is an active ingredient can be used in combination with one or more other drugs used for fatty liver as appropriate. wear.
• Other drugs that can be used in combination include, for example, polyphosphatidylcholine preparations and Daisaikoto.
• examples of the drug that may be used in combination with drugs other than those mentioned above include metformin, troglitazone, pioglitazone hydrochloride, bezafibrate or voglibose. It is done.
• the pharmaceutical composition of the present invention is a suitable excipient, a disintegrant, a binder, a lubricant, a diluent, and a buffering agent, depending on the method used for pharmacology itself or depending on the dosage form.
• a suitable excipient such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, etc.
• Fine granules, dry syrups, tablets, capsules, solutions, injections, ointments, suppositories, patches, etc. and can be administered orally or parenterally .
• sustained-release preparations including gastrointestinal mucosa-adhesive preparations and the like may be used (see, for example, WO99Z10010 pamphlet, WO99Z16606 pamphlet, and JP2001-2567).
• the dose of the compound represented by the general formula (I) is appropriately determined depending on the patient's age, sex, weight, disease severity, etc. In the case of oral administration, about 0.03 mg to In the case of parenteral administration in the range of about 30 Omg, the dose can be appropriately administered once or in several divided doses in the range of about 0.003 mg to about 30 mg per day for an adult.
• the dose of the compound represented by the general formula (I) is the compound represented by the general formula (I). The dose can be reduced according to the dose of other drugs.
• the pharmaceutical composition of the present invention containing the amino alcohol derivative represented by the above general formula (I) as an active ingredient reduces the content of liver fat, It has the effect of suppressing abnormal accumulation and is extremely suitable as a preventive or therapeutic agent for fatty liver. Therefore, by using the amino alcohol derivative represented by the above general formula (I), prevention of fatty liver without compulsory dietary restriction by conventional dietary therapy or exercise therapy that is difficult to maintain Alternatively, an excellent pharmaceutical composition for treatment can be provided.
• This methanesulfonic acid 4 bromo-2-isopropylphenol (0.71 g), palladium acetate (0.023 g), 1,3 bis (diphenylphosphino) propane (0.042 g) and trilamine (0.63 mL) Of methanol (6 mL) Z dimethyl sulfoxide (9 mL) was stirred overnight at 55 ° C. under a carbon oxide atmosphere. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: jetyl ether Zn-hexane 1Z10) to obtain the title compound (0.355 g).
• the mixture was stirred at 80 ° C for 24 hours.
• the reaction mixture was poured into water and extracted with ethyl acetate.
• the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
• Lithium hydroxide monohydrate (0.092 g) was added to a mixture of water (lmL) and 1,4 dioxane (lmL) of 4-ethoxycarbol 2-methoxyphenylboronic acid (0.049 g) at room temperature. Stir overnight. 2 mol ZL hydrochloric acid (1.09 mL) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The obtained residue was washed with water to give the title compound (0.035 g).
• Reference Example 30 The following compounds were obtained in the same manner as in Reference Example 29 using the corresponding arylpromide.
• Methanesolephonic acid 2 [2,6-Dimethinole 4- (4, 4, 5, 5—Tetramethinole 1, 3, 2-dioxaborolane-2-yl) phenoxy] ethyl
• Methanesulfonic acid 2 [4— (4, 4, 5, 5—tetramethyl-1, 3, 2 dioxaborolane 2—yl) phenoxy] ethyl
• Methanesulfonic acid 2 [4— (4, 4, 5, 5—tetramethyl-1,3,2 dioxaborolane —2-yl) phenoxy] ethyl (1.20 g) and 4 ((1R, 2S) — A mixture of 2 amino-1-hydroxypropyl) phenol (1.76 g) in N, N dimethylformamide (20 mL) was stirred at 80 ° C. for 5 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
• R group represents a binding site
• R group represents a binding site
• R group represents a binding site
• R group represents a binding site
• R group represents a binding site
• R group represents a binding site
• reaction mixture was diluted with tetrahydrofuran (2.5 mL) and conditioned with tetrahydrofuran, SCX ion exchange column (Argonone lg, washing solvent: tetrahydrofuran, elution solvent: 2 mol ZL ammonia methanol solution), then Reversed phase preparative column chromatography (Shiseido CAPCELL PAK C18
• reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate, the organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
• R group represents a binding site
• CD 3 OD 1.14-1.18 (3H, m), 2.24 (3H, s), 2.54 (3H, s), 3.32-3.45 (3H, m), 3.88 (3H, s), 4.19-4.33 (2H, m ), 4.85-4.90 (1H, m), 6.78-6.82 (2H, m), 7.02
• R group represents a binding site

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