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WO2000050392A1 - Derives de l'acide 2-mercaptocarboxylique - Google Patents

Derives de l'acide 2-mercaptocarboxylique Download PDF

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Publication number
WO2000050392A1
WO2000050392A1 PCT/JP2000/001045 JP0001045W WO0050392A1 WO 2000050392 A1 WO2000050392 A1 WO 2000050392A1 JP 0001045 W JP0001045 W JP 0001045W WO 0050392 A1 WO0050392 A1 WO 0050392A1
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group
phenyl
alkyl
substituents
substituent
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English (en)
Japanese (ja)
Inventor
Hiroshi Kurobe
Tetsuji Nunozawa
Tomokazu Sugawara
Kouei Moriguchi
Takeshi Endo
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Fuji Chemical Industries Co Ltd
Sankyo Co Ltd
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Fuji Chemical Industries Co Ltd
Sankyo Co Ltd
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Priority to AU26906/00A priority Critical patent/AU2690600A/en
Publication of WO2000050392A1 publication Critical patent/WO2000050392A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07C323/51—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 atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—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 atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • 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
    • C07C323/51—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 atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—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 atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms

Definitions

  • the present invention relates to a novel 2-mercaptocarboxylic acid derivative, a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof, and a thiazolidine-2,4-dione derivative used as a synthetic intermediate thereof.
  • the present invention provides a 2-mercaptocarboxylic acid derivative having an excellent insulin resistance improving action, a blood glucose lowering action, a lipid lowering action, an anti-inflammatory action, an immunoregulatory action, a lipid peroxide production inhibitory action, and a PPAR activating action.
  • a pharmacologically acceptable ester thereof, a pharmacologically acceptable salt thereof, and a thiazolidine-2,4-dione derivative used as a synthetic intermediate thereof.
  • the present invention relates to the above-mentioned 2-mercaptocarboxylic acid derivative, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof, and thiazolidine-2,4- used as a synthetic intermediate thereof.
  • Diabetes hyperlipidemia, obesity, impaired glucose tolerance, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neuropathy, coronary artery disease, etc.) containing a dione derivative as an active ingredient, arteriosclerosis Disease, cardiovascular disease (eg, ischemic heart disease, etc.), cell injury caused by atherosclerosis or ischemic heart disease (eg, brain injury caused by stroke, etc.)
  • inflammatory diseases eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, autoimmune disease, knee inflammation, etc.
  • preventive and / or therapeutic agents preferably) Is diabetes Or a prophylactic and / or therapeutic agent for hyperlipidemia.
  • the present invention provides a prophylactic or therapeutic agent for the above-mentioned diseases containing the above-mentioned compound as an active ingredient, a composition for preventing or treating the above-mentioned diseases containing the above-mentioned compound as an active ingredient, a prophylaxis or treatment for the above-mentioned diseases.
  • the present invention relates to the use of the above-mentioned compound for the manufacture of a medicament for the treatment of, or a method for preventing or treating the above-mentioned disease, wherein a pharmacologically effective amount of the above-mentioned compound is administered to a warm-blooded animal (preferably a human being).
  • biguanide compounds and sulfonylprea compounds have been used as therapeutic agents for diabetes.
  • biguanide compounds are rarely used at present because they cause acidosis.
  • sulfonyliderea compounds have potent hypoglycemic effects, they often cause severe hypoglycemia, and care must be taken when using them. Therefore, a therapeutic agent for diabetes having few side effects has been desired.
  • the present inventors have focused on 2-mercaptocarboxylic acid derivatives to search for a remedy for diabetes that does not have such a drawback, and made intensive studies.
  • 2-mercaptocarboxylic acid derivative for example, the following compounds and their pharmacological actions have been reported.
  • JP-A-6-65524 discloses a method of using a thioether carboxylic acid derivative as a cosmetic composition for topical application to skin, hair, and nails, especially to the skin,
  • references (1) to (8) do not describe the 2-mercaptocarboxylic acid derivative, which is the compound of the present invention, and the references (1) to (4) and (6) to (8) There is no description of using the above compound as a hypoglycemic or lipid lowering agent.
  • WO 92/1 7435 describes that a thioethercarboxylic acid derivative is useful as a therapeutic agent for diabetes, early stage diabetes, especially adult-onset diabetes.
  • JP-A-63-174948 states that thioethercarboxylic acid derivatives are useful as therapeutic agents for diabetes, prediabetes, especially allogeneic diabetes, and lipid metabolism disorders, and triglyceride and cholesterol levels. There is a statement that it has a lowering effect.
  • WO 98/28254 describes that thioether propionic acid derivatives have a hypoglycemic effect and a hypolipidemic effect.
  • WO 96/1 9466 states that thiolcarboxylic acid derivatives are useful as synthetic intermediates of rhodanine derivatives and as therapeutic agents for inflammatory bowel diseases.
  • JP-T 5-507920 discloses that thioethercarboxylic acid derivatives are useful as hypoglycemic agents.
  • JP-T-Hei 7-505647 describes that alkylthiocarboxylic acids are useful as therapeutic agents for type II diabetes.
  • references (9) to (14) describe only a relatively short-chain carboxylic acid derivative having 3 or less carbon atoms, such as a 2-substituted propionic acid, or a 2-arylthio or 2-alkylthiocarboxylic acid derivative. There is no description of a relatively long-chain carboxylic acid derivative having a mercapto group at the 2-position in the compound of the present invention.
  • a method via a thiazolidinedione compound is mainly employed as a synthetic intermediate.
  • Thiazolidinedione compounds include, for example, (15) W097 / 47612, (16) JP-A-8-104688, (17) JP-A-9-100280, (18) JP-A-9-13 6877, (19) JP-A-10-182461, (20) JP-A-9-176163, (21) JP-A-9-25273, (22) JP-A-9-235284, (23) JP-A-8-1 57473 (24) JP 8-208648, (25) JP 7-173 158, (26) JP 6-247945, (27) JP 7-309852, (28) JP 6-9629, (29) JP-A-5-21 391 3, (30) JP-A 1-227257, (31) JP-A 1-272573, (32) JP-A 64-13088, (33) JP-A 63-63 230689, (34) JP-A-64-56675, (35) JP-A-59-48471, (36) JP-A-58-118577, (37) JP-
  • the present inventors have conducted experiments for many years with the aim of searching for compounds having various physiological activities.As a result, the present inventors have found that 2-mercaptoforce ruponic acid derivatives having a novel structure or their pharmacologically acceptable properties. -2,4-dione derivatives used as esters or their pharmacologically acceptable salts and their synthetic intermediates have excellent insulin-resistance improving, hypoglycemic, lipid-lowering and anti-inflammatory properties The present inventors have found that they have an action, an immunoregulatory action, a lipid peroxide production inhibitory action, and a PPAR activating action, and have completed the present invention.
  • Another object of the present invention is to provide the above-mentioned 2-mercaptocarboxylic acid derivative, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof, and thiazolidine-2,4-dione used as a synthetic intermediate thereof.
  • Glycaturia hyperlipidemia, obesity, impaired glucose tolerance, fatty liver, diabetic complications (eg, retinopathy, nephropathy, neurosis, coronary artery disease, etc.) containing the derivative as an active ingredient, artery Cell damage caused by sclerosis, cardiovascular disease (eg, ischemic heart disease, etc.), atherosclerosis or ischemic heart disease (eg, brain damage caused by stroke, etc.) ), Inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, autoimmune disease, knee inflammation, etc.) (particularly diabetes and hyperlipidemia).
  • Prophylactic and Z or to provide a therapeutic agent The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that the compound represented by the following general formula (I) of the present invention exhibits excellent blood glucose lowering action, lipid lowering action and the like. The present invention has been completed.
  • the present invention provides a compound represented by the general formula (I):
  • A is CfC.
  • An aryl group which may have 1 to 3 substituents ⁇ described below
  • a heteroaromatic group which may have 1 to 3 substituent (s) described later).
  • X represents a bond, an oxygen atom, a sulfur atom, or a - ⁇ - group.
  • W and ⁇ are each independently a bond or-. Shows an alkylene group.
  • the -W- ⁇ - ⁇ - group does not show a methylene group.
  • R represents a hydrogen atom, a carbonyl alcohol group, or a C 7 -C endylaminocarbonyl group (the aryl may have 1 to 3 substituents / 3 described below. ).
  • substitution a is (i) C r C 2 .
  • An alkyl group may have 1 to 3 substituents
  • C 2 _C 2 may have 1 to 3 substituents described below
  • Cr may have 1 to 3 substituents described below.
  • (Substituted portion) 3 represents (i) a C r C 6 alkyl group, ( ⁇ ) ⁇ -C 6 alkoxy group, (iii) (-C 6 alkylthio group, (iv) halogen atom, (v) ⁇ -alkylene
  • An alkoxy group (vi) a nitro group, (vi i) a cyano group, (vi i-alkanoyl group, (ix) a carbamoyl group, (x) a C 2 -C 7 alkoxycarbonylamino group, or (xi ) Represents a phenyl group.
  • the present invention provides a 2-mercaptocarboxylic acid derivative having the above general formula (I) or a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, a synthetic intermediate thereof, and use thereof.
  • a 2-mercaptocarboxylic acid derivative having the above general formula (I) or a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, a synthetic intermediate thereof, and use thereof.
  • Racel refers to a monovalent group formed by the removal of one hydrogen atom bonded to the ring of an aromatic hydrocarbon.
  • Heteroaromatic ring refers to a monocyclic or polycyclic aromatic heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. .
  • Alkylene refers to a divalent group formed by the loss of two hydrogen atoms from the carbon atoms of a linear or branched aliphatic hydrocarbon.
  • alkanoyl group refers to a monovalent group generated by removing the 0H group from an aliphatic carboxylic acid (including formic acid :).
  • Arylaminocarbonyl refers to a monovalent group in which a hydrogen atom on the nitrogen atom of carbamoyl (NC0-) is substituted by aryl as described above.
  • Alkyl refers to a monovalent group formed by the loss of one atom of hydrogen from a linear or branched aliphatic hydrocarbon.
  • Alkoxy group refers to a monovalent group generated by the loss of a hydrogen atom of a hydroxyl group of a linear or branched alcohol.
  • “Monocyclic heteroaromatic group” means a 5- or 6-membered monocyclic aromatic group having 1 to 3 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. Refers to a heterocyclic group.
  • Alkyl refers to a monovalent group in which one hydrogen atom of the aforementioned alkyl group is substituted by the aforementioned aryl group.
  • Alkylcarbonyl refers to a monovalent group in which the terminal carbon of the alkyl portion of aralkyl is substituted by an oxo group.
  • aryloxy refers to a monovalent group in which an oxygen atom is bonded to the above aryl.
  • cycloalkylalkyloxy refers to a monovalent group in which one hydrogen atom of the above-mentioned alkyl group is substituted by a 3- to 6-membered cycloalkyl, and an oxygen atom is bonded to a terminal carbon of the alkyl moiety.
  • Alkyloxy refers to a monovalent group in which an oxygen atom is bonded to the terminal carbon of the alkyl portion of aralkyl described above.
  • Arylcarbonylalkyloxy means that the aralkyl is closest to the aryl portion of the alkyl portion, the carbon atom is substituted by an oxo group, and an oxygen atom is bonded to the terminal carbon of the alkyl portion. Refers to a monovalent group.
  • arylcarbonylalkyloxy refers to a monovalent group in which the carbon atom closest to the aryl part of the alkyl part of the above-mentioned arylalkyloxy is substituted by an oxo group.
  • “Mono-heteroaromatic alkyloxy” means that one hydrogen atom of the aforementioned alkyl group is A monovalent group substituted by the above-described monocyclic heteroaromatic ring and further having an oxygen atom bonded to a terminal carbon of the alkyl portion.
  • “Monocyclic heteroaromatic carbonylalkyloxy” refers to a monocyclic heteroaromatic ring alkyloxy as described above in which the carbon atom closest to the monocyclic heteroaromatic ring among the carbon atoms in the alkyl portion is substituted with an oxo group. A valence group.
  • Aryloxyalkyl refers to a monovalent group in which one hydrogen atom of the above-mentioned alkyl group has been substituted by the above-mentioned aryloxy.
  • Alkyloxyalkyl refers to a monovalent group in which one hydrogen atom of the above-mentioned alkyl is substituted by the above-mentioned aralkyloxy.
  • Carboxyalkoxy refers to a monovalent group in which one hydrogen atom of the above-mentioned alkoxy has been replaced by carboxy (—C00H).
  • alkylthio group is a monovalent group formed by losing the sulfur atom of a thiol group of a linear or branched thiol.
  • Alkylenedioxy group refers to a divalent group in which oxygen atoms are substituted at both ends of a linear or branched alkylene.
  • Alkoxycarbonylamino refers to a monovalent group in which the carbonyl carbon of carbonylamino (—C0NH—) has been substituted with alkoxy.
  • C m -C n means having m to n carbon atoms.
  • C 6 carbonyl alkyl carbonyl alkyl having 1 to 6 carbon atoms, i.e., alkyl of straight or branched are bound with a carbon number i to 5 to the carbonyl or carbonyl Group.
  • C 6 -C 10 When A represents a C 3 -C 10 aryl group (may have 1 to 3 substituents ⁇ to be described later.), “C 6 -C 10 ” and “aryl” are as described above. in the above formula refers to having 1 to 3 and same or different whether or substituent ⁇ no substituent ⁇ is "may have 1 to 3 the substituents Monument".
  • the aryl moiety may be, for example, phenyl or naphthyl, preferably phenyl.
  • ⁇ represents a heteroaromatic ring group (which may have 1 to 3 substituent (s) ⁇ described later), it may have “heteroaromatic ring” and “1 to 3 substituent (s) ⁇ ”. ", Synonymous with things.
  • heteroaromatic ring moiety examples include monocyclic heteroaromatic groups such as chenyl, furyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazuryl; or benzofuryl, isobenzofuryl, 2 , 3-Dihydrobenzofurinole, chromenil, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthaladur, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazole And a condensed heteroaromatic group such as enyl, ataridinyl or isoindolinyl, preferably a monocyclic hetero
  • W and Y are each independently (-. If an alkylene group, -...
  • the "and" ⁇ alkylene J is synonymous with those described above the C "C 2
  • the alkylene group eg if methylene, To methylmethylene, ethylene, propylene, trimethylene, tetramethylene, methyltrimethylene, methylpropylene, dimethylethylene, pentamethylene, methyltetramethylene, dimethyltrimethylene, hexamethylene, methylpentamethylene, dimethyltetramethylene, heptamethylene, methyl Xamethylene, ethylpentamethylene, octamethylene, methinoleheptamethylene, ethylhexamethylene, methylpentamethylene, nonamethylene, methyloctamethylene, ethylheptamethylene, decamethylene, methinolenomethylene, Etinoleoctamethylene, getylhexamethylene, pendecamethylene, methyldecam
  • Echinoledecamethylene Prop ⁇ Nonamethylen, Jethyloctamethylene, Tridecamethylene, Methyldodecamethylene, Ethylundecamethylene, Provirdecamethylene, Pentyloctamethylene, Tetradecamethylene, Methyltrideca Methylene, ethyldedecamethylene, propyldendecamethylene, butyldecamethylene, pentylnonamethylene, pentadecamethylene, methyltetradecamethylene, ethyltridecamethylene, propyldodecamethylene, pentyldecamethylene, hexadecamethylene, methylpentadecamethylene , Ethyltetradecamethylene, propyltridecamethylene, butyldodecamethylene, heptadecamethylene, methylhexadecamethylene, ethylpentadecamethylene, propyltetradecamethylene, pentyldodecamethylene, octadecamethylene,
  • An alkylene group more preferably a C ⁇ c 8 alkylene group, optimally c r c 6 alkylene group.
  • a straight-chain alkylene group is preferred.
  • R represents a c C 6 alkanoyl group
  • “C r C 6 J and“ alkanoyl group ” have the same meaning as described above.
  • the -c 6 alkanol group include formyl, acetyl, propionyl, butyryl, isobutyryl, S-butyryl, t-butyryl, and pentenoyl, and preferably a c 2 -c 5 alkanol group. And more preferably a c 2 -c 3 alkyl group, most preferably acetyl.
  • arylaminocarbonyl which may have 1 to 3 substituents jS described later on the aryl.
  • "-" And “arylaminocarbonyl” “Has the same meaning as described above, and” may have 1 to 3 substituents ⁇ “means” having no substituents] 3 or 1 to 3 having the same or different substituents. It means having oneself.
  • Examples of the arylaminocarbonyl moiety include phenylaminocarbonyl and naphthylaminocarbonyl, and preferably phenylaminocarbonyl.
  • alkyl moiety examples include methynole, ethyl, propynole, isopropynole, buty / re, s-butyl, t-butynole, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, and decyl , Pendecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or a
  • it is an alkyl group, more preferably a C r C 6 alkyl group, more preferably a C r C 4 alkyl group, and most preferably a C r C 4 alkyl group.
  • it is a c 2 alkyl group
  • Substituent a is C 2 -C 2 .
  • unsaturated hydrocarbon moieties include, but are not limited to, ethyl, ethyl, propyl, methyl propyl, ethyl propyl, propyl, butyr, methyl butyl, ethyl butyl, butynole, pentinole, methinole pentinole, pentinole, to Xeninole, isohexenizole, hepteninole, octeninole, noneninole, deseninole, pendeseninole, dodecenyl, tridecenyl, tetradecenyl, pentadeceninole, hexadesenolle, heptadecenyl, denactyl, denoctenyl, denoctenyl Eicosenyl can be mentioned, preferably having one double bond.
  • substitution ⁇ is.
  • "-c1 () " and "alkoxy group” have the same meanings as described above. Said-.
  • alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, S-butoxy, t-butoxy, pentoxy, isopentoxy, methylbutoxy, neopentoxy, hexyloxy, methylpentoxy, dimethylbutoxy, heptyloxy, and octyloxy.
  • Noniruokishi or Deshiruokishi can be mentioned, preferably a (- an alkoxy group, even more preferably (: a ⁇ C 6 alkoxy group, more preferably a - a c 4 alkoxy group, the optimal d-Alkoxy group.
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a fluorine atom, a chlorine atom, or a bromine atom. Preferably it is a fluorine atom or a chlorine atom, and most preferably a chlorine atom.
  • substitution ⁇ represents a C 6 -C 1Q aryl group (may have 1 to 3 substitutions / 3 described below.), “C 6 -C 10 ”, “aryl” ”And“ 1 to 3 substitutions i3 Is synonymous with the above. C 6- .
  • the aryl moiety may include, for example, phenyl or naphthyl, preferably phenyl.
  • the “monocyclic heteroaromatic ring group” and the “substituent” J has the same meaning as described above, and examples of the monocyclic heteroaromatic ring moiety include, for example, chenyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl, and flazanil.
  • the substituent may be a C 7 -C 16 aralkyl group (which may have 1 to 3 substituents 3 described later on the aryl, or may have 1 hydroxyl group as a substituent on the alkyl. ), “C 7 -C 16 ”, “aralkyl” and “may have 1 to 3 substituent (s) j3” are the same as those described above, "It may have one hydroxyl group as a substituent,” means that it has no hydroxyl group or has one hydroxyl group as a substituent.
  • aralkyl moiety examples include benzyl, naphthylmethyl, phenyl, naphthylethyl, phenylpropyl, naphthylpropyl, phenylbutyl, naphthylbutyl, phenylpentyl, naphthylpentyl, phenylhexynole, and naphthylhexyl.
  • a phenylene Ruarukiru group having c r c 6 alkyl more preferably a phenylalanine alkyl group having c r c 2 alkyl.
  • substituent ⁇ represents a C 7 -C 16 aralkylcarbonyl group (which may have 1 to 3 substituents described later on the aryl)
  • C 7 -C 16 aralkylcarbonyl group
  • aralkyl The carbonyl J and “may have 1 to 3 substituents
  • aralkylcarbonyl moiety examples include, for example, benzoyl, benzylcarbonyl, phenylethylcarbonyl, 3-phenylpropylcarbonyl, 5_phenylpentylcarbonyl, naphthylcarbonyl, naphthinolemethinolecarbonyl, or Naphthyl propyl carbonyl may be mentioned, preferably the fuel- ⁇ alkyl force A carbonyl group, more preferably a phenyl-alkylcarbonyl group, most preferably benzyl or benzylcarbonyl.
  • Substituent a is C 6- .
  • aryloxy” and “substituted "It may have 1 to 3 j3"" is the same as the above.
  • Examples of the C 6 -C 10 aryloxy moiety include phenoxy and naphthyloxy, and phenoxy is preferred.
  • substitution ⁇ represents a C 4 -C 12 cycloalkylalkyloxy group
  • C 4 -C 12 ” and “cycloalkylalkyloxy” have the same meanings as described above.
  • Examples of the C 4 -C 12 cycloalkylalkyloxy group include, for example, cyclopropyl methoxy, cyclobutyl methoxy, cyclopentyl methoxy, cyclohexyl methoxy, cyclopropizoleethoxy, cyclobutizoleethoxy, cyclopentinoleethoxy, cyclopentyl to carboxymethyl Noreetokishi, cycloalkyl Petit Honoré propoxy, key Shirubutokishi to carboxymethyl Honoré propoxy, cyclohexane cycloalkyl, or Kishiruokishi can be mentioned the cyclohexyl, preferably c 5 - a c 12 cycloalkylalkyl O al
  • Substituent ⁇ is C ⁇ C 16 Ararukiruokishi group (which may have a substituent] 3 to be described later on ⁇ Li Ichiru 1 ⁇ optimum three, with hydroxyl groups have one as substituents on the alkyl ) Indicates 1 to 3 of “C 7 -C 16 ”, “aralkyloxy”, “substituted portion” 3, J and “1 hydroxyl group as a substituted portion” "May be possessed” has the same meaning as described above.
  • aralkyloxy moiety examples include benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenylpentoxy, phenylhexyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, naphthylbutoxy, naphthylpentoxy, and naphthylhexyl.
  • Substituent a is C factory C 16 arylcarbonylalkyloxy group (described later on aryl) May have from 1 to 3 substituents. )), "C 7 -C 16 ", "aryl carbonylalkyloxy” and “may have 1 to 3 substituents! 3" are the same as those described above.
  • Examples of the arylcarbonylalkyloxy moiety include benzoyloxy, phenacyloxy, 3-phenyl-3-oxopropoxy, and 4-phenyl-4-oxobutoxy, and preferably phenyl C, -C 6 carbonyl. It is an alkyloxy group, more preferably a phenyl C, -C 4 radical alkyloxy group, most preferably benzoyloxy or phenacyloxy.
  • the substituent ⁇ is a monocyclic heteroaromatic ring (: an alkyloxy group (the monocyclic heteroaromatic ring may have 1 to 3 substituents / 3 described later, May have one group.), It may have 1 to 3 monocyclic heteroaromatic alkyloxy J, “C, -C 6 , substituted” 3 And “may have one hydroxyl group as a substituent” are the same as those described above ..
  • the monocyclic heteroaromatic alkyloxy portion for example, pyridylmethoxy, pyridylethoxy, pyridylpropoxy, pyridylptoxy, Pyridyl pentoxy, pyridyl hexoxy, pyrimidinyl methoxy, pyrimidinyl ethoxy, pyrimidinyl propoxy, pyrimidinyl butoxy, pyrimigel pentoxy, chenyl methoxy, thi Nilethoxy, Chenolepropoxy, Chenylbutoxy, Chenolenopentoxy, Flinolemethoxy, Furylbutoxy, Thiazolylmethoxy, Thiazolylbutoxy, Oxazolylmethoxy, Oxazolylethoxy, Oxazolylbutoxy, Isoxazolyxoloxy Zolylethoxy, isoxazolylpropoxy, or isoxazolylbutoxy; preferably a monocyclic heteroaromatic C
  • Substituent ⁇ is a monocyclic heteroaromatic ring-carbonylalkyloxy group (monocyclic heterocyclic
  • the aromatic ring may have 1 to 3 substituents 0 described later.
  • substituents 0 described later.
  • the term "monocyclic heteroaromatic ring-carbonyl-alkyl O carboxymethyl j," CC 6 "and” substituent] 3 which may have 1 to 3 "is synonymous with those described above.
  • Examples of the monocyclic heteroaromatic carbonylalkyloxy moiety include pyridylcarbonyloxy, 2-pyridyl-2-oxoethoxy, 3-pyridyl-3-oxopropoxy, 4-pyridyl-4-oxobutoxy, 5-pyridyl-5-oxopentoxy, 6-pyridyl-6-oxohexyloxy, pyrimidinylcarbonyloxy, 2-pyrimidinyl-2-oxoethoxy, 3-pyrimidinyl-3-oxopropoxy, 4-pyrimidinyl-4-oxobutoxy , 5-pyrimidinyl-5-oxopentoxy, phenylcarbonyl, 2-phenyl-2-oxoethoxy, 3-phenyl-3-oxopropoxy, 4-phenyl-4-oxobutoxy, 5-phenyl-5-phenyl Oxopentoxy, furylcarboxy / reoxy, 4-furyl-4-oxobut
  • monocyclic heteroaromatic ring having one or two atoms - carbonyl alkyl O key sheet group monocyclic heteroaromatic ring having one hetero atom further to preferably - at C 2 Cal isobornyl alkyl O alkoxy group Yes, optimally pyridylcarbonyloxy, 2-pyridyl-2-oxoethoxy, pyrimidinylcarbonyloxy, chenylcarboninoleo Shi, 2-thienyl - 2 Okisoetokishi, Furirukarubo two / Reokishi a Chiazorirukarubo Niruokishi, or O hexa benzisoxazolyl carbonyl O alkoxy.
  • substitution ⁇ represents a C 7 -C 16 aryloxyalkyl group (the aryl may have 1 to 3 substitutions described later.)
  • substitution ⁇ represents a C 7 -C 16 aryloxyalkyl group (the aryl may have 1 to 3 substitutions described later.)
  • (: Factory (: 16 ) The terms “aryloxyalkyl J and” may have 1 to 3 substituents / 3 "" are the same as those described above.
  • the C 7 -C 16 aryloxyalkyl moiety examples include: phenoxymethyl, naphthyloxymethyl, phenoxy-1-ethyl, phenoxy-2-ethyl, naphthinoleoxyshchinole, phenoxybutynole, naphthinoleoxypuccinole, phenoxyhexynole, Or a naphthyloxyhexyl, preferably a phenoxy-C 6 alkyl group, more preferably a phenoxy dC 4 alkyl group, more preferably a phenoxy ⁇ - ⁇ alkyl group, most preferably It is phenoxymethyl or 1-phenoxethyl.
  • substituent a represents a C 8 -C 22 aralkyloxyalkyl group (which may have 1 to 3 substituents 13 described later on the aryl)
  • C 8 -C 22 ",” aralkyloxyalkyl "and” may have 1 to 3 substituents "are as defined above.
  • the C 8 _C 22 aralkyloxyalkyl moiety includes, for example, benzyloxymethyl, benzyloxyshethyl, phenethyloxymethyl, phenethyloxyshethyl, naphthylmethyloxymethyl, naphthylmethyloxyshechnole, naphthyl Tiloxymethyl, naphthylethynoleoxyethynole, benzyloxybutyl, naphthylmethyloxybutyl, benzizoleoxyhexyl, or naphthylmethinoleoxyhexyl can be mentioned, and preferably phenyl (: Factory A C 6 alkyloxy C r C 6 alkyl group, more preferably phenyl _ ( 4 alkyloxy CC 4 alkyl group, even more preferably a phenyl c each independently having two C r C 2 alkyls r c 2 alkyloxy is a c r
  • carboxymethyl alkoxy groups such as carboxy Methoxy, carboxyethoxy, carboxypropoxy, carboxybutoxy, carboxypentoxy, carboxyhexyloxy, carboxyheptyloxy, carboxyoctyloxy, carboxynonyloxy, or carboxydecyloxy are preferred.
  • carboxymethyl alkoxy groups such as carboxy Methoxy, carboxyethoxy, carboxypropoxy, carboxybutoxy, carboxypentoxy, carboxyhexyloxy, carboxyheptyloxy, carboxyoctyloxy, carboxynonyloxy, or carboxydecyloxy are preferred.
  • the a c 2 -c 5 carboxy alkoxy group more preferably a c 2 -c 3 carboxyalkoxy group, a best carboxymethyl butoxy group.
  • alkyl is cc 2 as described above. This refers to alkyl having 1 to 6 carbon atoms. Examples of the C r C 6 alkyl group include the same groups as those having 1 to 6 carbon atoms in the alkyl group described in the definition of the substituent ⁇ .
  • Rukoto can, preferably a c r c 4 alkyl group, more preferably (: an ⁇ alkyl group.
  • C. alkoxy refers to an alkoxy group having 1 to 6 carbon atoms.
  • the alkoxy group is the alkyl group described in the definition of the substitution ⁇ . And preferably a C r C 4 alkoxy group, and more preferably a CC 2 alkoxy group, wherein the substituent ⁇ is a C r C 6 alkylthio group.
  • “factor” and “alkylthio group” have the same meanings as those described above.
  • Pentylthio isopentylthio, methylbutylthio, neopentylthio, hexylthio, or dimethylbutylthio.
  • The is a C 4 alkylthio group, more preferably (: a ⁇ Arukiruchio group.
  • the halogen atom may be the same atom as the halogen atom described in the definition of the substituent ⁇ , and is preferably a fluorine atom, a chlorine atom, or a bromine atom. And more preferably a fluorine atom or a chlorine atom, and most preferably a chlorine atom.
  • substituent ⁇ represents a C 4 ⁇ Ruki range O alkoxy group
  • substituent ⁇ represents a C 4 ⁇ Ruki range O alkoxy group
  • (- and the "alkylenedioxy Okishi group” is synonymous with that described above with the said C ⁇ C 4 alkylenedioxy O alkoxy group is, for example Mechirenjiokishi, E dust Denji O xylene, dimethicone range O alkoxy, there may be mentioned I Seo propylene diene O alkoxy, trimethylene O alkoxy, or tetramethylene O carboxymethyl, preferably a - C 2 Arukirenjio A xy group, and more preferably a methylenedioxy.
  • “—C 6 ” and “alkanoyl group” have the same meanings as described above.
  • Examples of the (: factory alkanoyl group include the same groups as the alkanoyl groups described in the definition of R, preferably C 2 -C 5 alkanoyl groups, more preferably It is a C 2 -C 3 alkanoyl group, most preferably acetyl.
  • alkoxycarbonylamino group having -alkoxy examples include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, s- Butoxycarbonylamino, t-butoxycarbonylamino, pentoxycarbonylamino, isopentoxycarbonylamino, methylbutoxycarbonylamino, neopentoxycarbonylamino, hexyloxycarbonylamino, or dimethylbutoxycarbonylamino Mino can be mentioned, preferably a C 2 - is C s alkoxycarbonyl amino group, more preferably a C 2 _C 3 alkoxycarbonyl ⁇
  • Phenylamino carboni A phenyl group (which may have 1 to 3 substituents / 3 on aryl). More preferably, a phenylamino carbonyl group (aryl Substitutions] may have 1 or 2 substitutions. And most preferably a phenylaminocarbonyl group (which may have one substituent ⁇ on aryl).
  • substitution ⁇ is C! -C 2 .
  • the group having a substituent includes, for example, methoxymethyl, methoxethyl, methoxybutyl, methoxybutyl, methoxyoctyl, Toxicoicosyl, methylthiomethyl, methylthiobutyl, fluoromethinole, fluorobutyl, hexoleno hexinole, chloromethinole, chlorobutynole, chlorohexinole, diphnoleolomethinole, trifinoleromethyl, trifinoleoxymethyl, nitromethinole, nitromethinole ⁇ , cyanomethyl, cyanobutyl, cyanohexyl, acetylmethyl, acetylbutyl, or acetylhexyl, preferably a C
  • substitution ⁇ is C 2 -C 2 .
  • 3 is, for example, methoxetenyl, methoxybutyr, methoxybutul, Methoxy eicosenyl, methylthioobenite, fenoleobnite, fenolenohexenol, chlorobuteninole, blackenhexenyl, trifrenoleoturet, nitrobutenyl, nitrohexenyl, cyanobutenyl, cyanohexenyl, acetylbutur, Acetylhexenyl can be mentioned, preferably-.
  • An unsaturated hydrocarbon group (which may have 1 to 3 substituents jS), and more preferably has one double bond (: an unsaturated hydrocarbon group (substitution 13 may have one.), and also optimally have one of C 2 -C 6 unsaturated hydrocarbon group (substituents that have a one double bond Les,).
  • the group having the substituent i3 is, for example, methylphenyl, dimethylphenyl / , Ethynolephenine, t-butynolephenine, methoxyphenine, ethoxyphenyl, methylthiophene, ethylthiophene, fluorophenyl, difluorene fenole, clofeneneole, dichlorophene , Bromophenyl, methylenedioxyphenyl, nitrophenyl, cyanophenyl, acetinolephenyl.
  • substituent ⁇ represents a monocyclic heteroaromatic ring group (which may have 1 to 3 substituents / 3)
  • examples of the group having a substituent / 3 include methylpyridyl and methoxy.
  • a monocyclic heteroaromatic group having 1 or 2 (optionally having 1 to 3 substituents / 3), more preferably a monocyclic heteroaromatic group having 1 or 2 hetero atoms It may have one or two aromatic ring groups (substituted portions) 3. And most preferably a monocyclic heteroaromatic ring group having one or two hetero atoms (which may have one substituent).
  • the group having no substitution or a hydroxyl group includes, for example, methylbenzyl, meth Xybenzyl, methylthiobenzyl, fluorobenzyl, cyclobenzyl, methylenedioxybenzyl, nitrobenzyl, cyanobenzyl, acetylbenzyl, levamoylbenzyl, t-butoxycarbamoylbenzyl, methylnaphthylmethyl, methoxynaphthylmethyl, methylthionaphthyl Methyl, fluoronaphthylmethyl, chloronaphthylmethyl, methylenedioxynaphthylmethyl, nitronaphthylmethyl, cyanona
  • the substituent ⁇ represents a C 7 -C 16 aralkylcarbonyl group (which may have 1 to 3 substituents 3 on aryl)
  • the group having 0 substituents is, for example, , Methinole Benzoinole, Methoxy Benzoinole, Methinolethio Benzoinole, Benzoinole with Funoreo mouth, Benzoin with black mouth, Methylenedioxybenzoinole, Nitrobenzoinole, Cyanbenzoinole, Cyanbenzoinole, Acetinole Benzoinole, Force / Levamoinolebenzoinole, t-butoxyl-lvamoylbenzoyl, methylbenzylcarbonyl, methoxybenzylcarbinole, methinolethiobenzinolecanoleboninole, fenoleone benzobenolenocanoleponyl, chlorobenzylcarbon
  • a C 7 -C 16 aralkylcarbonyl group which may have 1 substituent on aryl.
  • a phenyl ⁇ -(: 6 alkylcarbonyl group (may have one substituent 3 on the phenyl).
  • a phenyl-alkylcarbonyl group It may have one substituent 3 on the phenyl.
  • the group having the substituted group] 3 includes, for example, methylphenoxy, dimethylphenoxy, ethylphenoxy, t-butylphenoxy, methoxyphenoxy, ethoxyphenoxy, methylthiophenoxy, ethylthiophenoxy, Noleolophenoxy, diph / leolophenoxy, chlorophenoxy, dichlorophenoxy, bromophenoxy, methylenedioxyphenoxy, nitrophenoxy, cyanophenoxy, acetylphenoxy, kylarvamoylphenoxy, t-butoxy Enoxy, Methylnaphthyloxy, Methoxynaphthyloxy, Methylthionaphthyloxy, Fluoronaphthyloxy, Black Naphthyloxy, Methylenedioxynaphthyloxy, Nitronaphthyloxy, Black Naphthyloxy, Methylenedioxynaphth
  • Substituent ⁇ is C ⁇ C 16
  • Ararukiruokishi group may have 3 to 1 to 3 have a (substituent on ⁇ Li Ichiru), a hydroxyl group which may have one as substituents on alkyl. ),
  • the group having a substituted i3 or a hydroxyl group includes, for example, methylbenzyloxy, methoxybenzyloxy, methylthiobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, and 4-fluorobenzyloxy.
  • the C 7 _C 16 aralkyloxy group (ary May have one or two substituents 3 on the alkyl, and one alkyl group may have one hydroxyl group as a substituent on the alkyl. ), And it may further preferably may have one of the substituents on C ⁇ C 16 Ararukiruoki Shi group (Ariru having one hydroxyl group as substituents on the alkyl.) In Yes, more preferably, it may have one C 7 -C 14 aralkyloxy group (substituted on aryl) 3, or it may have one hydroxyl group on alkyl as a substituted part. ), And most preferably a phenyl CC 4 alkyloxy group (the phenyl may have one substituent 3) or the alkyl may have one hydroxyl group as a substituent.) It is.
  • substitution moiety indicates a C 7 -C 16 arylcarbonylalkyloxy group (which may have 1 to 3 substituents ⁇ on the aryl)
  • substituent having 3 substitutions examples include methyl benzoyloxy, methoxy benzoyloxy, methyl thiobenzoyloxy, phenolic benzoylene, benzoyloxy, chlorobenzoyloxy, methylylene benzoyloxy, nitrobenzoyloxy, and cyanobenzoyl.
  • Xyl acetyl benzoyloxy, carbamoyl benzoyloxy, t-butoxycarbamoyl benzoyloxy, methylnaphthylcarbonyloxy, methoxynaphthylcarbonyloxy, methylthionaphthylcarbonyloxy, fluoronaphthylcarbonyl Oxy, chloronaphthy / recarbonyloxy, methylenedioxy Sinaphthylcarbonyloxy, nitronaphthylcarbonyloxy, cyanonaphthylcarbonyloxy, acetylnaphthylcarbonyloxy, rubbamoylnaphthinolecarbone / reoxy, t-butoxycanolebamoinolephthanolecanoleboninoleoxy, Methynolefnasiloxy, methoxyphenasiloxy, methyl
  • it is a C 7 -C 16 arylcarbonylcarbonyloxy group (which may have one or two substituents on aryl). More preferably, it is a C 7 -C 16 arylcarbonylcarbonylalkyloxy group. Group (which may have one substituent j3 on the aryl). More preferably, it is a C 7 -C 14 arylcarbonylalkyloxy group (the aryl has one substituent i3 on the aryl). ), And most preferably a phenyl-carboxyalkyloxy group (which may have one substituent 3 on the phenyl).
  • Substituent ⁇ is a monocyclic heteroaromatic ring-Ce alkyloxy group (Monocyclic heteroaromatic ring may have 1 to 3 substitutions ⁇ , and alkyl has 1 hydroxyl group as a substitution ),
  • the group having a substituted group or a hydroxyl group includes, for example, methylpyridylmethoxy, phenylpyridylmethoxy, phenyl (methyl) pyridylmethoxy, 2 -Pyridyl-2-hydroxyethoxy, methyl phenyl methoxy, phenyl phenyl methoxy, phenyl (methyl) phenyl methoxy, 2-phenyl-2-hydroxy ethoxy, methyl thiazolyl methoxy, phenyl thiazolinole methoxy, Phenyl (methyl) thiazolyl methoxy, 2-thiazolyl-2-hydroxy methoxy, methyl oxazolyl me
  • Monocyclic heteroaromatic ring Factory C 4 alkyloxy group
  • the monocyclic heteroaromatic ring may have one or two substituents, and the alkyl may have one hydroxyl group as a substituent.
  • Monocyclic heteroaromatic ring having one or two telo atoms (: C 2 alkyloxy group (substituted on It may have one or two substitutions i3, and may have one hydroxyl group as a substitution on alkyl. ), And most preferably, methyl phenyl methoxy, 2-chloro-2-hydroxy ethoxy, phenylthiazolyl methoxy, or phenyl (methyl) oxazolyl ethoxy.
  • ⁇ represents a monocyclic heteroaromatic ring, C 6 C carbonylalkyloxy group (which may have 1 to 3 substituents 3 on the monocyclic heteroaromatic ring)
  • Examples of the group having a moiety ⁇ include methylpyridylcarbonyloxy, phenylvinylidylcarbonyloxy, phenyl (methyl) pyridylcarbonyloxy, 2- (methylpyridyl) -2-oxoethoxy, methylchenyl Carbonyloxy, phenylthienylcarbonyloxy, phenyl (methynole) phenylcarbonyloxy, 2- (methylenyl) -2-oxoethoxy, methylthiazolylcarbonyloxy, phenylthiazolylcarbonyloxy, phenyl (methyl) Thiazolyl canolebonyloxy, 2- (methylthiazolyl)-2-oxoethoxy, methyloxazolyl
  • the substituents 3 above may have one or two.
  • And is most preferably methyl carbonylcarbonyloxy or 2- (methyl phenyl) -2-oxoethoxy.
  • Substituted ⁇ is a C 7 -C 16 aryloxyalkyl group (substituted on aryl) You may have three. ),
  • the group having a substitution of / 3 includes, for example, methylphenoxymethyl, dimethylphenoxymethyl, ethylphenoxymethyl, t-butylphenoxymethyl, methoxyphenoxymethyl, Cimethyl, ethoxyphenoxymethyl, methylthiophenoxymethyl, ethylthiophenoxymethyl, phenol olophenoxymethyl, difluorophenoxymethyl, chlorophenoxymethinole, dichlorophenoxymethyl, bromophenoxymethyl, Methylenedioxyphenoxymethyl, nitrophenoxymethyl, cyanophenoxymethyl, acetylphenoxymethyl, rubamoylphenoxymethyl, t-butoxycarbamoylphenoxymethyl, methylnaphthyloxymethyl, methoxynaphthyloxy Methyl, methylthion
  • a xyalkyl group (which may have one or two substituents 3 on aryl); more preferably a C 7 -C 16 aryloxyalkyl group (aryl) May have one substitution / 3 on the above, and more preferably a C 7 -C 14 aryloxyalkyl group (having one substitution / 3 on the aryl) And more preferably a phenoxy-alkyl group (which may have one substituent j3 on the phenol).
  • ⁇ Most preferably a phenoxy-C 2 alkyl group (which may have one substituent on the phenyl).
  • substitution ⁇ represents a C 8 -C 22 aralkyloxyalkyl group (the aryl may have 1 to 3 substitution ⁇ ), the substitution having / 3
  • the substitution having / 3
  • the ⁇ ] 3 which may have one or two), and even more preferably C 8 - 1 pieces of substituents) 3 to C 22 ⁇ Lal Kill O alkoxyalkyl group (on ⁇ Li Lumpur You may have. ), And even more preferably C 8 - (:. To 18 Araru kill O the alkoxyalkyl group (substituents on ⁇ Li Ichiru] 3 may have one), and more preferably Hue This is a C 2- ⁇ alkyloxy C! -C alkyl group, most preferably a phenyl C r C 2 alkyl group.
  • a 6 may have 1 to 3 substituents.
  • the group includes, for example, feninole, methinolefeninole, dimethinolefeninole, ethinolefeninole, and butinolefenyl , S-petit / refeninole, t-butynolephenine, hexinolefenole, propeninolephenyl, (methylpropenyl) phenyl, butenylphenyl, (methinolebutenyl) phenyl, (trifluoromethyl) phenyl, (ditri) (Fluoromethyl) phenyl, (pentafluoroethyl) phenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl / ethoxy, ethoxyphen
  • Pyridyl methylpyridyl, methoxypyridyl, dimethoxypyridyl, propylpyridyl, hexyloxypyridyl, fluoropyridyl, difluoropyridyl, clopyridyl, dichloropyridyl, hydroxypyridyl, phenylpyridyl, cerylpyridyl, benzylpyridyl, ( Methylbenzyl) pyridyl, phenethylpyridyl, (cyclohexylmethoxy) pyridyl, benzyloxypyridyl, (chlorobenzyloxy) pyridyl, (cloguchibenzyloxy) pyridyl, phenethyloxypyridyl, (pyridylmethoxy) pyridyl, (pyridylethoxy) Pyridyl
  • Benzo Chennore Black Benzo Chenore, Funoreo Benzo Chennore, Mechinore Benzo Chen / Hydroxy Benzo Chennore, Methoxy Benzo Chenore, Hexinoleoxy Chenyl, Benzoxy Benzo Chen Nole, (cyclohexynolemethoxy) benzocenyl, (black benzonoleoxy) benzocheninole, phenetic / lebenzocenyl, phenethyloxy benzocenyl, (phenylpropoxy) benzoceninole, (phenoxymethyl) benzocenyl, (Phenoxyshethyl) benzocenyl, (black benzo / reoxy) benzocenyl, (methyltrimethoxy) benzocenyl, (methinobenzinole) benzocenyl, (methylbenzinoleoxy) benzocenyl, diclo benzocenino ,
  • 2,3-dihydrobenzofuryl black mouth-2,3-dihydrobenzofuryl, fluoro-2,3-dihydrobenzofuryl, methyl-2,3-dihydrobenzofuryl, hydroxy_2,3 -Dihydrobenzofuryl, methoxy-2,3-dihydrobenzofuryl, hexyloxy -2,3-dihydrobenzofuryl, benzyloxy-2,3-dihydrobenzofuryl, (cyclohexylmethoxy) -2 , 3-Dihydrobenzobenfuryl, (chlorobenzyloxy) -2,3-dihydrobenzofuryl, phenethyl-2,3-dihydrobenzofuryl, phenethyloxy-2,3-dihydrobenzofuryl, (phenylphenyl) Mouth oxy) -2,3-dihydrobenzozofuryl, (phenoxymethyl) -2,3
  • a carboxyl group is present when and in the basic structure, and the substitution ⁇ represents a carboxyalkoxy group. This carboxyl group is converted to a pharmacologically acceptable You can tell.
  • the pharmacologically acceptable ester of the 2-mercaptocarboxylic acid derivative having the general formula (I) is not particularly limited as long as it is used medically and is pharmacologically acceptable.
  • the ester residue of the 2-mercaptocarboxylic acid derivative having the general formula (I) of the present invention includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, and a 7 to 7 carbon atoms.
  • Carbon substituted with oxycarbonyl nitroxy A linear or branched alkyl group having 1 to 5 carbon atoms, or a linear or branched alkyl group having 1 to 5 carbon atoms substituted with arylcarbonyloxy having 6 to 10 carbon atoms A branched alkyl group, a linear or branched alkyl group having 1 to 5 carbon atoms and substituted with aryloxycarbonyloxy having 6 to 10 carbon atoms, and a 5-position A 2-oxo-1,3-dioxolen-4-ylmethyl group having a linear or branched alkyl having 1 to 6 carbon atoms as a substituent.
  • a linear or branched alkyl group having 1 to 4 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms are, for example, methyl, ethyl, propyl, isopropyl.
  • An aralkyl group having 7 to 19 carbon atoms is, for example, benzyl, phenethyl, It is phenylpropyl, phenylbutyl, naphthylmethyl or dibenzyl, preferably benzyl.
  • the cycloalkyl group having 5 to 7 carbon atoms is, for example, cyclopentyl, cyclohexyl, cycloheptyl, and preferably cyclohexanol.
  • the aryl group having 6 to 10 carbon atoms is, for example, phenyl or naphthyl, preferably phenyl.
  • ester residues include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetooxymethyl, 1- (acetoxoxy) ethyl, propionyloxymethyl, propionyl / reoxyethylinole, butylyl / reoxy.
  • the carboxyl group of the 2-mercaptocarboxylic acid derivative having the general formula (I) can be converted into a metal salt according to a conventional method.
  • Such salts include, for example, alkali metal salts such as lithium, sodium, and potassium; calcium, barium, and magnesium.
  • Alkaline earth metal salts such as gnesium; aluminum salts; and the like.
  • it is an alkali metal salt.
  • the 2-mercaptocarboxylic acid derivative of the general formula (I) of the present invention has a base moiety such as a pyridyl group or a quinolyl group, it can be converted to a salt.
  • a salt examples include hydrohalic acid salts such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; nitrates, perchlorates, sulfates, phosphates, and the like.
  • Inorganic acid salts such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; glutamic acid and aspartic acid
  • organic acids such as salts of carboxylic acids such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid and maleic acid.
  • the compounds of the present invention also include various isomers.
  • the 2-position carbon of the 2-mercaptocarboxylic acid derivative of the general formula (I) is an asymmetric carbon, and there may be an asymmetric carbon on the substituent, so that an optically active substance is present. I do.
  • those having a double bond on the carbon chain have geometrical isomerism.
  • the present invention includes all of these isomers.
  • the present invention provides a method for producing a 2-mercaptocarboxylic acid derivative represented by the general formula (I), a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof to form a solvate (eg, hydrate). If so, these are all included.
  • the present invention relates to a compound which is metabolized in a living body into a 2-mercaptocarbonic acid derivative of the general formula (I), a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof, It also includes all prodrugs.
  • A is preferably a C 6 -C 1 () aryl group (which may have one or two substituents ) .
  • A is C 6- .
  • Aryl group which may have 1 or 2 substituents
  • heteroaromatic group having 1 or 2 heteroatoms (which may have 1 or 2 substituents)
  • a pharmacologically acceptable ester thereof or a pharmacologically acceptable salt thereof.
  • A is Ce-.
  • An aryl group (which may have one or two substituents ⁇ ) or a heteroaromatic group having one hetero atom (which may have one substituent ⁇ ).
  • ⁇ is-.
  • An aryl group may have one substituent
  • a heteroaromatic group having one hetero atom may have one substituent ⁇ .
  • ⁇ is Cs-C!
  • (6) 2- is a 2-mercaptocarboxylic acid derivative represented by a heteroaromatic ring group having one heteroatom atom (may have one substituent ⁇ ), or a pharmacologically acceptable derivative thereof. Esters or pharmacologically acceptable salts thereof.
  • W and ⁇ are each independently a bond or a 2-mercaptocarboxylic acid derivative or a 2-alkylene group (the -W-XY- group does not represent a methylene group).
  • R is a hydrogen atom, or a - C 4 2-mercapto represented by Arukanoiru group carbonitrile phosphate derivative or its pharmacologically acceptable esters or their pharmacologically permissible Salt to tolerate.
  • R is a hydrogen atom or, - C 2 Arukanoiru Esuteru acids or pharmacologically allowable salts thereof represented is 2 _ mercapto-carbonitrile phosphate derivative or its pharmacologically acceptable is a group.
  • Substitution string (i) C r .
  • An alkyl group (which may have 1 to 3 substituents / 3), (ii) C 2- .
  • Unsaturated hydrocarbon group (may have one substituent;;), (iii) C r ⁇ .
  • Aryl group may have 1 or 2 substituents 3), (vii) monocyclic heteroaromatic ring group, (vi ii) C 7 -C 16 aralkyl group (substituted on aryl) Or one or two hydroxyl groups as alkyl groups, and may have one hydroxyl group as a substituent on the alkyl.), (Ix) C 7 -C 16 aralkylcarbonyl group (substituted moiety ] 3 or 1) .3)
  • Substituted ⁇ is (i) C factory C t .
  • An alkyl group (ii) C 2- .
  • Unsaturated hydrocarbon group (iii) C factory C 10 alkoxy group, (iv) halogen atom, (V) hydroxyl group, (vi) C 6- .
  • Aryl group may have one substituted moiety) 3), (vi i) a monocyclic heteroaromatic ring group, (vii i) phenyl alkyl group (substituted moiety Or may have two, and may have one hydroxyl group as a substituent on alkyl.), (Ix) phenyl-carbonylalkyl group (substituted on phenyl) is 1 or (X) a phenoxy group (may have one or two substituents / 3 on fuunyl), (x-C, a cycloalkylalkyloxy group) , (Xii) phenyl (: a C 6 alkyloxy group (which may have one or two substituents 3 on fuunyl, or may have one hydroxyl group as a substituent on alkyl.), ( xiii) phenyl-C 6 carbonylalkyloxy group (substituted on phenyl, it may have 1 or 2).
  • substituent ⁇ is, (i) C ⁇ C 6 alkyl group, (ii) C r C 8 alkoxy group, (iii) halogen atom, (iv) hydroxyl, (V) phenyl group (substituent
  • (1) may be substituted by 1), (vi) phenyl ⁇ - ⁇ alkyl group (substituted on phenyl, which may have 1/3, substituted as alkyl on alkyl (Vii) a phenyl C r C 4 carbonylalkyl group (which may have i substituents on the phenyl), (viii) (Ix) ⁇ - ⁇ , which may have one phenoxy group (substituted portion) 3).
  • Cycloalkyl Ruarukiruokishi group may be in one have a hydroxyl group as a substituent on (X) Fuweniru C r C 6 Arukiruokishi group (which may have one or two substituents ⁇ on the phenyl, the alkyl. ), (Xi) phenyl- ⁇ carbonylalkyloxy group (may have 1 or 2 substituents on phenyl,), (xii) 1 or 2 heteroatoms Monocyclic heteroaromatic ring _ (: 4 alkyloxy group (substituted on monocyclic heteroaromatic ring) may have one or two, and alkyl has one hydroxyl group as a substituent.
  • substitution ⁇ is (i) a C r C 4 alkyl group, (ii) a C r C 6 alkoxy group, (iii) a halogen atom, (iv) a hydroxyl group, (V) a phenyl group, ( vi) phenyl alcohol alkyl group (may have one hydroxyl group as a substituent on the alkyl.), (vii) phenyl C r C 4 carbonylalkyl group, (viii) phenoxy group, (Ix) ⁇ - ⁇ .
  • Cycloalkylalkyloxy group (X) phenyl- ⁇ alkyloxy group (substituted on phenyl) may have one, and alkyl may have one hydroxyl group as a substituted part. ), (Xi) phenyl C r C 4 carbonylalkyloxy group (which may have one substituent 3 on the phenyl,), (xi) one heteroatom Or a monocyclic heteroaromatic ring having four CC 4 alkyloxy groups (which may have one or two substituents on the monocyclic heteroaromatic ring and one hydroxyl group as a substituent on the alkyl may be in.), (xiii) one or two substituents 0 heteroatoms 1 or 2 having a monocyclic heteroaromatic ring-carbonyl C ⁇ C 4 Arukiruokishi group (monocyclic on heteroaromatic ring Yes (Xiv) phenyl-C 4 alkyloxy C maker C 4 alkyl group
  • substituents ⁇ is, (i) ⁇ - C 2 alkyl group, (ii) CC 6 alkoxy group, (iii) EnsoHara child, (iv) hydroxyl, (V) Hue sulfonyl - alkyl group (the alkyl (Vi) a phenyl-carbonylalkyl group, (vii) a phenyl-C ⁇ alkyloxy group (having one substituted j8 on the phenyl group). And (viii) a phenyl-C 4 carbonylalkyloxy group, or (ix) a monocyclic group having one or two heteroatoms.
  • Heteroaromatic ring-2-mercaptocarboxylic acid derivative represented by an alkyloxy group may have one substituent on a monocyclic heteroaromatic ring.
  • a pharmaceutically acceptable ester thereof Or their pharmacologically acceptable salts.
  • the substituent a is (i) a phenyl group, (ii) a phenyl-C 4 alkyl group (which may have one hydroxyl group as a substituent on the alkyl), and (iii) a phenyl group.
  • cycloalkenyl - C 4 carbonylation Ruarukiru group (iv) phenoxy group, (v) C 6 -.
  • phenyl (-(: a 4- carbonylalkyloxy group (which may have one substituent on phenyl)), (viii) a mono- or hetero-atom Cyclic heteroaromatic ring (alkyloxy group (monocyclic heteroaromatic ring may have one or two substituents, and alkyl may have one hydroxyl group as a substituent.)
  • substitution ⁇ is (i) a phenyl ⁇ -alkyl group (which may have one hydroxyl group as a substitution on the alkyl .;), (ii) phenyl (: “C 4 carbonylalkyl group, (iii) phenyl (: maker (: 4 alkyloxy group (which may have one substituent ⁇ on phenyl, The alkyl may have one hydroxyl group as a substituent on the alkyl.
  • substitution ⁇ is (i) a phenyl-C 4 alkyloxy group (which may have one substitution / 3 on the functional group, and has one hydroxyl group as a substitution on the alkyl ), (Ii) a phenyl- ⁇ carbonylalkyloxy group, or (iii) a monocyclic heteroaromatic C, -C 4 alkyloxy group having one or two heteroatoms (monocyclic It may have one substituent 3 on the formula heteroaromatic ring. ), A pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof.
  • Substituent ⁇ is (i) a phenyl ⁇ -C 2 alkyloxy group (which may have one substituent / 3 on the phenyl); (ii) phenyl (: Factory C 2 carbonylalkyl O alkoxy group, or (iii) have one of the substituents 13 heteroatoms 1 or 2 having a monocyclic heteroaromatic ring C ⁇ C 2 Arukiruo alkoxy group (monocyclic on heteroaromatic ring Or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof.
  • Substituent ⁇ is (i) C factory C 6 alkyl group, (ii) C factory C 6 alkoxy group, (iii) C r C 6 alkylthio group, (iv) halogen atom, (v) C factory C 4 alkylenedioxy O alkoxy group, (vi) nitro port group, (vii) Shiano group, (vii Ct-C 6 Arukanoiru group, or (ix) 2-mercapto carboxylic acid derivative represented by phenyl group or a pharmacologically Acceptable esters or pharmacologically acceptable salts thereof.
  • substituent j3 is, (C -! C 4 alkyl group, (ii) C ⁇ C 4 alkoxy group, (iii) halogen atom, or (iv) 2-mercapto carboxylic acid derivative represented by the phenyl group Or pharmacologically acceptable esters thereof or pharmacologically acceptable salts thereof.
  • 2-mercaptocarboxylic acid derivative represented by (i) C-factor C 2 alkyl group, (ii) C-factor C 2 alkoxy group, or (iii) halogen atom, or its pharmacology Acceptable esters or pharmacologically acceptable salts thereof.
  • A is selected from (1) to (6)
  • X is selected from (7) to (10)
  • select R from (15) to (18)
  • Compounds selected by combining are also favorable.
  • the 2-mercaptocarboxylic acid derivatives having the general formula (I) the following compounds are also suitable.
  • A is C6-C!
  • Aryl group may have one or two substituents ⁇ ) or heteroaromatic group having one or two heteroatoms (may have one or two substituents ⁇ ); Shows;
  • X represents a bond, an oxygen atom or a sulfur atom
  • W and ⁇ are each independently a bond or -c ,.
  • An alkylene group (the -W-X-Y- group does not represent a methylene group);
  • R represents a hydrogen atom or an alkanoyl group
  • Substituents ⁇ are, (Cf alkyl group, (ii) C 2 -. . Unsaturated hydrocarbon group, (iii) C ⁇ c 10 alkoxy group, (iv) a halogen atom, (V) hydroxyl group, (vi) C 6 -.Aryl group (substituted) 3 May be provided.
  • ⁇ is a C 6 alkyl group, (ii) a Cr C 6 alkoxy group, (iii) a halogen atom, (iv) a nitro group, (V) a cyano group, or (vi) a phenyl group Carbonic acid derivatives, pharmacologically acceptable esters thereof, or pharmacologically acceptable salts thereof.
  • A is Cs-C! An aryl group (which may have one or two substituents) or a heteroaromatic group having one hetero atom (which may have one substituent ⁇ );
  • X represents a bond or an oxygen atom
  • W and ⁇ are each independently a bond or c r c 8 alkylene group (provided that, - WXY- groups show no methylene groups.) Indicates; R represents a hydrogen atom;
  • substitution ⁇ is (i) C factory C 4 alkyl group, (ii) C r C 6 alkoxy group, (iii) halogen atom, (iv) hydroxyl group, (V) phenyl group, (vi) phenyl -C 4 alkyl group (may have one hydroxyl group as a substituent on the alkyl group) N (vii) phenyl-carbonylalkyl group, (vii) phenoxy group, (ix) C 6 - ⁇ . Cycloalkylalkyloxy group, (X) phenyl dialkyloxy group (may have one substituent on phenyl, and may have one hydroxyl group as a substituent on alkyl. ), (Xi) phenyl-C 4 carbonylalkyloxy group (which may have one substituent on phenyl),
  • A is -C ,.
  • An aryl group (which may have one substituent ⁇ );
  • W and ⁇ each independently represent a bond or a C 6 alkylene group (provided that -WX-Y- does not represent a methylene group);
  • R represents a hydrogen atom
  • Substitution ⁇ force (i) phenyl d-C 4 alkyloxy group (may have one substitution on phenyl or one hydroxyl group as substitution on alkyl.) , (ii) a phenyl- ⁇ carbonylalkyloxy group, or (iii) a monocyclic heteroaromatic ring having one or two heteroatoms ⁇ -alkyloxy group (on a monocyclic heteroaromatic ring [Substituent] 3. );
  • A may have 1 to 3 substituents ⁇ described below, an aryl group having 6 to 10 carbon atoms, or 1 to 3 substituents ⁇ described later.
  • X represents a bond, an oxygen atom, a sulfur atom, or a - ⁇ - group
  • W and ⁇ each independently represent a bond or a linear or branched alkylene group having 1 to 20 carbon atoms;
  • R represents a hydrogen atom, an alkanol group having 1 to 6 carbon atoms, or an aryl having 6 to 10 carbon atoms which may have 1 to 3 substituents ⁇ described later.
  • a luminocarbonyl group
  • Substituent ⁇ is represented by (i) a linear or branched carbon number of 1 to 20 which may have 1 to 3 substituents 3 (excluding an alkyl group) described later. (Ii) having a linear or branched carbon number of 2 to 20 which may have 1 to 3 substituents (excluding the alkyl group) described below (excluding the alkyl group).
  • Ariru and substituents hydroxyl one has optionally may linear even or branched carbon atoms 1 to 6 carbon chromatic as having (Ix) an aralkyl group having 6 to 10 carbon atoms which may have 1 to 3 substituents 3 described below, and (x) an aralkyl group having 3 to 6 carbon atoms.
  • a cycloalkyl and a cycloalkylalkyloxy group having a linear or branched alkyl having 1 to 6 carbon atoms, and (xi) may have 1 to 3 substituents ⁇ described later.
  • the substituent 0 is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkoxy group having 1 to 6 carbon atoms. (Iii) a linear or branched alkylthio group having 1 to 6 carbon atoms, (iv) a halogen atom, (V) an alkylenedioxy group having 1 to 4 carbon atoms, (vi) A nitro group, (vi i) a cyano group, (vi ii) an alkanoyl group having 1 to 6 carbon atoms, (ix) a carbamoyl group, or (X) a linear or branched carbon number 1 to 6 A 2-mercaptocarboxylic acid derivative represented by an alkoxycarbonylamino group having an alkoxyl group, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. Specific examples of the 2-mercaptocarboxylic acid derivative having the general
  • the compound represented by the general formula (I) of the present invention can be produced, for example, by the following production method.
  • the corresponding thiazolidine-2,4-dione compound (II) is hydrolyzed under aqueous conditions in the presence of a base to form an R compound of the 2-mercaptocarboxylic acid derivative represented by the general formula (I).
  • the base used is, for example, a hydroxide of an alkali metal such as lithium, potassium or sodium; an alkali metal bicarbonate such as lithium hydrogen carbonate or sodium hydrogen carbonate; an alkali metal carbonate such as carbon dioxide or sodium carbonate. And ammonia.
  • an alkali metal such as lithium, potassium or sodium
  • an alkali metal bicarbonate such as lithium hydrogen carbonate or sodium hydrogen carbonate
  • an alkali metal carbonate such as carbon dioxide or sodium carbonate.
  • ammonia ammonia.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and is, for example, water; alcohols such as methanol, ethanol, and propanol; ethers such as detinoleether, tetrahydrofuran, and dioxane; dimethylformamide Amides such as amide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and a mixed solvent of water and these organic solvents are preferably used.
  • the reaction is preferably carried out under ice cooling or heating to reflux.
  • the reaction time varies depending on the reaction reagent, reaction temperature, reaction amount and the like, but is usually 0.5 hours to 10 hours.
  • the reaction is preferably carried out in a solvent of water and an alcohol for 1 hour to 6 hours under ice cooling or heating to reflux.
  • R ′ represents the ester residue described above
  • R ′ ′′ represents an alkyl group having 1 to 6 carbon atoms, or a substituted carbon group having 1 to 3 carbon atoms.
  • R ′ represents the ester residue described above
  • R ′ ′′ represents an alkyl group having 1 to 6 carbon atoms, or a substituted carbon group having 1 to 3 carbon atoms.
  • R ′ represents the ester residue described above
  • R ′ ′′ represents an alkyl group having 1 to 6 carbon atoms, or a substituted carbon group having 1 to 3 carbon atoms.
  • L represents a leaving group.
  • the “leaving group” is not particularly limited as long as it is a group that is usually eliminated in a nucleophilic substitution reaction, and examples of the group include a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom; An alkanesulfonyloxy group having 1 to 4 carbon atoms such as methanesulfonyloxy or ethanesulfonyloxy; or an aryl group such as benzenesulfonyloxy or toluenesulfonyloxy having 1 carbon atom And an arylsulfonyloxy group having 6 to 10 carbon atoms which may have 1 to 3 alkyl having 1 to 3 alkyl groups. It is preferably a halogen atom, more preferably a bromine atom or an iodine atom.
  • Method B involves reacting a carboxylic acid ester (IV) having a substituent such as a halogen at the corresponding site with a protected sulfur nucleophile (R "S-) such as potassium thioacetate, and obtaining the protected 2-mercapto-substituted ester derivative (V) under aqueous conditions in the presence of a base
  • R "S- protected sulfur nucleophile
  • V 2-mercapto-substituted ester derivative
  • B 1 process
  • This step is a step of reacting compound (IV) with a sulfur nucleophile represented by R ′ ′′ S—.
  • Compound (IV) has the general formula AWX- Y- CH 2 - compound represented by C00R ', for example, a N- bromo succinic acid, obtained by reacted according to a conventional method for introducing an L group.
  • the reaction solvent for the compound (IV) and the nucleophile is not particularly limited, but is preferably a polar solvent such as dimethylformamide.
  • the reaction temperature is from under ice-cooling to room temperature.
  • the reaction time is not particularly limited, but is usually 0.5 to several hours.
  • This step is a method for producing the 2-mercaptocarboxylic acid derivative (VI) or (III) by hydrolyzing the corresponding 2-mercaptocarboxylic acid ester derivative (V) under aqueous conditions in the presence of a base. is there.
  • reaction is carried out in the same manner as in step A1 described above.
  • Method C comprises reacting a corresponding 1,3-dithiane-2-carboxylic acid ester represented by the general formula (VI I) with a compound represented by the general formula AW-X-YL to obtain a compound represented by the general formula (VII I)
  • the compound represented by is synthesized, the protecting group of the obtained compound (VIII) is removed, and the obtained ketone derivative is obtained. (Having a ketone at the position)) to synthesize a compound represented by the general formula (IX), introducing a protected thiol group at the ⁇ -position of the obtained compound (IX), and then hydrolyzing the compound. This is a method for producing (III).
  • 1,3-dithiane-2-carboxylic acid ester represented by the corresponding general formula (VI I) is converted to an alcoholate such as an alkali metal such as lithium, potassium, and sodium; or lithium hydride, potassium hydride,
  • An active derivative obtained by treatment with an alkali metal hydride such as sodium hydride is reacted with a compound represented by the general formula AW-) (-YL, to give a compound represented by the general formula (VIII). This is the step of synthesizing.
  • solvent used for preparing the active derivative examples include solvents such as dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, ethyl ether, dioxane, toluene, methanol, and ethanol.
  • the reaction temperature is from under ice-cooling to room temperature.
  • the reaction time varies depending on the compound used, the type of reagent, the reaction temperature, the reaction amount and the like, but is usually 0.5 to several hours.
  • reaction between the active derivative obtained by the above process and the compound represented by the general formula A-W-X- ⁇ -L is usually carried out by reacting the reaction mixture containing the active form with the general formula A-WXY-L.
  • the compound to be added is added.
  • reaction solvent used here the solvent used for preparing the above active derivative can be used.
  • the reaction temperature is from under ice-cooling to room temperature.
  • the reaction time varies depending on the compound used, the type of reagent, the reaction temperature, the reaction amount and the like, but is usually 0.5 to several hours.
  • the leaving group represented by L is the same as the above-described leaving group L, but is preferably an iodine atom.
  • step C2 the protecting group of compound (VIII) obtained in step C1 is removed, and the obtained ketone derivative (having a ketone at the ⁇ - position) is reduced to give a compound represented by general formula (IX). This is the process to obtain. Removal of the protecting group of compound (VIII) is carried out by reacting with N-bromosuccinimide in a solvent.
  • reaction solvent a mixed solvent of a polar solvent such as acetonitrile and tetrahydrofuran and water is used.
  • the reaction temperature is from under ice-cooling to room temperature.
  • the reaction time is not particularly limited, but is usually 0.5 to several hours.
  • the ketone derivative obtained by the above reaction is not usually isolated, but is subjected to a reduction treatment as it is to derive a compound represented by the general formula (IX).
  • the reduction is carried out according to a conventional method, using a reducing agent such as a metal hydride such as potassium borohydride or sodium borohydride in a solvent such as methanol or ethanol.
  • a reducing agent such as a metal hydride such as potassium borohydride or sodium borohydride in a solvent such as methanol or ethanol.
  • the reaction temperature is from under ice-cooling to room temperature.
  • the reaction time is not particularly limited, but is usually 0.5 to several hours.
  • This step is a step of introducing a protected thiol group at the cysteine of the compound (IX) obtained in the step C2, followed by hydrolysis.
  • the introduction of the thiol group is carried out by first converting the hydroxy group at the ⁇ -position of the compound ⁇ ) to the compound (IX) using an activator, for example, a sulfonic acid halide such as mesyl chloride or tosyl chloride. And then reacting with potassium thioacetate, sodium thioacetate and the like.
  • an activator for example, a sulfonic acid halide such as mesyl chloride or tosyl chloride.
  • the reaction solvent is not particularly limited, but is preferably methylene chloride, toluene, dimethylformamide or the like.
  • the reaction temperature is from under ice-cooling to room temperature.
  • the reaction time is not particularly limited, but is usually 0.5 to several hours.
  • the reaction product obtained by the above-mentioned production method is subjected to a conventional method, for example, in water, methanol, tetrahydrofuran or the like or a mixed solvent thereof in the presence of a base, for example, a hydroxide of an alkali metal.
  • a base for example, a hydroxide of an alkali metal.
  • the reaction can be performed in the presence of bicarbonate and carbonate.
  • the reaction temperature is from under ice-cooling to room temperature.
  • the reaction time is not particularly limited, but is usually 0.5 to several hours. Further, by bringing a 2-mercaptocarboxylic acid derivative represented by the general formula (I) into contact with a hydroxide of the metal in an aqueous solvent, a salt thereof can be obtained.
  • the 2-mercaptocarboxylic acid derivative represented by the general formula (I) of the present invention can be produced from a compound represented by the following general formula (II).
  • This compound group is useful as a starting material for the compound group represented by the general formula (I) of the present invention, and these compounds themselves exhibit a blood glucose lowering action, a lipid lowering action, etc., and are used for diabetes, hyperlipidemia, etc. And preventive and therapeutic agents.
  • Examples of the compound represented by the general formula (II) used in the synthesis of the compound represented by the general formula (I) of the present invention include the following compounds.
  • A, W, and X have the same meanings as described above, and Y ′ represents a bond or a linear or branched alkylene group having 1 to 19 carbon atoms. . However, the -W-X-Y'- group does not show a bond.
  • Method D is a method in which the corresponding aldehyde derivative is condensed with a thiazolidine-2,4-dione derivative (X) to obtain compound (XI), which is then reduced to obtain compound (XII).
  • Step D1 is a step of reacting thiazolidine (X) with an aldehyde derivative represented by the above general formula A-W-X-Y'-CH0.
  • thiazolidine (X) and a desired aldehyde derivative represented by the above general formula AW-XY'-CH0 are dissolved in an appropriate solvent, and heated and refluxed using a Din-Stark apparatus. This is a method in which the reaction is performed while removing water.
  • the solvent is not particularly limited as long as it is inert, but is preferably benzene or toluene, which easily azeotropes with water.
  • step D2 the double bond of compound (XI) obtained in step D1 is reduced with a reducing agent in an appropriate solvent in the presence of a transition metal salt-organic coordination compound, and the thiazolidinedione compound (XI I).
  • the solvent is not particularly limited as long as it is inert to the reaction.
  • water for example, water; alcohols such as methanol, ethanol, and propanol; ethers such as dimethyl ether, tetrahydrofuran, and dioxane; dimethylform Amides, such as amide, dimethylacetamide, and hexamethylphosphoric acid triamide; sulfoxides, such as dimethyl sulfoxide; and a mixed solvent of water and these organic solvents are preferably used.
  • alcohols such as methanol, ethanol, and propanol
  • ethers such as dimethyl ether, tetrahydrofuran, and dioxane
  • dimethylform Amides such as amide, dimethylacetamide, and hexamethylphosphoric acid triamide
  • sulfoxides such as dimethyl sulfoxide
  • a mixed solvent of water and these organic solvents are preferably used.
  • transition metal salt examples include halides such as nickel, cobalt, and copper. Preferably it is cobalt chloride.
  • Any organic coordination compound may be used as long as it forms an organic coordination compound with a transition metal salt, and is preferably, for example, dimethyldalioxime, getyldalioxime, or diphenyldalioxime.
  • metal borohydride examples include lithium borohydride, potassium borohydride, sodium borohydride, and the like.
  • the reaction temperature for the above reduction is usually from ice-cooled to room temperature.
  • the reaction time varies depending on the amount of compound (IV) used, the reaction temperature and the like, and is not particularly limited, but is usually 0.5 to 20 hours.
  • A, W, X, Y, and L have the same meanings as described above, and L preferably represents a halogen atom.
  • the compounds at positions 3 and 5 of thiazolidine-2,4-dione (X) are extracted with a base to prepare a compound (XIIII), which is represented by the corresponding general formula A-WX-YL.
  • a compound (XIII) is reacted with an active derivative, preferably a halide, to obtain a thiazolidine-2,4-dione derivative (II).
  • step 1 The synthesis of compound (XI II) from compound (X) in step 1 is usually carried out in a suitable solvent by reacting with a base.
  • the base is LDA, n-butyllithium or the like, and preferably LDA.
  • the solvent is not particularly limited as long as it is inert to the reaction, but is preferably a non-protonic solvent, more preferably ethers such as ethyl ether, dioxane and tetrahydrofuran, and hexamethyl phosphate amide. It is.
  • the reaction temperature is ice-cooled to room temperature.
  • Compound (II) can be obtained by directly reacting the reaction product obtained in the above step E1 with an active derivative represented by the general formula A-W-X-Y-L, preferably a halide.
  • the reaction is carried out by adding the active derivative represented by the general formula A-W-X-Y-L dropwise or all at once to a suspension of the reaction product obtained in the step E1 under ice-cooling.
  • the target compound obtained in each of the above steps can be purified, if necessary, by a conventional method, for example, column chromatography, recrystallization, reprecipitation, or the like.
  • the reaction solution is appropriately neutralized, then a solvent is added to the reaction solution for extraction, and the solvent is distilled off from the extract.
  • the obtained residue is purified by subjecting it to column chromatography using silica gel or the like, whereby a pure product of the target compound can be obtained.
  • the salt of the target compound can be obtained by distilling the solvent to some extent from the reaction solution and purifying it by a recrystallization method.
  • a protective group may be introduced into a substituent or the like to proceed the reaction, and the protective group may be removed as appropriate.
  • the carboxy group is protected as an ester group to proceed the reaction, and the protective group is removed as appropriate.
  • the 2-mercaptocarboxylic acid derivative having the general formula (I), the pharmacologically acceptable ester thereof, or the pharmacologically acceptable salt thereof, and the thiazolidinedione compound having the general formula ( ⁇ ) according to the present invention include: It is administered in various forms.
  • the dosage form is not particularly limited, and is determined according to various preparation forms, patient age, gender and other conditions, degree of disease, and the like.
  • tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules are orally administered.
  • they are administered intravenously, alone or as a mixture with ordinary replenishers such as glucose and amino acids, and if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally.
  • suppositories they are administered rectally.
  • it is oral administration.
  • carriers for molding into tablets, a wide variety of carriers conventionally known in the art can be used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and caic acid.
  • binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethinolese / rerose, shellac, methinoresenorelose, potassium phosphate, polyvinylinoleviridone, dry starch
  • Disintegrators such as sodium alginate, powdered agar, powdered laminarane, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; sucrose, stearin, cocoa butter , Hydrogenated Oils and other disintegration inhibitors; Quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate; humectants such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite, and colloidal keic acid
  • the tablet can be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet.
  • a wide variety of carriers conventionally known in the art can be used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; And binders such as tragacanth powder, gelatin and ethanol; and disintegrants such as laminaran agar.
  • excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc
  • binders such as tragacanth powder, gelatin and ethanol
  • disintegrants such as laminaran agar.
  • any carrier conventionally known in the art can be used.
  • examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
  • the liquid preparation and the suspension are preferably sterilized and isotonic with blood.
  • the agent any of those commonly used in this field can be used, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearino alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sonorebitan fatty acid esters, etc. be able to.
  • a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary solubilizing agents, buffers, soothing agents, etc. May be added.
  • coloring agents may be added.
  • the amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and may be appropriately selected in a wide range, but is usually 1 to 70% by weight in the whole composition. / 0 , preferably 1 to 30% by weight.
  • the dosage varies depending on symptoms, age, body weight, administration method, dosage form, etc., but it is usually 1 day for adults and the lower limit is O.OOlmg (preferably 0.01 mg, more preferably 0.1 mg). lmg), and an upper limit of 2,000 mg (preferably 200 mg, more preferably 20 mg) can be administered once or several times.
  • column chromatography means silica gel column chromatography unless otherwise specified.
  • Example 1 7- (4-chlorophenyl) -12-mercaptoheptanoic acid (exemplified compound number 18)
  • a solution of 12 ml of diisopropylamine in 100 ml of a tetrahydrofuran (THF) solution was cooled with ice-methanol, and 50 ml of 1.6 M n-butyllithium was added dropwise. After 10 minutes, a solution of 4.5 g of thiazolidine-1,4-dione dissolved in 14 ml of HMPA was added dropwise. The reaction solution was returned to room temperature and stirred for 1 hour. The reaction solution was cooled again with ice-methanol, and 5.5 g of 5- (4-chlorophenyl) pentyl iodide was added at one time, and the reaction solution was returned to room temperature and stirred for 1 hour.
  • THF tetrahydrofuran
  • reaction solution was acidified with dilute hydrochloric acid, and extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to column chromatography, and eluted with chloroform. The corresponding fraction was concentrated to dryness to give 2.17 g of the title compound as a pale yellow syrup (yield 40%).
  • Example 3 71- (4-benzyloxyphenyl) -1-mercaptoheptanoic acid (Example Compound No. 120)
  • Example 3 In the same manner as in 3) of Example 3, the title compound 0.54 was obtained from 0.75 g of 5- [6- (4-chlorophenyl) hexyl] thiazolidine-1,2,4-dione obtained in 2). g was obtained (78% yield).
  • Example 8 7- (3-chlorophenyl) -1-mercaptoheptanoic acid (exemplified compound number 11 7)
  • Example 3 In the same manner as in 3) of Example 3, the title compound 1.0 was obtained from 1.5-g of 5- (5- (3-chloromethylphenyl) pentyl] thiazolidine-2,4-dione obtained in 2). g was obtained as a colorless syrup (yield 73 ° / o).
  • Example 3 In the same manner as in 3) of Example 3, 0.42 g of the title compound was obtained from 0.65 g of 5- [7- (4-chlorophenyl) heptyl] thiazolidine-2,4-dione. (Yield 70%).
  • Example 1 7- (4-Hydroxyphenyl) 1-2-Mercaptoheptanoic acid (Example Compound No. 1-114)
  • Example 3 In the same manner as in 3) of Example 3, 0.75 g of the title compound was obtained as a colorless solid from 1.1 g of 5- [5- (4-hydroxyphenyl) pentyl] thiazolidine-1,2-dione. (Yield 75%).

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Abstract

L'invention porte sur des dérivés de l'acide 2-mercaptocarboxylique de formule générale (I) et les esters pharmacocompatibles des deux, qui présentent propriétés anti-hyperglycémiques et d'activation du récepteur PPAR. Dans la formule, A est phényle ou analogue, X est une valence libre ou analogue, W et Y sont chacun indépendamment alkylène ou analogue, et R est H ou analogue.
PCT/JP2000/001045 1999-02-24 2000-02-24 Derives de l'acide 2-mercaptocarboxylique Ceased WO2000050392A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26906/00A AU2690600A (en) 1999-02-24 2000-02-24 2-mercaptocarboxylic acid derivatives

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JP4683099 1999-02-24
JP11/46830 1999-02-24

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WO2000050392A1 true WO2000050392A1 (fr) 2000-08-31

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PCT/JP2000/001045 Ceased WO2000050392A1 (fr) 1999-02-24 2000-02-24 Derives de l'acide 2-mercaptocarboxylique

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083616A1 (fr) * 2001-04-10 2002-10-24 Sankyo Company, Limited DERIVE D'ACIDE GRAS φomega;-ARYLE α-SUBSTITUE
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
US7071181B2 (en) 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
US7132415B2 (en) 2001-09-21 2006-11-07 Schering Corporation Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors
US7192944B2 (en) 2003-03-07 2007-03-20 Schering Corp. Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7208486B2 (en) 2003-03-07 2007-04-24 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7235543B2 (en) 2003-03-07 2007-06-26 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
WO2005042002A3 (fr) * 2003-10-30 2008-01-10 Entelos Inc Traitement de la polyarthrite rhumatoide a l'aide d'antagonistes de la proteine flip
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
US7417039B2 (en) 2001-01-26 2008-08-26 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7560449B2 (en) 2002-11-06 2009-07-14 Schering Corporation Methods and therapeutic combinations for the treatment of demyelination
US7612058B2 (en) 2001-01-26 2009-11-03 Schering Corporation Methods for inhibiting sterol absorption
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2090591A (en) * 1980-12-15 1982-07-14 Ici Plc Amide derivatives
WO1994017036A1 (fr) * 1993-01-22 1994-08-04 Institut National De La Sante Et De La Recherche Medicale (Inserm) Composes s-carbonyle aliphatique lipophile [n-mercaptoacyl(acide amine ou peptide)] utilises comme antihypertenseurs
JPH10306076A (ja) * 1997-03-06 1998-11-17 Nippon Chemiphar Co Ltd プロピオン酸誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2090591A (en) * 1980-12-15 1982-07-14 Ici Plc Amide derivatives
WO1994017036A1 (fr) * 1993-01-22 1994-08-04 Institut National De La Sante Et De La Recherche Medicale (Inserm) Composes s-carbonyle aliphatique lipophile [n-mercaptoacyl(acide amine ou peptide)] utilises comme antihypertenseurs
JPH10306076A (ja) * 1997-03-06 1998-11-17 Nippon Chemiphar Co Ltd プロピオン酸誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CORIC, PASCALE ET. AL.: "Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors", J. MED. CHEM., vol. 39, no. 6, 1996, pages 1210 - 1219, XP002929114 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
US7071181B2 (en) 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
US7612058B2 (en) 2001-01-26 2009-11-03 Schering Corporation Methods for inhibiting sterol absorption
US7417039B2 (en) 2001-01-26 2008-08-26 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
WO2002083616A1 (fr) * 2001-04-10 2002-10-24 Sankyo Company, Limited DERIVE D'ACIDE GRAS φomega;-ARYLE α-SUBSTITUE
US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
US7132415B2 (en) 2001-09-21 2006-11-07 Schering Corporation Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors
US7560449B2 (en) 2002-11-06 2009-07-14 Schering Corporation Methods and therapeutic combinations for the treatment of demyelination
US7235543B2 (en) 2003-03-07 2007-06-26 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7368563B2 (en) 2003-03-07 2008-05-06 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7368562B2 (en) 2003-03-07 2008-05-06 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7378518B2 (en) 2003-03-07 2008-05-27 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7208486B2 (en) 2003-03-07 2007-04-24 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7192944B2 (en) 2003-03-07 2007-03-20 Schering Corp. Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
WO2005042002A3 (fr) * 2003-10-30 2008-01-10 Entelos Inc Traitement de la polyarthrite rhumatoide a l'aide d'antagonistes de la proteine flip
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés

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