WO2000020385A1 - Derives de dithiol - Google Patents

Derives de dithiol Download PDF

Info

Publication number
WO2000020385A1
WO2000020385A1 PCT/JP1999/005422 JP9905422W WO0020385A1 WO 2000020385 A1 WO2000020385 A1 WO 2000020385A1 JP 9905422 W JP9905422 W JP 9905422W WO 0020385 A1 WO0020385 A1 WO 0020385A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
con
compound
single bond
oohn
Prior art date
Application number
PCT/JP1999/005422
Other languages
English (en)
Japanese (ja)
Inventor
Takashi Fujita
Tomihisa Yokoyama
Original Assignee
Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU60012/99A priority Critical patent/AU6001299A/en
Publication of WO2000020385A1 publication Critical patent/WO2000020385A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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
    • C07C323/23—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—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
    • C07C323/60—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 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms

Definitions

  • the present invention relates to a dithiol derivative having an excellent activity of enhancing daltathione reductase activity, a method for producing the same, and use thereof.
  • Glutathione is widely found in tissues of living organisms, is a major intracellular reducing agent, and plays an important role in redox reduction.
  • reduced daltathione plays an important role in various cell defense and repair mechanisms, depending on the thiol group present in the molecule.
  • Glutathione peroxidase is an enzyme that catalyzes the reaction in which peroxides (such as hydrogen peroxide and lipid peroxide) are reduced by GSH, and is an important enzyme in the antioxidant mechanism.
  • daltathione reductase is an enzyme that reduces oxidized glutathione (oxidized daltathione: GSSG) in the presence of NADPH to regenerate it into GSH.
  • Antioxidant mechanisms including these compounds and enzymes, protect cells from the harmful effects of pro-oxidants (eg, the above peroxides and free radicals). Oxidative stress occurs when the balance between pro-oxidants and antioxidant mechanisms predominates [J. Appl. Physiol. 1996 Nov., 81 (5), pp. 2199-2202].
  • ischemic heart disease cataract
  • idiopathic pulmonary fibrosis adult respiratory distress syndrome, emphysema, asthma, and bronchopulmonary hypoplasia
  • Lung diseases such as interstitial pulmonary fibrosis
  • chronic renal failure peripheral nerves and central nervous system
  • peripheral nerves and central nervous system such as Parkinson's disease, schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, cerebral ischemia Nervous system diseases including: gastric ulcer; diabetes mellitus; necrosis and apoptosis of hepatocytes such as ethanol-induced liver damage; viral diseases such as influenza, hepatitis B, HIV; and colorectal cancer.
  • WO 94/12527 also states that compounds that promote the synthesis of endogenous GSH may contain glutathione deficiencies, such as those associated with oxidative tissue damage, especially those associated with excessive free radical damage. It is disclosed that it is suitable for the treatment of various diseases caused by, for example, excessive drinking of alcohol, xenobiotics, radiation damage, intracellular oxidation state caused by liver disease, drugs and chemicals.
  • Poisoning heavy metal poisoning, physiological aging of the brain (e.g., brain decline caused by a decrease in glutathione levels due to changes in defense mechanisms against oxidants, such as loss of memory and learning abilities) Parkinson's disease) and acute and chronic neurodegenerative diseases (acute medical conditions include acute ischemic conditions, especially cerebral seizures, hypoglycemia, and epileptic seizures; Is a Jo, amyotrophic lateral sclerosis, Alzheimer's disease, Hanchin tons chorea), dysfunction, in particular cancer immunotherapy immune system, infertility, in particular male infertility are mentioned. Furthermore, it is disclosed that the compound is also suitable for organ reperfusion following an ischemic condition, which is the main cause of free radicals.
  • JP-A-64-265615 discloses that a compound that increases daltathione concentration is useful for the treatment and prevention of various diseases including cataract, liver disease and kidney disease. ing.
  • dihydrolipoic acid compound of the following structural formula A
  • dihydrolipoic acid compound of the following structural formula A
  • the compound of the present invention has a structure different from that of dihydrolipoic acid, and has a daltathione reductase enhancing action in ⁇ .
  • the present inventors have conducted intensive studies on the synthesis of pharmacological agents and prophylactic and therapeutic agents for diseases caused by oxidative stress. As a result, dithiol derivatives showed excellent daltathione reductase activity enhancing activity and peroxidation. The present inventors have found that they have an object erasing effect and have low irritation to eyes, and have completed the present invention.
  • Another object of the present invention is to use a dithiol derivative for producing a drug (particularly, daltathione reductase activity enhancer) and a pharmaceutical (particularly, daltathione reductase activity enhancer) containing a dithiol derivative as an active ingredient.
  • An object of the present invention is to provide a method for preventing or treating a disease caused by oxidative stress, which comprises administering a pharmacologically effective amount of a dithiol derivative.
  • n 0 or 1 when m is 0, n represents 2, when m is 1, n represents 1,
  • k 0 or an integer of 1 to 12
  • R 1 is a hydrogen atom, a group selected from substituent group ⁇ , or
  • Substituent group ⁇ 1 to 3 substituents selected from Substituent group ⁇ and Substituent group y.
  • 1 to 12 carbon atoms which may have an oxygen atom and / or a sulfur atom interposed Represents an alkyl group of
  • A is a single bond, an oxygen atom, a carbonyl group, or one N (R 2 ) CO—,
  • R 2 , R3 and R4 are the same or different and are a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, An aralkyl group, an aralkyl group in which an aryl moiety is substituted with one to three groups selected from a substituent group, or one group selected from a substituent group ⁇ .
  • ⁇ is a single bond or —N (R5) — or — N (RN (R5) — [wherein, R 5 and R 6 are the same or different, and a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an aralkyl group, and an aryl moiety are substituted with 1 to 3 groups selected from a substituent group
  • ⁇ is one N (R 2 ) CO—, one N (R 2 ) CS—,
  • R 7 is selected from a lower alkyl group, a lower alkenyl group, an aralkyl group, an aralkyl group substituted with 1 to 3 groups selected from the substituent group i3 or a substituent group ⁇ . Represents one group to be obtained.
  • R 1 may be, in addition to the above definition, a hydroxyl group or a group OR? (Wherein, R? Has the same meaning as described above.).
  • A is an oxygen atom
  • B is a single bond or one N (R5) — wherein R5 has the same meaning as defined above.
  • A is one CO—O— or one N (R 2 ) O—, wherein R 2 has the same meaning as described above.
  • B is a single bond;
  • preferred compounds include
  • Rl force ' a heterocyclic group, a heterocyclic group substituted with 1 to 3 groups selected from substituent group i3, or 1 selected from substituent group ⁇ and substituent group 7
  • substituent group i3 a heterocyclic group substituted with 1 to 3 groups selected from substituent group i3, or 1 selected from substituent group ⁇ and substituent group 7
  • substituent group i3 a heterocyclic group substituted with 1 to 3 groups selected from substituent group i3, or 1 selected from substituent group ⁇ and substituent group 7
  • substituent group i3 a heterocyclic group substituted with 1 to 3 groups selected from substituent group i3, or 1 selected from substituent group ⁇ and substituent group 7
  • substituent group 7 With 3 to 3 substituents
  • R 1 force ; heterocyclic group; heterocyclic group substituted by 1 to 3 groups selected from substituent group
  • A is a carbonyl group, or the formula - CON (R 2) S 0 2 -, one N (R 2) CO-, one N: (R2) CS-, one CON (R 2) CO-, one N (R 2) COCO- or single N, (R2) S 0 2 "[ wherein, R 2 is a hydrogen atom, a 1 to 1 2 alkyl group or Njiru group carbon atoms.] group having A compound that is
  • R2 is 1 or hydrogen atom or a carbon atoms is 1 2 alkyl group.
  • (1 3) B is a single bond or a formula one N (R5) - or single N (R6) N (R5) - [ wherein, R 5 and R 6 are the same or different and represent a hydrogen atom, or 1 carbon atoms Shows 12 alkyl groups or benzyl groups.
  • (14) B is a single bond or a formula — N (R 5 ) — or one N (RN (R5) — [wherein, R 5 and are the same or different and are each a hydrogen atom or 1 to 12 carbon atoms.
  • R 5 and are the same or different and are each a hydrogen atom or 1 to 12 carbon atoms.
  • B force a compound that is a single bond, one NH—, one NCH 3 — or one NHNCH3—, or a pharmaceutically acceptable salt, thiol ester or other derivative thereof.
  • Particularly preferred compounds include
  • a pharmacologically acceptable salt, thiol ester or other derivative thereof can be mentioned.
  • the medicament (particularly, daltathione reductase activity enhancer) of the present invention is a compound according to any one of (1) to (15), a pharmacologically acceptable salt thereof, and a thiol ester. Or other derivatives are contained as an active ingredient.
  • aryl group of “aryl group” and “aryl group substituted with 1 to 3 groups selected from substituent group 3” is the number of carbon atoms It represents 6 to 14 aromatic hydrocarbon groups, and examples thereof include groups such as phenyl, indul, naphthyl, phenanthrenyl and anthracenyl. Preferably it is phenyl.
  • the “aryl group” may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include a group such as 2-indanyl.
  • heterocyclic group in “heterocyclic group” and “heterocyclic group substituted by 1 to 3 groups selected from substituent group / 3” refers to sulfur A 5- to 7-membered saturated or unsaturated heterocyclic group (preferably, an aromatic heterocyclic group) containing 1 to 3 atoms, oxygen atoms or 1 and 3 nitrogen atoms.
  • saturated heterocyclic group examples include, for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dithiolanyl, thiadiazolidinyl, oxaziazolidinyl, dithiazolin Ridininole, piperidyl, piperazur, morpholinyl, thiomorpholinyl, dioxanyl, homopiperazinyl and the like.
  • it contains at least one nitrogen atom, such as pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and further contains one sulfur atom, oxygen atom or nitrogen atom. And a 5- or 7-membered saturated heterocyclic group.
  • nitrogen atom such as pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and further contains one sulfur atom, oxygen atom or nitrogen atom.
  • a 5- or 7-membered saturated heterocyclic group such as pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and further contains one sulfur atom, oxygen atom or nitrogen atom.
  • saturated heterocyclic group may be substituted with an oxo group and / or a thioxo group.
  • examples of such a group include piperidonyl, pyrrolidonyl, thiazolidonyl, dioxothiazolidinyl. Thioxodithiazolidinyl, dioxoimidazolidinyl, dioxoxazolidinyl and the like.
  • saturated heterocyclic group may be condensed with another cyclic group, and examples of such a group include benzodioxanyl, indolinyl, isoindrinyl, benzoxazinyl Benzothiazolidinyl, benzothiazinyl, chromanyl, 6-acetoxy 2,5,7,8-tetramethylchroman-12-yl, isoindole-11,3-dione-12-yl .
  • aromatic heterocyclic group preferably, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxaziazolyl, triazolyl, tetrazolyl, thiadiazolyl
  • groups thereof include groups such as vilanyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazur, and are preferably a 5- to 7-membered aromatic containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom.
  • the “aromatic heterocyclic group” may be condensed with another cyclic group, and examples thereof include indolyl, benzofuryl, benzothenyl, benzoxazolyl, and benzoimidazo. Examples include groups such as ril, isoquinolyl, quinolyl, and quinoxalyl. Further, the above “aromatic heterocyclic group” may be substituted with an oxo group and / or a thioxo group. Examples of such a group include pyridonyl, oxazolonyl, villazolonyl, isoxazolonyl, and thioxodithiazolyl. And the like.
  • an alkyl group having 1 to 12 carbon atoms and, in the definition of R 1 , “1 to 3 substituents selected from a substituent group ⁇ ⁇
  • 6-Pindecyl 2-Methyldecyl, 3—Methyldecyl, 4-Methyldecyl, 5-Methyldecyl, 6-Methylenodecinole, 7—Methylenodecinole, 8—Methylenodecinole, 9-Methyldecyl, 7 —Echinolenoninole, Dodecyl, 2 Dodecyl, 3 1 Dodecyl.
  • R 1 ⁇ alkyl having from 1 to 3 carbon atoms which may be substituted with 1 to 3 substituents selected from substituent group Y and may be interposed with an oxygen atom and / or a sulfur atom
  • substituent group Y substituent group Y
  • group in which an oxygen atom and / or a sulfur atom are interposed among the groups include, for example, a group in which the above “alkyl group” is substituted with one “alkoxy group” or “alkylthio group”.
  • alkoxy group and 'alkylthio group mean the same groups as those defined in the substituent group and the substituent group ⁇ .
  • Examples of such a group include: For example, substituted with an alkoxyalkyl group having 2 to 10 carbon atoms, an alkylthioalkyl group having 2 to 10 carbon atoms, an alkyl group having 1 to 5 carbon atoms substituted with a benzyloxy group, and a benzylthio group
  • An alkyl group having 1 to 5 carbon atoms here, a benzyloxy group and a benzyl moiety of the benzyloxy group may be substituted with 1 to 3 groups selected from a substituent group ⁇ ). I can do it.
  • aralkyl group and “aralkyl group in which the aryl moiety is substituted with 1 to 3 groups selected from substituent group
  • benzyl 1 One feninole etinole, 2 — huenii.
  • acyl group refers to, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, vivaloyl, relinole, isolelinole, octanoienole, Nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, pendecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, Pentadecinolecanoleboninole, hexadecylcarbonyl, 1-methinolepentadecinolecanoleboninole, 14-methylpentadecylcarbonyl,
  • aliphatic acyl group “aromatic acyl group”, “alkoxycarbonyl group” and “lower alkane sulfonyl group” are preferable, and alkylcarbonyl group and lower alkoxy group are more preferable. It is carbonyl.
  • Examples of the “5- to 7-membered heterocyclic group” formed by R 1 and R 5 together with the nitrogen atom to which they are bonded include pyrrolidino, 3-thiazolidinyl, piperidino, piperazino, morpholino, thiomorpholino, A 5- to 7-membered heterocyclic group containing at least one nitrogen atom, such as homopiperazino, imidazolidinyl and imidazolyl, and which may further contain one sulfur atom, oxygen atom or nitrogen atom. Can be.
  • the “5- to 7-membered heterocyclic group” may be substituted with an oxo group and / or 1 to 3 groups selected from substituent group i3, and is condensed with another cyclic group. It may be ringed.
  • groups include, for example, N-methylbiperazino, Nt-butoxycarbylbiperazino, 1-indolinyl, 2-carboxy-1 monoindolinyl, 2-methoxycarbone-1,1-indolinolinole, 3,4-dimethinole Examples include indoline-1,5-dione-11-yl and isoindole-1,3-dione-1-yl.
  • the “lower alkyl group” of the “hydroxy lower alkyl group” in the definition means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ - Butyl, isobutyl, s-butynole, tert-butynole, n-pentynole, isopentynole, 2-methinolebutynole, neopentynole, 1-ethynole propynole, n-hexynole, isohexynole, 4-methyl
  • it is a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, and more preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Preferably, it is methyl.
  • “Lower alkenyl group” in the definition of R 7 includes vinyl, aryl, methallyl, 1-propenyl, isopropylidinole, 1-buteninole, 2-butenyl, 3-buteninol, 1
  • it is an alkenyl group having 2 to 4 carbon atoms, such as butyl, aryl, methallyl, 1-propenyl, isopropyl, butenyl, and more preferably aryl, 2-butenyl.
  • halogenated lower alkyl group in the definition of the “substituent group” refers to a group substituted by a halogen atom such as the above “lower alkyl group”, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • Examples of such groups include, for example, chloromethinole, dichloromethinole, trichloromethinole, trifrenoleolomethinole, 2-chloroethynole, 2-funoleolechinole, ⁇ 2-bromoethynole, 2-odoethynole, 2,2,2—trichloroethinole, 2,2,2—trinoleolochinole, 3—clopropinole, 3-fluoropropyl, 3-bromopropinole, 3-bromopropyl, 3,3,3-tri Krolov. Lopinore, 3,3,3—Trifunoleo Mouth Propinore, 4-Chlorobutinole, 4-Funole O-butyl, 4-bromobutyl and 4-monobutyl.
  • lower alkoxy group in “means a group wherein the above" lower alkyl group "is bonded to an oxygen atom, for example, methoxy, ethoxy, ⁇ -propoxy, isopropoxy, ⁇ -butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentyloxy, isopentinoleoxy, 2-methynolebutoxy, 1-ethynolepropoxy, n-hexynoleoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy , 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-d
  • lower alkylthio group in the definition of [substituent group
  • halogen atom in the definition of [substituent group / 3] and [substituent group "y”] represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • amine residue refers to an amino group; methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, getylamino, diisopropylamino, dibutylamino.
  • amino group substituted by one or two “lower alkyl groups” such as “cyclopentylamino, cyclohexylamino, dicyclopentylamino, dicyclohexylamino" and "a cycloalkyl group having 5 to 7 carbon atoms" 1 or 2 substituted amino groups; Saturated cyclic amine residues having a nitrogen atom in the ring, such as pyrrolidino, piperidino, piperazino, ⁇ -methylbiperazino, morpholino, thiomorpholino; anilino, benzylamino, ⁇ -tylanilino ⁇ , such as ⁇ -methylbenzylamino, nitrogen
  • the aryl atom may be substituted by "lower alkyl 3 ⁇ 4".
  • An aryl or aralkylamino group; a nitrogen atom such as pyridyl amiso, ⁇ -methylpyri.dilamino, ⁇ -ethylpyridylamino may be substituted by "lower alkyl”.
  • Examples thereof include an amine residue bonded by a nitrogen atom such as an optionally substituted heteroarylamino group, and an amino group; a “lower alkyl group”; an amino group substituted by 1 or 2 amino acids; A saturated cyclic amine residue having a nitrogen atom in the ring, such as pyrrolidino, piperidino, piperazino, p-methylbiperazino, morpholino, and thiomorpholino; and anilino, benzylamino, p-methylanilino, p-methyl. Even if the nitrogen atom is replaced by a “lower alkyl group” such as benzylamino, aryl or arylalkyl No group.
  • a “lower alkyl group” such as benzylamino, aryl or arylalkyl No group.
  • a rubamoyl group optionally substituted with a nitrogen atom refers to a group in which the above "amine residue” is bonded to a carbonyl group, and And a carbamoyl group in which a nitrogen atom is substituted with the above-mentioned “acyl group” or aminosulfonyl.
  • acyl group or aminosulfonyl. Examples of such a group include methanesulfonylaminocarbonyl and aminomethanesulfonyl.
  • 3] refers to a group in which the above “lower alkyl group” is substituted by a hydroxyl group. Examples of such a group include hydroxymethyl and hydroxy. Droxityl, hydroxypropyl and hydroxybutyl can be mentioned.
  • “Pharmacologically acceptable salt thereof” means that the compound (I) of the present invention has an amino group and an imine group. By reacting with an acid when it has a basic group such as a phenyl group, or by reacting with a base when it has an acidic group such as a carboxy group and / or an imido group. Since it can be made into a salt, the salt is shown.
  • the salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, carbonate Inorganic salts such as salts, sulfates and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid Salts such as arylsulfonate, acetic acid, malic acid, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, lactate, dalconate, benzoate Organic acid salts such as acid salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, orditin salts, glutamate salts, and aspart
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt, or a lithium salt, an alkaline earth metal salt such as a barium salt or a magnesium salt, or a calcium salt.
  • Metal salts such as aluminum salts, iron salts, etc .; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenyldaricin alkyl ester salts, ethylenediamine salts, and N-methylglucamine salts.
  • Guanidine salt methylamine salt, dimethylamine salt, getylamine salt, triethylamine salt, diisopropylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, ⁇ '-dibenzylethylenediamine salt, chloroprocaine salt, propower Yin salt, Jetanoamine salt, ⁇ Amine salts such as organic salts such as benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt; and glycine, lysine and arginine salts And amino acid salts such as orditin salt, glutamate and aspartate.
  • thiol ester or other derivative refers to a compound in which one or two thiol groups of the compound of the general formula (I) of the present invention are protected by a “thiol group-protecting group”. means.
  • Examples of the “thiol protecting group” include, for example, 1 to 1 such as Jill, phenetinole, 1-pheninolepropyl, ⁇ -naphthinolemethyl,
  • Aliphatic acyl group Benzoyl, ⁇ -naphthyl, j3-naphthoyl-like arylcarbonyl group, 2'-bromobenzoinole, 4-chlorobenzoylene-like arylcarbonyl group , 2, 4, 6-trimethylbenzoyl, lower alkylated arylcarbonyl groups such as 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisyl, 412trobenzyl, 2-trobenzoyl Such as a nitrated arylcarbonyl group such as a lower alkoxycarbonylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl, and an arylated arylcarbonyl group such as 4-phenylbenzoyl; Lower-group alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, but
  • an "aralkyl group” an "aliphatic acyl group”, an “aromatic acyl group”, an “alkoxycarbonyl group” and an “aralkyloxycarbonyl group”. It is methoxybenzyl, triphenylmethyl, acetinole, benzoyl, 4-nitrobenzoyl, tert-butoxycarbonyl, benzyloxycarbonyl or 4-nitro-2-benzyloxycarbonyl.
  • the compound (I) of the present invention when left in the air, it may absorb water and may become adsorbed water or form a hydrate, and such salts are also included in the present invention. Is done.
  • the compound (I) of the present invention has an asymmetric carbon in the molecule, and there are stereoisomers each of which is R-coordinate and S-coordination. Both are included in the present invention.
  • dithiol derivative of the present invention examples include the following compounds qd- (oooia)--HN-oo-oz
  • OOHNOOHN- 900 T o -OOHNOOHN- 1/00 T ⁇ 'South ⁇ OOHNOOHN- ⁇ ⁇ 9- ⁇ ⁇ - ⁇ ⁇ ⁇ 9 ⁇ [- ⁇ -OOHNOOHN- ⁇ nQ- 9 lA [-S-000H-I - ⁇ ud small ⁇ ⁇ ⁇ [- ⁇ ⁇ OOHNOOHN "p ⁇ ud-T OOH-T ⁇ South ⁇ OOHNOOHN" 666 n8 0009 ⁇

Abstract

L'invention concerne de nouveaux intensificateurs de l'activité de glutathione réductase, qui sont des composés représentés par la formule générale (I), y compris leurs sels pharmaceutiquement acceptables, les thioesters et autres dérivés correspondants. Dans ladite formule, m vaut 0 ou 1; n vaut 2 lorsque m est égal à 0, et n vaut 1 lorsque m est égal à 1; k est un entier compris entre 0 et 12; R1 est hydrogène, un élément sélectionné dans la série des substituants α, etc.; A est un groupe comprenant -N(R2)CO-, -CON(R2)CO-, ou -CON(R2)SO2- (R2 est hydrogène, alkyle, etc.), etc.; et B est une liaison unique, -N(R5)- (R5 est hydrogène, alkyle, etc.), etc. [Substituants α] aryles éventuellement substitués, groupes hétérocycliques éventuellement substitués [Substituants β]lkyles, alkyles inférieurs halogénés, etc. [Substituants η] alcoxys inférieurs, hydroxy, etc.
PCT/JP1999/005422 1998-10-02 1999-10-01 Derives de dithiol WO2000020385A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60012/99A AU6001299A (en) 1998-10-02 1999-10-01 Dithiol derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP28062198 1998-10-02
JP10/280621 1998-10-02

Publications (1)

Publication Number Publication Date
WO2000020385A1 true WO2000020385A1 (fr) 2000-04-13

Family

ID=17627609

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/005422 WO2000020385A1 (fr) 1998-10-02 1999-10-01 Derives de dithiol

Country Status (2)

Country Link
AU (1) AU6001299A (fr)
WO (1) WO2000020385A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076935A1 (fr) * 2001-03-19 2002-10-03 Senju Pharmaceutical Co., Ltd. Nouveau derive de l'acide lipoique et son utilisation
WO2004024139A1 (fr) * 2002-09-13 2004-03-25 Oga Research, Incorporated Inactivateur de la melanine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6426516A (en) * 1987-07-21 1989-01-27 Teijin Ltd Agent for increasing tissue glutathione level
FR2707983A1 (fr) * 1993-07-21 1995-01-27 Pf Medicament Nouveaux dérivés de l'acide lipoïque et dihydrolipoïque, leur préparation et leur application en thérapeutique humaine.
EP0947503A1 (fr) * 1998-04-01 1999-10-06 Galderma Research & Development, S.N.C. Dérivés de l'acide 6,8-dimercaptooctanoique substitués en 6-S et/ou 8-S par le radical (3-methylthiopropanoyl) et compositions pharmaceutiques destinées au traitement de tumeurs cancéreuses
WO1999050238A1 (fr) * 1998-03-26 1999-10-07 Santen Pharmaceutical Co., Ltd. Nouveaux derives d'uree

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6426516A (en) * 1987-07-21 1989-01-27 Teijin Ltd Agent for increasing tissue glutathione level
FR2707983A1 (fr) * 1993-07-21 1995-01-27 Pf Medicament Nouveaux dérivés de l'acide lipoïque et dihydrolipoïque, leur préparation et leur application en thérapeutique humaine.
WO1999050238A1 (fr) * 1998-03-26 1999-10-07 Santen Pharmaceutical Co., Ltd. Nouveaux derives d'uree
EP0947503A1 (fr) * 1998-04-01 1999-10-06 Galderma Research & Development, S.N.C. Dérivés de l'acide 6,8-dimercaptooctanoique substitués en 6-S et/ou 8-S par le radical (3-methylthiopropanoyl) et compositions pharmaceutiques destinées au traitement de tumeurs cancéreuses

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BORGULYA J. ET AL.: "Rearrangement of Derivatives of 1,3-Dithian-5-amine into Bicyclic 2-Thiazolidines. Crystal Structures of cis- and trans-1-(2-Aryl-1,3-dithian-5-yl)-2-thioureas and cis- and trans-5-Aryl-3-imino-7,7a-dihydro-1H,3H,5H-thiazolo(3,4-c)thiazoles", HELVETICA CHIMICA ACTA, vol. 67, no. 7, 1984, pages 1827 - 1842, XP002923633 *
DIKALOV S. ET AL.: "Determination of Rate Constants of the Reactions of Thiols with Superoxide Radical by Electron Paramagnetic Resonance: Critical Remarks on Spectrophotomeric Approaches", ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, vol. 326, no. 2, 1996, pages 207 - 218, XP002923632 *
KLIUKIENE R. ET AL.: "The protective effects of dihydrolipoamide and glutathione against photodynamic damage by A1-phtalocyanine tetraslfonate", BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL, vol. 41, no. 4, 1997, pages 707 - 713, XP002923631 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076935A1 (fr) * 2001-03-19 2002-10-03 Senju Pharmaceutical Co., Ltd. Nouveau derive de l'acide lipoique et son utilisation
US7700080B2 (en) 2001-03-19 2010-04-20 Senju Pharmaceutical Co., Ltd. Method of suppressing melanin production by metal chelates of lipoyl amino acid derivatives
WO2004024139A1 (fr) * 2002-09-13 2004-03-25 Oga Research, Incorporated Inactivateur de la melanine
CN100367949C (zh) * 2002-09-13 2008-02-13 有限会社绪方研究 黑色素消除制剂
US8048911B2 (en) 2002-09-13 2011-11-01 OGA Research, Inc. Melanin eliminator preparation

Also Published As

Publication number Publication date
AU6001299A (en) 2000-04-26

Similar Documents

Publication Publication Date Title
RU2165932C2 (ru) Дитиолановые производные и лекарственные средства на их основе
US10442782B2 (en) Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10766882B2 (en) 1,2-naphthoquinone based derivative and method of preparing the same
CZ20033296A3 (cs) Benzoylsulfonamidy a sulfonylbenzamidiny jako protinádorové sloučeniny
US20170001993A1 (en) Compounds, compositions, and methods for increasing cftr activity
CA2942387A1 (fr) Composes, compositions et procedes pour augmenter l'activite cftr
ES2931319T3 (es) Inhibidores de aldosa reductasa y usos de los mismos
JP4936666B2 (ja) カリウムチャンネル遮断薬としてのスルホンアミド
AU2017339104B2 (en) 2-amino-N-(arylsulfinyl)-acetamide compounds as inhibitors of bacterial aminoacyl-tRNA synthetase
WO2004050646A1 (fr) Derives de 1, 2, 5-thiadiazolidin-3-one 1, 1 dioxyde utilises en tant qu'inhibiteurs de la proteine tyrosine phosphatase ptp1b
PT1689726E (pt) Derivados de 5-(benz-(z)-ilideno)-tiazolidin-4-ona como agentes imunossupressores
JP2016505040A (ja) アルドース還元酵素阻害剤およびその使用
JPH11507081A (ja) 細胞保護剤としてのチアゾリジン−４−カルボン酸誘導体
EP0973727B8 (fr) Derives d'iode actives utilises dans le traitement du cancer et du sida
WO2012130299A1 (fr) Inhibiteurs de peptidase
WO2000020385A1 (fr) Derives de dithiol
EP3288949B1 (fr) Derives d'aminohydrothiazine fusionnee contenant du tetrahydrofurane utiles dans le traitement de la maladie d'alzheimer
ES2749657T3 (es) Derivados de O-alquil-bencilidenguanidina y su uso terapéutico para el tratamiento de trastornos asociados a una acumulación de proteínas mal plegadas
US5538966A (en) Carbonic anhydrase inhibitors
KR19980702707A (ko) 광학활성인 티아졸리디논 유도체
JP2000169443A (ja) ジチオ―ル誘導体
US20220169632A1 (en) Methods and materials for increasing or maintaining nicotinamide mononucleotide adenylyl transferase-2 (nmnat2) polypeptide levels
WO2010122294A1 (fr) Inhibiteurs thiophènes de la sérine-thréonine protéine kinase ikk-β
CN113387909A (zh) 2,3-环氧丁二酰衍生物的医药用途
CA3147471A1 (fr) Inhibiteurs de l'atgl humain

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN CZ HU ID IL IN KR MX NO NZ PL RU TR US ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase