WO2019107533A1 - Dérivé de pyridine et de benzène - Google Patents

Dérivé de pyridine et de benzène Download PDF

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Publication number
WO2019107533A1
WO2019107533A1 PCT/JP2018/044133 JP2018044133W WO2019107533A1 WO 2019107533 A1 WO2019107533 A1 WO 2019107533A1 JP 2018044133 W JP2018044133 W JP 2018044133W WO 2019107533 A1 WO2019107533 A1 WO 2019107533A1
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Prior art keywords
bis
amine
methylene
methyl
methanesulfonate
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PCT/JP2018/044133
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English (en)
Japanese (ja)
Inventor
雅巳 大塚
眞一郎 丹羽
大 小倉
嘉代子 井手
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サイエンスファーム株式会社
リンク・ジェノミクス株式会社
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Publication of WO2019107533A1 publication Critical patent/WO2019107533A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • 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
    • C07C323/24—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 having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—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 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
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to derivatives of pyridine and benzene.
  • the present invention relates to pyridine derivatives and benzene derivatives which are useful for treatment of various diseases and the like.
  • Cell transformation is a phenomenon that occurs in the body at the time of ontogeny, and by transforming and transforming plastically the cell's character from epithelial to mesenchymal, the cell gains mobility and shape change is induced, Tissues and organs are formed. This transformation also occurs in differentiated tissues, and a representative example is the wound healing process. This is because during reconstitution of tissue that has been destroyed once, epithelial cells in the tissue are dedifferentiated to transform into mesenchymal cells, resulting in enhanced mobility in the tissue and various extracellular matrices. It is a process to rebuild damaged tissue in a short period of time by acquiring new traits such as enhanced secretion of (Extracellular Matrix: ECM).
  • ECM Extracellular Matrix
  • this transformation is also induced by inflammation, and the cells of the tissue are transformed by the inflammation to enhance exercise capacity, ECM secretion ability, adhesion ability and the like, and various phenomena occur in vivo.
  • the cancerous cells are transformed to gain movement ability to cause metastasis to other tissues.
  • inflammation also occurs, so that transformation of cells occurs and ECM secretion ability is enhanced, and fibrosis due to the proliferation of collagen etc. remarkably occurs, which is a cause of onset of various diseases. .
  • EMT Epithelial-Mesenchymal Transition
  • An object of the present invention is to provide a transformation inhibitor or transformation inhibitor that can be used for suppression or prevention of onset and progression of various diseases caused by cell transformation.
  • the present inventors synthesize various compounds having a basic skeleton having two side chains at positions 2 and 6 of pyridine and 1 and 3 of benzene, and as compounds having activity to suppress cell transformation,
  • the compounds of the present invention represented by the general formulas (1) to (8) to be described in detail and salts thereof were found.
  • the compound of the present invention or a salt thereof has an activity of suppressing transformation leading to cell fibrosis and the like.
  • salt as used herein is used in the sense generally used in the art. “Salt” is a compound in which an anion derived from an acid (anion) and a cation derived from a base are ionically bonded in a broad sense, and in a narrow sense, an equiequivalent mixture of Arrhenius acid and Arrhenius base It is.
  • the salt is a neutralization reaction between an acid and a base, a reaction between an acid and a basic oxide or metal, a reaction between a base and an acidic oxide or a nonmetal, an acidic oxide and a base It can be produced by the reaction with metal oxides and the reaction of non-metallic substances with metals (Wikipedia).
  • Salts which the compound of the present invention forms with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine and the like; It is not limited to.
  • the salt may also be an acid addition salt, for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; and formic acid, acetic acid, trifluoroacetic acid, propionone
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid
  • organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, etc. It is not limited.
  • These salts may be pharmacologically acceptable and conventional.
  • the salts of the compounds according to the present invention can be produced by appropriately combining methods commonly used in the field of synthetic organic chemistry. Specifically, neutralization titration of a free solution of the compound according to the present invention with an alkaline solution or an acidic solution may, for example, be mentioned.
  • n is 1 or 2 and R 1 is H, methoxy (-OCH 3 ), or Cl, R 2 is H, -OCH 3 or Cl, R 3 is H, -OCH 3 , Cl or F, R 4 is H or hydroxyl (-OH), R 5 is H, -OH, Br, 3-methyl-2-butyl or phenyl; R 6 is H or -OH. And a salt thereof.
  • the above salts may be pharmacologically acceptable salts (the same applies hereinafter).
  • the present invention provides the following compounds and salts thereof.
  • the salts include methanesulfonate, hydrochloride and fumarate.
  • the present invention provides the following compounds and salts thereof.
  • the salt includes methanesulfonate.
  • n is 1 or 2 and R 1 is ethyl, propyl, 2-propyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl or 4-methoxyphenyl
  • R 2 is 2,4,6-trimethylphenyl (2,4,6-trimethylphenyl), 3-fluorophenyl (3-fluorophenyl), 4-fluorophenyl (4-fluorophenyl), phenyl, 3-methoxyphenyl (3 -methoxyphenyl), H or 1-naphthyl (1-naphthyl). And a salt thereof.
  • the present invention provides the following compounds and salts thereof.
  • the salt includes hydrochloride.
  • R 1 represents [2- (cyclohexen-1-yl) ethyl] amino, [2- (thiophen-2-yl) ethyl] amino, (2-phenylethyl) amino, [(R) -1- (hydroxymethyl) ) -2-phenylethyl] amino, [(S) -1- (hydroxymethyl) -2-phenylethyl] amino, (3-methylbutyl) amino, (2-ethoxyethyl) amino, 4-benzylpiperidinyl, [(Tetrahydrofuran-2-yl) methyl] amino or 2- (2-propyloxy) ethylamino, R 2 is [2- (cyclohexen-1-yl) ethyl] amino, [2- (thiophen-2-yl) ethyl] amino, ⁇ 2-[(2-propyl) oxy] ethyl ⁇ amino, [(R )-
  • the present invention provides the following compounds and salts thereof.
  • the salt includes methanesulfonate and hydrochloride.
  • the present invention provides the following compounds and salts thereof.
  • the salt includes methanesulfonate and hydrochloride.
  • the present invention provides the following compounds and salts thereof.
  • the salt includes methanesulfonate.
  • R 1 represents [(S) -2-hydroxymethylpyrrolidinyl] methyl, [(R) -2-methoxymethylpyrrolidinyl] methyl, (3-hydroxypyrrolidinyl) methyl, (2-methylpiperidine -Methyl, (3-hydroxymethylpiperidinyl) methyl, (4-tert-butylpiperidinyl) methyl, [(2-phenylethyl) amino] methyl, [3- (2-propyloxy) propylamino] Methyl, ⁇ 2-[(2-methoxyphenyl) oxy] ethylamino ⁇ methyl, [4- (ethylaminocarbonyloxymethyl) piperidinyl] methyl, or (4-methoxyphenyl) aminocarbonyl, R 2 is H or phenyl. And a salt thereof.
  • the present invention provides the following compounds and salts thereof.
  • the salt includes hydrochloride and methanesulfonate.
  • R 1 is hydroxymethyl, methoxycarbonyl, (4-hydroxymethylpiperidinyl) methyl, or [(R) -2-methoxymethylpyrrolidinyl] methyl
  • R 2 is [4-phenyl-3,6-dihydropyridine-1 (2H) yl] methyl, [(2-phenylethyl) amino] methyl, [4- (ethylaminocarbonyloxymethyl) piperidinyl] methyl, or (R) -2-methoxymethylpyrrolidinyl] methyl.
  • R 1 is hydroxymethyl, methoxycarbonyl, (4-hydroxymethylpiperidinyl) methyl, or [(R) -2-methoxymethylpyrrolidinyl] methyl
  • R 2 is [4-phenyl-3,6-dihydropyridine-1 (2H) yl] methyl, [(2-phenylethyl) amino] methyl, [4- (ethylaminocarbonyloxymethyl
  • the present invention provides the following compounds and salts thereof.
  • the salt includes hydrochloride.
  • the compound of the present invention are used as medicaments for treating various diseases. It can be used.
  • the subject may be a human or an animal (eg, a mammal other than a human).
  • the compounds of the present invention can be formulated as they are or as medicaments together with pharmaceutically acceptable carriers and the like, and can be administered to humans or animals for the treatment of various diseases.
  • the compounds of the present invention can also be used for the manufacture of a medicament for the treatment of various diseases.
  • the compound of the present invention or a pharmaceutical composition containing the same can be provided as one component of a medical (eg, therapeutic or prophylactic) kit and provided in the kit.
  • the kit may include, in addition to the compound or pharmaceutical composition, instructions for use, an application method, an application amount, and the like.
  • the terms “pharmaceutically acceptable” or “pharmaceutically acceptable” refer to reasonable benefits / risks without excessive toxicity, irritation, allergic reactions, or other problems or complications. Such compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment to be appropriate for use in contact with human and animal tissues, and Used to express.
  • any solvent, dispersion medium, coating, surfactant, antioxidant, preservative known to those skilled in the art (Eg antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, additives, disintegrants, lubricants, sweeteners, flavors, dyes, And / or their materials and combinations are included.
  • treatment means (i) preventing (eg, preventing) the onset of a pathological condition, (ii) preventing or preventing the development of a pathological condition. And (iii) reducing, ameliorating or curing the pathological condition, and / or reducing, ameliorating or curing the symptoms associated with the pathological condition.
  • the compounds of the present invention can be used as such or as their pharmacologically acceptable salts.
  • the pharmacologically acceptable salt includes an alkali metal salt such as sodium salt and potassium salt or ammonium salt.
  • a compound of the present invention or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition
  • an active ingredient that is the compound or a pharmaceutically acceptable salt thereof alone or in combination with conventional excipients.
  • It can be formulated and used for oral or parenteral administration as an appropriate dosage form such as a capsule, a tablet, an injection and the like.
  • a capsule can be prepared by mixing a compound of the present invention or a salt thereof with an excipient such as lactose, starch or a derivative thereof, a cellulose derivative or the like to be filled in a gelatin capsule.
  • tablets are mixed with a binder such as sodium carboxymethylcellulose, alginic acid, gum arabic and the like, water and kneaded, and if necessary formed into granules, further lubricated with talc, stearic acid etc.
  • a binder such as sodium carboxymethylcellulose, alginic acid, gum arabic and the like
  • the agents can be added and prepared into tablets using a conventional tablet press.
  • the compound of the present invention or a salt thereof is dissolved in sterile distilled water or sterile saline together with a solubilizing agent, and the solution is enclosed in an ampoule to give a preparation for injection. If necessary, stabilizers, buffer substances and the like may be contained. These parenteral preparations can be administered intravenously or by intravenous drip infusion.
  • the dosage of the compounds of the present invention will vary according to various factors such as the condition, severity, age, presence or absence of complications, etc. of the patient to be treated.
  • it varies depending on the administration route, dosage form, administration frequency and the like, generally, in the case of oral administration, as an active ingredient, it is usually 0.1 to 1000 mg / day / human, preferably 1 to It can be appropriately selected and administered within the range of 500 mg / day / human, and in the case of parenteral administration, in the range of about 1/100 to 1/2 of the dose in the case of oral administration.
  • the chloroform layer was dried over magnesium sulfate, and chloroform was evaporated under reduced pressure.
  • the residue was purified by alumina column chromatography (chloroform).
  • the obtained amine 200 mg was dissolved in isopropyl ether (5 ml), 4M hydrogen chloride solution in dioxane (0.5 ml) and isopropyl ether (10 ml) were added, and the mixture was stirred at room temperature for 15 minutes. The precipitated solid was filtered to obtain SLG-172.
  • EMT Epithelial-Mesenchymal Transition
  • EMT induction conditions of EMT in RPE cells The inventors conducted examination of EMT induction conditions on RPE cells (retinal pigmented epithelial cell line: ARPE-19, hereinafter the same). Stimulation was performed under conditions of 10 ways using cytokines such as TNF- ⁇ / IL-1 ⁇ / TGF- ⁇ and growth factors, and as a result, it was confirmed that all caused significant EMT induction.
  • TNF- ⁇ 100 ng / mL (2) IL-1 beta 100 ng / mL (3) IL-1 beta 20 ng / mL (4) TNF- ⁇ 500 ng / mL + TGF- ⁇ 5 ng / mL (5) TNF- ⁇ 200 ng / mL + TGF- ⁇ 5 ng / mL (6) TNF- ⁇ 100 ng / mL + TGF- ⁇ 5 ng / mL (7) TNF- ⁇ 100 ng / mL + TGF- ⁇ 10 ng / mL (8) TNF- ⁇ 100 ng / mL + TGF- ⁇ 25 ng / mL (9) IL-1 beta 100 ng / mL + TGF-beta 5 ng / mL (10) IL-1 ⁇ 20 ng / mL + TGF- ⁇ 5 ng / mL
  • EMT transdifferentiation
  • the lowest effective concentration is the lowest concentration that indicates the suppression of Focus formation confirmed by the experiment.
  • the compounds of the present invention may be used in pharmaceutical compositions or kits for treating various diseases, or in methods of treating such diseases using the same.
  • the compounds of the present invention or salts thereof are useful as agents for suppressing cell transformation.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé pour supprimer la transformation cellulaire, le composé étant représenté par la formule générale suivante (dans laquelle n vaut 1 ou 2 ; R1 représente H, méthoxy(-OCH3), ou Cl ; R2 représente H, -OCH3, ou Cl ; R3 représente H, -OCH3, Cl, ou F ; R4 représente H ou OH ; R5 représente H, hydroxyl (-OH), Br, 3-méthyl-2-butyl, ou phényle ; et R6 représente H ou -OH), ou un sel de celui-ci.
PCT/JP2018/044133 2017-12-01 2018-11-30 Dérivé de pyridine et de benzène WO2019107533A1 (fr)

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JP2017231973 2017-12-01

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB786215A (en) * 1955-03-14 1957-11-13 Allen & Hanburys Ltd New diamines and salts thereof
US3947389A (en) * 1973-11-05 1976-03-30 Showa Denko Kabushiki Kaisha Polyurethane product with gas fading inhibitor and method of inhibiting the gas fading of polyurethane product
JPS5245773B2 (fr) * 1971-02-12 1977-11-18
JP2007230909A (ja) * 2006-03-01 2007-09-13 Univ Of Tokyo 置換イソキサゾール誘導体
WO2018005336A1 (fr) * 2016-06-28 2018-01-04 Bristol-Myers Squibb Company Inhibiteurs macrocycliques de myeloperoxidase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB786215A (en) * 1955-03-14 1957-11-13 Allen & Hanburys Ltd New diamines and salts thereof
JPS5245773B2 (fr) * 1971-02-12 1977-11-18
US3947389A (en) * 1973-11-05 1976-03-30 Showa Denko Kabushiki Kaisha Polyurethane product with gas fading inhibitor and method of inhibiting the gas fading of polyurethane product
JP2007230909A (ja) * 2006-03-01 2007-09-13 Univ Of Tokyo 置換イソキサゾール誘導体
WO2018005336A1 (fr) * 2016-06-28 2018-01-04 Bristol-Myers Squibb Company Inhibiteurs macrocycliques de myeloperoxidase

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GASIOREK, MARTIN ET AL.: "Unwinding DNA and RNA with Synthetic Complexes: On the Way to Artificial Helicases", CHEMISTRY - A EUROPEAN JOURNAL, vol. 21, no. 50, 2015 - 27 October 2015 (2015-10-27), pages 18328 - 18332, XP055616357 *
HOSONO, TETSUJI ET AL.: "Antiviral activities against herpes simplex virus type 1 by HPH derivatives and their structure-activity relationships", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 1, 2008, pages 371 - 374, XP022410917, DOI: 10.1016/j.bmcl.2007.10.065 *
REHSE, KLAUS ET AL.: "Platelet aggregation-inhibiting and anticoagulant effects of oligoamines. III. 1,3-Phenylenebis(alkanamines", ARCHIV DER PHARMAZIE, vol. 320, no. 3, 1 March 1987 (1987-03-01), pages 228 - 233, XP009015645, DOI: 10.1002/ardp.19873200308 *

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