WO2015108038A1 - Composé d'éthylène glycol - Google Patents

Composé d'éthylène glycol Download PDF

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Publication number
WO2015108038A1
WO2015108038A1 PCT/JP2015/050676 JP2015050676W WO2015108038A1 WO 2015108038 A1 WO2015108038 A1 WO 2015108038A1 JP 2015050676 W JP2015050676 W JP 2015050676W WO 2015108038 A1 WO2015108038 A1 WO 2015108038A1
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group
phenyl
ethoxy
carbamoyl
compound
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PCT/JP2015/050676
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Japanese (ja)
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隆廣 片桐
瑞香 横山
正則 市川
明日香 河村
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第一三共株式会社
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    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—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
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound or a pharmacologically acceptable salt thereof useful for the prevention or treatment of hyperphosphatemia or a disease associated with hyperphosphatemia.
  • Phosphorus is present in various forms in the body as an important component of the body such as DNA, RNA, or bone, and plays an important role in life support activities.
  • Phosphoric acid is mainly absorbed from food in the form of inorganic phosphorus in the digestive tract and excreted in the form of urine from the kidney (Non-patent Document 1). Blood phosphorus levels are maintained at a constant level through the action of vitamin D, parathyroid hormone (PTH), etc., and absorption in the digestive tract, renal excretion, and bone absorption and metabolism are controlled.
  • PTH parathyroid hormone
  • Non-patent Document 2 Excess phosphate binds to blood calcium and causes ectopic calcification in the cardiovascular system, which is regarded as a risk factor for cardiovascular diseases such as myocardial infarction (Non-patent Document 2).
  • Hyperphosphatemia secondarily causes hypocalcemia and, as a compensation, develops hyperparathyroidism characterized by elevated blood PTH levels, which is a sign of renal osteodystrophy. It is also a major factor.
  • hyperphosphatemia in patients with chronic renal failure decreases the QOL of chronic renal failure patients such as fractures and bone pain, and is a major factor in the death of chronic renal failure patients.
  • Non-patent Document 3 Calcium preparations have been shown to promote vascular calcification due to hypercalcemia (Non-patent Document 3), and polymer preparations have problems with compliance with medication taken by several g a day and digestive symptoms such as constipation and diarrhea (Non-Patent Document 4).
  • Non-Patent Document 5 metal salt preparations accumulate in the body (Non-Patent Document 5), and there are currently no sufficient therapeutic agents for treating hyperphosphatemia. It is said that sodium-dependent phosphate transporter expressed in small intestinal epithelial cells plays an important role in the absorption of inorganic phosphate in the digestive tract (Non-patent Document 6). Compounds that effectively inhibit the absorption of phosphorus from the gastrointestinal tract more efficiently than oral adsorbents, and improve the compliance with medications, digestive symptoms, and accumulation problems that were problematic in oral adsorbents It is expected to be possible. In view of the circumstances as described above, it is desired to develop a drug for preventing or treating new hyperphosphatemia or diseases associated with hyperphosphatemia. As compounds related to the present invention, there are compounds described in WO2012 / 054110 and WO2012 / 006475, but the essential partial structure is different from the compounds of the present invention.
  • a compound useful as an active ingredient for the prevention and treatment of hyperphosphatemia or a pharmacologically acceptable salt thereof is provided.
  • the inventors of the present invention have completed the present invention as a result of intensive studies aimed at developing compounds useful as active ingredients for the prevention and treatment of hyperphosphatemia. That is, the present invention is as described below.
  • a compound having the general formula (I) or a pharmacologically acceptable salt thereof having the general formula (I) or a pharmacologically acceptable salt thereof.
  • each substituent is defined as follows.
  • X hydrogen atom, halogen atom, cyano group, trifluoromethyl group, C3-C6 cycl
  • the heterocyclic group optionally substituted on the heterocycle described in [3] is a halogen atom, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group,
  • [Five] L is any group selected from the following group (the substituent may be substituted with 1 or 2 substituents), any one selected from [2]-[4] 2.
  • the group which may be substituted with any group described in [5] is a halogen atom, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group Or a pharmacologically acceptable compound thereof according to [5], which is a group, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyloxy group, or a di-C1-C6 alkylamino group salt.
  • the heterocyclic group which may be substituted as described in [9] is a halogen atom, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group,
  • L is any group selected from the following group (the substituent may be substituted with 1 or 2 substituents), any one selected from [8]-[10] 2.
  • the group which may be substituted with any of the groups described in [11] is a halogen atom, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy Or a pharmacologically acceptable compound thereof according to [11], which is a group, a C1-C6 alkoxycarbonyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyloxy group, or a di-C1-C6 alkylamino group salt.
  • [15] A pharmaceutical composition comprising the compound according to any one of [14] or a pharmacologically acceptable salt thereof selected from [14].
  • [20] [1] A method for preventing or treating hyperphosphatemia by administering an effective amount of the compound according to any one of [14] or a pharmacologically acceptable salt thereof.
  • the compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used as a preventive and / or therapeutic agent for hyperphosphatemia and the like.
  • a benzene ring or a heterocycle in E Apartly from the description of the structural formula showing the compound having the general formula (I), the ring has a bond bonded to A and J.
  • Heterocycle in E A compound having a cyclic structure consisting of carbon atoms and heteroatoms (nitrogen atoms, oxygen atoms, sulfur atoms, etc.).
  • a 5- or 6-membered ring, or a 5- or 6-membered ring is condensed with another ring In some cases, it may consist of multiple rings. Specific examples include the following heterocycles.
  • the substituent is not particularly limited as long as it can be substituted on the heterocycle, and preferably a halogen atom, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a halogeno C1- C6 alkoxy group, C1-C6 alkoxycarbonyl group, C3-C6 cycloalkyl group, C3-C6 cycloalkyloxy group, or di-C1-C6 alkylamino group, particularly preferably a fluorine atom, a chlorine atom, cyano Group, methyl group, ethyl group, propyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, trifluoromethoxy group, methoxycarbonyl
  • Heterocyclic group in L A substituent having a cyclic structure consisting of carbon atoms and heteroatoms (nitrogen atoms, oxygen atoms, sulfur atoms, etc.).
  • a 5- or 6-membered ring or a 5- or 6-membered ring is condensed with other rings.
  • the ring may be a substituent composed of a plurality of rings. Specific examples include the heterocyclic groups shown below.
  • Heterocycle-methyl group in L A group in which a methyl group is bonded to the above-described heterocyclic group, and specifically includes the following heterocyclic-methyl group.
  • a phenyl group which may be substituted with 1 or 2 substituents a benzyl group which may be substituted with 1 or 2 substituents, a tetralin group which may be substituted with 1 or 2 substituents
  • the substituent is not particularly limited as long as it can be substituted, but preferably a halogen atom, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group, C1-C6 alkoxycarbonyl group, C3-C6 cycloalkyl group, C3-C6 cycloalkyloxy group or di-C1-C6 alkylamino group,
  • C3-C6 cycloalkylmethoxy group for X A group in which a methoxy group is bonded to a cycloalkyl group having 3 to 6 carbon atoms, such as a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, and the like.
  • Di-C1-C3 alkylamino group in X A group having two alkyl groups having 1 to 3 carbon atoms bonded to an amino group, such as a dimethylamino group, a diethylamino group, and a dipropylamino group.
  • Di-C1-C3 alkylaminocarbonyl group in X A group in which a carbonyl group is bonded to a di-C1-C3 alkylamino group, such as a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a dipropylaminocarbonyl group, and the like.
  • C3-C5 cycloaminoalkyl group for X A cyclic group composed of an alkyl group having 3 to 5 carbon atoms and one nitrogen atom, such as an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and the like.
  • the compound having the general formula (I) of the present invention is preferably a compound having the general formula (I ′) or a compound having the general formula (I ′′).
  • more preferable compounds are the compounds described below. 31- (3- ⁇ [4- (diethylamino) -2- (4- ⁇ [3- (trifluoromethyl) benzyl] carbamoyl ⁇ pyrimidin-2-yl) phenyl] carbamoyl ⁇ phenyl) -4,7,10, 13,16,19,22,25,28-Nonaoxahene triacontanoic acid 16- (3- ⁇ [4- (pyrimidin-1-yl) -2- ⁇ 4-[(1S) -1,2,3 , 4-Tetrahydronaphthalen-1-ylcarbamoyl] pyrimidin-2-yl ⁇ phenyl] carbamoyl ⁇ phenyl) -4,7,10,13-tetraoxahexadecanoic acid sodium salt 16- (3- ⁇ [4- (diethylamino)- 2- (4- ⁇ [3- (trifluoromethyl) benzyl]
  • the “pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the case of a compound having an acidic group or basic group, it can be converted into a “salt with a base” or an “acid addition salt” by reacting with a base or an acid, so that the salt is shown.
  • an alkali metal salt such as sodium salt, potassium salt or lithium salt
  • an alkaline earth metal salt such as magnesium salt or calcium salt
  • -Organic base salts such as methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt, lysine salt
  • Amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate, and preferably alkali metal salts.
  • the pharmacologically acceptable “acid addition salt” of the compound is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, Inorganic acid salts such as perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfone Allyl sulfonates such as acid salts, organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt and aspartate salt, most preferably hydrohalide salt (especially hydrochloride).
  • the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization.
  • the present invention also includes such various hydrates, solvates and polymorphic compounds.
  • the compound of the present invention may have tautomers and geometric isomers depending on the type of substituent.
  • the compound of the present invention may be described in only one form of an isomer.
  • the present invention includes other isomers, separated isomers, or a mixture thereof. Is also included.
  • the compounds of the present invention may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on these may exist.
  • the present invention also includes separated optical isomers or mixtures thereof.
  • the compound of the present invention also includes a label, that is, a compound in which one or more atoms of the compound are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.).
  • a label that is, a compound in which one or more atoms of the compound are substituted with an isotope (eg, 2 H, 3 H, 13 C, 14 C, 35 S, etc.).
  • the present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention.
  • a pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a force ruboxyl group or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include Prog. Med., 5, 2157-2161 (1985). Group described in the above.
  • the compound has an amino group
  • the amino group is acylated, alkylated or phosphorylated
  • the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4- Yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • the compound has a hydroxyl group
  • Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated.
  • the compounds of the present invention and pharmacologically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include protecting groups described in PGM Wuts and Green (TW Greene), Greene's Protective Groups in Organic Synthesis (4th edition, 2006). The reaction conditions may be appropriately selected according to the reaction conditions.
  • the desired compound after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
  • the prodrug of the compound of this invention can be manufactured by introduce
  • the reaction can be carried out by applying ordinary methods such as esterification, amidation, dehydration and the like.
  • the method for producing the compound is described below. However, the manufacturing method is not limited to the following method.
  • Method A is a method for producing compound (A4), which is a compound having general formula (I), and salt (A5) thereof. [Wherein each substituent is defined in the same manner as described above. M is an alkali metal, and particularly sodium in the formula. ]
  • Step A-1 can be activated by reacting (i) compound (A1) with oxalyl chloride and then reacting with compound (A2) to produce compound (A3) or (ii) compound (A1) and
  • compound (A3) is produced by reacting compound (A2) in the presence of a condensing agent.
  • a condensing agent for example, oxalyl chloride and a small amount of dimethylformamide are added to a methylene chloride solution of the compound (A1) at 0 ° C.-room temperature.
  • the compound (A2) and a base such as pyridine are added.
  • the reaction temperature is about room temperature -80 ° C
  • the reaction time is about 1-24 hours.
  • the reaction is carried out in a solvent in the presence of a condensing agent and a base.
  • the condensing agent used is 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (hereinafter sometimes referred to as HBTU), 2- (1H-7 -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter sometimes referred to as HATU), 4- (4,6-dimethoxy-1,3 , 5-Triazin-2-yl) -4-methylmorpholium chloride n-hydrate (hereinafter sometimes referred to as DMT-MM), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (hereinafter sometimes referred to as WSC or EDCI) and the like.
  • HBTU 1- [bis (dimethylamino
  • Examples of the base used include tertiary amines such as diisopropylethylamine, triethylamine and N-methylmorpholine.
  • Examples of the solvent used include methylene chloride, ethylene dichloride, dimethylformamide, dimethylacetamide, methanol and the like.
  • the reaction temperature is about room temperature -80 ° C.
  • the reaction time is about 1-24 hours.
  • Step A-2 is a step of producing the compound (A4) by decomposing the ester of the compound (A3) with an acid.
  • the acid used is preferably hydrochloric acid, trifluoroacetic acid or the like, and the solvent used is preferably a halogen solvent such as methylene chloride.
  • the reaction temperature is usually about 0-60 ° C., and the reaction time is usually about 1-24 hours.
  • the carboxylic acid of the compound (A4) is chlorinated by treating with an alkali metal alkoxide such as t-butoxy potassium or an alkali metal hydroxide such as sodium hydroxide, and the compound (A5) Is a process of manufacturing.
  • an alkali metal alkoxide such as t-butoxy potassium or an alkali metal hydroxide such as sodium hydroxide
  • the compound (A5) Is a process of manufacturing.
  • Various inorganic and organic salts can be produced by the same method. For example, after making the compound (A4) into a solution of acetonitrile, methanol or the like, chlorination is performed by adding an aqueous sodium hydroxide solution at about 0-40 ° C. to obtain a sodium salt.
  • Method B is a method for producing compound (B5) using compound (A2) used in method A as the case where substituent A is a single bond. [Wherein each substituent is defined in the same manner as described above. Halogen represents a halogen atom. ]
  • Step B-1 is a step of producing compound (B2) from compound (B1).
  • the reaction is carried out in a solvent in the presence of bis (pinacolato) diboron, a catalyst, and a base.
  • the catalyst used consists of various transition metals and various ligands such as [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane complex, bis (triphenylphosphine) palladium (II) dichloride, etc.
  • a catalyst is mentioned.
  • Examples of the base used include potassium acetate and sodium acetate.
  • Examples of the solvent used include ethers such as dimethoxyethane (hereinafter sometimes referred to as DME), tetrahydrofuran (hereinafter sometimes referred to as THF), and 1,4-dioxane.
  • DME dimethoxyethane
  • THF tetrahydrofuran
  • 1,4-dioxane 1,4-dioxane.
  • the reaction temperature is room temperature-100 ° C.
  • the reaction time is about 1-24 hours.
  • Step B-2 is a step of producing compound (B4) by combining compound (B2) and compound (B3).
  • the reaction is carried out in a solvent in the presence of a catalyst and a base.
  • the catalysts used are tetrakistriphenylphosphine palladium (0), bis (triphenylphosphine) palladium (II) dichloride, chloro (2-dicyclohexylphosphino-2 ', 4'6'-triisopropyl-1,1
  • Examples include catalysts composed of various transition metals and various ligands such as' -biphenyl) [2- (2'-amino-1,1'-biphenyl) palladium (II).
  • Examples of the base used include potassium phosphate, potassium acetate, sodium carbonate, tert-butoxy sodium and the like.
  • Examples of the solvent used include mixed solvents of ethers such as DME, THF, 1,4-dioxane and water.
  • the reaction temperature is room temperature-100 ° C.
  • the reaction time is about 1-24 hours.
  • Step B-3 is a step for producing the compound (B5) by reducing the nitro group of the compound (B4).
  • the reaction is performed in a solvent in the presence of a catalyst in a hydrogen atmosphere.
  • the catalyst used include 10% palladium carbon and 10% palladium hydroxide.
  • the solvent used include ethers such as THF, esters such as ethyl acetate, alcohols such as ethanol, or a mixture thereof. A solvent is mentioned.
  • the reaction pressure is normal pressure.
  • the reaction temperature is room temperature-60 ° C.
  • the reaction time is 1-24 hours.
  • this process can also be performed by heating and refluxing a reduction reaction with iron powder and ammonium chloride in an ethanol / water solvent.
  • Method C is another method of Method B for producing compound (A2) used in Method A, and is a method for producing compound (C4). [Wherein each substituent is defined in the same manner as described above. ]
  • Step C-1 is a step of producing compound (C2) from compound (C1), and can be performed in the same manner as Method B Step B-1.
  • Step C-2 is a step of producing compound (C4) by combining compound (C2) and compound (C3), and can be carried out in the same manner as Method B Step B-2.
  • Method D is a method for producing compound (B1) used in Method B as compound (D2).
  • Method D describes X as a diethylaminocarbonyl group as a production example when the substituent X of the compound (B1) is an amide. [Wherein each substituent is defined in the same manner as described above. ]
  • Step D-1 is a step of producing compound (D2) from compound (D1), and can be performed in the same manner as Method A Step A-1.
  • Method E is a method for producing compound (B4) used in Method B as compound (E3).
  • Method E describes X as a piperidinyl group as a production example when the substituent X of the compound (B4) is a C1-C3 alkylamino group or a C3-C5 cycloaminoalkyl group. [Wherein each substituent is defined in the same manner as described above. ]
  • Step E-1 is a step of producing compound (E2) from compound (E1), and can be performed in the same manner as Method B Step B-2.
  • Step E-2 is a step of producing compound (E3) by reacting compound (E2) with piperidine.
  • the reaction is performed in a solvent.
  • the solvent used is preferably an ether such as THF.
  • the reaction temperature is room temperature-80 ° C.
  • the reaction time is about 1-24 hours.
  • Method F is a method for producing the compound (B3) used in Method B as the compound (F3).
  • Method F is a production example when the substituent J of the compound (B3) is —CO—NH—. [Wherein each substituent is defined in the same manner as described above. ]
  • Step F-1 is a step of producing compound (F3) from compound (F1) and compound (F2), and can be performed in the same manner as Method A Step A-1.
  • Method G is a method for producing the compound (E2) used in Method E as the compound (G3).
  • Method G is a production example when the substituent J of the compound (E2) is —CO—NH—. [Wherein each substituent is defined in the same manner as described above. R G represents a protecting group for a carboxy group that can be deprotected by alkaline hydrolysis. ]
  • Step G-1 is a process for producing the compound (G2) by alkaline hydrolysis of the compound (G1).
  • the base used is preferably an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide
  • the solvent used is preferably a mixed solvent of water and tetrahydrofuran / methanol.
  • the reaction temperature is usually about 0-60 ° C., and the reaction time is usually about 1-24 hours.
  • Step G-2 is a step of producing compound (G3) from compound (G2) and compound (F2), and can be carried out in the same manner as Method A Step A-1.
  • Method H is a method for producing compound (G1) used in Method G as compound (H2).
  • Method H is a production example when the substituent E of the compound (G1) is an oxadiazole group. [Wherein each substituent is defined in the same manner as described above. R H represents a protecting group for a carboxy group that can be deprotected by alkaline hydrolysis. ]
  • StepH-1 is a step of producing hydrazide by condensing compound (H1) with hydrazine. Further, in StepH-2, cyclization with trifluoroacetic anhydride (TFAA) yields compound (H2 ).
  • Step H-1 is a step of performing the reaction in a solvent.
  • the solvent used is preferably an alcohol such as ethanol.
  • the reaction temperature is room temperature-80 ° C.
  • the reaction time is about 1-24 hours.
  • Step H-2 is a step of performing the reaction in a solvent in the presence of a base. Examples of the base used include pyridine and triethylamine.
  • the solvent used is preferably a halogen such as methylene chloride.
  • the reaction temperature is 0-60 ° C.
  • the reaction time is about 1-24 hours.
  • the compound produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
  • optical isomers exist when a compound or an intermediate of production has an asymmetric carbon. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography.
  • References for a method for resolving optical isomers from racemates include “Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by J. Jacques et al.
  • Rat 33 P phosphate oral loading test small intestine phosphate absorption inhibition test
  • a solvent such as 0.5% methylcellulose
  • Oral gavage was performed to achieve kg.
  • the solvent was administered at 5 mL / kg.
  • Dosage form administration is oral by tablet, pill, force pusher, granule, powder, liquid, etc., or injection of joint meat, vein meat, intramuscular, suppository, eye drops, eye ointment, transdermal Any form of parenteral administration such as a liquid, an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • Solid compositions for oral administration include Tablets, powders, or granules are used.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pip. Mixed with redone and / or magnesium aluminate metasilicate.
  • the composition contains an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium ruboxymethyl starch, a stabilizer and a solubilizing agent according to a conventional method. Also good. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration are: Contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and contains generally used inert diluents such as purified water or ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • Injection for parenteral administration Contains sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • the aqueous solvent include distilled water for injection or physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericidal agent or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • ointments As an external preparation, Includes ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
  • a transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid or semi-solid form, and can be produced according to a conventionally known method.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device or nebulizer such as a metered dose inhalation device, the compound is administered as a solution or suspension alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like may be used for single or multiple administrations, and a dry powder or a powder-containing power capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable gas such as a suitable propellant such as chlorofluoroalcohol, hydrofluoroalcohol or carbon dioxide.
  • a suitable gas such as a suitable propellant such as chlorofluoroalcohol, hydrofluoroalcohol or carbon dioxide.
  • the daily dose in general, in the case of oral administration, is about 0.001-100 mg / kg, preferably O.1-30 mg / kg, more preferably 0.1-10 mg / kg per body weight. Or do it in two or more divided doses.
  • the daily dose is suitably about 0.0001-10 mg / kg per body weight, and is administered once or divided into multiple doses per day.
  • a transmucosal agent about 0.001-100 mg / kg per body weight is administered once a day or divided into multiple times.
  • the dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the compound of the present invention can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • (Formulation Example 1) Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender. (Formulation Example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, add 300 g of 10% hydroxypropylcellulose aqueous solution and knead. This is granulated using an extrusion granulator and dried to obtain granules.
  • Example 1 31- (3- ⁇ [4- (diethylamino) -2- (4- ⁇ [3- (trifluoromethyl) benzyl] carbamoyl ⁇ pyrimidin-2-yl) phenyl] carbamoyl ⁇ phenyl) -4,7,10, 13,16,19,22,25,28-Nonaoxahene triacontanoic acid
  • Example 2 16- (3- ⁇ [4- (pyrimidin-1-yl) -2- ⁇ 4-[(1S) -1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl] pyrimidin-2-yl ⁇ phenyl ] Carbamoyl ⁇ phenyl) -4,7,10,13-tetraoxahexadecanoic acid sodium salt
  • reaction mixture was stirred at 90 ° C. for 6 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give 592 mg (100%) of the title compound as a colorless solid.
  • Example 3 16- (3- ⁇ [4- (diethylamino) -2- (4- ⁇ [3- (trifluoromethyl) benzyl] carbamoyl ⁇ pyrimidin-2-yl) phenyl] carbamoyl ⁇ phenyl) -4,7,10, 13-tetraoxahexadecanoic acid 3- (2,2-dimethyl-4-oxo-3,7,10,13,16) was added to the DMF (3 mL) solution of the compound (112 mg) obtained in Example (1d). -Pentaoxanonadecan-19-yl) benzoic acid (111 mg) and DMT-MM (147 mg) were added at room temperature.
  • reaction mixture was stirred at room temperature for 19 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to obtain 130 mg (59%) of the title compound as a yellow liquid.
  • reaction mixture was stirred at room temperature for 6 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to obtain 75 mg (40%) of the title compound as a yellow liquid.
  • N- ⁇ 4- [6- (cyclohexyloxy) pyridin-3-yl] phenyl ⁇ -5-fluoro-2-nitrobenzamide and 5-fluoro-2-nitrobenzoic acid mixture 258.0 mg was added to THF.
  • piperidine 600 ⁇ L was added and heated to reflux for 4 hours.
  • the solvent was distilled off under reduced pressure to obtain crude N- ⁇ 4- [6- (cyclohexyloxy) pyridin-3-yl] phenyl ⁇ -2-nitro-5- (piperidin-1-yl) benzamide. It was.
  • reaction mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to obtain 300 mg (84%) of the title compound as a yellow liquid.
  • reaction mixture was stirred at room temperature for 15 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to obtain 150 mg (41%) of the title compound as a yellow liquid.
  • Example 16 16- (3- ⁇ [4- (piperidin-1-yl) -2- ⁇ 5-[(1S) -1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl] -1,3-thiazole- 2-yl ⁇ phenyl] carbamoyl ⁇ phenyl) -4,7,10,13-tetraoxahexadecanoic acid sodium salt
  • the reaction mixture was stirred for 5 hours under heating to reflux. Dilute with water and extract with ethyl acetate. The aqueous layer was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and filtered. After evaporating the solvent under reduced pressure, the residue was evaporated to give 0.65 g (77%) of the title compound as a brown solid.
  • Example 17 16- [3-( ⁇ 2- [6- (tert-butoxycarbonyl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl] -4- (piperidin-1-yl) phenyl ⁇ Carbamoyl) phenyl] -4,7,10,13-tetraoxahexadecanoic acid sodium salt
  • Example 18 16- [3-( ⁇ 2- [6- (tert-butoxycarbonyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl] -4- (piperidine-1 -Yl) phenyl ⁇ carbamoyl) phenyl] -4,7,10,13-tetraoxahexadecanoic acid sodium salt
  • Example 20 16- (3- ⁇ [4- (piperidin-1-yl) -2- ⁇ 5-[(1S) -1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl] pyridazin-3-yl ⁇ phenyl ] Carbamoyl ⁇ phenyl) -4,7,10,13-tetraoxahexadecanoic acid sodium salt
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by column chromatography to obtain 162 mg (33%) of the title compound as a yellow solid.
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by column chromatography to obtain 253 mg (38%) of the title compound as a yellow solid.

Abstract

Le problème abordé par la présente invention est de pourvoir à : un composé qui est utile pour prévenir ou traiter l'hyperphosphatémie ou une maladie associée à l'hyperphosphatémie, et à un sel pharmacologiquement acceptable de celui-ci ; et autres. La solution selon l'invention porte sur un composé représenté par la formule générale (I) ou un sel pharmacologiquement acceptable de celui-ci. [Dans la formule, les substituants sont définis comme suit : A : liaison simple ou autre, E : cycle benzène ou autre, J : liaison simple ou autre, L : groupe phényle ou autre, X : atome d'hydrogène ou autre, Y : -CH2- ou autre, Z : -CH2-, -N(CH3)- ou autre, et n : entier choisi entre 3 et 8].
PCT/JP2015/050676 2014-01-17 2015-01-13 Composé d'éthylène glycol WO2015108038A1 (fr)

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WO2016171240A1 (fr) * 2015-04-24 2016-10-27 第一三共株式会社 Procédé de production d'un composé d'acide dicarboxylique
JP2017511336A (ja) * 2014-04-02 2017-04-20 バイエル・クロップサイエンス・アクチェンゲゼルシャフト 農薬としてのヘテロ環式化合物
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
CN115785018A (zh) * 2022-12-26 2023-03-14 湖北广济药业股份有限公司 一种非布司他脱羧杂质的制备方法
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

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WO2012006474A2 (fr) * 2010-07-07 2012-01-12 Ardelyx, Inc. Composés et procédés pour l'inhibition du transport de phosphate
WO2012006473A1 (fr) * 2010-07-07 2012-01-12 Ardelyx, Inc. Composés et procédés pour l'inhibition du transport de phosphate
WO2012054110A2 (fr) * 2010-07-07 2012-04-26 Ardelyx, Inc. Composés et procédés permettant d'inhiber le transport du phosphate
WO2014003153A1 (fr) * 2012-06-28 2014-01-03 協和発酵キリン株式会社 Composé amide substitué

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WO2012006474A2 (fr) * 2010-07-07 2012-01-12 Ardelyx, Inc. Composés et procédés pour l'inhibition du transport de phosphate
WO2012006473A1 (fr) * 2010-07-07 2012-01-12 Ardelyx, Inc. Composés et procédés pour l'inhibition du transport de phosphate
WO2012054110A2 (fr) * 2010-07-07 2012-04-26 Ardelyx, Inc. Composés et procédés permettant d'inhiber le transport du phosphate
WO2014003153A1 (fr) * 2012-06-28 2014-01-03 協和発酵キリン株式会社 Composé amide substitué

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017511336A (ja) * 2014-04-02 2017-04-20 バイエル・クロップサイエンス・アクチェンゲゼルシャフト 農薬としてのヘテロ環式化合物
WO2016171240A1 (fr) * 2015-04-24 2016-10-27 第一三共株式会社 Procédé de production d'un composé d'acide dicarboxylique
JPWO2016171240A1 (ja) * 2015-04-24 2018-02-15 第一三共株式会社 ジカルボン酸化合物の製法
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
CN115785018A (zh) * 2022-12-26 2023-03-14 湖北广济药业股份有限公司 一种非布司他脱羧杂质的制备方法

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