WO2013129435A1 - Dérivé de thiophène fusionné - Google Patents

Dérivé de thiophène fusionné Download PDF

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WO2013129435A1
WO2013129435A1 PCT/JP2013/055041 JP2013055041W WO2013129435A1 WO 2013129435 A1 WO2013129435 A1 WO 2013129435A1 JP 2013055041 W JP2013055041 W JP 2013055041W WO 2013129435 A1 WO2013129435 A1 WO 2013129435A1
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compound
substituent
mmol
optionally substituted
optionally
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Japanese (ja)
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勇樹 平田
慎太郎 細江
道寛 前本
正森 菅原
新 柳沢
潤 大内
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協和発酵キリン株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a fused thiophene derivative or a pharmaceutically acceptable salt thereof useful as a therapeutic and / or prophylactic agent for diseases (for example, hyperphosphatemia) affected by serum phosphorus concentration.
  • diseases for example, hyperphosphatemia
  • Serum phosphorus concentration is controlled by the balance of absorption of phosphorus from the intestinal tract, intracellular and bone accumulation, filtration into the original urine in the kidney and subsequent reabsorption in the tubule.
  • serum phosphorus concentration is 5.0 mg / dL or more, it is said to be hyperphosphatemia, which is a pathological condition that appears prominently in patients with end-stage renal disease or dialysis. Hyperphosphatemia secondarily leads to hypocalcemia and therefore induces secondary hyperparathyroidism, which is also a major factor in renal osteodystrophy.
  • a phosphate adsorbent having a function of adsorbing dietary phosphate with intake of food with a low phosphate content.
  • Use has been made.
  • diets with low phosphoric acid content cause malnutrition due to inadequate intake of other nutrients and are difficult to observe due to poor taste.
  • oral phosphate adsorbents include calcium preparations, magnesium preparations, and aluminum preparations, but calcium preparations and magnesium preparations induce hypercalcemia and hypermagnesemia, respectively, and aluminum preparations contain aluminum osteopathy. Induction of aluminum encephalopathy and dialysis dementia has been pointed out.
  • anion exchange resins have been developed as oral phosphate adsorbents, but these anion exchange resins have a lower phosphate adsorption capacity than the aforementioned phosphate adsorbents, and can be used at high doses. is necessary.
  • NaPi2b Sodium-dependent phosphorus transporter type 2b
  • CaPi2b knockout mice intestinal specific conditional knockout mice
  • a compound that inhibits NaPi2b can control serum phosphorus concentration, and is expected to be useful for the treatment of hyperphosphatemia in chronic kidney disease.
  • NaPi2b has been confirmed not only in the intestine but also in the lung and testis.
  • alveolar microlithiasis an inherited disorder with autosomal inferiority, in which minute stones are formed in the alveoli, it is thought to be caused by a defective phosphorus transport function on the alveoli due to NaPi2b dysfunction [Am J RespirCrit Care Med 175: 263-268, 2007].
  • a heterozygous gene mutation of NaPi2b has also been identified in patients with intratesticular microcalcification [Am. J. Hum. Genet. 79: 650-656, 2006].
  • NaPi2b inhibitor a compound that inhibits NaPi2b (NaPi2b inhibitor) is considered useful as a therapeutic and / or prophylactic agent for hyperphosphatemia, etc., while dysfunction in the lungs and testis occurs when NaPi2b inhibitor is systemically exposed. There is a risk. Therefore, there is a demand for a drug that inhibits NaPi2b in the intestinal tract and has reduced absorbability into blood (see Patent Document 1).
  • a compound that inhibits NaPi2b for example, a compound represented by the formula (A) (see Patent Document 2), a compound represented by the formula (B) (see Patent Document 1), and the like are known. Further, as a condensed thiophene derivative having a hydrazide at the 3-position, a compound represented by the formula (C) (see Non-Patent Document 1), a compound represented by the formula (D) (see Non-Patent Document 2), a formula (E) (See Non-Patent Document 3) and the like are known.
  • An object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof that inhibits NaPi2b in the intestinal tract and is useful as a therapeutic and / or prophylactic agent for diseases (for example, hyperphosphatemia) affected by serum phosphorus concentration. Is to provide.
  • the present invention relates to the following (1) to (17).
  • R 1 and R 2 represents a hydrogen atom
  • the other represents an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent
  • L represents phenyl, an aromatic heterocyclic group or an aliphatic heterocyclic group
  • each of the phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group is represented by the following formula (II): -(CH 2 ) h -ABYDC (II) ⁇
  • h represents an integer of 0 to 3
  • C is a hydrogen atom, halogen, hydroxy, nitro, amino, cyano, carboxy, carbamoyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, or optionally substituted.
  • R E is a hydrogen atom; halogen; carboxy; carboxylate (—COO ⁇ ); lower alkoxycarbonyl; or lower optionally substituted with hydroxy, lower alkoxy, carboxy or carboxylate (—COO ⁇ ).
  • X B represents a chlorine atom, a bromine atom, an iodine atom, or R DB SO 3 (wherein R DB has the same meaning as R DA ) (where R E is a carboxylate (—COO - ) Or carboxylate (—COO ⁇ ) in the case of substituted lower alkyl, X B— is missing)], or —OPO (OR E ) 2 (where R E is Represents a hydrogen atom or lower alkyl), D is (1) a bond, or (2) at least one CH 2 group is —O—, —S—, —SO 2 — and —NR 5 — (wherein R 5 is a hydrogen atom, lower Represents a linear C 3-30 alkylene optionally substituted with a group selected from alkyl, cycloalkyl, lower alkanoyl or lower alkoxycarbonyl), Y is (1) a bond, (2) -O-, (3) -S-
  • s3 and s4 are the same or different and each represents an integer of 0 to 2, and Y a represents a bond or —SO 2 —)]
  • the phenyl, the aromatic heterocyclic group and the aliphatic heterocyclic group may further have a substituent, n represents 1 or 2, m represents 1 or 2, Z is —CR 14 R 15 — ⁇ wherein R 14 and R 15 are the same or different and each has a hydrogen atom, halogen, carboxy, optionally substituted lower alkyl, or substituent.
  • Lower alkylcarbonyl which may be substituted, lower alkylcarbamoyl which may have a substituent, dilower alkylcarbamoyl which may have a substituent or aliphatic heterocyclic carbonyl which may have a substituent carded
  • B and / or D is at least one or more CH 2 groups -O -, - S- and -NR 5 - (wherein, R 5 is as defined above) or -NR 9 - (Wherein R 9 is as defined above) is a linear C 3-30 alkylene optionally substituted with a group selected from the above, and the total number of carbon atoms in the alkylene is 7 or less, Alternatively, when B and D are both bonds, R 14 and R 15 are simultaneously hydrogen atoms.
  • R 14 and R 15 together with adjacent carbon atoms form a cycloalkane, oxetane, oxolane or oxane ⁇ , —NR 16 —
  • R 16 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, Lower alkanoyl optionally having substituent, aroyl optionally having substituent, aliphatic heterocyclic carbonyl optionally having substituent, aromatic heterocyclic optionally having substituent Ring carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted A good arylsulfonyl, an optionally substituted aliphatic heterocyclic sulfonyl or an optionally substituted aromatic heterocyclic sulfonyl), Represents —O—, —S— or —SO 2 —
  • B is (1)-(CH 2 CH 2 W a ) qa- (CH 2 ) ra- (W a is -O-, -S-, -SO 2- , or -NR 9 -(Wherein R 9 is as defined above), qa represents an integer of 1 to 8, ra represents an integer of 0 to 3, and (2)-(CH 2 CH 2 CH 2 W aa ) ua — (CH 2 ) va — (wherein W aa is —O—, —S—, —SO 2 —, or —NR 9 — (wherein R 9 is as defined above).
  • Ua represents an integer of 1 to 6 and va represents an integer of 0 to 6), or (3) — (CH 2 ) ta — (where ta represents an integer of 1 to 30).
  • ta represents an integer of 1 to 30.
  • (9) D is (1)-(CH 2 CH 2 W b ) qb- (CH 2 ) rb- (where W b is -O-, -S-, -SO 2- , or -NR 5 -(Wherein R 5 is as defined above), qb represents an integer of 1 to 8, rb represents an integer of 0 to 3, and (2)-(CH 2 CH 2 CH 2 W bb ) ub- (CH 2 ) vb- (wherein W bb is -O-, -S-, -SO 2- , or -NR 5- (wherein R 5 is as defined above)).
  • Ub represents an integer of 1 to 6 and vb represents an integer of 0 to 6), or (3) — (CH 2 ) tb — (where tb represents an integer of 1 to 30).
  • An inhibitor of phosphorus uptake into blood comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a therapeutic and / or prophylactic agent for hyperphosphatemia comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting the uptake of phosphorus into blood comprising a step of administering an effective amount of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a method for treating and / or preventing hyperphosphatemia comprising a step of administering an effective amount of the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • a fused-ring thiophene derivative useful as a therapeutic and / or preventive agent for a disease that inhibits NaPi2b in the intestinal tract and is affected by serum phosphorus concentration (for example, hyperphosphatemia) or a pharmaceutically acceptable product thereof Salt and the like are provided.
  • Lower alkyl, and lower alkanoyl, lower alkoxycarbonyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxy, lower alkanoyloxy, lower alkylsulfonyloxy, lower alkylthio, and lower alkyl moiety of lower alkylsulfonyl include, for example, linear or Examples include branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl , Nonyl,
  • Examples of cycloalkyl and the cycloalkyl portion of cycloalkylcarbonyl, cycloalkyloxycarbonyl, cycloalkyloxy, cycloalkylcarbonyloxy, and a cycloalkyl portion of a cycloalkane formed together with adjacent carbon atoms include, for example, 3 to 8 carbon atoms. More specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
  • the straight chain C 3-30 alkylene means a straight chain alkylene having 3 to 30 carbon atoms, and more specifically, a general formula — (CH 2 ) m — (wherein m represents an integer of 3 to 30) ) Represents an alkylene represented by: That is, at least one CH 2 group defined by B and D is —O—, —S—, —SO 2 —, and —NR 9 — or —NR 5 — (wherein R 9 and R 5 They are each a hydrogen atom, a lower alkyl, cycloalkyl, the lower alkanoyl or lower alkoxy optionally a straight chain C 3-30 alkylene optionally substituted with a group selected from the a carbonyl), for example, the following equation (1) to And the group represented by (14).
  • Examples include methyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrylethyl and the like.
  • aryl and the aryl moiety of aroyl, aryloxycarbonyl, arylcarbamoyl, aryloxy, aroyloxy, arylsulfonyloxy, arylthio, and arylsulfonyl include aryl having 6 to 14 carbon atoms, and more specifically phenyl. , Naphthyl, azulenyl, anthryl and the like.
  • aliphatic heterocyclic group moiety of sulfonyl for example, a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Bicyclic or tricyclic condensed rings containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom are included, and more specifically, aziridinyl and azetidinyl , Pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-te
  • aromatic heterocyclic group moiety of sulfonyl for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • Examples thereof include a condensed bicyclic or tricyclic condensed ring aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically furyl, thienyl.
  • Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3 to 8 membered rings and containing at least one nitrogen atom (
  • the condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, Imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl,
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • the substituents in sulfonyloxy, optionally substituted lower alkylthio, and optionally substituted lower alkylsulfonyl are the same or different, for example, halogen, hydroxy having 1 to 3 substituents , Sulfanyl, nitro, cyano, carboxy, carbamoyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic compound Heterocyclic
  • An arylsulfonyl which may have a substituent, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent, an aromatic heterocyclic diyl which may have a substituent, a substituent
  • Cycloalkyl which may have a substituent, cycloalkylcarbonyl which may have a substituent, cycloalkyloxycarbonyl which may have a substituent, cycloalkyl which may have a substituent Oxy, optionally substituted cycloalkylcarbonyloxy, optionally substituted aliphatic heterocyclic group, optionally substituted aliphatic heterocyclic diyl, substituted An optionally substituted aliphatic heterocyclic carbonyl, an optionally substituted aliphatic heterocyclic oxycarbonyl, an optionally substituted aliphatic heterocyclic oxy, and optionally having a substituent Good aliphatic heterocyclic carbonyloxy, optionally substituted aliphatic heterocyclic thio, optionally substituted aliphatic heterocyclic sulfonyl, and optionally substituted adjacent Nitrogen field
  • C 1-10 alkyl as shown here and C 1-10 alkoxy, C 2-11 alkanoyloxy, C 1-10 alkylsulfanyl, C 2-11 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylcarbamoyl and
  • Examples of the C 1-10 alkyl moiety of diC 1-10 alkylcarbamoyl include the groups exemplified above for the lower alkyl.
  • the two C 1-10 alkyl moieties in the diC 1-10 alkylcarbamoyl may be the same or different.
  • the C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy, e.g. groups mentioned for illustrative said cycloalkyl is exemplified.
  • Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples.
  • Examples of the aralkyl moiety of C 7-16 aralkyl and C 7-16 aralkyloxy and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above examples of aralkyl.
  • the aliphatic heterocyclic group, aromatic heterocyclic group and halogen are as defined above.
  • Pharmaceutically acceptable salts of compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Examples of the pharmaceutically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, and maleic acid.
  • Organic salts such as salts, fumarate, citrate, benzoate, methanesulfonate and the like
  • pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt , Alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like.
  • Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium.
  • organic amine addition salts examples include addition salts such as morpholine and piperidine, and examples of pharmaceutically acceptable amino acid addition salts include lysine. And addition salts of glycine, phenylalanine, aspartic acid, glutamic acid and the like.
  • Production method 1 Compound (I) can be produced by the following method.
  • Process 1 Compound (a-3) is compound (a-1) and preferably 1 to 30 equivalents of (a-2) in the absence of or in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes. It can be produced by reacting for ⁇ 72 hours.
  • solvent examples include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dimethoxyethane (DME), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,4 -Dioxane, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, N-methylpyrrolidone (NMP), water and the like are used, and these are used alone or in combination.
  • DME 1,2-dichloroethane
  • DME 1,2-dimethoxyethane
  • DMF N-dimethylformamide
  • DMA N-dimethylacetamide
  • THF tetrahydrofuran
  • diethyl ether diisopropyl ether
  • benzene toluene
  • xylene pyridine
  • Compound (a-1) is obtained as a commercial product.
  • Compound (a-2) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, Volume 21, p. 1, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Process 2 Compound (a-5) is compound (a-3) and preferably 1 to 30 equivalents of compound (a-4) in a solvent, preferably 1 to 30 equivalents of a sulfur introducing agent and a base at room temperature. And a reaction between 5 minutes and 72 hours at a temperature between the boiling points of the solvents to be used.
  • Examples of the sulfur introducing agent include sulfur, diphosphorus pentasulfide, Lawesson's reagent, and the like.
  • Examples of the base include diethylamine, triethylamine, ethyldiisopropylamine, morpholine, piperidine, L-proline, basic alumina and the like.
  • Examples of the solvent include methanol, ethanol, 2-propanol, tert-butyl alcohol, THF, dioxane, toluene, xylene, water and the like, and these can be used alone or in combination.
  • Compound (a-4) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, Volume 21, p.149, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Process 3 Compound (I) is compound (a-5), preferably 1 to 10 equivalents of compound (a-6), preferably 1 to 20 equivalents of a base in the presence of a solvent at ⁇ 10 ° C. It can be produced by reacting at a temperature between the boiling points for 5 minutes to 72 hours.
  • Examples of the base include potassium acetate, sodium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate, pyridine, triethylamine, N-methylmorpholine, N -Methylpiperidine, piperidine, piperazine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • solvent examples include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, water, and the like. These may be used alone or in combination.
  • Compound (a-6) can be obtained as a commercial product, or can be obtained by a known method [for example, New Experimental Chemistry Course, 4th edition, Volume 22, p. 115, Maruzen Co., Ltd. (1992)] or the like. It can be obtained accordingly.
  • compound (I) may be compound (a-5) and preferably 1 to 30 equivalents of (a-7) in the absence of a solvent or in a solvent, preferably 1 to 30 equivalents of a condensing agent. It can also be produced by reacting at a temperature between ⁇ 30 ° C. and 150 ° C. for 5 minutes to 72 hours, if necessary, preferably in the presence of 1 to 30 equivalents of an additive.
  • Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC), EDC hydrochloride, O- (benzotriazol-1-yl) 2 -N , N, N ', N'-Tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP), hexafluorophosphoric acid (benzotriazol-1-yloxy)
  • Examples include tripyrrolidinophosphonium (PyBOP) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP).
  • Examples of the additive include 1-hydroxybenzotriazole monohydrate (HOBt ⁇ H 2 O), triethylamine, 4-dimethylaminopyridine (DMAP), and the like are used alone or in combination.
  • Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, water, and the like. These may be used alone or in combination.
  • Compound (a-7) can be obtained as a commercial product, or can be obtained by a known method [for example, New Experimental Chemistry Course, 4th edition, Volume 22, p. 1, Maruzen Co., Ltd. (1992)] or the like. It can be obtained similarly.
  • Manufacturing method 2 Compound (I) can also be produced according to the following steps.
  • R 20 represents a hydrogen atom or a protecting group for a carboxyl group such as methyl or ethyl
  • n, m, R 1 , R 2 , L, V 1 and Z are as defined above.
  • Compound (a-8) can be obtained as a commercial product.
  • Process 5 Compound (a-10) can be produced in the same manner as in production method 1, step 3 using compound (a-9) and compound (a-6) or compound (a-7).
  • Process 6 Compound (a-11) is obtained by reacting compound (a-10) without solvent or in a solvent in the presence of 1 to 100 equivalents of an aqueous hydrazine solution at a temperature between room temperature and 150 ° C. for 5 minutes to 72 hours. Can be manufactured.
  • Compound (a-11) can also be produced via compound (a-12).
  • Step 7a Compound (a-12) is obtained by reacting compound (a-10) in trifluoroacetic acid, preferably in the presence of 1 to 30 equivalents of trifluoroacetic anhydride, at a temperature between room temperature and 150 ° C. for 5 minutes to 72 hours. It can be manufactured by processing.
  • Compound (a-12) is also prepared using compound (a-10) according to the method described in WO2006 / 122200, Organic Letters, 16, 1013 (2006), Bioorganic Medicinal Chemistry, 18, 2803, (2000), etc. Can also be manufactured.
  • Step 7b Compound (a-11) can be produced in the same manner as in Step 6 above, using compound (a-12).
  • Process 8 Compound (I) can be produced in the same manner as in Step 1 above, using compound (a-11) and compound (a-2).
  • Production method 3 Among compounds (I), compound (Ib) in which A is an oxygen atom, B, Y and D are not simultaneously bonded and C is not a hydrogen atom can also be produced according to the following steps.
  • Step 9 Compound (Ib) is compound (Ia) obtained according to production method 1 or 2, preferably 1 to 30 equivalents of compound (a-13), without solvent or in a solvent, and preferably 1 to 30 equivalents. It can be produced by reacting at a temperature between ⁇ 10 ° C. and 150 ° C. for 5 minutes to 72 hours in the presence of a base.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, N -Methylpiperidine, pyridine, DBU and the like.
  • solvent examples include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.
  • Compound (a-13) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 19, p.363, Maruzen Co., Ltd. (1992)] or the like. Obtainable. Production method 4 Among compounds (I), compounds (Id), (Ie) and (If) in which A is —NR 10 —, —S— and —SO 2 — can also be produced according to the following steps, respectively.
  • V 3 represents a leaving group such as chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, L A , m, n, h, R 1. , R 2 , R 10 , B, Y, C, D and Z are as defined above)
  • Process 10 Compound (Id) is compound (Ic) obtained according to production method 1 or 2, preferably 1 to 30 equivalents of compound (a-14), without solvent or in a solvent, and preferably 1 to 30 equivalents if necessary. It can be produced by reacting at a temperature between ⁇ 10 ° C. and 150 ° C. for 5 minutes to 72 hours in the presence of a base.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, N -Methylpiperidine, pyridine, DBU and the like.
  • solvent examples include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.
  • Compound (a-14) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 20, p.279, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Step 11 Compound (Ie) can be obtained in the same manner as in Step 10 above, using compound (Ic) and compound (a-15).
  • Compound (a-15) can be obtained as a commercial product, or can be obtained by publicly known methods [for example, Experimental Chemistry Course, 4th edition, Volume 24, p.319, Maruzen Co., Ltd. (1992)] or the like. Can be obtained.
  • Process 12 Compound (If) comprises compound (Ie) in a solvent in an amount of 1 equivalent to a large excess, preferably 1 to 10 equivalents of oxidizing agent, at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 72 minutes. It can be manufactured by time processing.
  • Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, THF, 1,4-dioxane, dimethoxyethane, diethyl ether, diisopropyl ether, methanol, ethanol, 2-propanol, benzene, toluene, xylene, acetonitrile, ethyl acetate. , Water and the like, and these can be used alone or in combination. Preferred is dichloromethane.
  • oxidizing agent examples include metachloroperbenzoic acid, benzoyl peroxide, peracetic acid, hydrogen peroxide, sodium periodate, oxone, and the like, preferably metachloroperbenzoic acid.
  • Manufacturing method 5 Among compounds (I), compounds (Ii) and (Ij) in which Z is NR 11 can also be produced according to the following steps.
  • Process 13 Compound (Ii) can be obtained by using, for example, Protective Groups in Organic Synthesis, TW Greene, It can be produced according to the protecting group removal method described in, for example, John Wiley & Sons Inc. (1981).
  • the compound (Ii) is obtained by removing the compound (Ig) between -30 ° C. and 100 ° C. without solvent or in a solvent with 1 equivalent to a large excess of acid. It can be produced by treating at a temperature of 5 minutes to 72 hours.
  • the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and the like.
  • the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, toluene, ethyl acetate, dichloromethane, DMF, water and the like, and these can be used alone or in combination.
  • Compound (Ij) is compound (Ii) and preferably 1 to 20 equivalents of compound (a-16) in a solvent, preferably in the presence of 1 to 20 equivalents of a base, at ⁇ 10 ° C. It can be produced by reacting at a temperature between the boiling points for 5 minutes to 72 hours.
  • Examples of the base include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, DBU and the like.
  • Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, and the like. These are used alone or in combination.
  • Compound (a-16) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 4th edition, volume 19, p.363, Maruzen Co., Ltd. (1992), J. Am. Chem. Soc., 114, 1486, (1992), etc.] or the like.
  • the intermediates and target compounds in the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Some compounds (I) may have stereoisomers such as geometric isomers and optical isomers, tautomers and the like, but the present invention includes all possible isomers including these. And mixtures thereof.
  • a part or all of each atom in the compound (I) may be replaced with a corresponding isotope atom, and the present invention also includes a compound replaced with these isotope atoms.
  • some or all of the hydrogen atoms in the compound (I) may be hydrogen atoms having an atomic weight of 2 (deuterium atoms).
  • a compound in which part or all of each atom in Compound (I) is replaced with a corresponding isotope atom can be produced by a method similar to each of the above production methods using a commercially available building block.
  • a compound in which some or all of the hydrogen atoms in the compound (I) are replaced with deuterium atoms is, for example, 1) a method of deuterating carboxylic acid under basic conditions using deuterium peroxide (See U.S. Pat. No. 3,849,458), 2) A method of deuterating alcohol, carboxylic acid, etc. using iridium complex as a catalyst and deuterium as a deuterium source (J. Am. Chem. Soc., 124).
  • compound (I) When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be isolated or purified by dissolving or suspending and forming a salt by adding an acid or a base. Compound (I) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
  • Test Example 1 [ 33 P] Phosphorus Uptake Assay of Human NaPi2b-Expressing Cells (1) Construction of Human NaPi2b-Induced Expression Cells Human NaPi2b-induced expression plasmids conform to known methods (Analytical Biochemistry, 400, 163, (2006)) Made. DNA encoding human NaPi2b was obtained by PCR. Using human kidney DNA (Clontech) as a template, human NaPi2b cDNA-specific primer and Pyrobest DNA Polymerase (Takara Bio) were used to obtain DNA encoding human NaPi2b by PCR.
  • PCR was performed at 95 ° C. for 2 minutes, followed by 35 cycles of 94 ° C. for 15 seconds, annealing temperature 60 ° C. for 15 seconds, and 72 ° C. for 2 minutes.
  • the amplified PCR fragment was cleaved with HindIII and NotI, and then a human NaPi2b DNA fragment was recovered by agarose gel electrophoresis.
  • the fragment was inserted between the corresponding restriction enzyme sites (HindIII-NotI) of the inducible expression vector to construct an inducible expression plasmid for human NaPi2b. It was confirmed that the sequence of the obtained human NaPi2b DNA matched the registered sequence of GenBank (NM_006424).
  • an inducible expression cell of human NaPi2b using KJMGER8 cells (a cell line derived from Namalwa cells) as a host was constructed.
  • the induced expression cells were prepared by introducing the human NaPi2b induced expression plasmid prepared above into KJMGER8 cells by electroporation (Cytotechnology, 3, 133 (1990)).
  • Inducible expression of human NaPi2b was performed by culturing human NaPi2b-expressing cells in the presence of 10 nmol / L ⁇ -estradiol (manufactured by Sigma) for 24 hours.
  • Ice-cooled buffer B (0.9 mmol / L CaCl 2 , 0.5 mmol / L MgCl 2 ⁇ 6H 2 O, 2.7 mmol / L KCl, 1.5 mmol / L KH 2 PO 4 , 138 mmol / L NaCl, 8.1 mmol / L Na 2 HPO 4 ⁇ 7H 2 O) was added to stop the reaction, followed by filtration while washing with a cell harvester with filter paper (Whatman GF / Bunifilter) set.
  • the washed filter paper was dried with a rapid dryer for 30 minutes, 30 ⁇ L of scintillation cocktail Microscint 20 was added, and the radioactivity of the filter paper was measured with a multiplate scintillation counter TopCount (Perkin Elmer Japan).
  • the inhibition rate was determined by the following formula. The results at a test compound concentration of 1 ⁇ mol / L are shown in Table 12.
  • Rats are housed in a metal cage in a breeding room with a temperature of 19 to 25 ° C, humidity of 30 to 70%, and 12 hours a day (7am to 7pm). Feed (FR-2; Funabashi Farm) and water were freely available. At the time of urine collection, one animal was housed in a metal cage for individual breeding, and it was fasted and allowed to drink freely. In the test, an individual having no abnormal appearance and no diarrhea on the day before and on the day of the test (no dirt around the anus) was used.
  • urinary phosphorus excretion at 6 hours after administration decreased at the doses of 10 mg / kg and 30 mg / kg as compared with the MC administration group.
  • the effect was similar to that of lanthanum carbonate hydrate 100 mg / kg. From these results, Compound 26 showed an action of suppressing urinary phosphorus excretion from a dose of 10 mg / kg.
  • compound 26 has an action of inhibiting phosphorus uptake via NaPi2b. That is, it was suggested that Compound 26 has an action of suppressing urinary phosphorus excretion based on inhibiting NaPi2b in the intestinal tract and inhibiting phosphorus absorption from the intestinal tract. Similarly, it was suggested that Compound (I) or its pharmaceutically acceptable salt, which has an inhibitory action on phosphorus uptake through NaPi2b, also has an inhibitory action on urinary phosphorus excretion based on an inhibitory action on phosphorus absorption in the intestine. .
  • Test Example 3 Membrane permeability test [Parallel Artificial Membrane Permeability Assay (PAMPA)] PAMPA plates were purchased from BD Gentest TM (cat # 353015). The test was conducted according to the attached instructions, and the “P e ” (effective permeability) value of compound (I) was calculated.
  • PAMPA Paraallel Artificial Membrane Permeability Assay
  • compound (I) or a pharmaceutically acceptable salt thereof is considered to have low membrane permeability and low absorption in vivo (in the blood), and the drug concentration does not increase even when administered orally. It was.
  • Compound (I) or a pharmaceutically acceptable salt thereof inhibits the uptake of phosphorus into the living body by inhibiting NaPi2b in the digestive tract (intestinal tract) when administered orally, but its absorbability is low. Therefore, the drug concentration in the blood is low, and the drug itself has little effect on other organs.
  • Compound (I) or a pharmaceutically acceptable salt thereof is a disease in which side effects are reduced by locally inhibiting NaPi2b in the intestinal tract, and a serum phosphorus concentration affects the disease (for example, hyperphosphatemia, etc.) It is useful as a therapeutic and / or prophylactic agent.
  • Test Example 4 Plasma concentration when compound (I) was orally administered Compound (I) or a pharmaceutically acceptable salt thereof was orally administered to Sprague-Dawley rats, and 0.5, 1, 2, 4, after administration Plasma is collected at 7 and 24 hours. After adding acetonitrile to the plasma sample and stirring, the centrifuged supernatant is analyzed using LC-MS / MS to determine the concentration of the administered compound.
  • Test Example 5 [ 33 P] Phosphorus Uptake Assay of Human NaPi2b Expressing Cells (2) The same test as in Test Example 1 was conducted, and the inhibitory action of phosphorus uptake via NaPi2b of compound (I) was confirmed. The results at a test compound concentration of 1 ⁇ mol / L are shown in Table 13.
  • Compound (I) or a pharmaceutically acceptable salt thereof can inhibit NaPi2b in the intestinal tract, suppress phosphorus absorption from the intestinal tract, and diseases in which serum phosphorus concentration affects (for example, It was considered useful as a therapeutic drug for hyperphosphatemia and the like. From the above, compound (I) or a pharmaceutically acceptable salt thereof can locally inhibit NaPi2b in the intestinal tract and suppress phosphorus absorption, thereby controlling the concentration of phosphorus in the blood. It was considered useful as a therapeutic and / or prophylactic agent for diseases such as hyperphosphatemia affected by serum phosphorus concentration. In addition, since compound (I) or a pharmaceutically acceptable salt thereof is poorly absorbed into the living body, it is considered that side effects (for example, calcification in the lungs and testis) associated with systemic exposure can be suppressed. It was.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
  • the pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment.
  • These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.). Manufactured by any method.
  • the administration route it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
  • examples of the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
  • the dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of the condition to be treated, etc.
  • the dose is 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day.
  • parenteral administration such as intravenous administration
  • 0.001 to 1000 mg preferably 0.01 to 100 mg per adult is administered once to several times a day.
  • the dose and the number of doses vary depending on the various conditions described above.
  • Step 2 (E) -N ′-(4-Chloro-3- (trifluoromethyl) benzylidene) -2-cyanocarbohydrazide (4.40 g, 15.2 mmol) and acetic acid (3.48 mL, 60.8) obtained in Step 1 mmol) was dissolved in THF (44 mL) and 1,1,1,3,3,3-hexamethyldisilazane (6.37 mL, 30.4 mmol) and 4,4-dimethylcyclohexanone (2.30 g, 18.2) were cooled with ice. mmol) and stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate.
  • Step 3 (E) -N ′-(4-Chloro-3- (trifluoromethyl) benzylidene) -2-cyano-2- (4,4-dimethylcyclohexylidene) acetohydrazide obtained in Step 2 ( 5.00 g, 12.6 mmol) was dissolved in THF (30 mL), triethylamine (3.50 mL, 25.1 mmol) and sulfur (0.403 g, 12.6 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Methyl 3- (2,5,8,11,14,17,20,23-octoxapentacosan-25-yloxy) benzoate (2.70 g, 5.2 mmol) obtained in Step 1 was added to methanol ( 20 mL), 4 mol / L aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 3 hr. The mixture was washed with ethyl acetate, and then the pH of the aqueous layer was adjusted to about 2 with 6 mol / L hydrochloric acid and extracted with ethyl acetate.
  • Step 3 3- (2,5,8,11,14,17,20,23-octoxapentacosan-25-yloxy) benzoic acid (0.704 g, 1.40 mmol) and DMF (0.135) obtained in Step 2 mL) was dissolved in dichloromethane, thionyl chloride (0.51 mL, 7.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the mixture was dissolved in dichloromethane (5 mL), pyridine (1.13 mL, 14.0 mmol) and compound a (0.50 g, 1.16 mmol) obtained in Reference Example 1 were added, and the mixture was stirred at room temperature for 15 hours. Stir.
  • Carbodiimide hydrochloride (WSC ⁇ HCl) (10 mg, 0.053 mmol) and HOBt ⁇ H 2 O (HOBt ⁇ H 2 O) (8.0 mg, 0.053 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the resulting precipitate was collected by filtration to give compound 16 (10 mg, 23%).
  • Step 2 4- (2- (4-tert-Butoxycarbonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate benzyl (0.894 g, 1.80 mmol) obtained in Step 1 was added to THF (15 mL). ), Palladium hydroxide (0.253 g, 1.80 mmol) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After the mixture was filtered through celite, the solvent was evaporated under reduced pressure to give tert-butyl 4- (2- (piperazin-1-ylsulfonyl) ethyl) piperazine-1-carboxylate (0.594 g, 91%) Got.
  • Step 3 Compound 1 (0.313 g, 0.537 mmol) obtained in Example 1 was dissolved in DMF (5 mL), triethylamine (0.225 mL, 1.61 mmol) and 4- (2- (piperazine) obtained in Step 2 were used. -1-ylsulfonyl) ethyl) piperazine-1-carboxylate tert-butyl (0.292 g, 0.806 mmol) was added and stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 2 Benzyl 4- (2- (piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate (0.376 g, 0.948 mmol) obtained in Step 1 was dissolved in dichloromethane (15 mL) and triethylamine ( 0.397 mL, 2.84 mmol) and methanesulfonyl chloride (0.111 mL, 1.42 mmol) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 3 In the same manner as in Step 2 of Example 18, using benzyl 4- (2- (4- (methylsulfonyl) piperazin-1-yl) ethylsulfonyl) piperazine-1-carboxylate obtained in Step 2.
  • Step 4 Compound 20 (80.0 mg) was prepared in the same manner as in Step 3 of Example 18 using 1- (methylsulfonyl) -4- (2- (piperazin-1-ylsulfonyl) ethyl) piperazine obtained in Step 3. , 68%).
  • Pentaacetic acid 13R, 14S, 15R, 16R
  • -1- (3-((E) -2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -6,6-dimethyl -4,5,6,7-tetrahydrobenzo
  • Compound 25 50 mg, 0.063 mmol obtained in Example 25 was dissolved in dichloroethane (0.5 mL), trifluoroacetic acid (0.30 mL, 3.9 mmol) was added, and the mixture was stirred at 0 ° C.
  • Step 2 Dissolve methyl 2-(((3- (diethylamino) propyl) (methyl) amino) methyl) isonicotinate (390 mg, 1.33 mmol) obtained in Step 1 in 50% aqueous ethanol (4 mL) Lithium hydroxide monohydrate (112 mg, 2.66 mmol) was added, and the mixture was stirred overnight at room temperature. 3 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (6/1). The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 3 2-((((3- (Diethylamino) propyl) (methyl) amino) methyl) isonicotinic acid (180 mg, 0.644 mmol) obtained in Step 2 and compound a (100 mg) obtained in Reference Example 1 , 0.233 mmol) was dissolved in dichloromethane (3 mL) and 4-dimethylaminopyridine (56.8 mg, 0.465 mmol) and 2,4,6-trichlorobenzoic acid chloride (113 mg, 0.465 mmol) were added. Stir. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 2 Benzyl 1- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 1 (295 mg, 0.816 mmol) Was dissolved in DMF (5 mL), triethylamine (0.228 mL, 1.63 mol) and methanesulfonyl chloride (0.127 mL, 1.63 mmol) were added, and the mixture was stirred at room temperature overnight, and further stirred at 100 ° C. for 2 hr. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 3 Benzyl 1- (2- (2- (2-chloroethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 2 (223 mg, 0.587 mmol) was dissolved in DMF (5 mL), 2-diethylamine (1.84 mL, 17.6 mmol) was added, and the mixture was stirred at 100 ° C. overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 4 benzyl 1- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 3 (244 mg, 0.587 mmol) was dissolved in ethanol, palladium carbon (82.0 mg) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The mixture was filtered and the filtrate's solvent was removed under reduced pressure to give 1- (2- (2- (2- (diethylaminoethoxy) ethoxy) ethyl-6-oxo-1,6-dihydropyridine-3- Carboxylic acid (158 mg, 82%) was obtained.
  • Step 5 Step of Example 6 using 1- (2- (2- (2- (diethylaminoethoxy) ethoxy) ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid) obtained in Step 4 In the same manner as in 3, compound 45 (67.0 mg, 38%) was obtained.
  • Step 2 Compound 46 (0.610 g, 31%) was obtained in the same manner as in Step 3 of Example 18 using benzyl 2- (3-hydroxypropylamino) acetate obtained in Step 1.
  • Step 2 4-bromo-2- (7-ethoxy-7-oxoheptyloxy) in the same manner as in Step 1 of Example 8 using methyl 4-bromo-2-hydroxybenzoate obtained in Step 1 Methyl benzoate (0.865 g, 86%) was obtained.
  • Step 3 Methyl 4-bromo-2- (7-ethoxy-7-oxoheptyloxy) benzoate (0.865 g, 2.23 mmol), 1,1'-bis (diphenylphosphino) ferrocene palladium obtained in Step 2 (II) Dichloride-dichloromethane complex (0.182 g, 0.232 mmol), 1,1'-bis (diphenylphosphino) ferrocene (0.124 g, 0.223 mmol) and potassium acetate (1.10 g, 11.2 mmol) in DMSO (15 mL) And stirred at 80 ° C. for 3 hours under a carbon monoxide atmosphere.
  • Step 4 In the same manner as in Step 3 of Example 6 using 3- (7-ethoxy-7-oxoheptyloxy) -4- (methoxycarbonyl) benzoic acid obtained in Step 3, compound 55 (0.654 g , Quantitative).
  • Step 2 4-Bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoic acid (4.1 g, 11.2 mmol) obtained in Step 1 was dissolved in DMF (20 mL), and potassium carbonate (3.1 g, 22.5 mmol) and methyl iodide (1.05 mL, 16.8 mmol) were added, and the mixture was stirred at 45 ° C. for 2 hours.
  • Step 3 Methyl 4-bromo-2-((3- (methoxycarbonyl) phenoxy) methyl) benzoate obtained in Step 2 (1.14 g, 3.0 mmol), 1,1′-bis (diphenylphosphino) ferrocene Palladium (II) dichloride dichloromethane complex (0.49 g, 0.60 mmol), 1,1'-bis (diphenylphosphino) ferrocene (0.167 g, 0.30 mmol) and potassium acetate (2.95 g, 30 mmol) are dissolved in DMSO, The mixture was stirred at 80 ° C. for 12 hours in a carbon monoxide atmosphere.
  • Step 4 4- (methoxycarbonyl) -3-((3- (methoxycarbonyl) phenoxy) benzoic acid (0.144 g, 0.42 mmol) obtained in Step 3 and compound a obtained in Reference Example 1 (0.15 g, 0.35 mmol) was dissolved in dichloromethane (2 mL) and 4-dimethylaminopyridine (0.043 g, 0.35 mmol), triethylamine (0.177 g, 1.75 mmol) and 2,4,6-trichlorobenzoic acid chloride (0.17 g, 0.70). mmol) and stirred for 2 hours at 0 ° C.
  • Step 2 Methyl 3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzoate (5.61 g, 19.7 mmol) obtained in Step 1 was dissolved in DMF (100 mL) and triethylamine (8.25 mL, 59.2 mol) and methanesulfonyl chloride (4.61 mL, 59.2 mmol) were added, and the mixture was stirred at room temperature overnight. Sodium iodide (5.91 g, 39.4 mmol) was added to the mixture, and the mixture was stirred at 100 ° C. for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 Methyl 3- (2- (2- (2-iodoethoxy) ethoxy) ethoxy) benzoate obtained in Step 2 (3.25 g, 8.24 mmol) was dissolved in DMF (60 mL), and potassium carbonate ( 5.70 g, 41.2 mol) and 2-diethylamine (18.1 g, 247 mmol) were added, and the mixture was stirred at 100 ° C. overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 4 Dissolve methyl 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxybenzoate (2.77 g, 8.16 mmol) obtained in Step 3 in 50% aqueous ethanol (60 mL). Lithium hydroxide monohydrate (685 mg, 16.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours, 3 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (6/1).
  • Step 5 Using the 3- (2- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzoic acid obtained in Step 4, in the same manner as in Step 2 of Example 6, compound 69 (45.0 mg, 20%).
  • Step 2 ((E) -2-amino-3- (2- (4-chloro-3- (trifluoromethyl) benzylidene) hydrazinecarbonyl) -4,5,6,7-dihydrothieno [ Compound 71 (8.83 g, 85%) was obtained in the same manner as in Example 1 using tert-butyl 2,3-c] pyridine-6 (7H) -carboxylate.
  • Step 2 tert-butyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (24.0 g, 85 mmol) obtained in Step 1 is replaced with dichloromethane (130 mL), 3- (chloromethyl) benzoyl chloride (12.38 mL, 87 mmol) and pyridine (7.0 mL, 87 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated.
  • Step 3 tert-butyl 2- (3- (chloromethyl) benzoylamino) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in step 2 (10.0 g, 23 mmol) was dissolved in dichloromethane (50 mL), 4-hydroxypiperidine (6.98 g, 69 mmol) and triethylamine (9.6 mL, 69 mmol) were added, and the mixture was stirred at room temperature for 20 hours.
  • Step 4 2- (3-((4-Hydroxypiperidin-1-yl) methyl) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene obtained in Step 3
  • Tert-Butyl-3-carboxylate (8.92 g, 18 mmol) was dissolved in trifluoroacetic acid (27.6 mL), trifluoroacetic anhydride (6.23 mL) was added, and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated, dropped into a saturated aqueous sodium hydrogen carbonate solution at 0 ° C. to neutralize, and extracted with chloroform.
  • Step 5 N- (3- (hydrazinocarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -3-(( 4-Hydroxypiperidin-1-yl) methyl) benzamide (100 mg, 0.219 mmol) is dissolved in chloroform (2 mL), and 5,6-dichloronicotinaldehyde (77.0 mg, 0.438 mmol) is added. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
  • Step 2 Performed using tert-butyl 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 Similar to Example 8, 2- (3- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] Obtained tert-butyl thiophene-3-carboxylate (7.20 g, 90%).
  • Step 3 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo
  • b Dissolve tert-butyl thiophene-3-carboxylate (1.40 g, 2.62 mmol) in DMF (15 mL), add triethylamine (0.548 mL, 3.93 mmol) and methanesulfonyl chloride (0.307 mL, 3.93 mmol) at room temperature. And stirred overnight. After further stirring at 100 ° C. for 2 hours, water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Step 4 2- (3- (2- (2- (2-chloroethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [ b] 2- (3- (2- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide) -6, as in Example 10, using tert-butyl thiophene-3-carboxylate 6-Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (0.457 g, 82%) was obtained.
  • Step 5 2- (3- (2- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydro obtained in step 4 3- (2- (2- (2- (2- (2- (Diethylamino) ethoxy) ethoxy) ethoxy) -N-) using tert-butyl benzo [b] thiophene-3-carboxylate as in Step 4 of Example 86 (3- (hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (59.0 mg, 64%) was obtained.
  • Step 6 2,1,3-Benzoxadiazole-5-carbaldehyde and 3- (2- (2- (2- (diethylamino) ethoxy) ethoxy) ethoxy) -N- (3 obtained in Step 5
  • Compound 88 (25.0) was prepared in the same manner as in Step 5 of Example 86 using-(hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide. mg, 15%).
  • Step 2 Ethyl 2- (bromomethyl) thiazole-4-carboxylate (0.768 g, 3.07 mmol) obtained in Step 1 was dissolved in THF (10.0 mL), triethylamine (0.856 mL, 6.14 mmol) and N, N -Diethyl-N'-methylethane-1,2-diamine (0.745 mL, 4.61 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • Step 5 2-((((2- (Diethylamino) ethyl) (methyl) amino) methyl) thiazole-4-carboxylic acid (60 mg, 2.7 mmol) obtained in Step 3 was dissolved in dichloromethane (1.0 mL).
  • Step 2 Example 1 using tert-butyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylate obtained in Step 1 In a similar manner to tert-butyl 2- (3- (chloromethyl) benzamido) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylate (10.8 g, 89%).
  • Step 3 2- (3- (Chloromethyl) benzamido) -6-cyclopropyl-4,5,6,7-tetrahydrothieno [2,3-b] pyridine-3-carboxylic acid tert obtained in Step 2 6-Cyclopropyl-2- (3-(((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide) -4,5,6,7 in the same manner as in Example 59.
  • Tert-butyl (5.86 g, 94%) of 4-tetrahydrothieno [2,3-c] pyridine-3-carboxylate was obtained.
  • Step 4 6-Cyclopropyl-2- (3-((((3- (diethylamino) propyl) (methyl) amino) methyl) benzamide) -4,5,6,7-tetrahydrothieno obtained in Step 3 [ N- (6-Cyclopropyl-3- (hydrazinecarbonyl) -4,5,6, using tert-butyl 2,3-c] pyridine-3-carboxylate as in Step 5 of Example 88 7-tetrahydrothieno [2,3-c] pyridin-2-yl) -3-(((3-diethylamino) propyl) (methyl) amino) methyl) benzamide (1.22 g, 81%) was obtained.
  • Step 5 2,1,3-Benzoxadiazole-5-carbaldehyde and N- (6-cyclopropyl-3- (hydrazinecarbonyl) -4,5,6,7-tetrahydrothieno obtained in Step 4
  • Compound 90 [2,3-c] pyridin-2-yl) -3-(((3-diethylamino) propyl) (methyl) amino) methyl) benzamide was prepared in the same manner as in Step 5 of Example 86. 40.4 mg, 44%).
  • Step 2 (E) -2-amino-N ′-(4-chloro-3- (trifluoromethyl) benzylidene) -6-hydroxy-6-methyl-4,5,6,7 obtained in Step 1
  • Compound 91 (0.177 g, 87%) was obtained in the same manner as in Example 1 using -tetrahydrobenzo [b] thiophene-3-carbohydrazine.
  • Step 2 Lithium aluminum hydride (0.725 g, 19.1 mmol) suspended in THF (30 mL) and diethyl 4-dioxaspiro [4.5] decane-8,8-dicarboxylate obtained in Step 1 at 0 ° C (4.56 g, 15.9 mmol) was added. The mixture was stirred for 1 hour, lithium aluminum hydride (0.725 g, 19.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 3 1,4-Dioxaspiro [4.5] decane-8,8-diyldimethanol (3.17 g, 15.7 mmol) obtained in Step 2 is dissolved in THF (150 mL) and n-butyllithium at 0 ° C. (2.76 mol / L THF solution; 6.81 mL, 18.8 mmol) was added. The mixture was stirred for 30 minutes, a THF solution (30 mL) of 4-toluenesulfonyl chloride (3.59 g, 18.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 4 Dissolve 1,4,10-trioxaspiro [3.4.5] tridecane (0.20 g, 1.09 mmol) obtained in Step 3 in THF (5 mL) and add 10% hydrochloric acid (1 mL) at room temperature. ) And stirred overnight. Water was added to the mixture and extracted with ethyl acetate.
  • Step 5 Using 4-chloromethyl-4- (hydroxymethyl) cyclohexanone obtained in Step 4, in the same manner as in Step 1 of Example 86, 2-amino-6- (chloromethyl) -6- (hydroxymethyl) ) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (238 mg, 94%) was obtained.
  • 1 H-NMR (270 MHz, CDCl 3 , ⁇ ): 1.54 (s, 9H), 1.72 (t, J 6.6 Hz, 2H), 2.47 (s, 2H), 2.68-2.73 (m, 2H), 3.59 -3.67 (m, 4H), 5.91 (s, 2H).
  • Step 6 Using tert-butyl 2-amino-6- (chloromethyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 5
  • 6- (chloromethyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide) -6- ( Hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (1.68 g, 88%) was obtained.
  • Step 7 6- (Chloromethyl) -2- (3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide) -6- (hydroxymethyl) -4, obtained in Step 6 Using tert-butyl 5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate as in Step 4 of Example 86, N- (6- (chloromethyl) -3- (hydrazinecarbonyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide (0.62 g, 65%).
  • Step 8 N- (6- (chloromethyl) -3- (hydrazinecarbonyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl obtained in step 7 ) -3-(((2- (diethylamino) ethyl) (methyl) amino) methyl) benzamide was used in the same manner as in Step 5 of Example 86 to give compound 93 (0.64 g, 76%).
  • Step 2 Using 2-oxaspiro [3.5] nonan-7-one obtained in Step 1, in the same manner as in Step 1 of Example 86, 2-amino-5,7-dihydro-4H-spiro [benzo [benzo [ b] tert-butyl thiophene-6,3′-oxetane] -3-carboxylate (10.5 g, 58%) was obtained.
  • Step 3 Example 86 using tert-butyl 2-amino-5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylate obtained in Step 2 2- (3- (chloromethyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylic acid tert- Butyl (1.16 g, 76%) was obtained.
  • Step 4 2- (3- (Chloromethyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3′-oxetane] -3-carboxylic acid tert obtained in Step 3 2- (3-(((2- (diethylamino) propyl) (methyl) amino) methyl) benzamido) -5,7-dihydro-4H-spiro in the same manner as Example 86, step 3 [Benzo [b] thiophene-6,3′-oxetane] -3-carboxylate tert-butyl (1.56 g, 77%) was obtained.
  • Step 5 2- (3-(((2- (Diethylamino) propyl) (methyl) amino) methyl) benzamido) -5,7-dihydro-4H-spiro [benzo [b] thiophene- obtained in Step 4 3-((((3- (diethylamino) propyl) (methyl) amino) methyl) -N using tert-butyl 6,3′-oxetane] -3-carboxylate as in Step 4 of Example 86 -(3- (hydrazinecarbonyl) -5,7-dihydro-4H-spiro [benzo [b] thiophene-6,3'-oxetane] -2-yl) benzamide (79 mg, 70%) was obtained.
  • Step 6 3-((((3- (Diethylamino) propyl) (methyl) amino) methyl) -N- (3- (hydrazinecarbonyl) -5,7-dihydro-4H-spiro [benzo [ b] Thiophene-6,3′-oxetane] -2-yl) benzamide was used in the same manner as in Step 5 of Example 86 to give compound 94 (70 mg, 65%).
  • Compound 96 Compound 95 (1.96 g, 2.36 mmol) obtained in Example 95 was dissolved in dichloromethane (12 mL), and triethylamine (0.66 mL, 4.73 mmol) and mesyl chloride (0.277 mL, 3.55 mmol) were added at 0 ° C. The mixture was further stirred at room temperature for 1 hour. To the mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Compounds 99 to 104 Compounds 99 to 104 were obtained in the same manner as in Examples 97 and 98 using the corresponding benzyl 2-aminoacetate.
  • Compound 102 ESIMS m / z: 957 (M + H) + .
  • Compound 105 Compound 3 (7.00 g, 12.73 mmol) obtained in Example 3 was dissolved in DMF (50.0 mL), and cesium carbonate (8.29 g, 25.5 mmol) and 17-hydroxy-3,6,9,12, 15-Pentaoxaheptadecyl-4-methylbenzenesulfonate (11.11 g, 25.5 mmol) was added, and the mixture was stirred at 65 ° C. for 3 hours. Distilled water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Compounds 108 to 110 Compounds 108 to 110 were obtained in the same manner as in Example 102, using the corresponding amine instead of 3- (pyridin-3-yl) propanoic acid.
  • Compound 112 Compound 111 (0.749 g, 0.836 mmol) obtained in Example 104 was dissolved in ethanol (5.0 mL), and 4 mol / L aqueous sodium hydroxide solution (1.04 ml, 4.18 mmol) was added. Stir for hours. The mixture was neutralized with 1 mol / L hydrochloric acid, extracted with a mixed solvent of chloroform / methanol, and the organic layer was concentrated to obtain Compound 112 (0.685 g, 94%).
  • Compound 114 (0.800 g, 50%) was obtained in the same manner as in Example 12 using Compound 105 (1.50 g, 1.84 mmol) obtained in Example 100.
  • Compound 120 Compound 120 (0.384 g) in the same manner as in Example 13 using tert-butyl 3- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) propanoate (0.939 g, 3.39 mmol). , 56%).
  • Compound 121 (0.389 g, ⁇ quantitative) was obtained in the same manner as in Example 25, using Compound 120 (0.384 g, 0.378 mmol) obtained in Example 113.
  • Compound 123 was obtained in the same manner as in Examples 108 and 109 using ethyl 3- (methylamino) propanoate.
  • Compound 131 was obtained in the same manner as in Examples 122 and 123 using ethyl 3- (methylamino) propanoate. ESIMS m / z: 899, 901 (M + H) + .
  • Step 2 In the same manner as in Example 16, using Compound 36 obtained in Example 36 and 3- (2- (2- (2-(-tosyloxyethoxy) ethoxy) ethoxy) propanoic acid obtained in Step 1 Compound 132 (580 mg, 60%) was obtained.
  • Compound 133 Compound 133 (296 mg, 36%) was obtained in the same manner as in Example 97, using Compound 132 obtained in Example 125 and the compound obtained in Step 1 of Example 46.
  • 1 H-NMR 300 MHz, CDCl 3 , ⁇ ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.52 (s, 2H), 2.67-2.90 (m, 8H), 2.96-2.98 ( m, 3H), 3.43-3.49 (m, 2H), 3.53-3.62 (m, 10H), 3.73-3.86 (m, 4H), 4.64-4.67 (m, 2H), 5.12-5.14 (m, 2H), 7.27-7.39 (m, 5H), 7.44-7.58 (m, 3H), 7.89-7.97 (m, 3H), 8.04-8.06 (m, 1H), 8.25-8.29 (m, 1H), 9.36 (s, 1H ), 12.89 (br s, 1H).
  • Compounds 140 to 144 Compounds 140 to 144 were obtained in the same manner as in Example 15, Example 52, or Example 127 using Compounds 135, 136, 137, 138, and 139.
  • Compound 140 ESIMS m / z: 852 (M + H) + .
  • Compound 141 ESIMS m / z: 866 (M + H) + .
  • Compound 142 ESIMS m / z: 910 (M + H) + .
  • Compound 144 ESIMS m / z: 910 (M + H) + .
  • Compound 145 Compound 140 was obtained in the same manner as in Example 127, using 3-amino-1-propanol and the compound obtained in the same manner as in Example 36.
  • Compound 146 was obtained in the same manner as in Example 127, using a compound obtained in the same manner as in Example 36 using 3-amino-1,2-propanediol. ESIMS m / z: 956 (M + H) + .
  • Compound 147 was obtained in the same manner as in Example 127, using a compound obtained in the same manner as in Example 36 using 2-amino-1,3-propanediol.
  • Compound 148 Compound 36 (280 mg, 0.485 mmol) obtained in Example 36 was dissolved in dichloromethane (5 mL), and pyridine (0.047 mL, 0.582 mmol) and chloroacetyl chloride (0.047 mL, 0.582 mmol) were cooled with ice. ) And stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 The crude 20-hydroxy-3,6,9,12,15,18-hexaoxaicosan-1-acid (0.253 g, 0.744 mmol) obtained in Step 1 was added to THF (1 mL) and DMF (0.1 In an ice bath, sodium hydride (0.104 g, 2.60 mmol) was added and stirred for 10 minutes.
  • Compound 150 was obtained in the same manner as in Example 130, using 3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) propanoic acid. ESIMS m / z: 837 (MH) + .
  • Compound 152 Compound 152 (1.67 g, 64%) was obtained in the same manner as in Example 96, using Compound 151 (2.4 g, 2.67 mmol) obtained in Example 136.
  • Compound 153 (0.089 g, 14%) was obtained in the same manner as in Example 126, using Compound 152 (0.550 g, 0.563 mmol) obtained in Example 137.
  • 1 H-NMR 400 MHz, CDCl 3 , ⁇ ): 1.07 (s, 6H), 1.61-1.70 (m, 4H), 2.53 (s, 2H), 2.80-2.98 (m, 9H), 3.47-3.77 ( m, 27H), 4.25-4.36 (m, 2H), 4.67 (s, 2H), 5.14 (s, 2H), 7.32-7.37 (m, 5H), 7.40-7.59 (m, 3H), 7.87-7.99 ( m, 3H), 8.27-8.31 (m, 1H), 9.38 (s, 1H), 12.94 (s, 1H).
  • Compound 154 (0.065 g, 80%) was obtained in the same manner as in Example 47, using Compound 153 (0.089 g, 0.081 mmol) obtained in Example 138.
  • Compound 161 Compound 1 (254 mg, 0.436 mmol) obtained in Example 1 was dissolved in DMF (5 mL), cesium carbonate (426 mg, 1.31 mmol) and 1-mercapto-3,6,9,12, 15,18,21,24-Octaheptacosane-27 acid (200 mg, 0.436 mmol) was added and stirred at 50 ° C. for 7 hours. Citric acid (335 mg, 1.75 mmol) and water were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give compound 161 (328 mg, 75%).
  • Step 2 Benzyl 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine-3-carboxylate obtained in Step 1 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine in the same manner as in Step 4 of Example 45. -3-carboxylic acid (1.29 g, 91%) was obtained.
  • Step 3 1- (14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl) -6-oxo-1,6-dihydropyridine-3-carboxylic acid obtained in Step 2 was used to give compound 162 (762 mg, 44%) in the same manner as in Step 3 of Example 6.
  • Compound 164 (125 mg, 55%) was obtained in the same manner as in Example 16 using Compound 158 obtained in Example 148.
  • Compound 166 Compound 105 (0.25 g, 0.31 mmol) obtained in Example 100 was dissolved in THF (10 mL), and 1H-tetrazole (0.043 g, 0.61 mmol) and di-tert-butyldiethyl phosphoramidite (0.128 mL, 0.46 mmol) was added and stirred at room temperature for 12 hours. Add 1H-tetrazole (0.034 g, 0.49 mmol) and di-tert-butyldiethyl phosphoramidite (0.10 mL, 0.37 mmol), then add m-chloroperbenzoic acid (0.16 g, 0.68 mmol) at room temperature. For 10 minutes.
  • Compound 169 Compound 169 (0.513 g, 0.706 mmol) obtained in Example 153 was dissolved in DMF (1.5 ml), sodium hydroxide (0.085 g, 2.1 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. did. Under ice cooling, propargyl bromide (0.115 ml, 1.060 mmol) was added and stirred for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the mixture, and the mixture was extracted with ethyl acetate.
  • Compound 170 Compound 169 (0.136 g, 0.178 mmol) and 5-azidopentanoic acid (0.025 g, 0.178 mmol) obtained in Example 154 were dissolved in 1,4-dioxane (2.5 ml) and water (1 mL). , Sodium ascorbate (0.11 g, 0.53 mmol) and cupric sulfate pentahydrate (0.089 g, 0.36 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Aqueous ammonia was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Compounds 171 and 172 were obtained in the same manner as in Example 155, using the corresponding azide compounds.
  • Compound 173 was obtained in the same manner as in Example 10 by using 4,4-difluorocyclohexanone in the same manner as in Reference Example 1, Examples 2, 3, 8 and 96 and morpholine. .
  • Compound 174 was obtained in the same manner as in Example 17 using the compound obtained in the same manner as in Reference Example 1, Example 2 and 3 using tetrahydro-4H-pyran-4-one.
  • Step 2 Methyl 3,5-dihydroxybenzoate (0.35 g, 2.082 mmol) was dissolved in DMF (10.0 mL) and cesium carbonate (2.035 g, 6.24 mmol) and 2- (2- (2 -Methoxyethoxy) ethoxy) ethyl-4-methylbenzenesulfonate (1.988 g, 6.24 mmol) was added and stirred at 100 ° C. for 2 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 3 Methyl 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoate (0.85 g, 1.846 mmol) obtained in Step 2 was added to 6 mol / L hydrochloric acid (9.23 mL). Dissolved and stirred at 100 ° C. overnight. By azeotroping with toluene, 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) benzoic acid (0.8 g, 97%) was obtained.
  • Step 4 Dissolve 3,5-bis (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) benzoic acid (0.433 g, 0.971 mmol) obtained in Step 3 in dichloromethane (4 mL), 4,6-trichlorobenzoyl chloride (0.233 mL, 1.493 mmol), triethylamine (0.52 mL, 3.73 mmol), 4-dimethylaminopyridine (0.182 g, 1.493 mmol) and synthesized in the same manner as Reference Example 1 (E)- Add 2-amino-N '-(4-chloro-3- (trifluoromethyl) benzylidene) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carbohydrazide (0.3 g, 0.747 mmol) And stirred at room temperature for 3 hours.
  • Step 2 tert-butyl 2- (3-hydroxybenzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate obtained in Step 1 (20.0 g, 49.8 2- (3- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamido) -6,6-dimethyl-4,5,6, in the same manner as in Example 8. 7-Tetrahydrobenzo [b] thiophene-3-carboxylate tert-butyl (15.6 g, 59%) was obtained.
  • Step 3 2- (3- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b ] 2- (3- (2- (2- (2- (2-oxirane-2-)-2- (3- (2- (2- (2-oxirane-2-) oxirane-2-tert-butyl] thiophene-3-carboxylate (5.00 g, 9.37 mmol) in the same manner as in Example 12.
  • Step 4 2- (3- (2- (2- (2- (2- (2-oxiran-2-ylmethoxy) ethoxy) ethoxy) ethoxy) benzamide) -6,6-dimethyl-4,5, obtained in Step 3 2- (3- (13-Ethyl-11-hydroxy) as in Example 13 using tert-butyl 6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (3.16 g, 5.36 mmol) -3,6,9-trioxa-13-azapentadecyloxy) benzamide) tert-butyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (3.20 g , 90%).
  • Step 5 2- (3- (13-Ethyl-11-hydroxy-3,6,9-trioxa-13-azapentadecyloxy) benzamide) -6,6-dimethyl-4,5, obtained in Step 4 3- (13-Ethyl-11-hydroxy) as in Step 4 of Example 86 using tert-butyl 6,7-tetrahydrobenzo [b] thiophene-3-carboxylate (2.00 g, 3.02 mmol) -3,6,9-trioxa-13-azazapentadecyloxy) -N- (3- (hydrazinecarbonyl) -6,6-dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophene-2 -Yl) benzamide (1.50 g, 80%) was obtained.
  • Step 6 3- (13-Ethyl-11-hydroxy-3,6,9-trioxa-13-azazapentadecyloxy) -N- (3- (hydrazinecarbonyl) -6,6- Dimethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) benzamide (0.100 g, 0.161 mmol) and 4,5-dichlorothiazole-2-carbaldehyde synthesized by the method described in EP2080761 ( 0.040 g, 0.220 mmol), and in the same manner as in Step 5 of Example 86, compound 176 (E form) (19 mg, 15%) and compound 177 (Z form) (53 mg, 42%) were obtained. It was.
  • Compound 178 was obtained in the same manner as in Example 155, using 2-chloro-6- (trifluoromethyl) isonicotinaldehyde.
  • Tablet A tablet having the following composition is prepared by a conventional method.
  • Compound 26, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
  • the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • a condensed ring useful as a therapeutic and / or prophylactic agent for a disease that inhibits NaPi2b in the intestinal tract and has decreased absorbability into blood and is affected by serum phosphorus concentration (for example, hyperphosphatemia).
  • serum phosphorus concentration for example, hyperphosphatemia.
  • a thiophene derivative or a pharmaceutically acceptable salt thereof can be provided.

Abstract

L'invention concerne un composé représenté par la formule (I) [dans laquelle R1 et R2 représentent chacun un atome d'hydrogène ou similaire ; L représente un groupe phényle qui est substitué par un ou deux groupes représentés par la formule (II) -(CH2)h-A-B-Y-D-C (dans laquelle h représente un entier de 0-3 ; C représente un atome d'hydrogène ou similaire ; D représente une liaison ou similaire ; Y représente une liaison ou similaire ; B représente une liaison ou similaire ; et A représente une liaison ou similaire) ou similaire ; n est 1 ou 2 ; m est 1 ou 2 ; et Z représente -CR14R15- (où R14 et R15 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou similaire)]. L'invention concerne également un sel pharmaceutiquement acceptable de ce composé.
PCT/JP2013/055041 2012-02-28 2013-02-27 Dérivé de thiophène fusionné WO2013129435A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015064532A1 (fr) * 2013-10-30 2015-05-07 第一三共株式会社 Composé de morpholine
US9133210B2 (en) 2013-08-08 2015-09-15 Galapagos Nv Compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis
JP2015532295A (ja) * 2012-10-02 2015-11-09 エピセラピューティックス・エイ・ピー・エス ヒストン脱メチル化酵素の阻害剤
JP2017512804A (ja) * 2014-03-31 2017-05-25 ギリアード サイエンシーズ， インコーポレイテッド ヒストン脱メチル化酵素の阻害剤
EP3928779A1 (fr) 2014-09-12 2021-12-29 Chugai Seiyaku Kabushiki Kaisha Proproduits pharmaceutiques contenant un inhibiteur de transporteur de phosphate dépendant au sodium et un adsorbant de phosphore devant être utilisés pour la prévention, le traitement ou la suppression des maladies rénales chroniques, de l'artériosclérose associée à la calcification vasculaire ou de la calcification ectopique.

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US9895347B2 (en) 2013-08-08 2018-02-20 Galapagos Nv Compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis
US10568867B2 (en) 2013-08-08 2020-02-25 Galapagos Nv Compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis
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JP2017512804A (ja) * 2014-03-31 2017-05-25 ギリアード サイエンシーズ， インコーポレイテッド ヒストン脱メチル化酵素の阻害剤
EP3928779A1 (fr) 2014-09-12 2021-12-29 Chugai Seiyaku Kabushiki Kaisha Proproduits pharmaceutiques contenant un inhibiteur de transporteur de phosphate dépendant au sodium et un adsorbant de phosphore devant être utilisés pour la prévention, le traitement ou la suppression des maladies rénales chroniques, de l'artériosclérose associée à la calcification vasculaire ou de la calcification ectopique.

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