JP2019527734A - NaPi−IIb阻害剤として有用な縮合チオフェン誘導体 - Google Patents
NaPi−IIb阻害剤として有用な縮合チオフェン誘導体 Download PDFInfo
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- JP2019527734A JP2019527734A JP2019527785A JP2019527785A JP2019527734A JP 2019527734 A JP2019527734 A JP 2019527734A JP 2019527785 A JP2019527785 A JP 2019527785A JP 2019527785 A JP2019527785 A JP 2019527785A JP 2019527734 A JP2019527734 A JP 2019527734A
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- Prior art keywords
- amino
- methyl
- phenyl
- difluoro
- ethyl
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- 239000003112 inhibitor Substances 0.000 title description 5
- 150000003577 thiophenes Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 239000000203 mixture Substances 0.000 claims abstract description 113
- 150000003839 salts Chemical class 0.000 claims abstract description 74
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 37
- 201000005991 hyperphosphatemia Diseases 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 18
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 196
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 138
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 107
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 105
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 96
- -1 3-carboxypropyl Chemical group 0.000 claims description 89
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 65
- 239000005711 Benzoic acid Substances 0.000 claims description 64
- 235000010233 benzoic acid Nutrition 0.000 claims description 64
- 238000011282 treatment Methods 0.000 claims description 33
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 22
- 238000009472 formulation Methods 0.000 claims description 16
- AMOHQOVBWMGTAS-UHFFFAOYSA-N 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-hydroxybutylcarbamoyl)-2,2-dimethylpiperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid Chemical compound FC1=C(C(=CC(=C1)NC(=O)C1=C(SC2=C1CCCC2)NC(C1=CC(=CC=C1)CN1C(CN(CC1)C(NCCCCO)=O)(C)C)=O)F)CCC1=CC=C(C(=O)O)C=C1 AMOHQOVBWMGTAS-UHFFFAOYSA-N 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 239000007962 solid dispersion Substances 0.000 claims description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- PGAAEJYJRJMKJL-UHFFFAOYSA-N 4-[2-[2,6-difluoro-4-[[2-[[3-[(4-methoxycarbonyl-2,2-dimethylpiperazin-1-yl)methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid Chemical compound FC1=C(C(=CC(=C1)NC(=O)C1=C(SC2=C1CCCC2)NC(C1=CC(=CC=C1)CN1C(CN(CC1)C(=O)OC)(C)C)=O)F)CCC1=CC=C(C(=O)O)C=C1 PGAAEJYJRJMKJL-UHFFFAOYSA-N 0.000 claims description 3
- DTTIOFWMAXDFJA-UHFFFAOYSA-N 4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylcarbamothioyl)piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]-2,6-difluorophenyl]ethyl]benzoic acid Chemical compound CC1(N(CCN(C1)C(NC)=S)CC=1C=C(C(=O)NC=2SC3=C(C=2C(=O)NC2=CC(=C(C(=C2)F)CCC2=CC=C(C(=O)O)C=C2)F)CCCC3)C=CC=1)C DTTIOFWMAXDFJA-UHFFFAOYSA-N 0.000 claims description 3
- QGECXHAXODESAH-UHFFFAOYSA-N 4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylcarbamoyl)piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]-2,6-difluorophenyl]ethyl]benzoic acid Chemical compound CC1(N(CCN(C1)C(NC)=O)CC=1C=C(C(=O)NC=2SC3=C(C=2C(=O)NC2=CC(=C(C(=C2)F)CCC2=CC=C(C(=O)O)C=C2)F)CCCC3)C=CC=1)C QGECXHAXODESAH-UHFFFAOYSA-N 0.000 claims description 3
- ULNXZRHSOMHAIE-UHFFFAOYSA-N 4-[2-[4-[[2-[[3-[[2,2-dimethyl-4-(methylsulfamoyl)piperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]-2,6-difluorophenyl]ethyl]benzoic acid Chemical compound CC1(N(CCN(C1)S(NC)(=O)=O)CC=1C=C(C(=O)NC=2SC3=C(C=2C(=O)NC2=CC(=C(C(=C2)F)CCC2=CC=C(C(=O)O)C=C2)F)CCCC3)C=CC=1)C ULNXZRHSOMHAIE-UHFFFAOYSA-N 0.000 claims description 3
- ZNJVCPDXZUUIQR-UHFFFAOYSA-N 4-[2-[4-[[2-[[3-[[4-(2-carboxyethylcarbamoyl)-2,2-dimethylpiperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]-2,6-difluorophenyl]ethyl]benzoic acid Chemical compound C(=O)(O)CCNC(=O)N1CC(N(CC1)CC=1C=C(C(=O)NC=2SC3=C(C=2C(=O)NC2=CC(=C(C(=C2)F)CCC2=CC=C(C(=O)O)C=C2)F)CCCC3)C=CC=1)(C)C ZNJVCPDXZUUIQR-UHFFFAOYSA-N 0.000 claims description 3
- UBPIRRORRFGPNE-UHFFFAOYSA-N benzoic acid;formic acid Chemical compound OC=O.OC(=O)C1=CC=CC=C1 UBPIRRORRFGPNE-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- AKSLXDVWYUQVED-UHFFFAOYSA-N 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(3-hydroxypropyl)-2,2-dimethylpiperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid Chemical compound FC1=C(C(=CC(=C1)NC(=O)C1=C(SC2=C1CCCC2)NC(C1=CC(=CC=C1)CN1C(CN(CC1)CCCO)(C)C)=O)F)CCC1=CC=C(C(=O)O)C=C1 AKSLXDVWYUQVED-UHFFFAOYSA-N 0.000 claims description 2
- RHSJYHIKJJCPIW-UHFFFAOYSA-N 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(3-methoxypropyl)-2,2-dimethylpiperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid Chemical compound FC1=C(C(=CC(=C1)NC(=O)C1=C(SC2=C1CCCC2)NC(C1=CC(=CC=C1)CN1C(CN(CC1)CCCOC)(C)C)=O)F)CCC1=CC=C(C(=O)O)C=C1 RHSJYHIKJJCPIW-UHFFFAOYSA-N 0.000 claims description 2
- BCJPSDBOYKYMSF-UHFFFAOYSA-N 4-[2-[2,6-difluoro-4-[[2-[[3-[[4-(4-methoxybutylcarbamoyl)-2,2-dimethylpiperazin-1-yl]methyl]benzoyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonyl]amino]phenyl]ethyl]benzoic acid Chemical compound FC1=C(C(=CC(=C1)NC(=O)C1=C(SC2=C1CCCC2)NC(C1=CC(=CC=C1)CN1C(CN(CC1)C(NCCCCOC)=O)(C)C)=O)F)CCC1=CC=C(C(=O)O)C=C1 BCJPSDBOYKYMSF-UHFFFAOYSA-N 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 230
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
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- 239000007787 solid Substances 0.000 description 72
- 239000000243 solution Substances 0.000 description 69
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 66
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- 238000005481 NMR spectroscopy Methods 0.000 description 36
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Classifications
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- 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
- C07D333/66—Nitrogen atoms not forming part of a nitro radical
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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Abstract
Description
(式中、Yは縮合シクロヘキサン環または縮合フェニル環であり、
Aが、
式中、R2は、
−CH3、−(CH2)3OH、−(CH2)3OCH3、−(CH2)3CO2H、−COOCH3、−COCH3、−CO(CH2)3CH3、−COCH(CH3)2、−CO(CH2)2CO2H、−COCH2NH2、−COCH2N(CH3)2、−SO2N[(CH2)2OCH3]2、−SO2NHCH3、−SO2(CH2)2OCH3、−CONH(CH2)4OH、−CONH(CH2)4OCH3、−CONHCH3、−CONH(CH2)2CO2H、−CONH(CH2)2OCH3、−CON(CH2CH2OCH3)2、−CSNHCH3、
からなる群から選択され、式中、破線は結合点を表し、
式中、R’は−CO2Hまたは−CONH2である)の化合物、
またはその薬学的に許容可能な塩を提供する。
(式中、Rは、−(CH2)3OH、−(CH2)3OCH3、−(CH2)3CO2H、−CONH(CH2)4OH、−COCH2NH2、−SO2N[(CH2)2OCH3]2、−CONH(CH2)4OCH3、および−CO(CH2)2CO2Hからなる群から選択され、
式中、R’は−CO2Hまたは−CONH2である)の化合物、
またはその薬学的に許容可能な塩を提供する。
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[(2,2,4−トリメチルピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸ギ酸塩、
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルカルバモイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルカルバモチオイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[4−[[2−[[3−[[4−(2−カルボキシエチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(メチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル])アミノ]ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、ギ酸塩、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[(4−メトキシカルボニル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−(2,6−ジフルオロ−4−(2−(3−(((1R,5S)−8−ペンタノイル−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル)ベンズアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボキサミド)フェネチル)安息香酸、
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルスルファモイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(テトラヒドロピラン−4−イルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−[2−[4−[[2−[[3−[(8−アセチル−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(2−メトキシエチルスルホニル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(2−メトキシエチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(4−メトキシブチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[4−[[2−[[3−[[8−[ビス(2−メトキシエチル)カルバモイル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(2−メチルプロパノイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[4−[[2−[[3−[[8−[2−(ジメチルアミノ)アセチル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−[1−(メトキシメチル)シクロプロパンカルボニル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−[2−(4−メチルピペラジン−1−イル)アセチル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、および
4−[2−[4−[[2−[[3−[(4−アセチル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸。
スキーム1
スキーム2
スキーム3
スキーム4
スキーム5
以下の調製物および実施例は、本発明をさらに例示し、本発明の化合物の典型的な合成を表す。試薬および出発材料は、当業者が容易に入手可能であるか、または当業者によって容易に合成され得る。調製物および実施例は限定ではなく例示により説明され、当業者により様々な変更が行われ得ることが理解されるべきである。
4−[2−(4−アミノ−2,6−ジフルオロ−フェニル)エチニル]安息香酸メチル
4−[2−(4−アミノ−2,6−ジフルオロ−フェニル)エチル]安息香酸メチル
4−[(4−メトキシ−4−オキソ−ブチル)カルバモイル]−2,2−ジメチル−ピペラジン−1−カルボン酸tert−ブチル
4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−カルボン酸tert−ブチル
N−(4−ヒドロキシブチル)−3,3−ジメチル−ピペラジン−1−カルボキサミド塩酸塩
4−[2−[4−[[2−(tert−ブトキシカルボニルアミノ)−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[4−[(2−アミノ−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル)アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル塩酸塩
4−[2−[4−[[2−[[3−(クロロメチル)ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[[3−[[3−[[3,5−ジフルオロ−4−[2−(4−メトキシカルボニルフェニル)エチル]フェニル]カルバモイル]−4,5,6,7−テトラヒドロベンゾチオフェン−2−イル]カルバモイル]フェニル]メチル]−3,3−ジメチル−ピペラジン−1−カルボン酸tert−ブチル
4−[2−[4−[[2−[[3−[(2,2−ジメチルピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチルジヒドロクロリド
4−[2−[4−[[2−[[3−[[4−[ビス(2−メトキシエチル)スルファモイル]−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−メトキシ−4−オキソ−ブチル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(3−メトキシプロピル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[2−[4−[[2−[[3−[[4−[2−(tert−ブトキシカルボニルアミノ)アセチル]−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−メトキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[2−[4−[[2−[[3−[(4−tert−ブトキシカルボニル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−[[3−[[3−[[4−[2−(4−カルバアモイルフェニル)エチル]−3,5−ジフルオロ−フェニル]カルバモイル]−4,5,6,7−テトラヒドロベンゾチオフェン−2−イル]カルバモイル]フェニル]メチル]−3,3−ジメチル−ピペラジン−1−カルボン酸tert−ブチル
N−[4−[2−(4−カルバモイルフェニル)エチル]−3,5−ジフルオロ−フェニル]−2−[[3−[(2,2−ジメチルピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボキサミドジヒドロクロリド
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[(2,2,4−トリメチルピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[(3−メトキシ−3−オキソ−プロピル)カルバモイル]−2,2−ジメチル−ピペラジン−1−カルボン酸tert−ブチル
3−[(3,3−ジメチルピペラジン−1−カルボニル)アミノ]プロパン酸メチル塩酸塩
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(3−メトキシ−3−オキソ−プロピル)カルバモイル−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
3−[[3−[[3−[[3,5−ジフルオロ−4−[2−(4−メトキシカルボニルフェニル)エチル]フェニル]カルバモイル]−4,5,6,7−テトラヒドロベンゾチオフェン−2−イル]カルバモイル]フェニル]メチル]−3,8−ジアザビシクロ[3.2.1]オクタン−8−カルボン酸tert−ブチル
4−[2−[4−[[2−[[3−(3,8−ジアザビシクロ[3.2.1]オクタン−3−イルメチル)ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル二塩酸塩
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(メチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[2−[4−[[2−[[3−[(2,2−ジメチルピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[4−[[2−[[3−[(4−アセチル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−(2,6−ジフルオロ−4−(2−(3−(((1R,5S)−8−ペンタノイル−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル)ベンズアミド)))−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボキサミド)フェネチル)安息香酸メチル
4−(4−(2−(3−(((1R,5S)−8−(ジメチルグリシル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル)ベンズアミド)))−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボキサミド)−2,6−ジフルオロフェネチル)安息香酸メチル
4−[[3−[[3−[[3,5−ジフルオロ−4−[2−(4−メトキシカルボニルフェニル)エチル]フェニル]カルバモイル]−4,5,6,7−テトラヒドロベンゾチオフェン−2−イル]カルバモイル]フェニル]メチル]−3,3−ジメチル−ピペラジン−1−カルボン酸メチル
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルスルファモイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−[1−(メトキシメチル)シクロプロパンカルボニル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−[2−(4−メチルピペラジン−1−イル)アセチル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−イソシアントテトラヒドロピランを用いて調製、収率52%、MS(m/z)824[M−1]
塩化アセチルを用いて製造、収率83%、MS(m/z)741[M+1]
塩化2−メトキシエタンスルホニルを用いて調製、収率64%、MS(m/z)820[M−1]
1−イソシアナト−2−メトキシ−エタンを用いて調製、収率95%、MS(m/z)800[M+1]
1−イソシアナト−4−メトキシ−ブタンを用いて調製、収率90%、MS(m/z)827[M−1]
N,N−ビス(2−メトキシエチル)カルバモイルクロリドを用いて調製、収率54%、MS(m/z)857[M−1]
塩化2−メチルプロパノイルを用いて調製、収率100%、MS(m/z)767[M−1]
4−[[3−[[3−[[3,5−ジフルオロ−4−[2−(4−メトキシカルボニルフェニル)エチル]フェニル]カルバモイル]−4,5,6,7−テトラヒドロベンゾチオフェン−2−イル]カルバモイル]フェニル]メチル]−3,3−ジメチル−ピペラジン−1−カルボン酸tert−ブチル
4−[2−[4−[[2−[[3−[(2,2−ジメチルピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル二塩酸塩
4−[2−[4−[[2−(tert−ブトキシカルボニルアミノ)ベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[4−[(2−アミノベンゾチオフェン−3−カルボニル)アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル塩酸塩
4−[2−[4−[[2−[[3−(クロロメチル)ベンゾイル]アミノ]ベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸メチル
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸
噴霧乾燥の条件は以下の通りである。
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(3−ヒドロキシプロピル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸
4−[2−[4−[[2−[[3−[[4−[ビス(2−メトキシエチル)スルファモイル]−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸メチル
4−[2−[4−[[2−[[3−[[4−(3−カルボキシプロピル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(3−メトキシプロピル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、ギ酸塩
4−[2−[4−[[2−[[3−[[4−(2−アミノアセチル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−メトキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸
4−[4−[[3−[[3−[[4−[2−(4−カルバアモイルフェニル)エチル]−3,5−ジフルオロ−フェニル]カルバモイル]−4,5,6,7−テトラヒドロベンゾチオフェン−2−イル]カルバモイル]フェニル]メチル]−3,3−ジメチル−ピペラジン−1−イル]−4−オキソ−酪酸
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[(2,2,4−トリメチルピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸ギ酸塩
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルカルバモイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルカルバモチオイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−[2−[4−[[2−[[3−[[4−(2−カルボキシエチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(メチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル])アミノ]ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、ギ酸塩
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[(4−メトキシカルボニル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルスルファモイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−(2,6−ジフルオロ−4−(2−(3−(((1R,5S)−8−ペンタノイル−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル)ベンズアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボキサミド)フェネチル)安息香酸
以下の実施例17〜27は、実施例16と実質的に同様の方法で調製される。
収率17%、MS m/z 812[M+1]
収率85%、MS m/z 727[M+1]
収率70%、MS m/z 807[M+1]
収率28%、MS m/z 786[M+1]
収率84%、MS m/z 815[M+1]
23%の収率、MS m/z 844[M+1]
62%収率、MS m/z 755[M+1]
収率73%、MS m/z 770[M+1]
収率98%、MS m/z 797[M+1]
収率59%、MS m/z 825[M+1]
4−[2−[4−[[2−[[3−[(4−アセチル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸
33P取り込みの阻害は、ヒトおよびマウスのNaPi−IIb T−REX(商標)−CHO安定細胞株において測定される。NaPi−IIbのcDNAをプラスミドSLC34A2 pcDNA5/TO(ヒト)およびSLC34A2 pcDNA5/TO(マウス)にサブクローニングし、安定細胞株をそれぞれヒトとマウスの両方についてのクローン単離から作製する。マウスおよびヒトの安定株を増殖培地(ダルベッコ改変イーグル培地:栄養混合物F−12(3:1)、10%熱不活性化FBS、1%ペニシリン/ストレプトマイシン/ FUNGIEZONE(登録商標)(HYCLONE(商標))、20mMのHEPES、250μg/mLのハイグロマイシン、5μg/mLのブラスチシジン)中で連続培養で維持する。0.25%トリプシンを用いてT225細胞培養フラスコ(CORNING(登録商標))から細胞を採取し、100μLの増殖培地+100ng/mLのテトラサイクリン中に40,000細胞/ウェルで96穴CYTOSTAR−T(商標)シンチレーションマイクロプレート(Amersham Systems)に播種する。細胞プレートを37℃および5%CO2で一晩インキュベートする。翌日、化合物を100%DMSO中の1:3希釈を用いて段階希釈する。アッセイする準備ができるまで、細胞プレートをインキュベーター内に残し得る。細胞プレートをインキュベーターから取り出し、培地を除去する。細胞を、200μlのアッセイ緩衝液(137mMのNaCl、5.4mMのKCl、2.8mMのCaCl2、1.2mMのMgSO4、および14mMのTris−HCl緩衝液、pH約7.5)で3回洗浄し、洗浄の間にバッファーを除去する。DMSO中で段階希釈した化合物をアッセイ緩衝液でさらに50倍希釈し、50μLをCYTOSTAR−T(商標)アッセイプレートに添加し、続いてすぐに50μLの33P溶液(PERKIN−ELMER(登録商標),Walton,MA;0.05μCi/50μL)を添加する。CYTOSTAR−T(商標)アッセイプレートを光から保護するためにホイルで覆い、そして室温で60分間インキュベートする。60分のインキュベーション後、100μLの停止溶液(アッセイ緩衝液+400μMのフロレチン)をアッセイプレートに添加して33Pの取り込みを停止させる。停止溶液をウェル当たり1分刻みで加えた後、プレートを直ちにWallac MICROBETA(登録商標)Trilux液体シンチレーションカウンターおよびルミノメーターで読み取る。各々のプレートは別々に処理し得、時間的にずらされてもよいので、停止液が添加された後の計数において遅延がないようにすることができる。試験したすべての濃度における阻害パーセント(最終アッセイ濃度100〜0.005μM)を、1%DMSO(最小効果)、および100μMの十分に有効なNaPi−IIb阻害剤の効果(最大効果)に対して計算する。4パラメータロジスティック曲線フィッティング式を用いてIC50値を計算した。提示された数字は標準偏差(SD)を計算した幾何平均であり、nは実験回数である。したがって、表1は、ヒトNaPi−IIbおよびマウスNaPi−IIbのそれぞれに対する実施例1〜28の相対IC50値を記載する。
表1.T−REX(商標)チャイニーズハムスター卵巣安定細胞株におけるヒトおよびマウスのNaPi−IIbインビトロデータに対する実施例1〜28の相対IC50(rel IC50)値。
試験試料およびビヒクル対照の調製のために、ビヒクル、水中20%ヒドロキシプロピル−β−シクロデキストリン(HPBCD)を試験試料に添加する。必要に応じて超音波水浴中で粒子サイズを小さくするために超音波処理する。必要に応じて、ポリトロンを使用して試験試料溶液中の可視性の粒子を全て分解する。以下の表2に示すように1NのNaOHを添加する。ビヒクル対照のpHを1NのNaOHで8.0〜8.5に調整する。
表2 示した試験化合物に添加する1NのNaOHの量。
表3:実施例化合物4、6、および8のインビボデータ
表4:PVP−VA製剤における実施例1のインビボデータ
Claims (24)
- 下記式
(式中、Yが縮合シクロヘキサン環または縮合フェニル環であり、
Aが、
式中、R2が、
−CH3、−(CH2)3OH、−(CH2)3OCH3、−(CH2)3CO2H、−COOCH3、−COCH3、−CO(CH2)3CH3、−COCH(CH3)2、−CO(CH2)2CO2H、−COCH2NH2、−COCH2N(CH3)2、−SO2N[(CH2)2OCH3]2、−SO2NHCH3、−SO2(CH2)2OCH3、−CONH(CH2)4OH、−CONH(CH2)4OCH3、−CONHCH3、−CONH(CH2)2CO2H、−CONH(CH2)2OCH3、−CON(CH2CH2OCH3)2、−CSNHCH3、
式中、R’が−CO2Hまたは−CONH2である)の化合物、またはその薬学的に許容可能な塩。 - R’が−CO2Hである、請求項4に記載の化合物または塩。
- 以下からなる群から選択される、請求項1に記載の化合物、またはその薬学的に許容可能な塩:
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[(2,2,4−トリメチルピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸ギ酸塩、
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルカルバモイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルカルバモチオイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[4−[[2−[[3−[[4−(2−カルボキシエチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(メチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル])アミノ]ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、ギ酸塩、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[(4−メトキシカルボニル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−(2,6−ジフルオロ−4−(2−(3−(((1R,5S)−8−ペンタノイル−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル)ベンズアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボキサミド)フェネチル)安息香酸、
4−[2−[4−[[2−[[3−[[2,2−ジメチル−4−(メチルスルファモイル)ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(テトラヒドロピラン−4−イルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−[2−[4−[[2−[[3−[(8−アセチル−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(2−メトキシエチルスルホニル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(2−メトキシエチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(4−メトキシブチルカルバモイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[4−[[2−[[3−[[8−[ビス(2−メトキシエチル)カルバモイル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]ベンゾエート、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−(2−メチルプロパノイル)−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]ベンゾエート、
4−[2−[4−[[2−[[3−[[8−[2−(ジメチルアミノ)アセチル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−[1−(メトキシメチル)シクロプロパンカルボニル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[8−[2−(4−メチルピペラジン−1−イル)アセチル]−3,8−ジアザビシクロ[3.2.1]オクタン−3−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、
4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]ベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、および
4−[2−[4−[[2−[[3−[(4−アセチル−2,2−ジメチル−ピペラジン−1−イル)メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]−2,6−ジフルオロ−フェニル]エチル]安息香酸。 - 4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、二ナトリウムである、請求項1に記載の塩。
- 請求項1〜15のいずれか1項に記載の化合物または塩、および薬学的に許容可能な担体、希釈剤または賦形剤を含む、薬学的組成物。
- 4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、二ナトリウムの固体分散体製剤であって、前記製剤が、30%の4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、二ナトリウム、および70%のポリビニルピロリドン−ビニルアセテートを含む、固体分散体製剤。
- 高リン血症を治療する方法であって、前記治療を必要とする患者に、有効量の請求項1〜15のいずれか1項に記載の化合物または塩を投与することを含む、方法。
- 慢性腎疾患を治療する方法であって、前記治療を必要とする患者に、有効量の請求項1〜15のいずれか1項に記載の化合物または塩を投与することを含む、方法。
- 慢性腎疾患に関連する心血管疾患を治療する方法であって、前記治療を必要とする患者に、有効量の請求項1〜15のいずれか1項に記載の化合物または塩を投与することを含む、方法。
- 治療において使用するための、請求項1〜15のいずれか1項に記載の化合物または塩。
- 高リン血症の治療において使用するための、請求項1〜15のいずれか1項に記載の化合物または塩。
- 慢性腎疾患および慢性腎疾患に関連する心血管疾患の治療において使用するための、請求項1〜15のいずれか1項に記載の化合物または塩。
- 慢性腎疾患に関連する心血管疾患を治療する方法であって、前記治療を必要とする患者に、有効量の4−[2−[2,6−ジフルオロ−4−[[2−[[3−[[4−(4−ヒドロキシブチルカルバモイル)−2,2−ジメチル−ピペラジン−1−イル]メチル]ベンゾイル]アミノ]−4,5,6,7−テトラヒドロベンゾチオフェン−3−カルボニル]アミノ]フェニル]エチル]安息香酸、二ナトリウムである塩を投与することを含む、方法。
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