WO2018155398A1 - アミド誘導体 - Google Patents
アミド誘導体 Download PDFInfo
- Publication number
- WO2018155398A1 WO2018155398A1 PCT/JP2018/005852 JP2018005852W WO2018155398A1 WO 2018155398 A1 WO2018155398 A1 WO 2018155398A1 JP 2018005852 W JP2018005852 W JP 2018005852W WO 2018155398 A1 WO2018155398 A1 WO 2018155398A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- amino
- compound
- isovaline
- acceptable salt
- Prior art date
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- 150000001408 amides Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 260
- 150000003839 salts Chemical class 0.000 claims abstract description 79
- BXFFHSIDQOFMLE-UHFFFAOYSA-N indoxyl sulfate Chemical compound C1=CC=C2C(OS(=O)(=O)O)=CNC2=C1 BXFFHSIDQOFMLE-UHFFFAOYSA-N 0.000 claims abstract description 65
- 125000005843 halogen group Chemical group 0.000 claims abstract description 53
- 210000004369 blood Anatomy 0.000 claims abstract description 52
- 239000008280 blood Substances 0.000 claims abstract description 52
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 35
- 230000003907 kidney function Effects 0.000 claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 claims abstract description 31
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 27
- 230000006866 deterioration Effects 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 23
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000013078 crystal Substances 0.000 claims description 114
- 238000000034 method Methods 0.000 claims description 97
- -1 4-amino-5-chloro-2-methoxybenzoyl Chemical group 0.000 claims description 71
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims description 43
- 208000020832 chronic kidney disease Diseases 0.000 claims description 42
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 32
- 229910052802 copper Inorganic materials 0.000 claims description 32
- 239000010949 copper Substances 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
- 201000010099 disease Diseases 0.000 claims description 31
- 230000007704 transition Effects 0.000 claims description 30
- 238000012959 renal replacement therapy Methods 0.000 claims description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 17
- 238000002560 therapeutic procedure Methods 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
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- BQSJUEKXQBCYCW-OAHLLOKOSA-N (2R)-2-[(4-amino-5-fluoro-2-propoxybenzoyl)amino]-2-methylbutanoic acid Chemical compound [C@](CC)(C(=O)O)(NC(=O)C1=CC(F)=C(N)C=C1OCCC)C BQSJUEKXQBCYCW-OAHLLOKOSA-N 0.000 claims description 7
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- XOPDLXWXRBDZMQ-CYBMUJFWSA-N (2R)-2-[(4-amino-5-bromo-2-methoxybenzoyl)amino]-2-methylbutanoic acid Chemical compound [C@](CC)(C(=O)O)(NC(=O)C1=CC(Br)=C(N)C=C1OC)C XOPDLXWXRBDZMQ-CYBMUJFWSA-N 0.000 claims description 6
- AEIIESKASVGRJR-CQSZACIVSA-N (2R)-2-[(4-amino-5-chloro-2-ethoxybenzoyl)amino]-2-methylbutanoic acid Chemical compound NC1=CC(=C(C(=O)N[C@](C)(CC)C(=O)O)C=C1Cl)OCC AEIIESKASVGRJR-CQSZACIVSA-N 0.000 claims description 6
- GHKSGLLFAYQAOI-CYBMUJFWSA-N (2R)-2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-2-methylbutanoic acid Chemical compound NC1=CC(=C(C(=O)N[C@](C)(CC)C(=O)O)C=C1Cl)OC GHKSGLLFAYQAOI-CYBMUJFWSA-N 0.000 claims description 6
- RRCFNMDBUOLZRR-OAHLLOKOSA-N (2R)-2-[(4-amino-5-chloro-2-propoxybenzoyl)amino]-2-methylbutanoic acid Chemical compound [C@](CC)(C(=O)O)(NC(=O)C1=CC(Cl)=C(N)C=C1OCCC)C RRCFNMDBUOLZRR-OAHLLOKOSA-N 0.000 claims description 6
- QDQHNEMWJWMWFV-CYBMUJFWSA-N (2R)-2-[(4-amino-5-iodo-2-methoxybenzoyl)amino]-2-methylbutanoic acid Chemical compound NC1=CC(=C(C(=O)N[C@](C)(CC)C(=O)O)C=C1I)OC QDQHNEMWJWMWFV-CYBMUJFWSA-N 0.000 claims description 6
- XZAGVIJVPCTOFM-UHFFFAOYSA-N 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-2-ethylbutanoic acid Chemical compound NC1=CC(=C(C(=O)NC(C(=O)O)(CC)CC)C=C1Cl)OC XZAGVIJVPCTOFM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
- FHXBRFOUPUEDQO-CQSZACIVSA-N (2R)-2-[(4-amino-2-ethoxy-5-fluorobenzoyl)amino]-2-methylbutanoic acid Chemical compound NC1=CC(=C(C(=O)N[C@](C)(CC)C(=O)O)C=C1F)OCC FHXBRFOUPUEDQO-CQSZACIVSA-N 0.000 claims description 5
- RHASTJZNQWUHHY-CQSZACIVSA-N (2R)-2-[(4-amino-2-ethoxy-5-iodobenzoyl)amino]-2-methylbutanoic acid Chemical compound NC1=CC(=C(C(=O)N[C@](C)(CC)C(=O)O)C=C1I)OCC RHASTJZNQWUHHY-CQSZACIVSA-N 0.000 claims description 4
- UYILPONLAQMZQA-CQSZACIVSA-N (2R)-2-[(4-amino-5-bromo-2-ethoxybenzoyl)amino]-2-methylbutanoic acid Chemical compound NC1=CC(=C(C(=O)N[C@](C)(CC)C(=O)O)C=C1Br)OCC UYILPONLAQMZQA-CQSZACIVSA-N 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
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- 229940123075 Tryptophanase inhibitor Drugs 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- GCHPUFAZSONQIV-UHFFFAOYSA-N isovaline Chemical compound CCC(C)(N)C(O)=O GCHPUFAZSONQIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 30
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- 101710136122 Tryptophan 2,3-dioxygenase Proteins 0.000 abstract description 27
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- 238000004321 preservation Methods 0.000 abstract 1
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- 238000006243 chemical reaction Methods 0.000 description 66
- 239000007787 solid Substances 0.000 description 62
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- BXFFHSIDQOFMLE-UHFFFAOYSA-M indoxyl sulfate(1-) Chemical compound C1=CC=C2C(OS(=O)(=O)[O-])=CNC2=C1 BXFFHSIDQOFMLE-UHFFFAOYSA-M 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 32
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 16
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
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- ATEHRMOSMKEMMA-NUBCRITNSA-N (2R)-2-azaniumyl-2-methylbutanoate hydrate Chemical compound O.N[C@@](CC)(C)C(=O)O ATEHRMOSMKEMMA-NUBCRITNSA-N 0.000 description 8
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Classifications
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention relates to an amide derivative having an excellent tryptophanase inhibitory action or a pharmacologically acceptable salt thereof.
- Chronic kidney disease is a major social problem.
- Current pharmacotherapy for patients with chronic kidney disease is angiotensin II receptor antagonist (ARB), angiotensin converting enzyme (ACE) inhibitor and other renin-angiotensin inhibitors, first-line drugs, calcium antagonists and diuresis
- the drug is a second or third-line drug, and based on the disease or the primary disease that is combined, hyperuricemia, hyperlipidemia, diabetes, steroid / immunosuppressant , Antiplatelet / anticoagulant, hyperphosphatemia, erythropoiesis stimulating agent, analgesic, antiarrhythmic, antidepressant, Alzheimer's dementia, Parkinson's disease, proton pump inhibitor (PPI) ),
- Many oral drugs such as antiallergic drugs and antibacterial drugs are prescribed. However, development of better therapeutic agents for these diseases is desired.
- Indole which is produced using tryptophanase as a substrate by the enterobacterial tryptophanase, is a precursor of the uremic indoxyl sulfate (IS) that accelerates the progression of chronic kidney disease (Chronic kidney disease).
- IS chronic kidney disease
- Indoxyl sulfate produced from indole through hydroxylation and sulfation not only worsens kidney function and promotes transition to end-stage renal failure (transition to renal replacement therapy and kidney transplantation), but also causes deterioration and dysfunction of blood vessels. It causes cardiovascular disease and further increases in mortality, and is a uremic toxin that is deeply related to disorders of various organs such as nerves, bones, blood cells, skeletal muscles, and uremia symptoms.
- spherical adsorbent charcoal As a pharmaceutical capable of reducing blood indoxyl sulfate, spherical adsorbent charcoal is adsorbed that adsorbs indole produced by tryptophanase in the digestive tract lumen and excretes it together with feces.
- the effect of spherical adsorbed charcoal on reducing blood indoxyl sulfate is particularly weak in humans, and it is impossible and insufficient to reduce the concentration of indoxyl sulfate in blood to that of healthy individuals (Non-patent Document 1). ).
- kidney transplantation or dialysis based on renal dysfunction is increasing at the world level.
- the number of dialysis patients in Japan currently exceeds 310,000 and is still increasing.
- Dialysis generally requires three visits per week, and dialysis itself takes time.
- Dialysis is also a burden in the medical economy.
- Renal transplantation can be considered instead of dialysis, but the number of donors is limited, so preserving renal function for as long as possible is an important issue to be solved in relation to patient life support. In other words, it is very important to delay the transition to renal replacement therapy in patients with conservative therapy for chronic renal failure, and to gain time until a donor for kidney transplantation appears.
- it is important in terms of water regulation to suppress the deterioration of residual renal function and secure urine volume even after transition to renal replacement therapy.
- Indoxyl sulfate promotes the generation of ROS (Reactive oxygen species) in renal tubular epithelial cells and promotes cellular aging (Non-patent Document 2). Furthermore, it is known that renal glomerular epithelial cells also cause damage via AhR (Aryl hydrocarbon receptor) (Non-patent Document 3), and thus the production of indoxyl sulfate is reduced, and these cells are transferred to the kidney cells. It is expected that the kidney function will be preserved by suppressing the deterioration of kidney function by reducing the effects of the above.
- Non-Patent Document 4 describes ⁇ - (4-aminobenzamido) isobutyric acid and its iodinated product, but neither the tryptophanase inhibitory action of the present invention is described or suggested.
- the present inventors have an excellent tryptophanase inhibitory action, and by highly reducing the indoxyl sulfate concentration in blood and kidney by inhibiting the production of indole, a precursor of indoxyl sulfate.
- Various synthetic studies were conducted aiming at new medicines by suppressing the deterioration of kidney function and preserving the kidney.
- an amide derivative having a specific structure or a pharmacologically acceptable salt thereof has an excellent tryptophanase inhibitory action, and completed the present invention.
- the present invention provides an amide derivative having an excellent tryptophanase inhibitory action or a pharmacologically acceptable salt thereof and a pharmaceutical composition containing these.
- R 1 and R 2 are the same or different and each represents a C 1 -C 6 alkyl group, a halogeno C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, and n is 0,
- X is the same or different, and C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, halogen atom, cyano group, halogeno C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, halogeno C 1 -C 6 alkoxy group or C 3 -C 6 cycloalkoxy group,
- Y is a hydrogen atom, C 1 -C 6 alkoxy group, C 3 -C 6 cycloalkoxy group or halogeno C 1 A —C 6 alkoxy group; Or a pharmacologically acceptable salt thereof as an active ingredient, (2)
- IIa General formula (Ia)
- R 1 and R 2 are the same or different and each represents a C 1 -C 6 alkyl group, a halogeno C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, and n is 1 and X are the same or different and each represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a halogen atom, a cyano group, a halogeno C 1 -C 6 alkyl group, or a C 1 -C 6 alkoxy group.
- a halogeno C 1 -C 6 alkoxy group or a C 3 -C 6 cycloalkoxy group wherein Y is a C 1 -C 6 alkoxy group, a C 3 -C 6 cycloalkoxy group or a halogeno C 1 -C 6 alkoxy group
- R 1 is an ethyl group
- R 2 is a C 1 -C 6 alkyl group, a halogeno C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, and n is 0, 1 or 2
- X is the same or different and is a C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, halogen atom, cyano group, halogeno C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group or halogeno C 1 -C 6 alkoxy group
- Y is a hydrogen atom, provided that
- R 1 and R 2 are the same or different and each represents a C 1 -C 4 alkyl group or a C 3 -C 4 cycloalkyl group, n is 1, and X is the same or different, A C 1 -C 4 alkyl group, a C 3 -C 4 cycloalkyl group, a halogen atom, a cyano group or a halogeno C 1 -C 4 alkyl group, and Y is a C 1 -C 4 alkoxy group or halogeno C 1 -C 4. An alkoxy group; Or a pharmacologically acceptable salt thereof according to (2), (4) General formula (I-1a)
- R 1 and R 2 are the same or different and each represents a C 1 -C 3 alkyl group or a cyclopropyl group
- X represents a C 1 -C 3 alkyl group, a fluorine atom, a chlorine atom, a bromine atom
- Y is a C 1 -C 3 alkoxy group or a fluoro C 1 -C 3 alkoxy group.
- R 1 is an ethyl group
- R 2 is a C 1 -C 4 alkyl group or a C 3 -C 4 cycloalkyl group
- n is 0, 1 or 2
- X is The same or different, a C 1 -C 4 alkyl group, a C 3 -C 4 cycloalkyl group, a halogen atom, a cyano group or a halogeno C 1 -C 4 alkyl group
- Y is a hydrogen atom, provided that R 2 When is an ethyl group, X is not a halogen atom or a C 1 -C 4 alkoxy group, and when n is 2, any X is not a C 1 -C 4 alkoxy group.
- R 2 is a C 1 -C 3 alkyl group or a cyclopropyl group
- X is a C 1 -C 3 alkyl group, a fluorine atom, a chlorine atom or a bromine atom, provided that R 2 is When it is an ethyl group, X is not a fluorine atom, a chlorine atom or a bromine atom.
- Preventive or therapeutic agent for diseases caused by an increase in xylsulfate (26) A compound of any one of (2) to (14) or a pharmacologically acceptable salt thereof, or a crystal of the compound of (16) as an active ingredient Renal replacement therapy delay agent in patients with conservative therapy, (27) Transition to renal replacement therapy comprising the compound according to any one of (2) to (14) or a pharmacologically acceptable salt thereof, or the crystal of the compound according to (16) as an active ingredient An inhibitor of deterioration of residual renal function in later patients, (28) Use of the compound according to any one of (2) to (14) or a pharmacologically acceptable salt thereof or the crystal of the compound according to (16) for the manufacture of a pharmaceutical composition , (29) The use according to (28) for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease caused by an increase in indoxyl sulfate in the blood, (30) Use according to (28) for the manufacture of a pharmaceutical composition for delaying the transition to renal replacement therapy in patients with conservative therapy for chronic kidney disease
- a method for reducing indoxyl sulfate in blood comprising: (33) The method according to (32), wherein the mammal is a human, (34) An effective amount of the compound according to any one of (2) to (14) or a pharmacologically acceptable salt thereof, or the crystal of the compound according to (16) is administered to a mammal.
- a method for preventing or treating a disease comprising: (35) The method according to (34), wherein the mammal is a human, (36) The method according to (34) or (35), wherein the disease is a disease caused by an increase in indoxyl sulfate in the blood, (37) The compound according to any one of (2) to (14) or a pharmacologically acceptable salt thereof, or the use according to (16) for use in a method for prevention or treatment of a disease. Crystals of the compound of (38) The compound or pharmacologically acceptable salt thereof according to (37), wherein the disease is a disease caused by an increase in indoxyl sulfate in the blood.
- the “C 1 -C 6 alkyl group” is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, It may be an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, or a hexyl group, and is preferably a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms ( C 1 -C 4 alkyl group), more preferably a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms (C 1 -C 3 alkyl group), and even more preferably , A methyl group, an ethyl group or a propyl group, particularly preferably a methyl group or an ethyl group.
- the “halogen atom” is a fluorine atom, chlorine atom, bromine atom or iodine atom, preferably a fluorine atom, chlorine atom or bromine atom, more preferably a fluorine atom or It is a chlorine atom.
- the “halogeno C 1 -C 6 alkyl group” is the above “C 1 -C 6 alkyl group” substituted by the same or different 1 to 3 “halogen atoms”,
- it may be a monofluoromethyl group, monochloromethyl group, difluoromethyl group, dichloromethyl group, chlorofluoromethyl group, trifluoromethyl group or 2,2,2-trifluoroethyl group, preferably 1 to 3 A methyl group or an ethyl group substituted by one fluorine atom, more preferably a difluoromethyl group, a trifluoromethyl group or a 2,2,2-trifluoroethyl group, and particularly preferably a trifluoro It is a methyl group.
- the “C 3 -C 6 cycloalkyl group” is a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. Is a cyclic saturated hydrocarbon group having 3 to 4 carbon atoms, and more preferably a cyclopropyl group.
- the “C 1 -C 6 alkoxy group” is an oxygen atom to which the “C 1 -C 6 alkyl group” is bonded. Or a butoxy group, preferably an oxygen atom (C 1 -C 4 alkoxy group) to which the “C 1 -C 4 alkyl group” is bonded, and more preferably the “C 1 -C 3 alkoxy group”.
- the “halogeno C 1 -C 6 alkoxy group” is an oxygen atom to which the “halogeno C 1 -C 6 alkyl group” is bonded, and examples thereof include a monofluoromethoxy group, a difluoromethoxy group, and tri It may be a fluoromethoxy group, and is preferably a difluoromethoxy group or a trifluoromethoxy group.
- the “C 3 -C 6 cycloalkoxy group” is an oxygen atom to which the “C 3 -C 6 cycloalkyl group” is bonded, and examples thereof include a cyclopropyloxy group, a cyclobutyloxy group, It can be a cyclopentyloxy group or a cyclohexyloxy group, and is preferably a cyclopropyloxy group.
- suitable compounds include 2-[(4-amino-5-chloro-2-methoxybenzoyl) amino] -2-ethylbutanoic acid, (-)-N- (4-amino-5-fluoro-2-propoxybenzoyl) -D-isovaline, (+)-N- (4-amino-5-chloro-2-methoxybenzoyl) -L-isovaline, (-)-N- (4-amino-5-chloro-2-methoxybenzoyl) -D-isovaline, (+)-N- (4-amino-5-chloro-2-ethoxybenzoyl) -L-isovaline, (-)-N- (4-amino-5-chloro-2-ethoxybenzoyl) -D-isovaline, (-)-N- (4-amino-5-chloro-2-ethoxybenzoyl) -D-isovaline, (-)-N- (4-amino-5
- the “pharmacologically acceptable salt” refers to a salt that can be used as a medicine.
- a compound having an acidic group or basic group it can be converted into a “salt with a base” or an “acid addition salt” by reacting with a base or an acid, so that the salt is shown.
- an alkali metal salt such as sodium salt, potassium salt or lithium salt
- an alkaline earth metal salt such as magnesium salt or calcium salt
- -Organic base salts such as methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt, lysine salt
- An amino acid salt such as arginine salt, ornithine salt, glutamate salt and aspartate salt, and preferably an alkali metal salt or alkaline earth metal salt.
- the pharmacologically acceptable “acid addition salt” of the compound is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, Inorganic acid salts such as perchlorates, sulfates, phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfone Aryl sulfonates such as acid salts, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate and other organic acid salts; and Amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate, and most preferably hydrohalide (especially hydroch
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof may become a solvate when left in a solvent, and such a solvate is also encompassed in the present invention.
- the present compound (I) or a pharmacologically acceptable salt thereof includes those crystals.
- the crystal of the present invention refers to a solid whose internal structure is composed of three-dimensional regular repetitions of constituent primitives (or groups thereof), and is distinguished from an amorphous individual having no such regular internal structure. .
- crystals of the same compound may produce crystals (crystal polymorphs) having a plurality of different internal structures and physicochemical properties depending on the crystallization conditions. Any form may be sufficient and the mixture of two or more crystal polymorphs may be sufficient.
- the crystal of the present invention absorbs moisture by being left in the atmosphere, and forms hydrates by adhering water or heating to 25 to 150 ° C. under normal atmospheric conditions. There is a case. Furthermore, the crystal
- the crystal of the present invention may be represented based on powder X-ray diffraction data.
- the powder X-ray diffraction is usually measured and diffracted by an award used in this field, and can be performed, for example, by the method described in Examples.
- the lattice constant of hydrates and dehydrates changes depending on the attachment and detachment of crystal water, which may change the diffraction angle (2 ⁇ ) in powder X-ray diffraction.
- the intensity of the peak may change due to a difference (crystal habit) or the like of the crystal growth surface.
- the crystal of the present invention is expressed based on the powder X-ray diffraction data, in addition to the crystal having the same diffraction angle and X-ray diffraction diagram of the peak in the powder X-ray diffraction, the hydrate and dehydrate obtained therefrom are also included within the scope of the present invention.
- the interplanar spacing d is 7.51, 7.33, 2-[(4-amino-) showing peaks characteristic of 6.67, 6.15, 5.32, 5.24, 4.98, 4.79, 3.96, and 3.59 angstroms. Mention may be made of crystals of 5-chloro-2-methoxybenzoyl) amino] -2-ethylbutanoic acid.
- the vertical axis indicates the diffraction intensity in units of count / second (CPS), and the horizontal axis indicates the diffraction angle 2 ⁇ (degrees). .
- the interplanar spacing d is 10.02, 7.39, 5.47. , 5.00, 4.79, 4.70, 4.54, 4.39, 4.28, and ( ⁇ )-N- (4-amino- Mention may be made of crystals of 5-fluoro-2-propoxybenzoyl) -D-isovaline.
- the surface spacing d is 10.67, 10.06, 5.33. , 5.09, 5.02, 4.26, 4.14, 3.67, 3.47, and 2.96 angstroms, showing peaks characteristic of ( ⁇ )-N- (4-amino- Mention may be made of crystals of 5-chloro-2-ethoxybenzoyl) -D-isovaline.
- the interplanar spacing d is 8.89, 8.39, 6.07.
- (-)-N- (4-amino-) showing characteristic peaks at 5.63, 5.15, 5.01, 4.22, 3.59, 3.39, and 2.76 angstroms.
- Mention may be made of crystals of 5-chloro-2-propoxybenzoyl) -D-isovaline. The crystal shows the powder X-ray diffraction pattern of FIG. 5 when irradiated with copper K ⁇ rays (wavelength ⁇ 1.54 ⁇ ).
- the interplanar spacing d is 10.23, 6.38, 5.09. , 5.04, 4.17, 4.11, 3.49, and (-)-N- (4-amino-5-bromo-2-ethoxybenzoyl) showing peaks characteristic of 3.38 angstroms ) -D-isovaline crystals.
- the interplanar spacing d is 10.13, 6.35, 5.87. , 5.08, 4.76, 4.16, 4.09, 3.60, 3.48, and 3.37 angstroms, showing peaks characteristic of (+)-N- (4-amino- Mention may be made of crystals of 2-ethoxy-5-fluorobenzoyl) -L-isovaline.
- the interplanar spacing d is 10.23, 6.38, 5.09. , 5.04, 4.17, 4.11, 3.49, and (-)-N- (4-amino-2-ethoxy-5-fluorobenzoyl) showing peaks characteristic of 3.38 angstroms ) -D-isovaline crystals.
- the compound which converted the carboxyl group into the pharmacologically acceptable prodrug is also included by this invention.
- the “pharmacologically acceptable prodrug” is a compound that is converted into the compound (I) of the present invention by a reaction with an enzyme, stomach acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed, etc. Is a compound that is changed to the compound (I) of the present invention, or a compound that is changed to the compound (I) of the present invention by causing hydrolysis or the like with gastric acid or the like.
- Such prodrugs include compounds in which the carboxyl group of the compound (I) of the present invention is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl ester) , Pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl ester , Sulfate esterification, glucuronidation, glycosidation, galactosidation, methylamidated compounds, etc.).
- the pharmacologically acceptable prodrug of the compound (I) of the present invention can be easily produced from the compound (I) of the present invention by a known method.
- the prodrug of the compound of the present invention is changed into the compound (I) of the present invention under physiological conditions as described in Hirokawa Shoten 1990 "Drug Development", Volume 7, Molecular Design, pages 163 to 198. Something to do is also included.
- the compound (I) of the present invention may give rise to geometric isomers and tautomers depending on the selected substituent, and isolated compounds of these isomers and mixtures in any ratio are also included in the present invention. Is done.
- the present compound (I) may have an optical isomer based on an asymmetric center in the molecule. Unless otherwise specified, in the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.
- the mixture of these isomers can be separated by a known resolution means.
- the compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound.
- atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
- the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
- Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent tryptophanase inhibitory action, and is a reducing agent for blood indoxyl sulfate, a disease caused by an increase in blood indoxyl sulfate. It is useful as a prophylactic or therapeutic agent, an agent for delaying transition to renal replacement therapy in patients with chronic kidney disease during conservative therapy, and an agent for suppressing deterioration of residual renal function in patients after transition to renal replacement therapy.
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 6.
- the vertical axis indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 10.
- the vertical axis indicates the diffraction intensity in units of count / second (cps)
- the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 11.
- the vertical axis indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- 18 is a powder X-ray diffraction pattern of the crystals obtained in Example 15.
- FIG. In the figure, the vertical axis indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- FIG. 14 is a powder X-ray diffraction pattern of the crystals obtained in Example 16.
- the vertical axis indicates the diffraction intensity in units of count / second (cps)
- the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal obtained in Example 21 In the figure, the vertical axis indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal obtained in Example 23 In the figure, the vertical axis indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- FIG. 26 is a powder X-ray diffraction pattern of the crystals obtained in Example 25.
- the vertical axis indicates the diffraction intensity in units of count / second (cps)
- the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- FIG. 14 is a powder X-ray diffraction pattern of the crystals obtained in Example 27.
- the vertical axis indicates the diffraction intensity in units of count / second (cps)
- the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- the compounds of the invention and pharmacologically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic structure or the type of substituent.
- a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
- the prodrug of the compound of this invention can be manufactured by introduce
- the reaction can be carried out by applying ordinary methods such as esterification, amidation, dehydration and the like.
- Method A is a method for producing the compound (I) of the present invention.
- X, n, Y, R 1 and R 2 are as defined above.
- Step A Step of forming an amide by condensation This step is a step of producing compound (I) by reacting compound (II) and compound (III) with a condensing agent in the presence or absence of a base. is there.
- the reaction temperature in this step is usually room temperature-80 ° C., and the reaction time in this step is usually 1 hour-24 hours.
- the base used in this step is preferably a tertiary amine such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine.
- Examples of the condensing agent used in this step include O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, O- (7-azabenzotriazole -1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium Hexafluorophosphate is mentioned.
- N, N-dimethylformamide and N, N-dimethylacetamide are suitable.
- Compound (II) can be obtained as a commercial product, or can be produced by a known method, a method based thereon, or a method described later.
- Compound (III) can be obtained as a commercial product, or can be produced by a known method (for example, Tetrahedron: ronAsymmetry, 2007, 18, 569-623) or a method analogous thereto.
- Method B is a method for producing compound (II) used in Method A.
- R 3 represents a C 1 -C 6 alkyl group such as a methyl group, an ethyl group or a propyl group.
- Step B-1 Step of reducing nitro group to amino group
- a solution of compound (IV-a) is subjected to a reduction reaction in a hydrogen atmosphere in the presence of a metal catalyst such as 10% palladium carbon.
- compound (V) is obtained.
- the solvent used in this step is preferably an alcohol such as methanol or ethanol.
- the reaction temperature in this step is usually room temperature, and the reaction time in this step is usually 1 to 12 hours.
- Step B-2 Step of hydrolysis of ester This step is a step of obtaining compound (II) by hydrolyzing the ester group of compound (V) in a solvent in the presence of a base.
- the base used in this step is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide
- the solvent used in this step is preferably a mixed solvent of water and tetrahydrofuran / methanol, for example. is there.
- the reaction temperature in this step is usually room temperature-80 ° C., and the reaction time in this step is usually 1 hour-24 hours.
- Compound (IV) can be obtained as a commercial product, or can be obtained by a known method, a method analogous thereto, or by protecting the carboxylic acid moiety of compound (IV-b) (for example, Uts (P. G M. Wuts) and Greene (T. W. Greene), Greene's Protective Groups Organic Synthesis (4th edition, 2006)).
- Method C is a method for producing compound (II) used in Method A, and is another method of Method B.
- X, n, Y and R 3 are as defined above.
- Step C-1 Step of introducing an amino group
- benzophenone imine is added to the solution of compound (VI) in the presence of a catalyst, a ligand and a base, followed by treatment with an acid.
- This is a step for producing compound (V).
- the catalyst used in this step is, for example, palladium (II) acetate or tris (dibenzylideneacetone) dipalladium (0), and the ligand is, for example, 4,5-bis (diphenylphosphino)- Examples of 9,9-dimethylxanthene or 2,2′-bis (diphenylphosphino) -1,1′-binaphthalene and examples of the base include cesium carbonate and sodium tert-butoxide.
- ethers such as 1,4-dioxane or toluene are suitable.
- the reaction temperature in this step is usually 80-100 ° C., and the reaction time in this step is usually 1 hour-24 hours.
- Step C-2 Step for Hydrolyzing Ester This step is a step for producing compound (II) under the same conditions as in Method B-2, Step B-2.
- Compound (VI) can be obtained as a commercially available product, or can be produced by a known method or a method analogous thereto.
- Method D is a method for producing a compound represented by the formula (II-a) among the compounds (II) used in Method A, and is another method of Method B and Method C.
- Method B and Method C the substituent corresponding to X 1 has already been introduced in the first step, but when the substituent corresponding to X 1 is a substituent corresponding to a halogen atom or a haloalkyl group, D As in the method, it can also be produced through the D-1 step and the D-2 step.
- Y and R 3 are as defined above, and X 1 represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a haloalkyl group such as a trifluoromethyl group.
- Step D-1 Step of introducing a substituent into the adjacent position of the amino group
- This step is a step of introducing a halogen atom such as a chlorine atom, a bromine atom or an iodine atom into the adjacent position of the amino group of the compound (VII), or trifluoro
- a haloalkyl group such as a methyl group is introduced.
- N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, or 2-chloro-1,3-bis (methoxycarbonyl) guanidine (Palau ') is added to the solution of compound (VII).
- Chlor registered trademark
- chlorotris (trimethylsilyl) silane, (3,3-dimethyl-1- (trifluoromethyl) -1,2-benziodoxol, etc. is added. To react.
- halogens such as dichloromethane, chloroform or carbon tetrachloride, acetonitrile or ethyl acetate is preferable.
- the reaction temperature in this step is usually room temperature-80 ° C.
- Step D-2 Step of hydrolysis of ester This step is a step of producing compound (II-a) under the same conditions as in Method B, Step B-2.
- Compound (VII) can be obtained as a commercially available product, or can be produced by a known method, a method analogous thereto, or a method described later.
- Method E is a method for producing compound (VII-a) in which Y is a C 1 -C 6 alkoxy group in compound (VII) used in Method D.
- Y a is a C 1 -C 6 alkoxy group
- R 3 is as defined above.
- Step E-1 Step of alkylating phenolic hydroxyl group, etc.
- compound (IX) is produced by adding C 1 -C 6 alkyl halide to the solution of compound (VIII) in the presence of a base. It is a process to do.
- an inorganic base such as potassium carbonate or cesium carbonate is suitable.
- Examples of the solvent used in this step include various solvents such as N, N-dimethylformamide, acetone or acetonitrile.
- the reaction temperature in this step is usually room temperature-80 ° C., and the reaction time in this step is usually 1 hour-24 hours.
- Step E-2 Step of reducing nitro group to amino group This step is a step for producing compound (VII-a) under the same conditions as in Method B, Step B-1.
- Compound (VIII) can be obtained as a commercially available product, or can be produced by a known method or a method analogous thereto.
- Method F is a method for producing a compound represented by the formula (II-b) among the compounds (II) used in Method A, and is another method of Method B, Method C and Method D.
- the substituent corresponding to X 2 is a nitrile group, it can also be produced through the F-1 step as in Method F.
- Y is as defined above, and X 2 represents a nitrile group.
- Step F-1 Step of coupling using transition metal catalyst
- potassium hexacyanoferrate (II) is added to a solution of compound (Vb) in the presence of a catalyst, a ligand and a base.
- compound (II-b) is produced by adding hydrate or the like.
- Examples of the catalyst used in this step include [2- (di-tert-butylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl] [2- (2- Aminoethyl) phenyl] palladium (II) chloride is a ligand used in this step.
- 2-di-tert-butylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl is As a base used for this process, potassium acetate is mentioned, for example.
- solvent used in this step examples include ethers and various solvents such as N, N-dimethylformamide, toluene or acetonitrile.
- the reaction temperature in this step is usually from room temperature to 110 ° C., and the reaction time in this step is usually from 1 hour to 24 hours.
- Compound (Vb) can be obtained as a commercial product, or can be produced by a known method, a method analogous thereto, or Method D.
- Method G is a method for producing the compound (I) of the present invention, and is another method of Method A.
- X, n, Y, R 1 and R 2 are as defined above, and R 4 represents a C 1 -C 6 alkyl group such as a methyl group, an ethyl group or a propyl group.
- Step G-1 Step of Forming Amide by Condensation
- compound (II) is reacted with compound (X) having a carboxylic acid moiety protected with a C 1 -C 6 alkyl group to give compound (IX ) And can be carried out under the same conditions as in Method A, Step A-1.
- Step G-2 Step of Hydrolyzing Ester This step is a step for producing compound (I) under the same conditions as in Method B, Step B-2.
- compound (X) can be obtained as a commercial product, or a known method, a method according thereto, or the carboxylic acid moiety of compound (III) is protected (for example, Uts (P. G. M. Wuts) And Green (T. W. Greene), Greene's Protective Groups in Organic Synthesis (4th edition, 2006)).
- X, n, Y, R 1 , R 2 , R 3 and R 4 are as defined above.
- Method H is a method for producing the compound (I) of the present invention, and is another method of Method A and Method G.
- Step H-1 Step of protecting amino group with tert-butoxy group This step is usually performed by di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine and triethylamine in a dichloromethane solution of compound (V). Is a step for producing compound (XI).
- the reaction temperature in this step is usually room temperature, and the reaction time in this step is usually 1 to 24 hours.
- Step H-2 Step of Hydrolyzing This step is a step for producing compound (XII) under the same conditions as in Method B-2, Step B-2.
- Step H-3 Step of forming an amide by condensation
- compound (XII) in which the amino group moiety is protected is reacted with compound (X) in which the carboxylic acid moiety is protected to give compound (XIII).
- This is a manufacturing step, and can be performed under the same conditions as in step A-1 of method A.
- Step H-4 Step of removing tert-butoxy group with acid
- 4N hydrochloric acid-ethyl acetate solution or trifluoroacetic acid is added to the solution of compound (XIII) to carry out a deprotection reaction.
- This is a step for producing compound (XIV).
- the reaction temperature in this step is usually room temperature, and the reaction time in this step is usually 1 to 12 hours.
- Step H-5 Step for Hydrolyzing Ester This step is a step for producing compound (I) under the same conditions as in Method B-2, Step B-2.
- Compound (II-b) can be obtained as a commercial product, or can be produced by a known method, a method analogous thereto, Method C, Method D or Method E.
- the compound produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
- optical isomer when the compound or the intermediate of production has an asymmetric carbon, an optical isomer exists.
- These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography.
- References for a method for resolving optical isomers from racemates include “Enantiomers, Racemates ⁇ and Resolution, John Wiley And Sons, Inc.” by J. Jacques et al.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof can reduce indoxyl sulfate in blood.
- “reducing blood indoxyl sulfate” means lowering the human blood indoxyl sulfate concentration before administration of the compound of the present invention, and preferably human blood indoxyl sulfate. This is to lower the sulfuric acid concentration by a decrease of 0.1 mg / dL or more with respect to the value before administration of the compound of the present invention.
- the blood indoxyl sulfate concentration of kidney disease patients in CKD-stage 4 averages 0.45 mg / dL, but it is desirable to reduce it to 0.24 mg / dL, the concentration of kidney disease patients in CKD-stage 3. It is more desirable to reduce the concentration to 0.13 mg / dL, which is the concentration of kidney disease patients in -stage 2, and most desirably to 0.075 mg / dL or less, which is the level of a person who does not suffer from kidney disease.
- Blood indoxyl sulfate concentration in patients with end-stage renal disease including dialysis patients in CKD-stage 5, averages 1.30 / mg / dL, but should be reduced to 0.45 mg / dL, the concentration in patients with kidney disease in CKD-stage4 It is more desirable to lower the concentration of kidney disease patients in CKD-stage 3 to 0.24 mg / dL, and further to 0.13 mg / dL of kidney disease patients in CKD-stage 2 Desirably, it is most desirable to reduce to 0.075 mg / dL or less, which is the level of a person who does not suffer from kidney disease (ELLIS-RJ Nephrology 21-170-177 (2016)).
- the concentration of blood indoxyl sulfate can be quantified by using liquid chromatography (fluorescence detection) alone or in combination with a subsequent mass spectrometer.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof can suppress deterioration of renal function.
- “suppressing deterioration of renal function” means reducing leakage of albumin and other proteins into urine, suppressing a decrease in GFR (Glomerular filtration rate), or impaired renal function It shows that the rise of the biochemical marker in the blood and urine reflecting is suppressed.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof can prevent or treat a disease caused by an increase in blood indoxyl sulfate.
- the “disease caused by an increase in blood indoxyl sulfate” is chronic kidney disease (CKD), renal anemia, obstructive arteriosclerosis or ischemic heart disease, particularly chronic kidney disease. is there.
- prevention refers to reducing the onset probability of a disease caused by an increase in indoxyl sulfate in the blood.
- CKD the disease caused by an increase in indoxyl sulfate in the blood
- the blood suPAR concentration in a person with normal renal function whose blood soluble urokinase type plasminogen activator receptor (suPAR) concentration is higher than 4020 pg / mL is 2373 pg.
- This is shown by reducing the probability of developing future CKD (more than 3 times, HR: 3.13: Hayek-SS, N Engl J Med 373: 1916-1925, 2015) for those with normal renal function lower than 1 / mL.
- the onset of CKD can be confirmed by an estimated GFR: ⁇ 60 mL / min / 1.73 m 2 .
- treatment refers to suppressing or improving the pathological state or progression of a disease caused by an increase in blood indoxyl sulfate.
- “suppressing the progression or progression” means not to increase the leakage of proteins such as albumin into the urine, maintaining GFR, It refers to inhibiting the maintenance or elevation of blood and urinary biochemical markers reflecting renal dysfunction. For example, by maintaining 0.3 g / gCr proteinuria in CKD patients and albuminuria of 100 mg / gCr or more for 6 months to 1 year, CKD patients have 30 ml / min / 1.73 m 2 eGFR from 6 months. It can be confirmed by keeping it as it is for one year. “Improve pathology” refers to reducing the severity of CKD to a lower rank.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof can delay the transition to renal replacement therapy in patients with chronic kidney disease during conservative therapy.
- “conservative therapy for chronic kidney disease” means that the renal function that gradually declines after diagnosis is further reduced by reducing the burden on the kidney whose function is reduced in patients diagnosed with chronic kidney disease. It means to prevent it from occurring, or to reduce damage to other organs caused by decreased renal function.
- “delaying the transition to renal replacement therapy for patients with conservative therapy for chronic kidney disease” means a period of time until the criteria are met in the introduction of hemodialysis, the introduction of peritoneal dialysis, and the prior renal transplantation. It means extending. For example, in the case of chronic kidney disease patients who plan to introduce peritoneal dialysis, this means extending the period until GFR, which is the recommended introduction standard, drops to about 6 mL / min / 1.73 m 2 .
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof can suppress the deterioration of the residual renal function of the patient after transition to renal replacement therapy.
- “deterioration of residual renal function of a patient after transition to renal replacement therapy” refers to, for example, a decrease in urine volume per day before and after introduction of dialysis. The amount of urine that was 400 mL or more per day is less than 400 mL. Deterioration of residual renal function can also be evaluated by measuring creatinine clearance and Kt / V values ⁇ (urine urea concentration) / (blood urea concentration) ⁇ (daily urine volume) ⁇ 7 days ⁇ . can do.
- “suppressing deterioration of residual renal function of a patient after transition to renal replacement therapy” means avoiding an anuria state.
- PD peritoneal dialysis
- HD hemodialysis
- Examples of the dosage form of the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof include oral administration such as tablets, granules, powders, capsules or syrups.
- the compound of the present invention (I) or a pharmacologically acceptable salt thereof, or an oral pharmaceutical form of these crystals includes tablets (including orally disintegrating tablets), pills, granules, powders, capsules, Examples include liquids (including sprays), suspensions, emulsions, syrups, pastes, and elixirs.
- These forms of pharmaceuticals are pharmaceutically acceptable, such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffering agents, or wetting agents.
- the additive can be prepared according to a conventional method using additives appropriately selected as necessary.
- the dose of the preparation of the present invention varies depending on symptoms, age, weight, etc., and is 0.1 to 1000 mg, preferably 1 to 300 mg per adult, once to several times a day.
- the preparation of the present invention can also be administered to mammals other than humans.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof can be used in combination with other drugs.
- concomitant drugs that can be used include cardiovascular systems such as angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, calcium antagonists, diuretics, and spherical adsorbent charcoal preparations used in pharmacotherapy for patients with chronic kidney disease
- cardiovascular systems such as angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, calcium antagonists, diuretics, and spherical adsorbent charcoal preparations used in pharmacotherapy for patients with chronic kidney disease
- Angiotensin II receptor antagonist corresponds to losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, azilsartan and the like.
- Angiotensin-converting enzyme inhibitors include captopril, enalapril, alacepril, delapril, cilazapril, lisinopril, benazepril, imidapril, temocapril, quinapril, trandolapril, and perindopril erbumine.
- Calcium antagonists include nifedipine, amlodipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nilvadipine, varnidipine, felodipine, benidipine, manidipine, azelnidipine, alanidipine, diltiazem and the like.
- “Diuretics” include trichloromethiazide, benzylhydrochlorothiazide, hydrochlorothiazide, methiclan, indabamide, tripamide, mefluside, furosemide, triamterene and the like.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof can also be used as a compounding agent with the above-mentioned combination control therapeutic agent.
- the compounding ratio of the concomitant drug can be arbitrarily set.
- the compounding ratio of the compound of the present invention or a pharmacologically acceptable salt thereof and the therapeutic drug to be used in combination is usually in the range of 1: 0.0001 to 200 by weight ratio. Particularly preferably, it is in the range of 1: 0.001 to 10.
- the elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography).
- TLC observation silica gel 60F 254 manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method.
- column chromatography an automated chromatography apparatus (Purif- ⁇ 2) manufactured by Shoko Scientific was used.
- the elution solvent was determined based on TLC observation.
- For high performance liquid chromatography a preparative purification HPLC system manufactured by Gilson and a column (Develosil Combi-RP-5 28 ⁇ 100) manufactured by NOMURA CHEMICAL were used.
- 1 H NMR nuclear magnetic resonance
- MS Mass spectrometry
- Table 1 shows peaks having a relative intensity of 14 or more when the maximum peak intensity is 100 in FIG.
- Example 9b 4-[(tert-Butoxycarbonyl) amino] -5-chloro-2- (propan-2-yloxy) benzoic acid obtained in Example 9b (660 mg, 2.00 mmol) in the same manner as in Example 1.
- 2-methylalanine methyl hydrochloride (CAS Registry Number 15028-41-8) (330 mg, 2.15 mmol) afforded 360 mg (57%, 3 steps) of the title compound as a solid.
- MS m / z 315, 317 (M + H) + .
- the resulting solid was filtered and washed with water and dried under reduced pressure to obtain 1.26 g of a crude product.
- Acetonitrile (200 mL) was added to 1.1 g of the obtained crude product and heated to reflux. After dissolution, the mixture was allowed to stand at room temperature for 24 hours, and the resulting solid was filtered and washed with acetonitrile to obtain a solid (0.72 g).
- Table 2 shows peaks having a relative intensity of 22 or more when the maximum peak intensity is 100 in FIG.
- the obtained solid was a crystal.
- Table 3 shows peaks having a relative intensity of 3 or more when the maximum peak intensity is 100 in FIG.
- Table 4 shows peaks having a relative intensity of 4 or more when the maximum peak intensity is 100 in FIG.
- Table 5 shows peaks having a relative intensity of 8 or more when the maximum peak intensity is 100 in FIG.
- Methyl 4-bromo-2-ethoxy-5-fluorobenzoate (CAS Registry Number 1823348-15-7) (1.12 g, 4.04 mmol), palladium acetate (907 mg, 0.404 mmol), 4,5-bis ( To a suspension of diphenylphosphino) -9,9-dimethylxanthene (351 mg, 0.606 mmol) and cesium carbonate (2.63 g, 8.08 mmol) in 1,4-dioxane (20 mL) was added benzophenone imine (1.10 g). , 6.06 mmol), and the mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere.
- reaction solution was cooled to room temperature, filtered, washed with n-hexane, and the filtrate was concentrated under reduced pressure.
- the obtained residue was dissolved in THF (5 mL), 2N hydrochloric acid (5 mL, 10 mmol) was added, and the mixture was stirred at room temperature for 1 hr.
- the reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
- Example 23a To a solution of methyl 4-amino-2-ethoxy-5-fluorobenzoate (810 mg, 3.8 mmol) obtained in Example 23a in methanol (5 mL) was added 1N sodium hydroxide solution (5 mL, 5 mmol). And stirred at room temperature for 2 hours. Furthermore, 4N potassium hydroxide solution (3 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 3 with 1N hydrochloric acid, water (300 mL) was added, and the resulting solid was filtered and washed with water to obtain 630 mg (83%) of the title compound. .
- Example 14d 4-amino-5-chloro-2-propoxybenzoic acid (200 mg, 0.87 mmol) and (R) - ⁇ -ethylalanine monohydrate obtained in Example 14d. (120 mg, 0.89 mmol) afforded 160 mg (56%) of the title compound as a solid. The obtained solid was a crystal.
- Example 23a methyl 4-bromo-5-fluoro-2-propoxybenzoate (1.1 g, 3.9 mmol), palladium acetate (879 mg, 0.39 mmol) obtained in Example 27a, From 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (340 mg, 0.59 mmol), cesium carbonate (2.55 g, 7.8 mmol) and benzophenone imine (1.06 g, 5.9 mmol), 550 mg (62%) of the title compound were obtained.
- Table 10 shows peaks having a relative intensity of 6 or more when the maximum peak intensity is 100 in FIG.
- Example 31a 4-amino-5-chloro- (2-difluoromethoxy) benzoic acid (37 mg, 0.16 mmol) and (R) - ⁇ -ethylalanine ⁇ 1 obtained in Example 31a were used. From the hydrate (22 mg, 0.16 mmol), 18 mg (34%) of the title compound was obtained as a solid.
- Tryptophanase enzyme inhibitory activity Tryptophanase inhibitory activity was evaluated by a method using lactate dehydrogenase (LDH).
- LDH lactate dehydrogenase
- the reaction time-dependent NADH decrease rate conjugated by enzymatic reaction of pyruvate generated by enzymatic reaction with tryptophanase using L-tryptophan as a substrate was measured with a spectrophotometer (Phillips-RS et al , Biochemistry, 23, 6228-6234 (1984)).
- the enzyme inhibitory activity when no test compound was added (DMSO only) in the presence of tryptophanase was used as a control.
- Bacteroides tetaiotaomicron tryptophanase (Genbank accession number: HC914434.1) was used as the enzyme.
- test compound was dissolved in DMSO at an arbitrary concentration (10 ⁇ common ratio from 30 ⁇ m to 30 ⁇ m) to prepare a test compound solution.
- LDH, NADH, and L-tryptophan were prepared in distilled water to a concentration of 80 units / mL, 10 mM, and 50 mM, respectively.
- Bacteroides tryptophanase was prepared at 30 mg / mL.
- a potassium-phosphate buffer was used as the buffer. Table 11 shows the composition of the reaction solution.
- Reaction solution A was dispensed into a 96-well plate at 284.8 ⁇ L per 1-well, and the test compound solution was added at 3.2 ⁇ L per 1-well to a final concentration of 1/100 (reaction solution B). After incubating reaction solution B at 37 ° C for 30 minutes, add 32 ⁇ L of L-tryptophan at a final concentration of 10 ⁇ mM to a final concentration of 10 ⁇ mM (reaction solution C). In order to monitor, the enzyme reaction was performed while measuring the absorbance at 340 nm. The tryptophanase inhibitory activity of the compounds was evaluated based on the disappearance rate of NADH.
- the compound of the present invention exhibits an excellent tryptophanase inhibitory activity, a reducing agent for blood indoxyl sulfate, a preventive or therapeutic agent for diseases caused by an increase in blood indoxyl sulfate, It is useful as a medicament for the transition delay agent of renal replacement therapy in patients with conservative therapy for chronic kidney disease and the deterioration inhibitor of residual renal function of patients after transition to renal replacement therapy.
- the above-mentioned viable cell suspension prepared so that the final concentration of the compound is from 1 ⁇ M to 10 mM is dispensed into 96-well plates in an amount of 200 ⁇ L and cultured anaerobically at 37 ° C. for 2 to 4 hours, and then OD and ATP concentrations ( BacTiter-Glo (Promega) can be quantified), and the indole concentration in the culture supernatant (which can be quantified using the Erlich reaction) is measured.
- the inhibitory effect of tryptophanase inhibitory compounds on indole production from live bacteria can be evaluated by the degree of indole concentration reduction in the culture supernatant.
- Antibacterial activity that is generally carried out with a positive control such as a decrease in OD, a decrease in ATP concentration, and levofloxacin, etc. It can be confirmed by a test (MIC (Minimum Growth Inhibitory Concentration) test).
- MIC Minimum Growth Inhibitory Concentration
- Bacteroides the indole production inhibitory activity was measured for the example compounds shown in Table 13 by the method described above, and the indole production inhibitory effect was evaluated. The results are shown in Table 13.
- the compound of the present invention showed excellent indole production inhibitory activity. Therefore, the compound of the present invention is used as a reducing agent for blood indoxyl sulfate, a prophylactic or therapeutic agent for diseases caused by an increase in blood indoxyl sulfate, and the transition to renal replacement therapy for patients with chronic kidney disease during conservative therapy. It is useful as a drug for a delay agent and an inhibitor of deterioration of residual renal function of a patient after transition to renal replacement therapy.
- the test compound administration group uses a 0.5% methylcellulose (MC) solution as a solvent, and a tryptophanase compound dissolved or suspended to 0.01 to 10 mg / mL as a solvent control.
- the group is orally administered by gavage with a 0.5% ⁇ MC solution in a volume of 10 mL / kg each.
- L-tryptophan which is a substrate for tryptophanase, is orally administered by gavage at a dose of 1 to 3 g / kg.
- L-tryptophan is suspended in a 0.5% tragacanth solution.
- Plasma Blood is collected from the tail vein using a hematocrit tube over time for 12 hours after administration of L-tryptophan. Plasma is collected by centrifuging the obtained blood at 11,000 rpm for 5 minutes, and the concentration of indoxyl sulfate in plasma is measured by using liquid chromatography (fluorescence detection) alone or in combination with a subsequent mass spectrometer. . Compare the in vivo efficacy of each compound by calculating the ratio of the indoxyl sulfate concentration in the plasma of the test substance administration group to the plasma indoxyl sulfate concentration in the solvent control group. be able to.
- the compound of the present invention showed an excellent plasma indoxyl sulfate lowering action. Therefore, the compound of the present invention is used as a reducing agent for blood indoxyl sulfate, a prophylactic or therapeutic agent for diseases caused by an increase in blood indoxyl sulfate, and the transition to renal replacement therapy for patients with chronic kidney disease during conservative therapy. It is useful as a drug for a delay agent and an inhibitor of deterioration of residual renal function of a patient after transition to renal replacement therapy.
- Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
- Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
- the compound (I) of the present invention or a pharmacologically acceptable salt thereof, or a crystal thereof has an excellent tryptophanase inhibitory action, shows an action of reducing blood indoxyl sulfate, and suppresses deterioration of renal function.
- the compound of the present invention is an agent for reducing blood indoxyl sulfate, a prophylactic or therapeutic agent for diseases caused by an increase in blood indoxyl sulfate, and renal replacement for patients with chronic kidney disease (CKD) during conservative therapy. It is useful as an agent for delaying the transition to therapy and an agent for suppressing the deterioration of the residual renal function of the patient after transition to the renal replacement therapy.
- CKD chronic kidney disease
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Abstract
Description
(1) 一般式(I)
(2) 一般式(Ia)
(3) 一般式(I-1)
(4) 一般式(I-1a)
(5) R1及びR2が、同一又は異なって、メチル基、エチル基、プロピル基又はシクロプロピル基である、(4)に記載の化合物又はその薬理上許容される塩、
(6) R1及びR2が、同一又は異なって、メチル基又はエチル基である、(4)に記載の化合物又はその薬理上許容される塩、
(7) Xが、フッ素原子、塩素原子、臭素原子又はヨウ素原子である、(4)-(6)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(8) Xが、フッ素原子又は塩素原子である、(4)-(6)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(9) Yが、メトキシ基、エトキシ基、又は、プロポキシ基である、(4)-(8)のいずれか1項に記載の化合物又はその薬理上許容される塩、
(10) 一般式(I-2)
(11) 一般式(I-2a)
(12) R2が、メチル基、エチル基又はシクロプロピル基である、(11)に記載の化合物又はその薬理上許容される塩、
(13) Xが、メチル基又は塩素原子である、(11)又は(12)に記載の化合物又はその薬理上許容される塩、
(14) 2-[(4-アミノ-5-クロロ-2-メトキシベンゾイル)アミノ]-2-エチルブタン酸、
(-)-N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-D-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-D-イソバリン
(+)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-L-イソバリン、
及び、
(-)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-D-イソバリン
からなる群から選ばれる、(2)に記載の化合物又はその薬理上許容される塩、
(15) (2)~(14)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物、
(16) 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折において、
面間隔dが、7.51、7.33、6.67、6.15、5.32、5.24、4.98、4.79、3.96、及び、3.59オングストロームに特徴的なピークを示す、2-[(4-アミノ-5-クロロ-2-メトキシベンゾイル)アミノ]-2-エチルブタン酸の結晶、
面間隔dが、10.02、7.39、5.47、5.00、4.79、4.70、4.54、4.39、4.28、及び、2.95オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、6.61、5.96、5.16、5.10、4.85、4.68、4.50、 4.08、3.43、及び、69オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、10.67、10.06、5.33、5.09、5.02、4.26、4.14、3.67、3.47、及び、2.96オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、8.89、8.39、6.07、5.63、5.15、5.01、4.22、 3.59、3.39、及び、2.76オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、10.37、9.40、6.12、5.17、4.87、4.20、3.89、3.45、3.05、及び、2.84オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-D-イソバリンの結晶
面間隔dが、10.23、6.38、5.09、5.04、4.17、4.11、3.49、及び、3.38オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、12.00、5.99、5.53、5.17、5.08、3.68、3.35、3.06、2.86、及び、2.39オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、10.13、6.35、5.87、5.08、4.76、4.16、4.09、3.60、3.48、及び、3.37オングストロームに特徴的なピークを示す、(+)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-L-イソバリンの結晶、及び、
面間隔dが、10.23、6.38、5.09、5.04、4.17、4.11、3.49、及び、3.38オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-D-イソバリンの結晶からなる群から選ばれる、(2)に記載の化合物の結晶、
(17) (16)に記載の化合物の結晶のいずれか1つを有効成分として含有する医薬組成物、
(18) 医薬組成物が、トリプトファナーゼ阻害薬である、(1)、(15)又は(17)に記載の医薬組成物、
(19) 医薬組成物が、血中のインドキシル硫酸を低減するための医薬組成物である、(1)、(15)又は(17)に記載の医薬組成物、
(20) 医薬組成物が、腎機能の悪化を抑制するための医薬組成物である、(1)、(15)又は(17)に記載の医薬組成物、
(21) 医薬組成物が、血中のインドキシル硫酸の増加により引き起こされる疾患の予防若しくは治療のための、(1)、(15)又は(17)に記載の医薬組成物、
(22) 医薬組成物が、慢性腎臓病の保存療法期患者の腎代替療法移行を遅延させるための医薬組成物である、(1)、(15)又は(17)に記載の医薬組成物、
(23) 医薬組成物が、腎代替療法移行後の患者の残存腎機能の悪化を抑制するための医薬組成物である、(1)、(15)又は(17)に記載の医薬組成物、
(24) (2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶を有効成分として含有する、血中のインドキシル硫酸の低減剤、
(25) (2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶を有効成分として含有する、血中のインドキシル硫酸の増加により引き起こされる疾患の予防剤若しくは治療剤、
(26) (2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶を有効成分として含有する、慢性腎臓病の保存療法期患者の腎代替療法移行遅延剤、
(27) (2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶を有効成分として含有する、腎代替療法移行後の患者の残存腎機能の悪化抑制剤、
(28) 医薬組成物の製造のための、(2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶の使用、
(29) 血中のインドキシル硫酸の増加により引き起こされる疾患の予防若しくは治療のための医薬組成物の製造のための、(28)に記載の使用、
(30) 慢性腎臓病の保存療法期患者の腎代替療法移行の遅延のための医薬組成物の製造のための、(28)に記載の使用、
(31) 腎代替療法移行後の患者の残存腎機能の悪化の抑制のための医薬組成物の製造のための、(28)に記載の使用、
(32) (2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶の有効量を、哺乳動物に投与することからなる、血中のインドキシル硫酸の低減方法、
(33) 哺乳動物が、ヒトである、(32)に記載の方法、
(34) (2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶の有効量を、哺乳動物に投与することからなる、疾患の予防若しくは治療のための方法、
(35) 哺乳動物が、ヒトである、(34)に記載の方法、
(36) 疾患が、血中のインドキシル硫酸の増加により引き起こされる疾患である、(34)又は(35)に記載の方法、
(37) 疾患の予防若しくは治療のための方法における使用のための、(2)~(14)のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、(16)に記載の化合物の結晶、及び、
(38) 疾患が、血中のインドキシル硫酸の増加により引き起こされる疾患である、(37)に記載の化合物又はその薬理上許容される塩。
2-[(4-アミノ-5-クロロ-2-メトキシベンゾイル)アミノ]-2-エチルブタン酸、
(-)-N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-D-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-D-イソバリン
(+)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-L-イソバリン、
及び、
(-)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-D-イソバリンを挙げることができる。
A法は、本発明の化合物(I)を製造する方法である。
本工程は、化合物(II)及び化合物(III)を、塩基の存在又は非存在下、縮合剤と反応させて、化合物(I)を製造する工程である。
B法は、A法で使用される化合物(II)を製造する方法である。
本工程は、化合物(IV-a)の溶液を、水素雰囲気下、10%パラジウム炭素等の金属触媒の存在下、還元反応を行い、化合物(V)を得る工程である。
本工程は、化合物(V)のエステル基を塩基の存在下、溶媒中で加水分解して、化合物(II)を得る工程である。
C法は、A法で使用される化合物(II)を製造する方法であり、B法の別法である。
本工程は、化合物(VI)の溶液に、触媒、配位子及び塩基の存在下、ベンゾフェノンイミンを加えて反応を行った後、酸で処理することにより、化合物(V)を製造する工程である。
(C-2工程)エステルを加水分解する工程
本工程は、B法B-2工程と同様の条件により、化合物(II)を製造する工程である。
D法は、A法で使用される化合物(II)のうち、式(II-a)で表される化合物を製造する方法であり、B法及びC法の別法である。B法及びC法ではX1に相当する置換基が、すでに最初の工程で導入されているが、X1に相当する置換基がハロゲン原子又はハロアルキル基に相当する置換基の場合には、D法のように、D-1工程及びD-2工程を経ることによっても製造することができる。
本工程は、化合物(VII)のアミノ基の隣接位に塩素原子、臭素原子若しくはヨウ素原子等のハロゲン原子、又は、トリフルオロメチル基等のハロアルキル基を導入する工程である。
本工程は、B法B-2工程と同様の条件により、化合物(II-a)を製造する工程である。
E法は、D法で使用される化合物(VII)において、YがC1-C6アルコキシ基である化合物(VII-a)を製造する方法である。
本工程は、化合物(VIII)の溶液に、塩基の存在下、C1-C6ハロゲン化アルキルを加えて、化合物(IX)を製造する工程である。
本工程は、B法B-1工程と同様の条件により、化合物(VII-a)を製造する工程である。
F法は、A法で使用される化合物(II)のうち、式(II-b)で表される化合物を製造する方法であり、B法、C法及びD法の別法である。X2に相当する置換基がニトリル基の場合には、F法のように、F-1工程を経ることによっても製造することができる。
本工程は、化合物(V-b)の溶液に、触媒、配位子及び塩基の存在下、ヘキサシアノ鉄(II)酸カリウム三水和物等を加えて、化合物(II-b)を製造する工程である。
G法は、本発明の化合物(I)を製造する方法であり、A法の別法である。
本工程は、化合物(II)を、カルボン酸部分がC1-C6アルキル基で保護された化合物(X)と反応させて、化合物(IX)を製造する工程であり、A法A-1工程と同様の条件により行うことができる。
本工程は、B法B-2工程と同様の条件により、化合物(I)を製造する工程である。
本工程は、通常、化合物(V)のジクロロメタン溶液中で、4-ジメチルアミノピリジン及びトリエチルアミン存在下、二炭酸ジ-tert-ブチルを加えて、化合物(XI)を製造する工程である。
本工程は、B法B-2工程と同様の条件により、化合物(XII)を製造する工程である。
本工程は、アミノ基部分が保護された化合物(XII)をカルボン酸部分が保護された化合物(X)と反応させて、化合物(XIII)を製造する工程であり、A法A-1工程と同様の条件により行うことができる。
本工程は、通常、化合物(XIII)の溶液に、4N塩酸-酢酸エチル溶液、又はトリフルオロ酢酸等を加えて脱保護反応を行い、化合物(XIV)を製造する工程である。
本工程は、B法B-2工程と同様の条件により、化合物(I)を製造する工程である。
DMF:N,N-ジメチルホルムアミド
THF:テトラヒドロフラン
HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロホスファート
Me:メチル
Boc:tert-ブトキシカルボニル。
2-[(4-アミノベンゾイル)アミノ]-2-エチルブタン酸
2-({4-[(tert-ブトキシカルボニル)アミノ]ベンゾイル}アミノ)-2-エチルブタン酸メチル
MS m/z: 365 (M+H)+。
2-[4-アミノベンゾイル)アミノ]-2-エチルブタン酸メチル
MS m/z: 265 (M+H)+。
2-[(4-アミノベンゾイル)アミノ]-2-エチルブタン酸
MS m/z: 251 (M+H)+。
2-[(4-アミノ-3-メチルベンゾイル)アミノ]-2-エチルブタン酸
MS m/z: 265 (M+H)+。
2-[(4-アミノ-3,5-ジメチルベンゾイル)アミノ]-2-エチルブタン酸
2-([3,5-ジメチル-4-ニトロベンゾイル]アミノ)-2-エチルブタン酸メチル
MS m/z: 323 (M+H)+。
2-[(4-アミノ-3,5-ジメチルベンゾイル)アミノ]-2-エチルブタン酸メチル
MS m/z: 293 (M+H)+。
2-[(4-アミノ-3,5-ジメチルベンゾイル)アミノ]-2-エチルブタン酸
MS m/z: 279 (M+H)+。
2-[(4-アミノ-3-メチルベンゾイル)アミノ]-2-シクロプロピルブタン酸
MS m/z: 277 (M+H)+。
2-[(4-アミノ-3-クロロベンゾイル)アミノ]-2-シクロプロピルブタン酸
MS m/z: 297, 299 (M+H)+。
2-[(4-アミノ-5-クロロ-2-メトキシベンゾイル)アミノ]-2-エチルブタン酸
1H-NMR (400MHz, CD3OD) δ: 0.78 (7H, t, J = 7.7 Hz), 1.84-1.90 (2H, m), 2.46-2.55 (2H, m), 3.96 (3H, s), 6.52 (1H, s), 7.79 (1H, s), 9.05 (1H, s).
MS m/z: 315, 317 (M+H)+。
4-[ビス(tert-ブトキシカルボニル)アミノ]-3-クロロ-5-フルオロ安息香酸メチル
4-[(tert-ブトキシカルボニル)アミノ]-3-クロロ-5-フルオロ安息香酸
2-[(4-アミノ-3-クロロ-5-フルオロベンゾイル)アミノ]-2-エチルブタン酸
MS m/z: 303, 305 (M+H)+。
N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-2-メチルアラニン
MS m/z: 301, 303 (M+H)+。
N-[4-アミノ-5-クロロ-2-(プロパン-2-イルオキシ)ベンゾイル)-2-メチルアラニン
4-アミノ-5-クロロ-2-(プロパン-2-イルオキシ)安息香酸メチル
MS m/z: 244, 246 (M+H)+。
4-[(tert-ブトキシカルボニル)アミノ]-5-クロロ-2-(プロパン-2-イルオキシ)安息香酸
MS m/z: 330, 332 (M+H)+。
N-(4-アミノ-5-クロロ-2-(プロパン-2-イルオキシ)ベンゾイル)-2-メチルアラニン
MS m/z: 315, 317 (M+H)+。
(-)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-D-イソバリン
MS m/z: 301, 303 [M+H]+.
[α]D 25 -19.82° (c 0.5, Methanol)。
1H-NMR (400MHz, CD3OD) δ: 0.85 (3H, t, J = 7.3 Hz), 1.52 (3H, t, J = 7.0 Hz), 1.64 (3H, s), 1.87-1.96 (1H, m), 2.26-2.35 (1H, m), 4.16 (2H, q, J = 6.9 Hz), 6.49 (1H, s), 7.79 (1H, s), 8.83 (1H, s).
MS m/z: 315, 317 [M+H]+.
[α]D 25 -19.44° (c 0.5, Methanol)。
(+)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-L-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.64 (3H, s), 1.87-1.96 (1H, m), 2.27-2.36 (1H, m), 3.95 (3H, s), 6.52 (1H, s), 7.79 (1H, s).
MS m/z: 301, 303 [M+H]+.
[α]D 25 +20.73° (c 0.5, Methanol)。
(+)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-L-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.85 (3H, t, J = 7.3 Hz), 1.52 (3H, t, J = 7.0 Hz), 1.64 (3H, s), 1.87-1.96 (1H, m), 2.26-2.35 (1H, m), 4.15 (2H, q, J = 6.9 Hz), 6.50 (1H, s), 7.80 (1H, s).
MS m/z: 315, 317 [M+H]+.
[α]D 25 +22.47° (c 0.5, Methanol)。
N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-2-メチル-アラニン
4-ニトロ-2-プロポキシ安息香酸プロピル
1H-NMR (400MHz, CDCl3) δ: 1.03 (3H, t, J = 7.3 Hz), 1.09 (3H, t, J = 7.6 Hz), 1.78-1.80 (2H, m), 1.88-1.92 (2H, m), 4.09 (2H, t, J = 6.7 Hz), 4.30 (2H, t, J = 6.7 Hz), 7.80-7.86 (3H, m)。
4-アミノ-2-プロポキシ安息香酸プロピル
4-アミノ-5-クロロ-2-プロポキシ安息香酸プロピル
1H-NMR (400MHz, CDCl3) δ: 1.01 (3H, t, J = 7.6 Hz), 1.06 (3H, t, J = 7.3 Hz), 1.75 (2H, td, J = 14.0, 7.3 Hz), 1.85 (2H, td, J = 14.0, 7.3 Hz), 3.91 (2H, t, J = 6.4 Hz), 4.20 (2H, t, J = 6.7 Hz), 4.38 (2H, s), 6.27 (1H, s), 7.83 (1H, s).
MS m/z: 272, 274 [M+H]+。
4-アミノ-5-クロロ-2-プロポキシ安息香酸
1H-NMR (400MHz, CD3OD) δ: 1.06 (3H, t, J = 7.6 Hz), 1.85 (2H, q, J = 6.9 Hz), 4.04 (2H, t, J = 6.4 Hz), 6.47 (1H, s), 7.75 (1H, s).
MS m/z: 230, 232 [M+H]+。
N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-2-メチル-アラニン
1H-NMR (400MHz, CD3OD) δ: 1.09 (3H, t, J = 7.6 Hz), 1.60 (6H, s), 1.93 (2H, q, J = 6.7 Hz), 4.06 (2H, t, J = 6.4 Hz), 6.48 (1H, s), 7.78 (1H, s).
MS m/z: 315 [M+H]+。
(-)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.63 (3H, s), 1.95-1.86 (1H, m), 2.36-2.27 (1H, m), 3.95 (3H, s), 6.52 (1H, s), 7.95 (1H, s).
MS m/z: 345, 347 [M+H]+.
[α]D 25 -18.34° (c 0.5, Methanol)。
(-)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.63 (3H, s), 1.95-1.86 (1H, m), 2.36-2.26 (1H, m), 3.94 (3H, s), 6.50 (1H, s), 8.17 (1H, s).
MS m/z: 393 [M+H]+.
[α]D 25 -15.73° (c 0.5, Methanol)。
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.64 (3H, s), 1.96-1.86 (1H, m), 2.36-2.27 (1H, m), 3.95 (3H, s), 6.52 (1H, s), 7.95 (1H, s).
MS m/z: 345, 347 [M+H]+.
[α]D 25 +18.12° (c 0.5, Methanol)。
(+)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-L-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.63 (3H, s), 1.95-1.86 (1H, m), 2.36-2.27 (1H, m), 3.94 (3H, s), 6.49 (1H, s), 8.16 (1H, s).
MS m/z: 393 [M+H]+.
[α]D 25 +16.17° (c 0.5, Methanol)。
(+)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-L-イソバリン
1H-NMR (400MHz, DMSO-D6) 1H-NMR (DMSO-D6) δ: 0.76 (3H, t, J = 7.3 Hz), 1.44 (3H, t, J = 7.0 Hz), 1.51 (3H, s), 1.83-1.74 (1H, m), 2.21-2.12 (1H, m), 4.09 (2H, q, J = 7.1 Hz), 5.91 (1H, br s), 6.48 (1H, s), 7.85 (1H, s), 8.43 (1H, s), 12.82 (1H, br s).
MS m/z: 359, 361 [M+H]+.
[α]D 25 +20.45° (c 0.5, Methanol)。
(+)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-L-イソバリン
1H-NMR (400MHz, DMSO-D6) δ: 0.76 (3H, t, J = 7.6 Hz), 1.44 (3H, t, J = 7.0 Hz), 1.51 (3H, s), 1.74-1.83 (1H, m), 2.20-2.11 (1H, m), 4.08 (2H, q, J = 6.9 Hz), 5.70 (1H, br s), 6.46 (1H, s), 8.06 (1H, s), 8.41 (1H, s).
MS m/z: 407 [M+H]+.
[α]D 25 +19.67° (c 0.5, Methanol)。
(-)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-D-イソバリン
1H-NMR (400MHz, DMSO-D6)δ: 0.76 (3H, t, J = 7.3 Hz), 1.45 (3H, t, J = 7.0 Hz), 1.51 (3H, s), 1.83-1.75 (1H, m), 2.21-2.12 (1H, m), 4.09 (2H, q, J = 7.1 Hz), 6.49 (1H, s), 7.85 (1H, s), 8.43 (1H, s), 12.83 (1H, br s)..
MS m/z: 359, 361 [M+H]+.
[α]D 25 -20.79° (c 0.5, Methanol)。
(-)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-D-イソバリン
1H-NMR (400MHz, DMSO-D6) δ: 0.76 (3H, t, J = 7.6 Hz), 1.44 (6H, t, J = 7.0 Hz), 1.51 (6H, s), 1.83-1.74 (1H, m), 2.20-2.11 (1H, m), 4.08 (2H, q, J = 6.9 Hz), 5.63 (1H, br s), 6.46 (1H, s), 8.06 (1H, s), 8.41 (1H, s).
MS m/z: 407 [M+H]+.
[α]D 25 -19.24° (c 0.5, Methanol)。
(-)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-D-イソバリン
4-アミノ-2-エトキシ-5-フルオロ安息香酸メチル
1H-NMR (400MHz, CDCl3) δ: 1.45 (3H, t, J = 7.0 Hz), 3.83 (3H, s), 4.02 (2H, q, J = 7.1 Hz), 4.10 (2H, s), 6.30 (1H, d, J = 7.3 Hz), 7.56 (1H, d, J = 11.6 Hz).
MS m/z: 214 [M+H]+。
4-アミノ-2-エトキシ-5-フルオロ安息香酸
1H-NMR (400MHz, CD3OD) δ: 1.44 (3H, t, J = 7.0 Hz), 4.16 (2H, q, J = 6.9 Hz), 6.48 (1H, d, J = 7.3 Hz), 7.48 (1H, d, J = 12.2 Hz).
MS m/z: 200 [M+H]+。
(-)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.86 (3H, t, J = 7.3 Hz), 1.51 (3H, t, J = 7.0 Hz), 1.64 (3H, s), 1.88-1.97 (1H, m), 2.25-2.34 (1H, m), 4.14 (2H, q, J = 7.1 Hz), 6.48 (1H, d, J = 7.9 Hz), 7.52 (1H, d, J = 12.8 Hz).
MS m/z: 299 [M+H]+.
[α]D 25 -22.71° (c 0.5, Methanol)。
1H-NMR (400MHz, CD3OD) δ: 0.86 (3H, t, J = 7.3 Hz), 1.51 (3H, t, J = 7.0 Hz), 1.64 (3H, s), 1.88-1.97 (1H, m), 2.25-2.34 (1H, m), 4.15 (2H, q, J = 6.9 Hz), 6.49 (1H, d, J = 7.3 Hz), 7.52 (1H, d, J = 12.8 Hz).
MS m/z: 299 [M+H]+.
[α]D 25 +21.96° (c 0.5, Methanol)。
(-)-N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.76 (3H, t, J = 7.6 Hz), 0.96 (3H, t, J = 7.3 Hz), 1.82-1.85 (3H, m), 2.19 (1H, td, J = 14.3, 7.3 Hz), 3.95 (2H, t, J = 6.4 Hz), 6.39 (1H, s), 7.70 (1H, s).
MS m/z: 329 [M+H]+.
[α]D 25 -21.14° (c 0.5, Methanol)。
(-)-N-(4-アミノ-2-メトキシ-5-(トリフルオロメチル)ベンゾイル)-D-イソバリン
4-アミノ-2-メトキシ-5-(トリフルオロメチル)安息香酸メチル
1H-NMR (400MHz, CD3OD) δ: 3.79 (3H, s), 3.84 (3H, s), 6.43 (1H, s), 7.93 (1H, s).
MS m/z: 250 [M+H]+。
4-アミノ-2-メトキシ-5-(トリフルオロメチル)安息香酸
1H-NMR (400MHz, CD3OD) δ: 3.89 (3H, s), 6.45 (1H, s), 8.01 (1H, s).
MS m/z: 236 [M+H]+。
(-)-N-(4-アミノ-2-メトキシ-5-(トリフルオロメチル)ベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.64 (3H, s), 1.87-1.96 (1H, m), 2.29-2.38 (1H, m), 3.99 (3H, s), 6.49 (1H, s), 8.06 (1H, s).
MS m/z: 335 [M+H]+.
[α]D 25 -16.80° (c 0.4, Methanol)。
(-)-N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-D-イソバリン
4-ブロモ-5-フルオロ-2-プロポキシ安息香酸メチル
1H-NMR (400MHz, CDCl3) δ: 1.07 (3H, t, J = 7.3 Hz), 1.81-1.90 (2H, m), 3.89 (3H, s), 3.96 (2H, t, J = 6.4 Hz), 7.13 (1H, d, J = 5.5 Hz), 7.58 (1H, d, J = 8.5 Hz).
MS m/z: 291, 293 [M+H]+。
4-アミノ-5-フルオロ-2-プロポキシ安息香酸メチル
1H-NMR (400MHz, CDCl3) δ: 1.07 (3H, t, J = 7.3 Hz), 1.81-1.89 (2H, m), 3.83 (3H, s), 3.91 (2H, t, J = 6.4 Hz), 4.09 (2H, s), 6.29 (1H, d, J = 7.3 Hz), 7.56 (1H, d, J = 12.2 Hz).
MS m/z: 228 [M+H]+。
4-アミノ-5-フルオロ-2-プロポキシ安息香酸
1H-NMR (400MHz, CD3OD) δ: 1.06 (3H, t, J = 7.6 Hz), 1.81-1.90 (2H, m), 4.05 (2H, t, J = 6.4 Hz), 6.48 (1H, d, J = 7.3 Hz), 7.48 (1H, d, J = 12.2 Hz).
MS m/z: 214 [M+H]+。
(-)-N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.86 (3H, t, J = 7.3 Hz), 1.06 (3H, t, J = 7.3 Hz), 1.63 (3H, s), 1.89-1.98 (3H, m), 2.24-2.33 (1H, m), 4.05 (2H, t, J = 6.7 Hz), 6.48 (1H, d, J = 7.3 Hz), 7.53 (1H, d, J = 12.2 Hz), 8.85 (1H, br s).
MS m/z: 313 [M+H]+.
[α]D 25 -20.69° (c 0.5, Methanol)。
N-(4-アミノ-2-メトキシ-5-メチルベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.85 (3H, t, J = 7.6 Hz), 1.63 (3H, s), 1.87-1.96 (1H, m), 2.10 (3H, s), 2.25-2.33 (1H, m), 3.93 (3H, s), 6.45 (1H, s), 7.62 (1H, s).
MS m/z: 281 [M+H]+。
(-)-N-(4-アミノ-5-シアノ-2-エトキシベンゾイル)-D-イソバリン
4-アミノ-5-シアノ-2-メトキシ安息香酸
MS m/z: 207 [M+H]+。
(-)-N-(4-アミノ-5-シアノ-2-エトキシベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.54 (3H, t, J = 7.0 Hz), 1.64 (3H, s), 1.87-1.96 (1H, m), 2.28-2.37 (1H, m), 4.21 (2H, q, J = 6.9 Hz), 6.43 (1H, s), 7.98 (1H, s).
MS m/z: 306 [M+H]+.
[α]D 25 -26.77° (c 0.5, Methanol)。
(-)-N-(4-アミノ-5-フルオロ-2-メトキシベンゾイル)-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.84 (3H, t, J = 7.3 Hz), 1.63 (3H, s), 1.91 (1H, dd, J = 14.0, 7.3 Hz), 2.31 (1H, dd, J = 14.0, 7.3 Hz), 3.94 (3H, s), 6.50 (1H, d, J = 7.3 Hz), 7.52 (1H, d, J = 12.1 Hz), 8.96 (1H, s).
MS m/z: 285 [M+H]+.
[α]D 25 -18.93° (c 0.5, Methanol)。
(-)-N-[4-アミノ-5-クロロ-2-(ジフルオロメトキシ)ベンゾイル]-D-イソバリン
4-アミノ-5-クロロ-(2-ジフルオロメトキシ)安息香酸
MS m/z: 238 [M+H]+。
(-)-N-[4-アミノ-5-クロロ-2-(ジフルオロメトキシ)ベンゾイル]-D-イソバリン
1H-NMR (400MHz, CD3OD) δ: 0.88 (3H, t, J = 7.6 Hz), 1.60 (3H, s), 1.94 (1H, td, J = 14.3, 7.1 Hz), 2.18 (1H, td, J = 14.5, 7.1 Hz), 6.61 (1H, s), 6.89 (1H, t, J = 72.9 Hz), 7.73 (1H, s).
MS m/z: 337 [M+H]+.
[α]D 25 -14.44° (c 0.5, Methanol)。
N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-2-メチルアラニン
1H-NMR (400MHz, CD3OD) δ: 1.09 (3H, t, J = 7.3 Hz), 1.60 (6H, s), 1.91-1.94 (2H, m), 4.05 (2H, t, J = 6.4 Hz), 6.49 (1H, d, J = 7.3 Hz), 7.52 (1H, d, J = 12.8 Hz).
MS m/z: 299 [M+H]+。
乳酸脱水素酵素(LDH)を用いる方法によって、トリプトファナーゼ阻害活性を評価した。基質をL-トリプトファンとして、トリプトファナーゼと酵素反応させることで生じるピルビン酸をLDHと酵素反応させることで共役する反応時間依存的なNADH減少速度を分光光度計で測定した(Phillips-RS et al., Biochemistry, 23, 6228-6234 (1984))。トリプトファナーゼ存在下で試験化合物未添加時(DMSOのみ)の酵素阻害活性を対照とした。酵素は、Bacteroides tetaiotaomicronのトリプトファナーゼ(Genbank accession number: HC914434.1)を使用した。
トリプトファナーゼ阻害化合物の生菌からのインドール産生抑制効果を評価するためには以下のような操作によって行うことができる。
Bacteroidesを用いて、表13に示す実施例化合物について、上述の方法によりインドール産生阻害活性を測定して、インドール産生抑制効果を評価した。結果を表13に示す。
(試験例3)マウスにおける血漿中インドキシル硫酸濃度低下作用効果
マウスにおけるトリプトファナーゼ阻害化合物の血漿中インドキシル硫酸濃度低下作用効果を評価するためには以下のような操作によって行うことができる。
標準二分式ハ-ドゼラチンカプセルの各々に、100mgの粉末状の実施例1の化合物、150mgのラクト-ス、50mgのセルロ-ス及び6mgのステアリン酸マグネシウムを充填することにより、単位カプセルを製造し、洗浄後、乾燥する。
消化性油状物、例えば、大豆油、綿実油又はオリ-ブ油中に入れた、実施例2の化合物の混合物を調製し、正置換ポンプでゼラチン中に注入して、100mgの活性成分を含有するソフトカプセルを得、洗浄後、乾燥する。
常法に従って、100mgの実施例3の化合物、0.2mgのコロイド性二酸化珪素、5mgのステアリン酸マグネシウム、275mgの微結晶性セルロ-ス、11mgのデンプン及び98.8mgのラクト-スを用いて製造する。
5mL中に、100mgの微粉化した実施例4の化合物、100mgのナトリウムカルボキシ基メチルセルロ-ス、5mgの安息香酸ナトリウム、1.0gのソルビト-ル溶液(日本薬局方)及び0.025mLのバニリンを含有するように製造する。
Claims (38)
- 一般式(Ia)
[上記式中、(A)R1及びR2は、同一又は異なって、C1-C6アルキル基、ハロゲノC1-C6アルキル基又はC3-C6シクロアルキル基であり、nは1であり、Xは、同一又は異なって、C1-C6アルキル基、C3-C6シクロアルキル基、ハロゲン原子、シアノ基、ハロゲノC1-C6アルキル基、C1-C6アルコキシ基、ハロゲノC1-C6アルコキシ基又はC3-C6シクロアルコキシ基であり、YはC1-C6アルコキシ基、C3-C6シクロアルコキシ基又はハロゲノC1-C6アルコキシ基であり、あるいは、(B)R1はエチル基であり、R2は、C1-C6アルキル基、ハロゲノC1-C6アルキル基又はC3-C6シクロアルキル基であり、nは、0、1又は2であり、Xは、C1-C6アルキル基、C3-C6シクロアルキル基、ハロゲン原子、シアノ基、ハロゲノC1-C6アルキル基、C1-C6アルコキシ基又はハロゲノC1-C6アルコキシ基であり、Yは水素原子であり、但し、R2がエチル基のときXはハロゲン原子又はC1-C6アルコキシ基ではなく、nが2のときいずれのXもC1-C6アルコキシ基ではない。]で表される化合物又はその薬理上許容される塩。 - R1及びR2が、同一又は異なって、メチル基、エチル基、プロピル基又はシクロプロピル基である、請求項4に記載の化合物又はその薬理上許容される塩。
- R1及びR2が、同一又は異なって、メチル基又はエチル基である、請求項4に記載の化合物又はその薬理上許容される塩。
- Xが、フッ素原子、塩素原子、臭素原子又はヨウ素原子である、請求項4-6のいずれか1項に記載の化合物又はその薬理上許容される塩。
- Xが、フッ素原子又は塩素原子である、請求項4-6のいずれか1項に記載の化合物又はその薬理上許容される塩。
- Yが、メトキシ基、エトキシ基、又は、プロポキシ基である、請求項4-8のいずれか1項に記載の化合物又はその薬理上許容される塩。
- R2が、メチル基、エチル基又はシクロプロピル基である、請求項11に記載の化合物又はその薬理上許容される塩。
- Xが、メチル基又は塩素原子である、請求項11又は12に記載の化合物又はその薬理上許容される塩。
- 2-[(4-アミノ-5-クロロ-2-メトキシベンゾイル)アミノ]-2-エチルブタン酸、
(-)-N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-D-イソバリン、
(-)-N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-D-イソバリン
(+)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-L-イソバリン、
(-)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-D-イソバリン、
(+)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-L-イソバリン、
及び、
(-)-N-(4-アミノ-2-エトキシ-5-ヨードベンゾイル)-D-イソバリン
からなる群から選ばれる、請求項2に記載の化合物又はその薬理上許容される塩。 - 請求項2~14のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折において、
面間隔dが、7.51、7.33、6.67、6.15、5.32、5.24、4.98、4.79、3.96、及び、3.59オングストロームに特徴的なピークを示す、2-[(4-アミノ-5-クロロ-2-メトキシベンゾイル)アミノ]-2-エチルブタン酸の結晶、
面間隔dが、10.02、7.39、5.47、5.00、4.79、4.70、4.54、4.39、4.28、及び、2.95オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-フルオロ-2-プロポキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、6.61、5.96、5.16、5.10、4.85、4.68、4.50、 4.08、3.43、及び、69オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-クロロ-2-メトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、10.67、10.06、5.33、5.09、5.02、4.26、4.14、3.67、3.47、及び、2.96オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-クロロ-2-エトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、8.89、8.39、6.07、5.63、5.15、5.01、4.22、 3.59、3.39、及び、2.76オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-クロロ-2-プロポキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、10.37、9.40、6.12、5.17、4.87、4.20、3.89、3.45、3.05、及び、2.84オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-ブロモ-2-メトキシベンゾイル)-D-イソバリンの結晶
面間隔dが、10.23、6.38、5.09、5.04、4.17、4.11、3.49、及び、3.38オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-ブロモ-2-エトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、12.00、5.99、5.53、5.17、5.08、3.68、3.35、3.06、2.86、及び、2.39オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-5-ヨード-2-メトキシベンゾイル)-D-イソバリンの結晶、
面間隔dが、10.13、6.35、5.87、5.08、4.76、4.16、4.09、3.60、3.48、及び、3.37オングストロームに特徴的なピークを示す、(+)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-L-イソバリンの結晶、及び、
面間隔dが、10.23、6.38、5.09、5.04、4.17、4.11、3.49、及び、3.38オングストロームに特徴的なピークを示す、(-)-N-(4-アミノ-2-エトキシ-5-フルオロベンゾイル)-D-イソバリンの結晶からなる群から選ばれる、請求項2に記載の化合物の結晶。 - 請求項16に記載の化合物の結晶のいずれか1つを有効成分として含有する医薬組成物。
- 医薬組成物が、トリプトファナーゼ阻害薬である、請求項1、15又は17に記載の医薬組成物。
- 医薬組成物が、血中のインドキシル硫酸を低減するための医薬組成物である、請求項1、15又は17に記載の医薬組成物。
- 医薬組成物が、腎機能の悪化を抑制するための医薬組成物である、請求項1、15又は17に記載の医薬組成物。
- 医薬組成物が、血中のインドキシル硫酸の増加により引き起こされる疾患の予防若しくは治療のための、請求項1、15又は17に記載の医薬組成物。
- 医薬組成物が、慢性腎臓病の保存療法期患者の腎代替療法移行を遅延させるための医薬組成物である、請求項1、15又は17に記載の医薬組成物。
- 医薬組成物が、腎代替療法移行後の患者の残存腎機能の悪化を抑制するための医薬組成物である、請求項1、15又は17に記載の医薬組成物。
- 請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶を有効成分として含有する、血中のインドキシル硫酸の低減剤。
- 請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶を有効成分として含有する、血中のインドキシル硫酸の増加により引き起こされる疾患の予防剤若しくは治療剤。
- 請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶を有効成分として含有する、慢性腎臓病の保存療法期患者の腎代替療法移行遅延剤。
- 請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶を有効成分として含有する、腎代替療法移行後の患者の残存腎機能の悪化抑制剤。
- 医薬組成物の製造のための、請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶の使用。
- 血中のインドキシル硫酸の増加により引き起こされる疾患の予防若しくは治療のための医薬組成物の製造のための、請求項28に記載の使用。
- 慢性腎臓病の保存療法期患者の腎代替療法移行の遅延のための医薬組成物の製造のための、請求項28に記載の使用。
- 腎代替療法移行後の患者の残存腎機能の悪化の抑制のための医薬組成物の製造のための、請求項28に記載の使用。
- 請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶の有効量を、哺乳動物に投与することからなる、血中のインドキシル硫酸の低減方法。
- 哺乳動物が、ヒトである、請求項32に記載の方法。
- 請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶の有効量を、哺乳動物に投与することからなる、疾患の予防若しくは治療のための方法。
- 哺乳動物が、ヒトである、請求項34に記載の方法。
- 疾患が、血中のインドキシル硫酸の増加により引き起こされる疾患である、請求項34又は35に記載の方法。
- 疾患の予防若しくは治療のための方法における使用のための、請求項2~14のいずれか1項に記載の化合物若しくはその薬理上許容される塩、又は、請求項16に記載の化合物の結晶。
- 疾患が、血中のインドキシル硫酸の増加により引き起こされる疾患である、請求項37に記載の化合物又はその薬理上許容される塩。
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