JPWO2012124311A1 - 新規なフェニルピリジン誘導体及びこれを含有する医薬 - Google Patents
新規なフェニルピリジン誘導体及びこれを含有する医薬 Download PDFInfo
- Publication number
- JPWO2012124311A1 JPWO2012124311A1 JP2013504561A JP2013504561A JPWO2012124311A1 JP WO2012124311 A1 JPWO2012124311 A1 JP WO2012124311A1 JP 2013504561 A JP2013504561 A JP 2013504561A JP 2013504561 A JP2013504561 A JP 2013504561A JP WO2012124311 A1 JPWO2012124311 A1 JP WO2012124311A1
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- pyridin
- oxo
- dihydropyrimidin
- butyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000005359 phenylpyridines Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 125000005843 halogen group Chemical group 0.000 claims abstract description 34
- 102000000536 PPAR gamma Human genes 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 32
- 108010016731 PPAR gamma Proteins 0.000 claims abstract description 30
- 230000004913 activation Effects 0.000 claims abstract description 21
- 230000009471 action Effects 0.000 claims abstract description 20
- 206010020772 Hypertension Diseases 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 13
- 208000019622 heart disease Diseases 0.000 claims abstract description 12
- 230000003042 antagnostic effect Effects 0.000 claims abstract description 10
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 10
- 102000008873 Angiotensin II receptor Human genes 0.000 claims abstract description 9
- 108050000824 Angiotensin II receptor Proteins 0.000 claims abstract description 9
- 230000003449 preventive effect Effects 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 257
- -1 5-ethoxypyrimidin-2-yl Chemical group 0.000 claims description 230
- 150000003839 salts Chemical class 0.000 claims description 56
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 53
- 238000011282 treatment Methods 0.000 claims description 52
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 239000012453 solvate Substances 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 23
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- 238000000034 method Methods 0.000 claims description 21
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 14
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 14
- 208000016097 disease of metabolism Diseases 0.000 claims description 13
- 208000031773 Insulin resistance syndrome Diseases 0.000 claims description 12
- 208000017169 kidney disease Diseases 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 12
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- 208000002249 Diabetes Complications Diseases 0.000 claims description 11
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 11
- 206010012655 Diabetic complications Diseases 0.000 claims description 11
- 230000002490 cerebral effect Effects 0.000 claims description 11
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 11
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 11
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- 230000008878 coupling Effects 0.000 claims description 10
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- SYNIXGWDJNBQOP-UHFFFAOYSA-N 3-[2-[5-[[1-(5-ethoxypyrimidin-2-yl)-6-oxo-2-propan-2-yl-4-propylpyrimidin-5-yl]methyl]pyridin-2-yl]phenyl]-2h-1,2,4-oxadiazol-5-one Chemical compound O=C1C(CC=2C=NC(=CC=2)C=2C(=CC=CC=2)C=2NC(=O)ON=2)=C(CCC)N=C(C(C)C)N1C1=NC=C(OCC)C=N1 SYNIXGWDJNBQOP-UHFFFAOYSA-N 0.000 claims description 9
- 206010038372 Renal arteriosclerosis Diseases 0.000 claims description 9
- RQDSQSAOFZTAAA-UHFFFAOYSA-N 3-[2-[5-[[1-(5-ethoxypyrimidin-2-yl)-4-ethyl-6-oxo-2-propan-2-ylpyrimidin-5-yl]methyl]pyridin-2-yl]phenyl]-2h-1,2,4-oxadiazol-5-one Chemical compound N1=CC(OCC)=CN=C1N1C(=O)C(CC=2C=NC(=CC=2)C=2C(=CC=CC=2)C=2NC(=O)ON=2)=C(CC)N=C1C(C)C RQDSQSAOFZTAAA-UHFFFAOYSA-N 0.000 claims description 8
- KKDVUJRGMGHAOG-UHFFFAOYSA-N 3-[2-[5-[[1-(5-ethoxypyrimidin-2-yl)-6-oxo-4-pentyl-2-propan-2-ylpyrimidin-5-yl]methyl]pyridin-2-yl]phenyl]-2h-1,2,4-oxadiazol-5-one Chemical compound O=C1C(CC=2C=NC(=CC=2)C=2C(=CC=CC=2)C=2NC(=O)ON=2)=C(CCCCC)N=C(C(C)C)N1C1=NC=C(OCC)C=N1 KKDVUJRGMGHAOG-UHFFFAOYSA-N 0.000 claims description 8
- PNNKISQBGIITSO-UHFFFAOYSA-N 3-[2-[5-[[2-cyclopropyl-1-(5-ethoxypyrimidin-2-yl)-6-oxo-4-pentylpyrimidin-5-yl]methyl]pyridin-2-yl]phenyl]-2h-1,2,4-oxadiazol-5-one Chemical compound N=1C=C(OCC)C=NC=1N1C(=O)C(CC=2C=NC(=CC=2)C=2C(=CC=CC=2)C=2NC(=O)ON=2)=C(CCCCC)N=C1C1CC1 PNNKISQBGIITSO-UHFFFAOYSA-N 0.000 claims description 8
- KTJROCSEBPVYQG-UHFFFAOYSA-N 3-[2-[5-[[2-cyclopropyl-1-(5-ethoxypyrimidin-2-yl)-6-oxo-4-propylpyrimidin-5-yl]methyl]pyridin-2-yl]phenyl]-2h-1,2,4-oxadiazol-5-one Chemical compound N=1C=C(OCC)C=NC=1N1C(=O)C(CC=2C=NC(=CC=2)C=2C(=CC=CC=2)C=2NC(=O)ON=2)=C(CCC)N=C1C1CC1 KTJROCSEBPVYQG-UHFFFAOYSA-N 0.000 claims description 8
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 8
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 8
- 230000002093 peripheral effect Effects 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- 206010003210 Arteriosclerosis Diseases 0.000 abstract description 5
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 3
- CTQPPUPWHLGKOB-UHFFFAOYSA-N 4h-oxadiazol-5-one Chemical group O=C1CN=NO1 CTQPPUPWHLGKOB-UHFFFAOYSA-N 0.000 abstract 1
- 125000003831 tetrazolyl group Chemical group 0.000 abstract 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 199
- 238000005160 1H NMR spectroscopy Methods 0.000 description 100
- 238000006243 chemical reaction Methods 0.000 description 73
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 34
- 239000003921 oil Substances 0.000 description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 29
- 230000000694 effects Effects 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 25
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 229950006323 angiotensin ii Drugs 0.000 description 18
- 102000005862 Angiotensin II Human genes 0.000 description 17
- 101800000733 Angiotensin-2 Proteins 0.000 description 17
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 17
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- KAHHAPNRIQLSFT-UHFFFAOYSA-N 5-methoxypyrimidin-2-amine Chemical compound COC1=CN=C(N)N=C1 KAHHAPNRIQLSFT-UHFFFAOYSA-N 0.000 description 14
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- NGWGYIGTWBAKAN-UHFFFAOYSA-N 5-ethoxypyrimidin-2-amine Chemical compound CCOC1=CN=C(N)N=C1 NGWGYIGTWBAKAN-UHFFFAOYSA-N 0.000 description 11
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 11
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- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
Description
一方、特許文献6には、次式(A):
[1]次の一般式(I):
XはC−R5又は窒素原子を示し、
R1は、C1−6アルキル基を示し、
R2は、C1−6アルキル基又はC3−8シクロアルキル基を示し、
R3、R4、R5は、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又は置換基を有してもよいC1−6アルコキシ基を示す。なお、式中の波線は隣接する基との結合位置であることを示している。〕
で表される化合物若しくはその塩、又はそれらの溶媒和物。
[3]前記一般式(I)における環Bが前記した式(V)である、前記[1]又は[2]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
[4]前記一般式(I)におけるR2が、分岐したC3−6アルキル基又はC3−8シクロアルキル基である、前記[1]〜[3]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。
[5]前記一般式(I)におけるR1が、C1−3アルキル基又はC5−6アルキル基である前記[1]〜[4]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。
[6]前記一般式(I)における環Aが前記した式(II)であり、環Bが前記した式(V)である前記[1]〜[5]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。
[7]前記一般式(I)におけるXが窒素原子であり、R3、R4が、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又はC1−6アルコキシ基である前記[1]〜[6]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。
[8]前記一般式(I)におけるR3、R4が、それぞれ独立して、水素原子、又はC1−6アルコキシ基である前記[7]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−メトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−エチル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−エチルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−イソプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−イソプロピルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロペンチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロヘキシル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−メチル−3−{5−[2−(メチルチオ)エトキシ]ピリミジン−2−イル}ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−メチル−3−{5−[2−(メチルスルホニル)エトキシ]ピリミジン−2−イル}ピリミジン−4(3H)−オン、
3−{2−{5−{[4−ブチル−2−メチル−6−オキソ−1−(ピリジン−2−イル)−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−メチル−1−(4−メチルピリジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−メトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−エチル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−イソプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロペンチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロヘキシル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{{4−ブチル−2−メチル−1−{5−[2−(メチルチオ)エトキシ]ピリミジン−2−イル}−6−オキソ−1,6−ジヒドロピリミジン−5−イル}メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{{4−ブチル−2−メチル−1−{5−[2−(メチルスルホニル)エトキシ]ピリミジン−2−イル}−6−オキソ−1,6−ジヒドロピリミジン−5−イル}メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−2−メチル−3−(ピリジン−2−イル)ピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(5−メトキシピリジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−[3−クロロ−5−(トリフルオロメチル)ピリジン−2−イル]−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(5−メトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(4,6−ジメトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
3−{2−{6−{[4−ブチル−1−(5−メトキシピリジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{6−{[4−ブチル−1−(5−メトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{6−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{6−{[4−ブチル−1−(4,6−ジメトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン
からなる群から選ばれる化合物である、前記[1]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−イソプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−イソプロピルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロペンチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロヘキシル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
3−{2−{5−{[4−ブチル−2−イソプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロペンチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロヘキシル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン
からなる群から選ばれる化合物である、前記[1]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン
からなる群から選ばれる化合物である、前記[1]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
なお、上記化合物の命名を含む本明細書において、ブチルなどのアルキル基は、特に指定されていない限り直鎖(ノルマル)のものを表わしている。
[13]一般式(I)における環Aが前記した式(II)であり、Xが窒素原子である、前記[12]に記載の医薬組成物。
[14]一般式(I)における環Bが前記した式(V)である、前記[12]又は[13]に記載の医薬組成物。
[15]一般式(I)におけるR2が、分岐したC3−6アルキル基又はC3−8シクロアルキル基である、前記[12]〜[14]のいずれかに記載の医薬組成物。
[16]一般式(I)におけるR1が、C1−3アルキル基又はC5−6アルキル基である前記[12]〜[15]のいずれかに記載の医薬組成物。
[17]一般式(I)における環Aが前記した式(II)であり、環Bが前記した式(V)である前記[12]〜[16]のいずれかに記載の医薬組成物。
[18]一般式(I)におけるXが窒素原子であり、R3、R4が、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又はC1−6アルコキシ基である前記[12]〜[17]のいずれかに記載の医薬組成物。
[19]一般式(I)におけるR3、R4が、それぞれ独立して、水素原子、又はC1−6アルコキシ基である前記[18]に記載の医薬組成物。
[20]アンジオテンシンII受容体拮抗作用及びPPARγ活性化作用を併せ持つ、前記[12]〜[19]のいずれかに記載の医薬組成物。
[22]循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症である、前記[21]に記載の医薬組成物。
[23]代謝性疾患の予防及び/又は治療剤である、前記[12]〜[20]のいずれかに記載の医薬組成物。
[24]代謝性疾患が、2型糖尿病、糖尿病性合併症(糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症)、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である、前記[23]に記載の医薬組成物。
[25]治療を必要としている患者に、前記[1]〜[11]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする循環器系疾患の予防及び/又は治療方法。
[26]循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症である、前記[25]に記載の方法。
[27]治療を必要としている患者に、前記[1]〜[11]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする代謝性疾患の予防及び/又は治療方法。
[28]代謝性疾患が、2型糖尿病、糖尿病性合併症(糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症)、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である、前記[27]に記載の方法。
[29]治療を必要としている患者に、前記[1]〜[11]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする循環器系疾患及び代謝性疾患の予防及び/又は治療方法。
[30]循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症であり、代謝性疾患が、2型糖尿病、糖尿病性合併症(糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症)、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である、前記[29]に記載の方法。
[31]循環器系疾患の予防及び/又は治療のための製剤を製造するための、前記[1]〜[11]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の使用。
[32]循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症である、前記[31]に記載の使用。
[34]代謝性疾患が、2型糖尿病、糖尿病性合併症(糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症)、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である、前記[33]に記載の使用。
[35]循環器系疾患の予防及び/又は治療のための医薬組成物として使用するための前記[1]〜[11]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。
[36]循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症である、前記[35]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
[37]医薬組成物の有効成分が、アンジオテンシンII受容体拮抗作用及びPPARγ活性化作用の両方の作用を併せ持つ化合物若しくはその塩、又はそれらの溶媒和物である、前記[35]又は[36]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
[38]代謝性疾患の予防及び/又は治療のための医薬組成物として使用するための前記[1]〜[11]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。
[39]代謝性疾患が、2型糖尿病、糖尿病性合併症(糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症)、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である、前記[38]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
[40]医薬組成物の有効成分が、アンジオテンシンII受容体拮抗作用及びPPARγ活性化作用の両方の作用を併せ持つ化合物若しくはその塩、又はそれらの溶媒和物である、前記[38]又は[39]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
[41]循環器系疾患及び代謝性疾患の予防及び/又は治療のための医薬組成物として使用するための前記[1]〜[11]のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。
[42]循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症であり、代謝性疾患が、2型糖尿病、糖尿病性合併症(糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症)、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である、前記[41]に記載の化合物若しくはその塩、又はそれらの溶媒和物。
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−メトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−エチル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−エチルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−イソプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−イソプロピルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロペンチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロヘキシル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−メチル−3−{5−[2−(メチルチオ)エトキシ]ピリミジン−2−イル}ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−メチル−3−{5−[2−(メチルスルホニル)エトキシ]ピリミジン−2−イル}ピリミジン−4(3H)−オン、
3−{2−{5−{[4−ブチル−2−メチル−6−オキソ−1−(ピリジン−2−イル)−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−メチル−1−(4−メチルピリジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−メトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−エチル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−イソプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロペンチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロヘキシル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{{4−ブチル−2−メチル−1−{5−[2−(メチルチオ)エトキシ]ピリミジン−2−イル}−6−オキソ−1,6−ジヒドロピリミジン−5−イル}メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{{4−ブチル−2−メチル−1−{5−[2−(メチルスルホニル)エトキシ]ピリミジン−2−イル}−6−オキソ−1,6−ジヒドロピリミジン−5−イル}メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−2−メチル−3−(ピリジン−2−イル)ピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(5−メトキシピリジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−[3−クロロ−5−(トリフルオロメチル)ピリジン−2−イル]−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(5−メトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
5−{{5−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−2−イル}メチル}−6−ブチル−3−(4,6−ジメトキシピリミジン−2−イル)−2−メチルピリミジン−4(3H)−オン、
3−{2−{6−{[4−ブチル−1−(5−メトキシピリジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{6−{[4−ブチル−1−(5−メトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{6−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{6−{[4−ブチル−1−(4,6−ジメトキシピリミジン−2−イル)−2−メチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−3−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
からなる群から選ばれる化合物を挙げることができる。
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−イソプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−3−(5−エトキシピリミジン−2−イル)−2−イソプロピルピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロプロピル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−メトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロブチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロペンチル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
5−{{6−[2−(1H−テトラゾール−5−イル)フェニル]ピリジン−3−イル}メチル}−6−ブチル−2−シクロヘキシル−3−(5−エトキシピリミジン−2−イル)ピリミジン−4(3H)−オン、
3−{2−{5−{[4−ブチル−2−イソプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−メトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロブチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロペンチル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[4−ブチル−2−シクロヘキシル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン
からなる群から選ばれる化合物を挙げることができる。
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン
からなる群から選ばれる化合物を挙げることができる。
1.B環が式(IV)である化合物(Ia)の製造方法
本発明の一般式(I)で表される化合物のうち、一般式(Ia)で表される化合物は以下の方法により製造することができるが、これに限定されるものではない。即ち、下記反応経路図1に記載の通り、ピリジニルメチルハライド(VI)とβ−ケトエステル(VII)とを反応させ、得られた化合物(VIII)と酢酸アンモニウムを反応させ、次いで酸無水物(IX)又は酸クロリド(X)を反応させると、アシルアミノ化物(XI)が得られる。アシルアミノ化物(XI)にアミノ化合物(XII)を反応させると、ピリミジノン誘導体(XIII)が得られる。ピリミジノン誘導体(XIII)にアジド化合物を反応させると、本発明の一般式(Ia)で表される化合物を製造することができる。
[反応経路図1]
また、本発明の一般式(I)で表される化合物のうち、一般式(Ib)で表される化合物は以下の方法により製造することができるが、これに限定されるものではない。即ち、下記反応経路図2に記載の通り、ピリミジノン誘導体(XIII)とヒドロキシルアミンを反応させると、アミドオキシム体(XIV)が得られる。アミドオキシム体(XIV)とカルボニル試薬を反応させると、本発明の一般式(Ib)で表される化合物を製造することができる。
[反応経路図2]
s:シングレット(singlet)
d:ダブレット(doublet)
t:トリプレット(triplet)
q:カルテット(quartet)
m:マルチプレット(multiplet)
br:ブロード(broad)
J:カップリング定数(coupling constant)
Hz:ヘルツ(Hertz)
CDCl3:重クロロホルム
DMSO−d6:重ジメチルスルホキシド
1H-NMR:プロトン核磁気共鳴
IR:赤外線吸収スペクトル
0.87(3H, t, J=7 Hz), 1.18-1.32(2H, m), 1.47-1.59(2H, m), 2.34-2.39(1H, m), 2.55-2.67(1H, m), 3.20-3.29(2H, m), 3.73(3H, s), 3.84(1H, t, J=7 Hz), 7.50(1H, td, J=8, 1 Hz), 7.63-7.74(3H, m), 7.76-7.87(2H, m), 8.61(1H, s).
0.91(3H, t, J=7 Hz), 1.33-1.45(2H, m), 1.46-1.57(2H, m), 2.18(3H, s), 2.94(2H, t, J=6 Hz), 3.71(3H, s), 3.75(2H, s), 7.50(1H, t, J=8 Hz), 7.58(1H, d, J=8 Hz), 7.63-7.72(2H, m), 7.75-7.83(2H, m), 8.60(1H, s), 11.9(1H, s).
0.95(3H, t, J=7 Hz), 1.36-1.48(2H, m), 1.58-1.70(2H, m), 2.16(3H, s), 2.63-2.72(2H, m), 3.97(2H, s), 4.01(2H, s), 7.47(1H, m), 7.60-7.71(2H, m), 7.72-7.83(3H, m), 8.54(2H, s), 8.70(1H, d, J=1 Hz).
0.93(3H, t, J=7 Hz), 1.33-1.48(2H, m), 1.55-1.73(2H, m), 2.16(3H, s), 2.58-2.72(2H, m), 3.95(2H, s), 4.00(3H, s), 7.20-7.35(1H, m), 7.38-7.58(3H, m), 7.62-7.82(1H, m), 8.00-8.22(1H, m), 8.54(2H, s), 8.50-8.63(1H, m).
0.94(3H, t, J=7 Hz), 1.38-1.46(2H, m), 1.51(3H, t, J=7 Hz), 1.60-1.68(2H, m), 2.16(3H, s), 2.65-2.69(2H, m), 3.97(2H, s), 4.22(2H, q, J=7 Hz), 7.47(1H, m), 7.64-7.81(5H, m), 8.51(2H, s), 8.70(1H, d, J=1 Hz).
0.94(3H, t, J=7 Hz), 1.38-1.44(2H,m), 1.51(3H, t, J=7 Hz), 1.61-1.68(2H, m), 2.17(3H, s), 2.66-2.70(2H, m), 3.97(2H, s), 4.22(2H, q, J=7 Hz), 7.37(1H, m), 7.48-7.58(3H, m), 7.78(1H, m), 8.21(1H, m), 8.51(2H, s), 8.62(1H, m).
0.91(3H, t, J=7 Hz), 1.23(3H, t, J=8 Hz), 1.34-1.51(4H, m), 2.43 (2H, q, J=8 Hz), 2.89-2.99(2H, m), 3.70(3H, s), 3.75(2H, s), 7.49 (1H, td, J=8, 1 Hz), 7.58(1H, dd, J=8, 2 Hz), 7.64-7.73(2H, m), 7.77-7.86(2H, m), 8.60(1H, s), 11.88(1H, s).
0.94(3H, t, J=7 Hz), 1.18(3H, t, J=7 Hz), 1.35-1.46(2H, m),1.62-1.74(2H, m), 2.32(2H, q, J=7 Hz), 2.69(2H, t, J=8 Hz),3.96(2H, s), 4.00(3H, s), 7.47(1H, td, J=8, 1 Hz), 7.61-7.70(2H, m), 7.73-7.82(3H, m), 8.53(2H, s), 8.69(1H, s).
0.94(3H, t, J=7 Hz), 1.18(3H, t, J=7 Hz), 1.34-1.47(2H, m),1.60-1.75 (2H, m), 2.32(2H, q, J=7 Hz), 2.70(2H, t, J=8 Hz),3.96(2H, s), 4.01 (3H, s), 7.29-7.38(1H, m), 7.43-7.59(3H, m),7.76(1H, d, J=8 Hz), 8.18 (1H, s), 8.54(2H, s), 8.61(1H, br s).
0.94(3H, t, J=7 Hz), 1.18(3H, t, J=7 Hz), 1.37-1.47(2H, m),1.51(3H, t, J=7 Hz), 1.62-1.72(2H, m), 2.32(2H, q, J = 7 Hz), 2.66-2.72(2H, m), 3.97(2H, s), 4.22(2H, q, J=7 Hz), 7.47(1H, t, J=8 Hz), 7.64-7.69(2H, m), 7.74-7.83(3H, m), 8.51(2H, s), 8.70(1H, d, J=2 Hz).
0.94(3H, t, J=7 Hz), 1.18(3H, t, J=7 Hz), 1.36-1.47(2H, m), 1.51(3H, t, J=7 Hz), 1.61-1.74(2H, m), 2.33(2H, q, J=7 Hz), 2.70(2H, t, J=8 Hz), 3.97(2H, s), 4.22(2H, q, J=7 Hz), 7.38(1H, d, J=8 Hz), 7.47-7.60(3H, m), 7.78(1H, dd, J=8, 2 Hz), 8.20-8.28(1H, m), 8.51(2H, s), 8.64(1H, s).
0.90(3H, t, J=7 Hz), 1.25(6H, d, J=7 Hz), 1.33-1.55(4H, m),2.49-2.63(1H, m), 2.90-2.99(2H, m), 3.71(3H, s), 3.75(2H, s),7.49(1H, td, J=8, 1 Hz), 7.59(1H, dd, J=8, 2 Hz), 7.64-7.73(2H, m), 7.79(1H, dd, J=8, 1 Hz), 7.83(1H, dd, J=8, 1 Hz), 8.61(1H, d, J=1 Hz), 11.90(1H, s).
0.94(3H, t, J=7 Hz), 1.20(6H, d, J=7 Hz), 1.33-1.49(2H, m), 1.62-1.75 (2H, m), 2.21-2.35(1H, m), 2.69(2H, t, J=8 Hz), 3.95(2H, s), 4.00(3H, s), 7.46(1H, td, J=8, 1 Hz), 7.61-7.70(2H, m), 7.74-7.83(3H, m), 8.53(2H, s), 8.69(1H, d, J=1 Hz).
0.94(3H, t, J=7 Hz), 1.20(6H, d, J=7 Hz), 1.33-1.47(2H, m), 1.60-1.75 (2H, m), 2.22-2.35(1H, m), 2.70(2H, t, J=8 Hz), 3.95(2H, s), 4.01(3H, s), 7.33(1H, d, J=8 Hz), 7.45-7.57(3H, m), 7.77(1H, d, J=7 Hz), 8.18(1H, br s), 8.53(2H, s), 8.61(1H, s).
0.94(3H, t, J=7 Hz), 1.19(6H, d, J=7 Hz), 1.35-1.45(2H, m), 1.51 (3H, t, J=7 Hz), 1.63-1.74(2H, m), 2.22-2.35(1H, m), 2.69(2H, t, J=8 Hz), 3.95(2H, s), 4.22(2H, q, J=7 Hz), 7.46(1H, td, J=8, 1 Hz), 7.62-7.70(2H, m), 7.75-7.83(3H, m), 8.50(2H, s), 8.67-8.71(1H, m).
0.94(3H, t, J=7 Hz), 1.20(6H, d, J=7 Hz), 1.35-1.46(2H, m), 1.51(3H, t, J=7 Hz), 1.63-1.75(2H, m), 2.22-2.35(1H, m), 2.71(2H, t, J=7 Hz), 3.96(2H, s), 4.22(2H, q, J=7 Hz), 7.37-7.45(1H, m), 7.48-7.63(3H, m), 7.81(1H, dd, J=8, 2 Hz), 8.25-8.33(1H, m), 8.51(2H, s), 8.67 (1H, s).
0.78-0.98(5H, m), 1.02-1.12(2H, m), 1.31-1.65(5H, m), 2.88-3.02(2H, m), 3.72(3H, s), 3.76(2H, s), 7.50(1H, t, J=8 Hz), 7.60(1H, d, J=8 Hz), 7.63-7.74(2H, m), 7.76-7.87(2H, m), 8.61(1H, s), 12.2(1H, s).
0.82-0.87(2H, m), 0.92(3H, t, J=7 Hz), 1.07-1.15(1H, m), 1.21-1.27 (2H, m), 1.32-1.41(2H, m), 1.53-1.64(2H, m), 2.61(2H, t, J=8 Hz), 3.94(2H, s), 4.01(3H, s), 7.44-7.49(1H, m), 7.66(2H, t, J=8 Hz), 7.74-7.82(3H, m), 8.56(2H, s), 8.68(1H, d, J=2 Hz).
0.82-0.89(2H, m), 0.92(3H, t, J=7 Hz), 1.06-1.15(1H, m), 1.21-1.27 (2H, m), 1.31-1.43(2H, m), 1.56-1.67(2H, m), 2.63(2H, t, J=8 Hz), 3.94(2H, s), 4.01(3H, s), 7.40(1H, d, J=8 Hz), 7.47-7.62(3H, m), 7.75-7.82(1H, m), 8.23-8.32(1H, m), 8.56(2H, s), 8.65(1H, s).
0.91(3H, t, J=7 Hz), 1.33-1.54(4H, m), 2.19-2.44(6H, m), 2.95(2H, t, J=8 Hz), 3.12-3.25(1H, m), 3.70(3H, s), 3.75(2H, s), 7.49(1H, td, J=8, 1 Hz), 7.58(1H, dd, J=8, 2 Hz), 7.64-7.73(2H, m), 7.76-7.86(2H, m), 8.60(1H, s), 11.78(1H, s).
0.96(3H, t, J=7 Hz), 1.34-1.51(2H, m), 1.65-1.83(6H, m), 2.36-2.51(2H, m), 2.71(2H, t, J=8 Hz), 3.07-3.17(1H, m), 3.96(2H, s), 4.00 (3H, s), 7.46(1H, td, J=8, 1 Hz), 7.61-7.70(2H, m), 7.73-7.82(3H, m), 8.52(2H, s), 8.69(1H, d, J=1 Hz).
0.95(3H, t, J=7 Hz), 1.34-1.50(2H, m), 1.65-1.83(6H, m), 2.37-2.51 (2H, m), 2.72(2H, t, J=8 Hz), 3.04-3.20(1H, m), 3.96(2H, s), 4.01(3H, s), 7.31(1H, d, J=8 Hz), 7.45-7.56(3H, m), 7.76(1H, d, J=8 Hz), 8.16(1H, br s), 8.52(2H, s), 8.59(1H, s).
0.96(3H, t, J=7 Hz), 1.39-1.47(2H, m), 1.51(3H, t, J=7 Hz), 1.61-1.84 (6H, m), 2.36-2.51(2H, m), 2.67-2.75(2H, m), 3.03-3.16(1H, m), 3.96(2H, s), 4.22(2H, q, J=7 Hz), 7.48(1H, dd, J=8, 1 Hz), 7.62-7.70 (2H, m), 7.72-7.83(3H, m), 8.49(2H, s), 8.69(1H, d, J=2 Hz).
0.95(3H, t, J=7 Hz), 1.36-1.47(2H, m), 1.51(3H, t, J=7 Hz), 1.63-1.85 (6H, m), 2.37-2.50(2H, m), 2.73(2H, t, J=8 Hz), 3.07-3.18(1H, m), 3.97(2H, s), 4.22(2H, q, J=7 Hz), 7.40(1H, d, J=8 Hz), 7.48-7.62(3H, m), 7.76-7.82(1H, m), 8.24-8.31(1H, m), 8.49(2H, s), 8.66(1H, s).
0.90(3H, t, J=7 Hz), 1.33-2.03(12H, m), 2.70-2.82(1H, m), 2.89-2.99 (2H, m), 3.71(3H, s), 3.75(2H, s), 7.49(1H, td, J=8, 1 Hz), 7.59(1H, dd, J=8, 2 Hz), 7.64-7.73(2H, m), 7.76-7.86(2H, m), 8.60(1H, s), 11.89(1H, s).
0.94(3H, t, J=7 Hz), 1.34-1.54(7H, m), 1.60-1.80(6H, m), 1.90-2.03 (2H, m), 2.42-2.48(1H, m), 2.64-2.70(2H, m), 3.95(2H, s), 4.22(2H, q, J=7 Hz), 7.47(1H, td, J=8, 1 Hz), 7.63-7.69(2H, m), 7.77(2H, dd, J=8, 1 Hz), 7.80(1H, dd, J=8, 1 Hz), 8.51(2H, s), 8.69(1H, d, J=2 Hz).
0.94(3H, t, J=7 Hz), 1.52(3H, t, J=7 Hz), 1.57-1.78(8H,m),1.81-1.93(5H, m), 2.70(2H, t, J=8 Hz), 3.94(2H, s), 4.23(2H, q, J=7 Hz), 7.38(1H, d, J=9 Hz), 7.47-7.62(3H, m), 7.78(1H, d, J=8 Hz), 8.22-8.29(1H, m), 8.52(2H, s), 8.65(1H, s).
0.90(3H, t, J=7 Hz), 1.16-2.03(14H, m), 2.45-2.59(1H, m), 2.89-2.98(2H, m), 3.71(3H, s), 3.75(2H, s), 7.49(2H, td, J=8, 1 Hz), 7.58(1H, dd, J=8, 2 Hz), 7.63-7.74(2H, m), 7.76-7.86(2H, m), 8.61(1H, s), 11.84(1H, br s).
0.94(3H, t, J=7 Hz), 1.16-1.91(17H, m), 2.65-2.71(2H, m), 3.95(2H, s), 4.23(2H, q, J=7 Hz), 7.47(1H, td, J=8, 1 Hz), 7.63-7.68(2H, m), 7.75-7.82(3H, m), 8.51(2H, s), 8.69(1H, d, J=1 Hz).
0.94(3H, t, J=7 Hz), 1.51(3H, t, J=7 Hz), 1.61-1.82(8H, m), 1.90-2.05(5H, m), 2.46(2H, t, J=8 Hz), 2.69(2H, t, J=7 Hz), 3.95(2H, s), 4.22(2H, q, J=7 Hz), 7.39(1H, d, J=8 Hz), 7.48-7.62(3H, m), 7.79(1H, dd, J=8, 2 Hz), 8.22-8.31(1H, m), 8.51(2H, s), 8.65(1H, s).
0.95(3H, t, J=7 Hz), 1.33-1.48(2H, m), 1.57-1.73(2H, m), 2.17(3H, s), 2.24(3H, s), 2.67(2H, t, J=8 Hz), 2.96(2H, t, J=7 Hz), 3.97(2H, s), 4.33(2H, t, J=7 Hz), 7.47(1H, t, J=8 Hz), 7.62-7.70(2H, m), 7.73-7.83(3H, m), 8.55(2H, s), 8.70(1H, s).
0.82-1.00(3H, m), 1.33-1.47(2H, m), 1.55-1.73(2H, m), 2.15(3H, s), 2.23(3H, s), 2.55-2.76(2H, m), 2.95(2H, t, J=7 Hz), 3.82-4.03(2H, m), 4.33(2H, t, J=7 Hz), 7.07-7.33(1H, m), 7.35-7.57(3H, m), 7.59-7.80(1H, m), 7.85-8.15(1H, m), 8.47-8.62(1H, m), 8.55(2H, s).
0.94(3H, t, J=7 Hz), 1.34-1.47(2H, m), 1.54-1.71(2H, m), 2.16(3H, s), 2.66(2H, t, J=8 Hz), 3.09(3H, s), 3.55(2H, t, J=5 Hz), 3.93(2H, s), 4.64(2H, t, J=5 Hz), 7.10-7.24(1H, m), 7.31-7.55(3H, m), 7.65-7.77(1H, m), 7.92-8.04(1H, m), 8.45-8.53(1H, m), 8.59(2H, s).
0.95(3H, t, J=7 Hz), 1.43(2H, sextet, J=8 Hz), 1.61-1.69(2H, m), 2.17(3H, s), 2.66-2.70(2H, m), 3.97(2H, s), 7.36-7.50(3H, m), 7.65-7.69(2H,m), 7.76-7.81(3H, m), 7.93(1H, m), 8.67-8.70(2H, m).
0.94(3H, t, J=7 Hz), 1.42(2H, sextet, J=8 Hz), 1.60-1.68(2H, m), 2.17(3H, s), 2.64-2.68(2H, m), 3.93(2H, s), 7.33-7.56(6H, m), 7.74-7.77(2H, m), 7.95(1H, dd, J=8,2 Hz), 8.45(1H, s), 8.67(1H, d, J=4 Hz).
0.95(3H, t, J=7 Hz), 1.42(2H, sextet, J=8 Hz), 1.60-1.69(2H, m), 2.17(3H, s), 2.45(3H. s), 2.66-2.70(2H, m), 3.96(2H, s), 7.19(1H, s), 7.24-7.27(2H, m), 7.48(1H, m), 7.65-7.69(2H, m),7.76-7.82(2H, m), 8.51(1H, d, J=5 Hz), 8.70(1H, s).
0.95(3H, t, J=7 Hz), 1.42(2H, sextet, J=8 Hz), 1.61-1.69(2H, m), 2.17(3H, s), 2.46(3H, s), 2.65-2.69(2H, m), 3.94(2H, s), 7.21(1H, s), 7.24-7.28(2H, m), 7.37-7.60(3H, m), 7.78(1H, dd, J=8,2 Hz), 7.85(1H, d, J=7 Hz), 8.50-8.51(2H, m).
0.94(3H, t, J=7 Hz), 1.43(2H, quint, J=8 Hz), 1.61-1.68(2H, m), 2.17(3H, s), 2.65-2.69(2H, m), 3.95(2H, s), 4.01(3H, s), 7.36-7.69(4H, m), 7.76-7.86(2H, m), 8.51(1H, br), 8.54(2H, s).
0.95(3H, t, J=7 Hz), 1.38-1.48(2H, m), 1.51(3H, t, J=7 Hz), 1.62-1.68(2H, m),2.17(3H, s), 2.66-2.70(2H, m),3.95(2H, s), 4.22(2H, q, J=7 Hz), 7.38-7.61(4H, m), 7.79(1H, d, J=7 Hz), 7.90(1H, d, J=7 Hz), 8.51(2H, s), 8.54(1H, s).
0.95(3H, t, J=7 Hz), 1.18(3H, t, J=7 Hz), 1.36-1.50(2H, m), 1.61-1.75(2H, m), 2.32(2H, q, J=7 Hz), 2.71(2H, t, J=8 Hz), 3.95(2H, s), 4.00(3H, s), 4.79(1H, br s), 7.38(1H, d, J=8 Hz), 7.45(1H, dd, J=8, 1 Hz), 7.51(1H, dd, J=8, 1 Hz), 7.59(1H, td, J=8, 2 Hz), 7.79(1H, dd, J=8, 2 Hz), 7.89(1H, dd, J=8, 1 Hz), 8.52-8.55(3H, m).
0.94(3H, t, J=7 Hz), 1.18(3H, t, J=7 Hz), 1.34-1.47(2H, m), 1.51(3H, t, J=7 Hz), 1.60-1.74(2H, m), 2.32(2H, q, J=7 Hz), 2.70(2H, t, J=8 Hz), 3.94(2H, s), 4.22(2H, q, J=7 Hz), 7.36(1H, d, J=8 Hz), 7.41-7.61(3H, m), 7.77(1H, dd, J=8, 2 Hz), 7.85(1H, dd, J=8, 1 Hz), 8.48-8.53(3H, m).
0.95(3H, t, J=7 Hz), 1.19(6H, d, J=7 Hz), 1.31-1.49(2H, m), 1.60-1.75(2H, m), 2.23-2.35(1H, m), 2.70(2H, t, J=8 Hz), 3.93(2H, s), 4.00(3H, s), 7.36(1H, d, J=8 Hz), 7.43(1H, dd, J=7, 1 Hz), 7.49(1H, dd, J=7, 1 Hz), 7.57(1H, td, J=8, 1 Hz), 7.79(1H, dd, J=8, 2 Hz), 7.85(1H, dd, J=8, 1 Hz), 8.50(1H, d, J=2 Hz), 8.53(2H, s).
0.95(3H, t, J=7 Hz), 1.20(6H, d, J=7 Hz), 1.36-1.46(2H, m), 1.51(3H, t, J=7 Hz), 1.62-1.74(2H, m), 2.23-2.35(1H, m), 2.72(2H, t, J=8 Hz), 3.94(2H, s), 4.22(2H, q, J=7 Hz), 7.40(1H, d, J=9 Hz), 7.46(1H, dd, J=8, 1 Hz), 7.52(1H, td, J=8, 2 Hz), 7.61(1H, td, J=8, 2 Hz), 7.82(1H, dd, J=8, 2 Hz), 7.95(1H, dd, J=8, 1 Hz), 8.51(2H, s), 8.58(1H, d, J=2 Hz).
0.81-0.89(2H, m), 0.93(3H, t, J=7 Hz), 1.06-1.15(1H, m), 1.24(2H, t, J=4 Hz), 1.32-1.44(2H, m), 1.55-1.67(2H, m), 2.63(2H, t, J=8 Hz), 3.92(2H, s), 4.00(3H, s), 7.37(1H, d, J=8 Hz), 7.45(1H, d, J=8 Hz), 7.51(1H, dd, J=8, 1 Hz), 7.59(1H, td, J=8, 1 Hz), 7.78(1H, dd, J=8, 2 Hz), 7.89(1H, d, J=7 Hz), 8.52(1H, d, J=2 Hz), 8.56(2H, s).
0.79-0.87(2H, m), 0.92(3H, t, J=8 Hz), 1.09-1.16(1H, m), 1.18-1.29(2H, m), 1.30-1.43(2H, m), 1.51(3H, t, J=7 Hz), 1.54-1.66(2H, m), 2.61(2H, t, J=8 Hz), 3.94(2H, s), 4.22(2H, q, J=7 Hz), 7.47(1H, t, J=8 Hz), 7.57-7.69(2H, m), 7.71-7.83(3H, m), 8.54(2H, s), 8.68(1H, s).
0.76-0.87(2H, m), 0.92(3H, t, J=7 Hz), 1.05-1.15(1H, m), 1.16-1.28(2H, m), 1.32-1.44(2H, m), 1.51(3H, t, J=7 Hz), 1.54-1.66(2H, m), 2.61(2H, t, J=8 Hz), 3.91(2H, s), 4.22(2H, q, J=7 Hz), 7.34(1H, d, J=8 Hz), 7.38-7.50(2H, m), 7.51-7.59(1H, m), 7.71-7.86(2H, m), 8.46(1H, s), 8.54 (2H, s).
0.96(3H, t, J=7 Hz), 1.35-1.51(2H, m), 1.64-1.85(6H, m), 2.37-2.53(2H, m), 2.72(2H, t, J=8 Hz), 3.04-3.20(1H, m), 3.94(2H, s), 4.00(3H, s), 7.34(1H, d, J=8 Hz), 7.39-7.44(1H, m), 7.44-7.49(1H, m), 7.51-7.59(1H, m), 7.74-7.83(2H, m), 8.48(1H, d, J=2 Hz), 8.52(2H, s).
0.97(3H, t, J=7 Hz), 1.35-1.47(2H, m), 1.48-1.83(9H, m), 2.38-2.52(2H, m), 2.74(2H, t, J=8 Hz), 3.03-3.18(1H, m), 3.95(2H, s), 4.22(2H, q, J=7 Hz), 7.40(1H, d, J=8 Hz), 7.46(1H, d, J=8 Hz), 7.54(1H, dd, J=8, 2 Hz), 7.61(1H, td, J=8, 2 Hz), 7.81(1H, dd, J=8, 2 Hz), 7.95(1H, dd, J=8, 1 Hz), 8.49(2H, s), 8.58(1H, d, J=2 Hz).
0.94(3H, t, J=7 Hz), 1.32-1.57(7H, m), 1.60-1.85(6H, m), 1.90-2.06(2H, m), 2.36-2.52(1H, m), 2.68(2H, t, J=7 Hz), 3.93(2H, s), 4.22(2H, q, J=7 Hz), 7.35(1H, d, J=8 Hz), 7.40-7.60(3H, m), 7.78(1H, dd, J=8, 2 Hz), 7.83(1H, dd, J=8, 1 Hz), 8.49(1H, d, J=2 Hz), 8.51(2H, s).
0.89-1.07(5H, m), 1.34-1.94(16H, m), 2.68(2H, t, J=8 Hz), 3.92(2H, s), 4.23(2H, q, J=7 Hz), 7.34(1H, d, J=8 Hz), 7.39-7.49(2H, m), 7.50-7.59(1H, m), 7.74-7.83(2H, m), 8.47(1H, d, J=2 Hz), 8.51(2H, s).
0.95(3H, t, J=7 Hz), 1.40-1.46(2H, m), 1.50-1.70(2H, m), 2.17(3H, s), 2.24(3H, s), 2.68-2.71(2H, m), 2.96(2H, t, J=7 Hz), 3.96(2H, s), 4.33(2H, t, J=7 Hz), 7.40-7.62(4H, m), 7.66-7.97(2H, m), 8.55(2H, s), 8.58(1H, s).
0.95(3H, t, J=7 Hz), 1.40-1.46(2H, m), 1.65-1.70(2H, m), 2.18(3H, s), 2.67-2.71(2H, m), 3.09(3H, s), 3.53-3.55(2H, m), 3.92(2H, s), 4.63-4.66(2H, m), 7.36-7.60(4H, m), 7.74(1H, d, J=8 Hz), 7.88(1H, d, J=8 Hz), 8.59(1H, s), 8.60(2H, s).
0.89(3H, t, J=7 Hz), 1.24-1.34(2H, m), 1.54-1.61(2H, m), 2.59-2.76(2H, m), 3.37-3.55(2H, m), 3.73(3H, s), 4.37(1H, t, J=7 Hz), 7.33(1H, d, J=8 Hz), 7.50(2H, t, J=7 Hz), 7.66-7.70(1H, m), 7.78-7.83(2H, m), 8.63(1H, d, J=2 Hz).
0.89(3H, t, J=7 Hz), 1.27-1.40(2H, m), 1.47-1.59(2H, m), 2.24(3H, s), 3.14(2H, t, J=8 Hz), 3.78(3H, s), 3.88(2H, s), 7.42-7.56(3H, m), 7.65-7.91(3H, m), 8.63(1H, s), 10.9(1H, s).
0.93(3H, t, J=7 Hz), 1.42(2H, sextet, J=8 Hz), 1.60-1.75(2H, m), 2.17(3H, s), 2.74-2.78(2H, m), 4.17(2H, s), 7.38-7.50(5H, m), 7.67(1H, m), 7.77-7.80(2H, m), 7.93(1H, m), 8.65(1H, d, J=2 Hz), 8.68(1H, d, J=3 Hz).
0.89(3H, t, J=7 Hz), 1.30-1.35(2H, m), 1.50-1.58(2H, m), 2.18(3H, s), 2.51-2.54(2H, m), 3.75(2H, s), 6.99(1H, d, J=8 Hz), 7.16(1H, d, J=8 Hz), 7.31-7.36(3H, m), 7.48- 7.56(2H, m), 7.83-7.87(2H, m), 7.97(1H, s), 8.56(1H, d, J=4 Hz).
0.93(3H, t, J=7 Hz), 1.37-1.46(2H, m), 1.58-1.66(2H, m), 2.18(3H, s), 2.76(2H, t, J=8 Hz), 3.92(3H, s), 4.16(2H, s), 7.27-7.30(1H, m), 7.38-7.49(4H, m), 7.65-7.69(1H, m), 7.77-7.79(2H, m), 8.30(1H, d, J=3 Hz), 8.65(1H, d, J=2 Hz).
0.87(3H, t, J=7 Hz), 1.21-1.30(2H, m), 1.40-1.48(2H, m), 2.09(3H, s), 2.38(2H, t, J=8 Hz), 3.60(2H, s), 3.90(3H, s), 7.00(1H, d, J=8 Hz), 7.14(2H, dd, J=8, 2 Hz), 7.20(1H, d, J=9 Hz), 7.34-7.38(2H, m), 7.53-7.61(2H, m), 7.84(1H, d, J=7 Hz), 7.90(1H, s), 8.21(1H, d, J=3 Hz).
0.94(3H, t, J=7 Hz), 1.37-1.47(2H, m), 1.57-1.68(2H, m), 2.16(3H, s), 2.70-2.83(2H, m), 4.19(2H, s), 7.38(1H, d, J=8 Hz), 7.46-7.53(2H, m), 7.65-7.69(1H, m), 7.77-7.83(2H, m),7.89(1H, m), 8.65(1H, d, J=2 Hz), 8.84(1H, s).
0.87(3H, t, J=7 Hz), 1.22-1.30(2H, m), 1.43-1.50(2H, m), 2.09(3H, s), 2.35-2.43(2H, m), 3.55(2H, dd, J=19, 16 Hz), 6.95(1H, d, J=8 Hz), 7.11-7.14(1H, m), 7.38-7.40(1H, m), 7.54-7.61(2H, m), 7.86-7.89(1H, m), 7.94(1H, m), 8.18(1H, d, J=2 Hz), 8.81(1H, s).
0.93(3H, t, J=7 Hz), 1.36-1.45(2H, m), 1.57-1.65(2H, m), 2.16(3H, s), 2.75(2H, t, J=8 Hz), 4.00(3H, s), 4.17(2H, s), 7.40-7.49(3H, m), 7.64-7.69(1H, m), 7.77-7.79(2H, m), 8.54(2H, s), 8.65(1H, d, J=2 Hz).
0.86(3H, t, J=7 Hz), 1.20-1.29(2H, m), 1.41-1.49(2H, m), 2.09(3H, s), 2.43(2H, t, J=8 Hz), 3.62(2H, s), 3.98(3H, s), 7.00(1H, d, J=8 Hz), 7.13(1H, dd, J=8, 2 Hz), 7.39(1H, d, J=8 Hz), 7.51-7.60(2H, m), 7.84(1H, d, J=8 Hz), 7.95(1H, d, J=2 Hz), 8.48(2H, s).
0.92(3H, t, J=7 Hz), 1.36-1.45(2H, m), 1.51(3H, t, J=7 Hz), 1.57-1.65(2H, m), 2.16(3H, s), 2.75(2H, t, J=8 Hz), 4.18(2H, s), 4.22(2H, q, J=7 Hz), 7.41-7.52(3H, m), 7.64-7.68(1H, m), 7.77-7.81(2H, m), 8.52(2H, s), 8.63-8.65(1H, m).
0.86(3H, t, J=7 Hz), 1.18-1.29(2H, m), 1.40-1.50(2H, m), 1.49(3H, t, J=7 Hz), 2.09(3H, s), 2.42(2H, t, J=8 Hz), 3.61(2H, s), 4.20(q, 2H, J=7 Hz), 7.00(1H, d, J=8 Hz), 7.12(1H, dd, J=8, 2 Hz), 7.39(1H, d, J=8 Hz), 7.51-7.61(2H, m), 7.86(1H, d, J=7 Hz), 7.74(1H, d, J=2 Hz), 8.46(2H, s).
0.93(3H, t, J=7 Hz), 1.38-1.47(2H, m), 1.56-1.67(2H, m), 2.24(3H, s), 2.76(2H, t, J=8 Hz), 3.96(6H, s), 4.19(2H, s), 6.12(1H, s), 7.45-7.50(3H, m), 7.65-7.69(1H, m), 7.77-7.82(2H, m), 8.66(1H, d, J=2 Hz).
0.88(3H, t, J=7 Hz), 1.22-1.32(2H, m), 1.43-1.50(2H, m), 2.17(3H, s), 2.42(2H, t, J=8 Hz), 3.62(2H, s), 3.89(6H, s), 6.06(1H, s), 7.02(1H, d, J=8 Hz), 7.14(1H, dd, J=8, 2 Hz), 7.40(1H, d, J=8 Hz), 7.53-7.62(2H, m), 7.31(1H, d, J=8 Hz), 7.95(1H, s).
0.90(3H, t, J=7 Hz), 1.34-1.43(2H, m), 1.54-1.62(2H, m), 2.16(3H, s), 2.71(2H, t, J=8 Hz), 3.91(3H, s), 4.13(2H, s), 4.50(2H, s), 7.29-7.42(5H, m), 7.45-7.49(1H, m), 7.55-7.57(1H, m), 7.66-7.69(1H, m), 8.29(1H, d, J=3 Hz), 8.60(1H, d, J=2 Hz).
0.92(3H, t, J=7 Hz), 1.30-1.39(2H, m), 1.49-1.57(2H, m), 2.11(3H, s), 2.51(2H, t, J=8 Hz), 3.62(2H, s), 3.91(3H, s), 7.15(1H, d, J=8 Hz), 7.23(2H, d, J=9 Hz), 7.32-7.39(2H, m), 7.48-7.52(2H, m), 7.57-7.61(1H, m), 7.70(1H, d, J=8 Hz), 7.99(1H, s), 8.18(1H, d, J=3 Hz).
0.90(3H, t, J=7 Hz), 1.34-1.43(2H, m), 1.54-1.62(2H, m), 2.15(3H, s), 2.73(2H, t, J=8 Hz), 3.99(3H, s), 4.13(2H, s), 4.50(2H, s), 7.28-7.42(3H, m), 7.45-7.49(1H, m), 7.53-7.57(1H, m), 7.66-7.69(1H, m), 8.53(2H, s), 8.59(1H, d, J=2 Hz).
0.90(3H, t, J=7 Hz), 1.27-1.36(2H, m), 1.45-1.53(2H, m), 2.11(3H, s), 2.45(2H, t, J=8 Hz), 3.56(2H, s), 4.00(3H, s), 7.12(1H, d, J=8Hz), 7.38(1H, d, J=8 Hz), 7.50-7.60(2H, m), 7.60-7.64(1H, m), 7.72(1H, d, J=1 Hz), 7.90(1H, s), 8.51(2H, s).
0.90(3H, t, J=7 Hz), 1.35-1.43(2H, m), 1.50(3H, t, J=7 Hz), 1.51-1.62(2H, m), 2.15(3H, s), 2.72(2H, t, J=8 Hz), 4.13(2H, s), 4.21(2H, q, J=7 Hz), 4.51(2H, s), 7.28-7,49(4H, m), 7.55-7.57(1H, m), 7.66-7.69(1H, m), 8.50(2H, s), 8.59-8.60(1H, m).
0.90(3H, t, J=7 Hz), 1.27-1.36(2H, m), 1.45-1.52(5H, m), 2.11(3H, s), 2.49(2H, t, J=8 Hz), 3.59(2H, s), 4.22(2H, q, J=7 Hz), 7.18(1H, d, J=8 Hz), 7.38(1H, d, J=8 Hz), 7.50-7.55(2H, m), 7.60-7.64(1H, m), 7.72(1H, d, J=8 Hz), 7.93-7.97(1H, m), 8.49(2H, s).
0.92(3H, t, J=7 Hz), 1.36-1.45(2H, m), 1.56-1.64(2H, m), 2.23(3H, s), 2.73(2H, t, J=8 Hz), 3.95(6H, s), 4.14(2H, s), 4.49(2H, s), 6.12(1H, s), 7.32-7.43(3H, m), 7.46-7.50(1H, m), 7.56-7.58(1H, m), 7.69-7.71(1H, m), 8.57-8.61(1H, m).
0.92(3H, t, J=7 Hz), 1.31-1.40(2H, m), 1.50-1.58(2H, m), 2.18(3H, s), 2.51(2H, t, J=8 Hz), 3.67(2H, s), 3.92(6H, s), 6.08(1H, s), 7.21(1H, d, J=8 Hz), 7.41(1H, d, J=8 Hz), 7.50-7.56(2H, m), 7.63(1H, t, J=8 Hz), 7.74(1H, d, J=8 Hz), 8.01(1H, d, J=2 Hz).
0.87(3H, t, J=7.4 Hz), 1.50-1.55(2H, m), 2.36-2.68(2H, m), 3.21-3.27(2H, m), 3.73(3H, s), 3.84(1H, t, J=7.6 Hz), 7.50(1H, td, J=7.6, 1.4 Hz), 7.64-7.73(3H, m), 7.77-7.85(2H, m), 8.61(1H, br s).
0.99(3H, t, J=7.4 Hz), 1.19-1.29(8H, m), 2.49-2.62(1H, m), 2.88-2.97(2H, m), 3.71(3H, s), 3.76(2H, s), 7.51(1H, dd, J=7.6, 1.3 Hz), 7.59(1H, dd, J=8.1, 2.1 Hz), 7.64-7.73(2H, m), 7.77-7.86(2H, m), 8.60(1H, s), 11.90(1H, s).
0.97(3H, t, J=7.4 Hz), 1.17(6H, d, J=6.6 Hz), 1.49(3H, t, J=6.9 Hz), 1.66-1.77(2H, m), 2.19-2.32(1H, m), 2.60-2.70(2H, m), 3.93(2H, s), 4.10(2H, q, J=7.1 Hz), 7.45(1H, td, J=7.7, 1.1 Hz), 7.60-7.67(2H, m), 7.73-7.80(3H, m), 8.49(2H, s), 8.67(1H, d, J=1.3 Hz).
0.98(3H, t, J=7.3 Hz), 1.19(6H, d, J=6.6 Hz), 1.51(3H, t, J=7.0 Hz), 1.68-1.78(2H, m), 2.25-2.32(1H, m), 2.63-2.70(2H, m), 3.92(2H, s), 4.22(2H, q, J=6.9 Hz), 4.72(2H, br s), 7.40(1H, td, J=7.5, 1.3 Hz), 7.43(1H, d, J=8.5 Hz), 7.49(1H, td, J=7.6, 1.5 Hz), 7.55(1H, dd, J=7.6, 1.2 Hz), 7.58(1H, dd, J=7.8, 1.2 Hz), 7.66(1H, dd, J=8.2, 2.3 Hz), 8.51(2H, s), 8.60(1H, d, J=1.7 Hz).
1.01(3H, t, J=7.3 Hz), 1.19(6H, d, J=6.6 Hz), 1.51(3H, t, J=7.0 Hz), 1.71-1.82(2H, m), 2.26-2.32(1H, m), 2.66-2.73(2H, m), 3.95(2H, s), 4.22(2H, q, J=7.0 Hz), 7.39(1H, d, J=8.1 Hz), 7.45(1H, d, J=8.1 Hz), 7.51(1H, t, J=7.6 Hz), 7.60(1H, t, J=7.7 Hz), 7.83(1H, dd, J=8.1, 1.7 Hz), 7.93(1H, d, J=7.8 Hz), 8.51(2H, s), 8.56(1H, s).
0.83-1.10(8H, m), 1.58-1.62(2H, m), 2.87-2.96(2H, m), 3.71(3H, s), 3.76(2H, s), 7.49(1H, td, J=7.6, 1.3 Hz), 7.58(1H, dd, J=8.1, 2.1 Hz), 7.65-7.72(2H, m), 7.77-7.86(2H, m), 8.61(1H, s), 12.15(1H, s).
0.80-0.87(2H, m), 0.96(3H, t, J=7.5 Hz), 1.08-1.14(1H, m), 1.21-1.25(2H, m), 1.51(3H, t, J=7.0 Hz), 1.61-1.72(2H, m), 2.57-2.61(2H, m), 3.94(2H, s), 4.22(2H, q, J=6.9 Hz), 7.47(1H, td, J=7.6, 1.1 Hz), 7.63-7.69(2H, m), 7.74-7.82(3H, m), 8.54(2H, s), 8.68(1H, d, J=1.8 Hz).
0.79-0.88(2H, m), 0.94(3H, t, J=7.4 Hz), 1.06-1.15(1H, m), 1.19-1.26(2H, m), 1.51(3H, t, J=7.1 Hz), 1.59-1.71(2H, m), 2.53-2.64(2H, m), 3.91(2H, s), 4.22(2H, q, J=7.0 Hz), 4.73(2H, s), 7.40(1H, td, J=7.3, 1.6 Hz), 7.43(1H, d, J=7.6 Hz), 7.49(1H, td, J=7.6, 1.5 Hz), 7.55(1H, dd, J=7.6, 1.0 Hz), 7.58(1H, dd, J=7.7, 0.9 Hz), 7.64(1H, dd, J=8.2, 2.3 Hz), 8.54(2H, s), 8.59(1H, d, J=2.2 Hz).
0.81-0.89(1H, m), 0.97(3H, t, J=7.4 Hz), 1.06-1.15(1H, m), 1.21-1.27(2H, m), 1.51(3H, t, J=7.0 Hz), 1.66-1.70(2H, m), 2.61(2H, t, J=7.4 Hz), 3.94(2H, s), 4.22(2H, q, J=6.8 Hz), 7.39(1H, d, J=8.3 Hz), 7.45(1H, d, J=7.6 Hz), 7.52(1H, t, J=7.6 Hz), 7.60(1H, t, J=7.2 Hz), 7.81(1H, dd, J=7.9, 1.8 Hz), 7.94(1H, d, J=7.8 Hz), 8.54(2H, s), 8.55(1H, s).
0.86(3H, t, J=6.9 Hz), 1.19-1.32(4H, m), 1.49-1.55(2H, m), 2.35-2.67(2H, m), 3.20-3.26(2H, m), 3.73(3H, s), 3.84(1H, t, J=7.4 Hz), 7.50(1H, td, J=7.6, 1.3 Hz), 7.64-7.73(3H, m), 7.77-7.85(2H, m), 8.61(1H, br s).
0.90(3H, t, J=6.8 Hz), 1.20(6H, d, J=6.8 Hz), 1.32-1.39(4H, m), 1.51(3H, t, J=7.0 Hz), 1.65-1.75(2H, m), 2.24-2.33(1H, m), 2.65-2.71(2H, m), 3.95(2H, s), 4.22(2H, q, J=7.0 Hz), 7.47(1H, td, J=7.6, 1.1 Hz), 7.63-7.69(2H, m), 7.76-7.82(3H, m), 8.51(2H, s), 8.70(1H, d, J=1.5 Hz).
0.90(3H, t, J=7.0 Hz), 1.21(6H, t, J=12.2 Hz), 1.30-1.39(4H, m), 1.51(3H, t, J=7.0 Hz), 1.65-1.74(2H, m), 2.25-2.32(1H, m), 2.68(2H, t, J=7.6 Hz), 3.92(2H, s), 4.22(2H, q, J=7.0 Hz), 4.73(2H, br s), 7.40(1H, td, J=7.6, 1.4 Hz), 7.43(1H, d, J=8.5 Hz), 7.49(1H, td, J=7.5, 1.3 Hz), 7.55(1H, dd, J=7.6, 1.2 Hz), 7.58(1H, dd, J=7.6, 1.2 Hz), 7.66(1H, dd, J=8.2, 2.3 Hz), 8.51(2H, s), 8.59(1H, d, J=2.0 Hz).
0.90(3H, t, J=7.0 Hz), 1.20(6H, d, J=6.6 Hz), 1.31-1.42(4H, m), 1.51(3H, t, J=7.1 Hz), 1.67-1.77(2H, m), 2.26-2.32(1H, m), 2.71(2H, t, J=7.6 Hz), 3.95(2H, s), 4.22(2H, q, J=7.0 Hz), 7.41(1H, d, J=8.1 Hz), 7.45(1H, dd, J=7.8, 1.2 Hz), 7.53(1H, td, J=7.7, 1.2 Hz), 7.61(1H, td, J=7.6, 1.5 Hz), 7.84(1H, d, J=8.3 Hz), 7.97(1H, d, J=7.6 Hz), 8.51(2H, s), 8.59(1H, s).
0.81-0.91(5H, m), 1.07-1.14(1H, m), 1.21-1.26(2H, m), 1.29-1.36(4H, m), 1.49-1.53(3H, m), 1.60-1.65(2H, m), 2.57-2.63(2H, m), 3.94(2H, s), 4.22(2H, q, J=7.1 Hz), 7.44-7.50(1H, m), 7.63-7.69(2H, m), 7.73-7.83(3H, m), 8.54(2H, s), 8.69(1H, s).
0.81-0.86(2H, m), 0.89(3H, t, J=6.8 Hz), 1.06-1.15(1H, m), 1.19-1.25(2H, m), 1.28-1.35(4H, m), 1.51(3H, t, J=7.1 Hz), 1.58-1.65(2H, m), 2.60(2H, t, J=7.9 Hz), 3.90(2H, s), 4.22(2H, q, J=7.0 Hz), 4.73(2H, br s), 7.40(1H, td, J=7.5, 1.5 Hz), 7.43(1H, d, J=7.8 Hz), 7.49(1H, td, J=7.6, 1.5 Hz), 7.55(1H, dd, J=7.6, 1.5 Hz), 7.58(1H, dd, J=7.9, 1.1 Hz), 7.64(1H, dd, J=8.1, 2.4 Hz), 8.54(2H, s), 8.58(1H, d, J=1.7 Hz).
0.82-0.93(5H, m), 1.07-1.15(1H, m), 1.21-1.27(2H, m), 1.29-1.38(4H, m), 1.51(3H, t, J=7.0 Hz), 1.59-1.70(2H, m), 2.62(2H, t, J=7.7 Hz), 3.93(2H, s), 4.22(2H, q, J=7.0 Hz), 7.40(1H, d, J=7.8 Hz), 7.45(1H, d, J=7.6 Hz), 7.53(1H, td, J=7.6, 1.2 Hz), 7.61(1H, td, J=7.7, 1.4 Hz), 7.81(1H, dd, J=7.9, 2.1 Hz), 7.96(1H, d, J=7.8 Hz), 8.54(2H, s), 8.57(1H, s), 7.60(1H, t, J=7.2 Hz), 7.81(1H, dd, J=7.9, 1.8 Hz), 7.94(1H, d, J=7.8 Hz), 8.54(2H, s), 8.55(1H, s).
1.05(3H, t, J=7 Hz), 2.44(1H, dq, J=22, 7 Hz), 2.66(1H, dq, J=22, 7 Hz), 3.24(2H, dd, J=7, 7 Hz), 3.73(3H, s), 3.84(1H, t, J=7 Hz), 7.50(1H, dd, J=8, 1 Hz), 7.67-7.70(3H, m), 7.78(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz), 8.60(1H, d, J=2 Hz).
1.17(3H, t, J=7 Hz), 1.25(6H, d, J=7 Hz), 2.57(1H, sept, J=7 Hz), 3.0(2H, q, J=7 Hz), 3.71(3H, s), 3.77(2H, s), 7.49(1H, dd, J=8, 1 Hz), 7.60(1H, dd, J=8, 2 Hz), 7.70(2H, m), 7.79(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz), 8.61(1H, d, J=2 Hz), 11.9(1H, s).
1.20(6H, d, J=7 Hz), 1.25(3H, t, J=8 Hz), 1.52(3H, t, J=7 Hz), 2.29(1H, sept, J=7 Hz), 2.72(2H, q, J=8 Hz), 4.0(2H, s), 4.21(2H, q, J=7 Hz), 7.47(1H, dd, J=8, 1 Hz), 7.64-7.68(2H, m), 7.76-7.78(3H, m), 8.51(2H, s), 8.70(1H, d, J=2 Hz).
1.19(6H, d, J=7 Hz), 1.22(3H, t, J=8 Hz), 1.50(3H, t, J=7 Hz), 2.29(1H, sept, J=7 Hz), 2.69(2H, q, J=8 Hz), 3.91(2H, s), 4.20(2H, q, J=7 Hz), 4.78(2H, br), 7.37-7.40(2H, m), 7.44-7.51(2H, m), 7.56(1H, dd, J=8, 1 Hz), 7.63(1H, dd, J=8, 2 Hz), 8.50(2H, s), 8.57(1H, d, J=2 Hz).
1.19(6H, d, J=7 Hz), 1.24(3H, t, J=8 Hz), 1.51(3H, t, J=7 Hz), 2.28(1H, sept, J=7 Hz), 2.69(2H, q, J=8 Hz), 3.93(2H, s), 4.22(2H, q, J=7 Hz), 7.30(1H, d, J=8 Hz), 7.37-7.41(2H, m), 7.49(1H, dd, J=8, 1 Hz), 7.67(1H, d, J=8 Hz), 7.77(1H, dd, J=8, 2 Hz), 8.39(1H, d, J=2 Hz), 8.51(2H, s).
0.85-0.90(2H, m), 1.05-1.08(3H, m), 1.16(3H, t, J=8 Hz), 2.98(2H, q, J=8 Hz), 3.72(3H, s), 3.77(2H, s), 7.49(1H, dd, J=8, 1 Hz), 7.59(1H, dd, J=8, 2 Hz), 7.66-7.72(2H, m), 7.79(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz), 8.62(1H, d, J=2 Hz), 12.1(1H, s).
2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}ベンゾニトリル(収率:13%)を得た。
0.82-0.88(2H, m), 1.08-1.15(1H, m), 1.18(3H, t, J = 8 Hz),1.23-1.28(2H, m), 1.50(3H, t, J=7 Hz), 2.63(2H, q, J=8 Hz), 3.95(2H, s), 4.21(2H, q, J=7 Hz), 7.44-7.48(1H, m), 7.64-7.66(2H, m), 7.76-7.78(3H, m), 8.53(2H, s), 8.7(1H, d, J=2 Hz).
0.82-0.88(2H, m), 1.04-1.12(1H, m), 1.15(3H, t, J=8 Hz), 1.22-1.28(2H, m), 1.50(3H, t, J=7 Hz), 2.62(2H, q, J=8 Hz), 3.90(2H, s), 4.21(2H, q, J=7 Hz), 4.76(2H, br), 7.38-7.40(2H, m), 7.47-7.51(2H, m), 7.57(1H, d, J=8 Hz), 7.61(1H, d, J=8 Hz), 8.53(2H, s), 8.57(1H, s).
0.82-0.90(2H, m), 1.08-1.11(1H, m), 1.18(3H, t, J=8 Hz),1.23-1.26(2H, m), 1.51(3H, t, J=7 Hz), 2.63(2H, q, J=8 Hz), 3.91(2H, s), 4.21(2H, q, J=7 Hz), 7.31(1H, d, J=8 Hz), 7.37-7.44(2H, m), 7.51(1H, dd, J=8, 2 Hz), 7.73(1H, d, J=8 Hz), 7.76(1H, dd, J=8, 2 Hz), 8.40(1H, d, J=2 Hz), 8.54(2H, s).
本発明の化合物のアンジオテンシンIIタイプ1受容体に対する拮抗作用は、ウサギ摘出血管標本を用いてアンジオテンシンIIによる血管収縮反応に対する用量−反応曲線により算出した。即ち、ウサギ(New Zealand White:雄性,2.4〜3.0kg)の胸部大動脈リング標本をKrebs-Henseleite液(組成:118mM NaCl,4.7mM KCl,2.55mM CaCl2,1.18mM MgSO4,1.18mM KH2PO4,24.88mM NaHCO3,11.1mM D-glucose)で充填したマグヌス槽に懸垂し、各試験化合物の存在下(1nmol/L〜10μmol/L)のアンジオテンシンII(10nM)収縮反応を得た。測定中はマグヌス槽内を37℃に保温し、十分な混合ガス(95% O2,5% CO2)で連続的に通気した。アンジオテンシンII収縮反応は、試験化合物の非存在下のアンジオテンシンII(0.1μM)による収縮に対する相対値(%)に換算した。
本発明化合物のPPARγに対するアゴニスト活性は、アフリカミドリザルの腎由来細胞株であるCOS7細胞(DSファーマバイオメディカル、大阪)を用いたトランスフェクションアッセイ法により測定した。COS7細胞の培養は5%のCO2濃度で行い、培養液には10%のウシ胎児血清、グルタミン酸及び抗生物質を含有するDMEM培地を用いた。
発現ベクターとしては、酵母の転写因子であるGal4のDNA結合領域と、ヒトPPARγ2のリガンド結合領域を融合したキメラ体、即ち、Gal4転写因子の1から147番目のアミノ酸及びヒトPPARγ2の182から505番目のアミノ酸を融合したものを用いた。また、レポーターベクターとして、プロモーター領域に5個のGal4認識配列が含まれているホタルルシフェラーゼを用いた。細胞へのプラスミドのトランスフェクションはjetPEI(フナコシ、東京)を用いた方法により行った。更にβ−ガラクトシダーゼの発現ベクターを内部標準として用いた。
細胞へのトランスフェクションの後、試験化合物を添加したDMEM培地(1%血清含有)に交換し,更に16時間の培養を行った。その後、細胞溶解液中のルシフェラーゼ活性及びβ−ガラクトシダーゼ活性を測定した。
なお、本実験では試験化合物の溶解・希釈にはジメチルスルホキシド(DMSO)を用い、細胞への処理の際はDMEM培地(1%血清含有)中のDMSO濃度が0.1%になるように調整した。陽性化合物としてロシグリタゾン(ALEXIS Corporation, Switzerland)を用い、ロシグリタゾン(3−10μmol/L)のルシフェラーゼ活性を100%、試験化合物非添加時のルシフェラーゼ活性を0%とした時の各試験化合物(1−30μmol/L)のルシフェラーゼ活性から百分率(%)を算出した。各試験化合物の50%効果濃度(EC50、50% effect concentration)は統計解析プログラム、SAS前臨床パッケージVer5.0(SAS institute Japan Co., 東京)を用いて算出した。
Claims (22)
- 一般式(I)における環Aが式(II)であり、環Bが式(V)である請求項1に記載の化合物若しくはその塩、又はそれらの溶媒和物。
- 一般式(I)におけるXが窒素原子であり、R3、R4が、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又はC1−6アルコキシ基である請求項1又は2に記載の化合物若しくはその塩、又はそれらの溶媒和物。
- 一般式(I)におけるR3、R4が、それぞれ独立して、水素原子、又はC1−6アルコキシ基である請求項3に記載の化合物若しくはその塩、又はそれらの溶媒和物。
- 一般式(I)で表される化合物が、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン
からなる群から選ばれる化合物である、請求項1〜4のいずれか1項に記載の化合物若しくはその塩、又はそれらの溶媒和物。 - 一般式(I)におけるR1が、C1−3アルキル基又はC5−6アルキル基である請求項6に記載の医薬組成物。
- 一般式(I)における環Aが式(II)であり、環Bが式(V)である請求項6又は7に記載の医薬組成物。
- 一般式(I)におけるXが窒素原子であり、R3、R4が、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又はC1−6アルコキシ基である請求項6〜8のいずれか1項に記載の医薬組成物。
- 一般式(I)におけるR3、R4が、それぞれ独立して、水素原子、又はC1−6アルコキシ基である請求項9に記載の医薬組成物。
- 一般式(I)で表される化合物が、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−プロピル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−2−イソプロピル−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−6−オキソ−4−ペンチル−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、
3−{2−{5−{[1−(5−エトキシピリミジン−2−イル)−4−エチル−2−イソプロピル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン、及び、
3−{2−{5−{[2−シクロプロピル−1−(5−エトキシピリミジン−2−イル)−4−エチル−6−オキソ−1,6−ジヒドロピリミジン−5−イル]メチル}ピリジン−2−イル}フェニル}−1,2,4−オキサジアゾール−5(4H)−オン
からなる群から選ばれる化合物である、請求項6〜10のいずれか1項に記載の医薬組成物。 - アンジオテンシンII受容体拮抗作用及びPPARγ活性化作用を併せ持つ、請求項6〜11のいずれか1項に記載の医薬組成物。
- 循環器系疾患の予防及び/又は治療剤である、請求項6〜11のいずれか1項に記載の医薬組成物。
- 循環器系疾患が、高血圧症、心疾患、狭心症、脳血管障害、脳循環障害、虚血性末梢循環障害、腎疾患又は動脈硬化症である請求項13に記載の医薬組成物。
- 代謝性疾患の予防及び/又は治療剤である、請求項6〜11のいずれか1項に記載の医薬組成物。
- 代謝性疾患が、2型糖尿病、糖尿病性合併症(糖尿病網膜症、糖尿病性神経障害又は糖尿病性腎症)、インスリン抵抗性症候群、メタボリックシンドローム又は高インスリン血症である請求項15に記載の医薬組成物。
- 治療を必要としている患者に、次の一般式(I):
XはC−R5又は窒素原子を示し、
R1は、C1−6アルキル基を示し、
R2は、C1−6アルキル基又はC3−8シクロアルキル基を示し、
R3、R4、R5は、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又は置換基を有してもよいC1−6アルコキシ基を示す。なお、式中の波線は隣接する基との結合位置であることを示している。〕
で表される化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする循環器系疾患の予防及び/又は治療方法。 - 治療を必要としている患者に、次の一般式(I):
XはC−R5又は窒素原子を示し、
R1は、C1−6アルキル基を示し、
R2は、C1−6アルキル基又はC3−8シクロアルキル基を示し、
R3、R4、R5は、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又は置換基を有してもよいC1−6アルコキシ基を示す。なお、式中の波線は隣接する基との結合位置であることを示している。〕
で表される化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする代謝性疾患の予防及び/又は治療方法。 - 治療を必要としている患者に、次の一般式(I):
XはC−R5又は窒素原子を示し、
R1は、C1−6アルキル基を示し、
R2は、C1−6アルキル基又はC3−8シクロアルキル基を示し、
R3、R4、R5は、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又は置換基を有してもよいC1−6アルコキシ基を示す。なお、式中の波線は隣接する基との結合位置であることを示している。〕
で表される化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする循環器系疾患及び代謝性疾患の予防及び/又は治療方法。 - 循環器系疾患及び代謝性疾患の予防及び/又は治療に用いるための、次の一般式(I):
XはC−R5又は窒素原子を示し、
R1は、C1−6アルキル基を示し、
R2は、C1−6アルキル基又はC3−8シクロアルキル基を示し、
R3、R4、R5は、それぞれ独立して、水素原子、ハロゲン原子、C1−6アルキル基、ハロC1−6アルキル基又は置換基を有してもよいC1−6アルコキシ基を示す。なお、式中の波線は隣接する基との結合位置であることを示している。〕
で表される化合物若しくはその塩、又はそれらの溶媒和物。
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