WO2011007856A1 - トリアゾロピリジン化合物、ならびにそのプロリル水酸化酵素阻害剤およびエリスロポエチン産生誘導剤としての作用 - Google Patents
トリアゾロピリジン化合物、ならびにそのプロリル水酸化酵素阻害剤およびエリスロポエチン産生誘導剤としての作用 Download PDFInfo
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- WO2011007856A1 WO2011007856A1 PCT/JP2010/062037 JP2010062037W WO2011007856A1 WO 2011007856 A1 WO2011007856 A1 WO 2011007856A1 JP 2010062037 W JP2010062037 W JP 2010062037W WO 2011007856 A1 WO2011007856 A1 WO 2011007856A1
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- pharmaceutically acceptable
- acceptable salt
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- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 39
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- 238000002360 preparation method Methods 0.000 description 21
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- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 238000004440 column chromatography Methods 0.000 description 19
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
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- 229920006395 saturated elastomer Polymers 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
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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 14
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
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- 238000012360 testing method Methods 0.000 description 12
- 235000011054 acetic acid Nutrition 0.000 description 11
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- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical group FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 10
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
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- 102000053692 human EGLN1 Human genes 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000002243 precursor Substances 0.000 description 8
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 7
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
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- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 6
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
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- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000005730 ring rearrangement reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QIQCZROILFZKAT-UHFFFAOYSA-N tetracarbon dioxide Chemical group O=C=C=C=C=O QIQCZROILFZKAT-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Definitions
- the present invention relates to a novel triazolopyridine compound having a prolyl hydroxylase (hereinafter also referred to as “PHD”) inhibitory action and an erythropoietin (hereinafter also referred to as “EPO”) production inducing ability.
- PLD prolyl hydroxylase
- EPO erythropoietin
- the present invention also relates to a prolyl hydroxylase inhibitor (hereinafter also referred to as “PHD inhibitor”) and an erythropoietin production inducer (hereinafter also referred to as “EPO production inducer”) containing the triazolopyridine compound.
- EPO is a hormone that promotes the production of erythrocytes consisting of 165 amino acids. EPO is mainly produced in the kidney and part of the liver, and its production increases under hypoxic conditions.
- Anemia refers to a state in which the amount of red blood cells or hemoglobin in the blood has decreased. Symptoms stem from hypoxia associated with red blood cell loss, or changes in circulatory dynamics due to increased breathing and heart rate to compensate for oxygen deficiency, such as “whole body”, “easy to get tired”, “shortness of breath”, “ There are “palpitations”, “head feeling”, “vertigo”, “bad complexion”, “shoulder shoulder”, “difficult to get up in the morning”.
- anemia associated with autoimmune diseases, malignant tumors, chronic infections, plasma cell abnormalities, etc.
- anemia associated with endocrine diseases hyperthyroidism, multi-gland autoimmune syndrome, type IA diabetes, irregular uterine bleeding, etc.
- Examples include anemia associated with chronic heart failure, anemia associated with ulcer, anemia associated with liver disease, senile anemia, drug anemia, renal anemia (anemia associated with renal failure), anemia associated with chemotherapy, and the like.
- a recombinant human EPO product was applied to the treatment of renal anemia, anemia associated with AZT treatment for HIV-infected patients, anemia associated with chemotherapy for cancer patients, and reduction of blood transfusion volume for patients undergoing surgery. FDA). Furthermore, the indication has spread to anemia of premature infants.
- Renal anemia is treated with an erythropoiesis stimulating factor preparation (ESA). Renal anemia is mainly caused by a decrease in EPO production in stromal cells around the renal tubular tubule, and is also an indication that a high proportion of recombinant human erythropoietin is used from the viewpoint of supplementation. Recombinant human erythropoietin has greatly contributed to the improvement of ADL (Activities of Daily Living) and QOL (Quality of Life) by drastically reducing the number of patients who require regular blood transfusions and improving various symptoms associated with anemia. . However, on the other hand, it is expensive because it is a biologic, and the burden of medical expenses is large.
- ADL Activity of Daily Living
- QOL Quality of Life
- blood half-life is short, and hemodialysis patients require intravenous administration from a dialysis circuit 2 to 3 times a week, which reduces the number of injections from the viewpoint of preventing medical accidents, medical workload, and waste. It is desired.
- peritoneal dialysis patients and patients with renal failure in the conservative phase need to be administered once a week or once every two weeks even if subcutaneous administration is performed for a long duration, and only for administration of recombinant human erythropoietin. This is often a burden on the patient.
- EPO has been modified with new sugar chains and PEG chains to extend the blood half-life of intravenous and subcutaneous injections.
- ESA that can be administered orally is desired. Furthermore, if ESA is orally administrable, it is expected that the range of treatment is widened not only for renal anemia but also for anemia caused by various causes.
- HIF hypoxia inducing factor
- the ⁇ subunit is not ubiquitinated under hypoxia because it is not hydroxylated by PHD, and binds to a hypoxia response element (HRE) in the nucleus, and the EPO located downstream of it binds to the hypoxia response element (HRE). Promotes transcription. Therefore, inhibiting PHD activity prevents and stabilizes HIF ubiquitination, resulting in increased EPO production.
- HRE hypoxia response element
- ischemic heart diseases angina, myocardial infarction, etc.
- ischemic cerebrovascular disorders cerebral infarction, cerebral embolism, Transient cerebral ischemic attack
- chronic renal failure ischemic nephropathy, tubulointerstitial disorder, etc.
- diabetic complications diabetic wound, etc.
- cognitive impairment disementia, Alzheimer's disease, Parkinson's disease, Huntington) Disease, etc.
- an object of the present invention is to provide a drug having a prolyl hydroxylase (PHD) inhibitory action. Moreover, this invention makes it a subject to provide the chemical
- the present inventors have found a compound having a prolyl hydroxylase (PHD) inhibitory action and an EPO production inducing ability, and completed the present invention. More specifically, the present invention is as follows. [1] A compound represented by the following general formula [I] (hereinafter also referred to as “the compound of the present invention”) or a pharmaceutically acceptable salt thereof, or a solvate thereof:
- R 1 is (1) a hydrogen atom, (2) a C 1-6 alkyl group, (3) a C 6-14 aryl group, (4) a C 3-8 cycloalkyl group, (5) a C 6-14 aryl-C 1-6 alkyl group, or (6) a C 3-8 cycloalkyl-C 1-6 alkyl group;
- R 2 is (1) a hydrogen atom, (2) a C 1-10 alkyl group, (3) a C 6-14 aryl group optionally substituted by 1 to 5 substituents selected from the following group B, (4) a C 3-8 cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from the following group B; (5) a C 3-8 cycloalkenyl group which may be substituted with the same or different 1 to 5 substituents selected from the following group B; (6) A heteroaryl group which may be substituted with the same or different 1 to 5 substituents selected from the following group B (wherein the heteroaryl
- Group B (A) a halogen atom, (B) a C 1-6 alkyl group, (C) a C 3-8 cycloalkyl group, (D) a cyano group, and (e) a halo-C 1-6 alkyl group. ]; [2] Partial structural formula:
- a pharmaceutically acceptable salt thereof, or a solvate thereof which is a group represented by the formula: [6] The compound according to any one of the above [1] to [5], wherein R 4 and R 5 are both hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof; [7] The compound according to any one of the above [1] to [5], wherein R 3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof; [8] The compound according to any one of the above [1] to [5], wherein R 1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof; [9] R 2 is (1) a C 1-10 alkyl group, (2) a C 6-14 aryl group which may be substituted with the same or different 1 to 5 substituents selected from the group B; (3) a C 6-14 aryl-C 1-6 alkyl group (the C 6-14 aryl may be substituted with the same or different 1
- R 11 is (1) a hydrogen atom, (2) a C 1-6 alkyl group, (3) a phenyl group, (4) a C 3-8 cycloalkyl group, (5) a phenyl-C 1-6 alkyl group, or (6) a C 3-8 cycloalkyl-C 1-6 alkyl group;
- R 21 is (1) a hydrogen atom, (2) a C 1-10 alkyl group, (3) a phenyl group which may be substituted with the same or different 1 to 5 substituents selected from the following group B; (4) a C 3-8 cycloalkyl group, (5) a C 3-8 cycloalkenyl group, (6) a thienyl group which may be substituted with 1 to 5 substituents which are the same or different from the following group B; (7) a phenyl-C 1-6 alkyl group (the phenyl may be substituted with 1 to 5 substituents which are the same or different from the following group B), or
- Group B (A) a halogen atom, (B) a C 1-6 alkyl group, (C) a C 3-8 cycloalkyl group, (D) a cyano group, and (e) a halo-C 1-6 alkyl group. ]; [15] The following formula:
- a pharmaceutical composition containing the compound according to any one of [1] to [25] above or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier hereinafter referred to as “ Also referred to as “the pharmaceutical composition of the present invention”
- An erythropoietin production inducer containing the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof
- a therapeutic agent for renal anemia containing the compound according to any one of the above [1] to [30] A therapeutic
- [36] A method for inducing erythropoietin production, comprising administering an effective amount of the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal.
- [37] A method for treating anemia, comprising administering an effective amount of the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal.
- Treatment of renal anemia comprising administering an effective amount of the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal.
- the pharmaceutical composition according to [26] above, and the pharmaceutical composition can or should be used for the treatment or prevention of a disease selected from anemia and renal anemia.
- the pharmaceutical composition according to [26] above, and the pharmaceutical composition can be used for or should be used for the treatment or prevention of a disease selected from anemia and renal anemia.
- a kit comprising a description related to the described pharmaceutical composition.
- Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- the “C 1-10 alkyl group” represents a linear or branched alkyl group having 1 to 10 carbon atoms, preferably a linear or branched alkyl group having 1 to 7 carbon atoms.
- Examples include hexyl group, 2-ethylbutyl group, 3,3-dimethylbutyl group, 3,3-dimethylpentyl group, heptyl group, octyl group, nonyl group, decyl group and the like.
- the “C 1-6 alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear or branched alkyl group having 1 to 3 carbon atoms.
- a linear or branched alkyl group having 1 to 3 carbon atoms For example, among those exemplified above for the “C 1-10 alkyl group”, those having 1 to 6 carbon atoms can be mentioned.
- the “C 1-3 alkyl group” represents a linear or branched alkyl group having 1 to 3 carbon atoms.
- the “C 1-10 alkyl group” the one having 1 to 3 carbon atoms Things.
- the “C 6-14 aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, for example, a phenyl group, a naphthyl group, an anthryl group, an indenyl group, an azulenyl group, a fluorenyl group, a phenanthryl group, a pentarenyl group. Etc., preferably a phenyl group.
- the “C 3-8 cycloalkyl group” is a saturated cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 5 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, A cyclooctyl group etc. are mentioned.
- the “C 3-5 cycloalkyl group” is a saturated cycloalkyl group having 3 to 5 carbon atoms.
- the “C 3-8 cycloalkyl group” those having 3 to 5 carbon atoms Is mentioned.
- C 6-14 aryl-C 1-6 alkyl group means that the C 6-14 aryl moiety is the “C 6-14 aryl group” defined above and the C 1-6 alkyl moiety is as defined above.
- Examples of the C 6-14 aryl-C 1-6 alkyl group include a phenylmethyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl group, a phenylpentyl group, a phenylhexyl group, a naphthylmethyl group, a naphthylethyl group, and a naphthyl group.
- Examples thereof include a propyl group, a naphthylbutyl group, a naphthylpentyl group, a naphthylhexyl group, an anthrylmethyl group, an indenylmethyl group, an azulenylmethyl group, a fluorenylmethyl group, a phenanthrylmethyl group, and a pentarenylmethyl group.
- C 3-8 cycloalkyl-C 1-6 alkyl group means that the C 3-8 cycloalkyl moiety is the “C 3-8 cycloalkyl group” as defined above, and the C 1-6 alkyl moiety is a C 3-8 cycloalkyl -C 1-6 alkyl group is "C 1-6 alkyl group" defined above, e.g., cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, a cyclopropyl butyl , Cyclopropylpentyl group, cyclopropylhexyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclobutylpropyl group, cyclobutylbutyl group, cyclobutylpentyl group, cyclobutylhexyl group, cyclopentylmethyl group, cyclopentylethyl group
- the “C 3-8 cycloalkenyl group” is a cycloalkenyl group having 3 to 8 carbon atoms, and contains at least 1, preferably 1 or 2, double bonds.
- heteroaryl group refers to the number of atoms constituting a ring having 1 to 6 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms as atoms constituting the ring. Is an aromatic heterocycle having 3 to 14 and includes monocyclic and condensed rings.
- the “monocyclic heteroaryl group” is preferably a monocyclic heteroaryl group having 1 to 4 heteroatoms, such as a thienyl group (eg, thiophen-2-yl, thiophen-3-yl). , Furyl groups (eg, furan-2-yl, furan-3-yl, etc.), pyrrolyl groups (eg, 2-pyrrolin-1-yl group, 3-pyrrolin-3-yl, etc.), oxazolyl groups (eg, oxazole) -2-yl, oxazol-4-yl, oxazol-5-yl, etc.), isoxazolyl groups (eg, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl etc.), thiazolyl groups ( Examples: thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, etc.), isothiazoly
- fused ring heteroaryl group examples include quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl group, phthalazinyl group, cinnolinyl group, naphthyridinyl group, indolyl group, benzimidazolyl group, indolinyl group, benzofuranyl group, benzothienyl group.
- benzoxazolyl group benzothiazolyl group, benzodioxinyl group, benzothiazolyl group, tetrahydroquinolyl group, dihydrobenzofuranyl group, dihydrobenzothienyl group, dihydrobenzodioxinyl group, indenothiazolyl group, tetrahydro Benzothiazolyl group, 5,7-dihydropyrrolo [3,4-d] pyrimidinyl group, 6,7-dihydro-5H-cyclopentapyrimidinyl group, imidazo [2,1-b] thiazolyl group, pteridinyl group, purinyl Group It is.
- halo-C 1-6 alkyl group is a “C 1-6 alkyl group” defined above, which is substituted with 1 to 5 halogen atoms which are the same or different, for example, chloromethyl, fluoromethyl , Difluoromethyl, trifluoromethyl, bromomethyl, chloroethyl, fluoroethyl, bromoethyl, chloropropyl, fluoropropyl, bromopropyl and the like.
- Group B refers to the following groups of substituents (a) to (e).
- A “halogen atom” as defined above
- B a “C 1-6 alkyl group” as defined above
- C a “C 3-8 cycloalkyl group” as defined above
- D a cyano group
- a “halo-C 1-6 alkyl group” as defined above.
- C 6-14 aryl group optionally substituted by 1 to 5 substituents selected from group B is the same or different from “C 6-14 aryl group” defined above. It may be substituted with up to 5 substituents and includes an unsubstituted C 6-14 aryl group.
- the substituents are the same or different and are selected from “Group B” defined above.
- C 3-8 cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from group B means that “C 3-8 cycloalkyl group” as defined above is the same or different. And optionally substituted with 1 to 5 substituents, including unsubstituted C 3-8 cycloalkyl groups.
- the substituents are the same or different and are selected from “Group B” defined above.
- C 3-8 cycloalkenyl group optionally substituted with the same or different 1 to 5 substituents selected from group B means that “C 3-8 cycloalkenyl group” as defined above is the same or different. And optionally substituted with 1 to 5 substituents, including unsubstituted C 3-8 cycloalkenyl groups.
- the substituents are the same or different and are selected from “Group B” defined above.
- heteroaryl group which may be substituted with the same or different 1 to 5 substituents selected from group B means 1 to 5 substituents with the same or different “heteroaryl group” as defined above And may include an unsubstituted heteroaryl group.
- the substituents are the same or different and are selected from “Group B” defined above.
- R 1 is (1) a hydrogen atom, (2) a C 1-6 alkyl group, (3) a C 6-14 aryl group, (4) a C 3-8 cycloalkyl group, (5) a C 6-14 aryl-C 1-6 alkyl group, or (6) a C 3-8 cycloalkyl-C 1-6 alkyl group.
- R 1 is preferably (1) a hydrogen atom, (2) C 1-3 alkyl group (eg, methyl), (3) C 6-14 aryl group (eg, phenyl), (4) C 3-5 cycloalkyl group (eg, cyclopropyl), (5) a C 6-14 aryl (eg, phenyl) -C 1-3 alkyl (preferably linear C 1-3 alkyl, eg, ethyl) group, and (6) C 3-8 cycloalkyl (eg, cyclohexyl) -C 1-3 alkyl (eg, ethyl) group, and the like.
- R 1 is more preferably a hydrogen atom.
- R 2 is (1) a hydrogen atom, (2) a C 1-10 alkyl group, (3) a C 6-14 aryl group which may be substituted with the same or different 1 to 5 substituents selected from the group B; (4) a C 3-8 cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from the group B; (5) a C 3-8 cycloalkenyl group which may be substituted with the same or different 1 to 5 substituents selected from the group B; (6) A heteroaryl group which may be substituted with the same or different 1 to 5 substituents selected from Group B above (wherein the heteroaryl is a nitrogen atom, an oxygen atom and a carbon atom in addition to a carbon atom) Having 1 to 6 heteroatoms selected from sulfur atoms), (7) a C 6-14 aryl-C 1-6 alkyl group (the C 6-14 aryl may be substituted with the same or different 1 to 5 substituents selected from Group B), or (8) C 3-8
- R 2 is preferably (1) a hydrogen atom, (2) a C 1-10 alkyl group, (3) a C 6-14 aryl group which may be substituted with the same or different 1 to 5 substituents selected from the group B; (4) C 3-8 cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloheptyl), (5) C 3-8 cycloalkenyl group (eg, cyclohexenyl), (6) Group B above (Eg, (a) halogen atom (eg, chlorine atom), and (b) C 1-6 alkyl group (eg, methyl))
- a heteroaryl group preferably a monocyclic heteroaryl group, eg, thienyl which may be substituted with the same or different 1 to 5 (eg, 1) substituents selected from (Here, the heteroaryl has 1 to 6 (eg, 1 to 4) heteroatoms selected from a nitrogen atom, an oxygen atom, and a
- C 1-10 alkyl group eg, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tert-pentyl, hexyl, 1-ethylpropyl, 2-ethylbutyl, 3,3-dimethylbutyl, 3, 3-dimethylpentyl
- Group B above E.g., (a) halogen atom (e.g., chlorine atom, fluorine atom), (B) a C 1-3 alkyl group (eg, methyl), (C) a C 3-5 cycloalkyl group (eg, cyclopropyl), (D) a cyano group, and (e) a halo-C 1-3 alkyl group (eg, trifluoromethyl))
- a C 6-14 aryl group eg, phenyl which may be substituted with the same or different 1
- R 2 More preferably as R 2 , (1) C 1-6 alkyl group (eg, butyl, pentyl, 1-ethylpropyl), (2) (a) a halogen atom (eg, chlorine atom, fluorine atom), (B) a C 1-3 alkyl group (eg, methyl), (C) a C 3-5 cycloalkyl group (eg, cyclopropyl), and (d) a halo-C 1-3 alkyl group (eg, trifluoromethyl). Phenyl optionally substituted by the same or different 1 to 3 substituents selected from (3) phenylethyl, (4) cyclopentylethyl.
- R 2 is particularly preferably butyl, phenylethyl, 4-fluoro-3-trifluoromethylphenyl.
- R 2 is preferably (1) a C 1-10 alkyl group, or (2) C 6-14 aryl-C 1-6 alkyl group (the C 6-14 aryl may be substituted with the same or different 1 to 5 substituents selected from Group B) It is.
- R 3 is (1) a hydrogen atom, (2) a halogen atom, (3) a C 1-6 alkyl group, (4) a C 6-14 aryl group, (5) a C 3-8 cycloalkyl group, or (6) a C 6-14 aryl-C 1-6 alkyl group.
- R 3 is preferably (1) a hydrogen atom, (2) halogen atoms (eg, chlorine atoms), (3) C 1-6 alkyl group (eg, ethyl, pentyl), (4) C 6-14 aryl group (eg, phenyl), (5) a C 6-14 aryl (eg, phenyl) -C 1-6 alkyl (preferably linear C 1-6 alkyl, eg, ethyl) group.
- R 3 is more preferably a hydrogen atom.
- R 4 and R 5 are each independently (1) a hydrogen atom or (2) represents a C 1-6 alkyl group.
- R 4 and R 5 are preferably each independently (1) a hydrogen atom or (2) A C 1-3 alkyl group (eg, methyl).
- R 4 and R 5 are more preferably both hydrogen atoms.
- R 1a is (1) a hydrogen atom, (2) C 1-3 alkyl group (eg, methyl), (3) C 6-14 aryl group (eg, phenyl), (4) C 3-5 cycloalkyl group (eg, cyclopropyl), (5) a C 6-14 aryl (eg, phenyl) -C 1-3 alkyl (preferably linear C 1-3 alkyl, eg, ethyl) group, or (6) a C 3-8 cycloalkyl (eg, cyclohexyl) -C 1-3 alkyl (eg, ethyl) group;
- R 2a is (1) a hydrogen atom, (2) a C 1-10 alkyl group, (3) a C 6-14 aryl group which may be substituted with the same or different 1 to 5 substituents selected from the group B; (4) C 3-8 cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloh
- R 1a is a hydrogen atom
- R 2a is (1) C 1-10 alkyl group (eg, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tert-pentyl, hexyl, 1-ethylpropyl, 2-ethylbutyl, 3,3-dimethylbutyl, 3, 3-dimethylpentyl), (2) Group B above (E.g., (a) halogen atom (e.g., chlorine atom, fluorine atom), (B) a C 1-3 alkyl group (eg, methyl), (C) a C 3-5 cycloalkyl group (eg, cyclopropyl), (D) a cyano group, and (e) a halo-C 1-3 alkyl group (eg, trifluoromethyl))
- A halogen atom
- B a C 1-3 alkyl group
- R 11 is (1) a hydrogen atom, (2) C 1-6 alkyl group (eg, methyl), (3) a phenyl group, (4) C 3-8 cycloalkyl group (eg, cyclopropyl), (5) a phenyl-C 1-6 alkyl group, or (6) a C 3-8 cycloalkyl-C 1-6 alkyl group;
- R 21 is (1) a hydrogen atom, (2) C 1-10 alkyl group (eg, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, 3,3-dimethylpentyl), (3) a phenyl group which may be substituted with the same or different 1 to 5 substituents selected from the group
- R 11 is (1) a hydrogen atom, (2) C 1-6 alkyl group (eg, methyl), (3) a phenyl group, or (4) a C 3-8 cycloalkyl group (eg, cyclopropyl);
- R 21 is (1) a hydrogen atom, (2) C 1-10 alkyl group (eg, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, 3,3-dimethylpentyl), (3) a phenyl group which may be substituted with the same or different 1 to 5 substituents selected from the group B (eg, fluorine atom, chlorine atom, methyl, cyano, cyclopropyl, trifluorine atom, chlorine atom,
- Examples 1 to 122 the compounds described in Examples 1 to 122 are preferable. Examples 1, 2, 21, 31, 40, 44, 47, 52, 60 74, 79, 116, 118, 119, 120, 121 and 122 are particularly preferred.
- the pharmaceutically acceptable salt of the compound represented by the general formula [I] may be any salt that forms a non-toxic salt with the compound of the present invention.
- the salt with an inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
- salts with organic acids for example, oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
- examples of the salt with an inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
- salts with organic bases include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, guanidine , Salts with pyridine, picoline, choline, cinchonine, meglumine and the like.
- the salt with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid and the like. According to a known method, each salt can be obtained by reacting the compound represented by the general formula [I] with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid.
- the “solvate” is a compound in which a solvent molecule is coordinated to a compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, and includes a hydrate.
- the solvate is preferably a pharmaceutically acceptable solvate.
- the hydrate, ethanol hydrate, dimethyl sulfoxide hydrate, etc. of the compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof may be mentioned.
- the hemihydrate, monohydrate, dihydrate or monoethanolate of the compound represented by the general formula [I] or the sodium salt of the compound represented by the general formula [I] Monohydrate or 2/3 ethanol hydrate of dihydrochloride.
- a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof can be obtained according to a known method.
- E isomer and Z isomer exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers as stereoisomers based on these exist. Moreover, when axial asymmetry exists, the stereoisomer based on these exists. There may also be tautomers. Accordingly, the scope of the present invention includes all these isomers and mixtures thereof.
- the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof may be labeled with an isotope (eg, 3 H, 14 C, 35 S, etc.).
- the compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof is a substantially purified compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof. Or a solvate thereof. More preferably, the compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof, purified to a purity that can be used as a pharmaceutical product.
- a prodrug of the compound represented by the general formula [I] can also be a useful drug.
- a “prodrug” has a group that can be chemically or metabolically decomposed, and is administered to a living body, for example, by hydrolysis, solvolysis, or decomposition under physiological conditions.
- This compound is a derivative of the compound of the present invention which is restored to the compound of the present invention and exhibits the original medicinal effect, and includes complexes and salts not based on covalent bonds.
- Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site. Examples of the modification site include highly reactive functional groups such as a hydroxyl group, a carboxyl group, and an amino group in the compound of the present invention.
- hydroxyl modifying group examples include acetyl group, propionyl group, isobutyryl group, pivaloyl group, palmitoyl group, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group, dimethylaminomethylcarbonyl group, sulfo group, alanyl group, A fumaryl group etc. are mentioned. Further, a sodium salified 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group and the like can be mentioned.
- the modifying group of the carboxyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pivaloyloxymethyl group, a carboxymethyl group, a dimethylaminomethyl group, 1- (acetyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, (5-methyl-2-oxo- 1,3-dioxol-4-yl) methyl group, benzyl group, phenyl group, o-tolyl group, morpholinoethyl group, N, N-diethylcarbamoylmethyl group, phthalidyl group and the like.
- amino group-modifying group examples include tert-butyl group, docosanoyl group, pivaloylmethyloxy group, alanyl group, hexylcarbamoyl group, pentylcarbamoyl group, 3-methylthio-1- (acetylamino) propylcarbonyl group 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, (5-methyl-2-oxo) -1,3-dioxol-4-yl) methoxycarbonyl group, tetrahydrofuranyl group, pyrrolidylmethyl group and the like.
- Examples of the “pharmaceutical composition” include tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions and other oral preparations, external preparations, suppositories, injections, eye drops, and nasal preparations. And parenteral agents such as transpulmonary agents.
- the pharmaceutical composition of the present invention comprises a compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof according to a method known in the technical field of pharmaceutical preparations. It is produced by mixing an appropriate amount of the above-accepted carrier and the like as appropriate.
- the content of the compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc. 0.1 to 100% by weight.
- the “pharmaceutically acceptable carrier” examples include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid formulations, Or the solvent in a liquid formulation, a solubilizing agent, a suspending agent, an isotonizing agent, a buffering agent, a soothing agent etc. are mentioned. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners and the like are used as necessary.
- excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low substituted hydroxypropyl
- examples include cellulose and gum arabic.
- disintegrant examples include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.
- binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.
- fluidizing agent examples include light anhydrous silicic acid, magnesium stearate and the like.
- lubricant examples include magnesium stearate, calcium stearate, talc and the like.
- solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
- Examples of the “solubilizing agent” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
- suspending agent examples include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like.
- isotonic agent examples include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
- buffering agent examples include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
- Examples of the soothing agent include benzyl alcohol.
- preservative examples include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
- antioxidant examples include sodium sulfite and ascorbic acid.
- colorant examples include food dyes (eg, food red No. 2 or 3, food yellow No. 4 or 5, etc.), ⁇ -carotene and the like.
- sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.
- the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof has EPO production-inducing activity due to a prolyl hydroxylase (PHD) inhibitory action, and various diseases and pathologies (disorders) resulting from a decrease in EPO production. ) Can be used for prevention or treatment. Examples of various diseases and pathological conditions (disorders) caused by a decrease in EPO production include anemia.
- anemia anemia due to hematopoiesis abnormality in the bone marrow, iron, anemia due to deficiency of vitamin B 12 or folic acid, accident or surgery at the time of the effective date of bleeding, chronic inflammation (autoimmune diseases, malignant tumors, chronic infections, Anemia associated with plasma cell abnormalities, etc., anemia associated with endocrine disorders (hypothyroidism, multi-gland autoimmune syndrome, type IA diabetes, irregular uterine bleeding, etc.), anemia associated with chronic heart failure, anemia associated with ulcer, liver Examples include anemia associated with diseases, senile anemia, drug-induced anemia, renal anemia (anemia associated with renal failure), anemia associated with chemotherapy, and the like.
- ischemic heart disease angina, myocardial infarction, etc.
- ischemic cerebrovascular disorders cerebral infarction, cerebral embolism
- Transient ischemic attack etc.
- chronic renal failure ischemic nephropathy, tubulointerstitial disorder, etc.
- diabetic complications diabetic wound, etc.
- cognitive impairment disementia, Alzheimer's disease, Parkinson's disease
- the prolyl hydroxylase (PHD) inhibitor and EPO production inducer of the present invention are preferably used as an anemia treatment agent, more preferably as a renal anemia treatment agent.
- the pharmaceutical composition of the present invention can be applied not only to humans but also to mammals other than humans (eg, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.). , Orally or parenterally (eg, topical, rectal, intravenous administration, etc.).
- the dose varies depending on the subject of administration, disease, symptom, dosage form, administration route, etc.
- the dose for oral administration to an adult patient is as the compound of the present invention as an active ingredient.
- body weight body weight: about 60 kg
- these amounts can be administered once to several times.
- the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof inhibits PHD and induces production of EPO, and therefore can be used as an active ingredient of a therapeutic or preventive agent for anemia.
- “Inhibits PHD” means to specifically inhibit the function as prolyl hydroxylase to eliminate or attenuate its activity. For example, based on the conditions of Test Example 1 described later, prolyl water It means specifically inhibiting the function of oxidase.
- “Inhibiting PHD” is preferably “inhibiting human PHD”.
- the “PHD inhibitor” is preferably a “human PHD inhibitor”.
- “Inducing the production of EPO” means that the production of erythropoietin in the kidney or the like is promoted. For example, the production of erythropoietin is induced based on the conditions of Test Example 2 described later. To do.
- the “inducing production of EPO” is preferably “inducing production of human EPO”.
- the “EPO production inducer” is preferably a “human EPO production inducer”.
- the compound represented by the above general formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof is converted into one or a plurality of other drugs (hereinafter referred to as “one drug”) by a general method performed in the pharmaceutical field , Also referred to as “combination drug”) (hereinafter also referred to as “combination”).
- the administration time of the compound represented by the above general formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a concomitant drug is not limited. Alternatively, both preparations may be administered simultaneously or at regular intervals. Moreover, you may use as a pharmaceutical characterized by being a kit which consists of this invention pharmaceutical composition and a concomitant drug.
- the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, disease, symptom, dosage form, administration route, administration time, combination and the like.
- the administration form of the concomitant drug is not particularly limited as long as the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof and the concomitant drug are combined.
- the concomitant drug include a therapeutic agent and / or preventive agent for anemia, and can be used in combination with the compound of the present invention.
- the “anemia treatment and / or prevention agent” include ferrous citrate and iron sulfate.
- PHD includes PHD2 and PHD3.
- the present invention is not limited to these production methods.
- the order of the reaction can be appropriately changed. The reaction may be performed from a process or substitution site that seems to be reasonable.
- a substituent conversion (substituent conversion or further modification) step may be appropriately inserted between the respective steps.
- protection and deprotection may be appropriately performed.
- reagents other than the illustrated reagent can be used suitably.
- raw material compounds whose production methods are not described are commercially available or can be easily prepared by combining known synthetic reactions.
- the compound obtained in each step can be purified by a conventional method such as distillation, recrystallization, column chromatography, etc., but in some cases, it can proceed to the next step without isolation and purification.
- room temperature means 1 to 40 ° C.
- R 11a and R 11c are carboxyl-protecting groups such as a methyl group, an ethyl group, a benzyl group, and a tert-butyl group
- R 11b is an acetyl group, a benzyl group, a methyl group, an ethyl group
- Protecting groups for hydroxyl groups such as isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group
- X 11a and X 11b are a chlorine atom and a bromine atom, respectively.
- a leaving group such as a halogen atom such as iodine atom or fluorine atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc.
- Step 1 Compound [I-1-2] can be obtained by metalation of compound [I-1-1] according to a conventional method and then introducing a carboxyl group using carbon dioxide.
- a carboxyl group using carbon dioxide For metalation, n-butyllithium, sec-butyllithium, lithium diisopropylamide, lithium bis () in a single or mixed solvent such as hexane, benzene, toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, etc. under low temperature conditions.
- Compound [I] is obtained by reacting with an organometallic reagent such as trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium amide, or sodium amide, and then reacting with carbon dioxide. -1-2] can be obtained.
- organometallic reagent such as trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium amide, or sodium amide
- Step 2 Compound [I-1-3] can be obtained by introducing a protecting group into the carboxyl group of compound [I-1-2] according to a conventional method.
- the protecting group is a tert-butyl group, p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, hydrogen chloride under low temperature to warming conditions , Hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid in the presence of hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide , N, N-dimethylformamide, acetonitrile and the like alone or in a mixed solvent, the compound [I
- Step 3 Compound [I-1-4] can be obtained by introducing a hydroxyl group protected with a protecting group represented by R 11b into compound [I-1-3] according to a conventional method. For example, when a hydroxyl group protected with a benzyl group is introduced, the compound [I-1-3] is converted to triethylamine, potassium tert-butoxide, potassium carbonate, sodium hydride, n-butyllithium under low temperature to warming conditions.
- Compound [I-1-4] is subjected to chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide under low temperature to warming conditions, Compound [I-1-5] can be obtained by reacting with hydrazine monohydrate alone or in a mixed solvent such as N, N-dimethylformamide, acetonitrile and water.
- a mixed solvent such as N, N-dimethylformamide, acetonitrile and water.
- Step 5 Compound [I-1-5] is heated under low temperature to warming conditions under conditions of p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide, hydrogen chloride, hydrogen bromide
- acids such as phosphoric acid and sulfuric acid, hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide
- N Compound [I-1-6] can be obtained by reaction with orthoester compounds such as trimethyl orthoformate and triethyl orthoformate or formic acid, alone, in a mixed solvent or in the absence of solvent such as N-dimethylformamide and acetonitrile. .
- Step 6 Compound [I-1-6] is allowed to react with hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1, in the presence of a base such as sodium hydroxide, morpholine, piperidine, pyrrolidine under room temperature to warming conditions.
- a base such as sodium hydroxide, morpholine, piperidine, pyrrolidine
- Step 7 Compound [I-1-8] can be obtained by deprotecting the protecting group for the carboxyl group of compound [I-1-7] according to a conventional method.
- R 11a is a tert-butyl group, hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, P-Toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride in single or mixed solvents such as 2-propanol, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, water, etc.
- Compound [I-1-8] can be obtained by reacting with an acid such as boron tribromide, aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid or trifluoroacetic acid.
- an acid such as boron tribromide, aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid or trifluoroacetic acid.
- R 11a is a methyl group, an ethyl group or a tert-butyl group
- the compound [I-1-7] is subjected to sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide under low temperature to warming conditions.
- Step 8 Compound [I-1-9] can be obtained by introducing a protecting group into the carboxyl group of compound [I-1-8] according to a conventional method.
- the protecting group is an ethyl group, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, under low temperature to warming conditions
- Compound [I-1-9] is obtained by reacting compound [I-1-8] with N, N-dimethylformamide diethyl acetal in a single or mixed solvent such as dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like.
- Step 9 Compound [I-1-10] can be obtained by introducing a leaving group onto the pyridine ring of compound [I-1-9] according to a conventional method.
- the disubstituted compound [I-1-11] may be obtained.
- the leaving group is an iodine atom, n-butyllithium, sec-butyl in a single or mixed solvent such as hexane, toluene, 1,2-dimethoxyethane, diethyl ether, 1,4-dioxane, tetrahydrofuran under low temperature conditions
- organometallic reagents such as lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium amide, sodium amide, etc., followed by reaction with iodine To obtain compound [I-1-10] and compound [I-1-11].
- R 12a is a protecting group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, and the other symbols are as described above. [1-2-1] even if the substituents other than R 2 are as defined in [1-2-4], by performing an appropriate substituent conversion, eventually it may become as defined.)
- Step 1 Compound [I-2-1] can be obtained by introducing substituent R 2 or a precursor thereof into compound [I-1-10] according to a conventional method.
- R 2 is a butyl group
- the compound [I-1-10] is subjected to [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, tetrakis (triphenylphosphine) under room temperature to warming conditions.
- Palladium catalysts such as palladium, bis (triphenylphosphine) palladium (II) dichloride, palladium acetate-triphenylphosphine, and potassium acetate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, triethylamine, diisopropylethylamine, phosphoric acid
- a silver salt such as silver carbonate, silver nitrate or silver (I) oxide is added as necessary, and hexane, N, N-dimethylformamide, N, N-dimethylacetamide, Acetonitrile, 1,2-dimethoxyethane, te
- Compound [I-2-1] can be obtained by reacting with butylboronic acid in a single or mixed solvent such as trahydrofuran, 1,4-dioxane, toluene, and water.
- Step 2 Compound [I-2-2] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [I-2-1] in the same manner as in Step 7 of Production Method I-1. it can.
- Step 3 Compound [I-2-3] is condensed with compound [I-2-2] by a glycine derivative represented by H 2 NC (R 4 ) (R 5 ) COOR 12a according to a conventional method. Can be obtained.
- compound [I-2-2] can be converted into dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a salt thereof, diphenyl under low temperature to warming conditions.
- a condensing agent such as phosphorylazide and optionally N-hydroxysuccinimide, 1-hydroxybenzotriazole, dimethylaminopyridine and the like, potassium carbonate, sodium bicarbonate, cesium carbonate, triethylamine, diisopropylethylamine, morpholine as necessary
- a base such as pyridine is added, and it is represented by H 2 NC (R 4 ) (R 5 ) COOR 12a in a solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene.
- a solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene.
- Step 4 Compound [I-2-4] can be obtained by deprotecting hydroxyl-protecting group R 11b of compound [I-2-3] according to a conventional method.
- R 11b is a benzyl group
- hexane in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, platinum carbon, Raney nickel, under room temperature to heating conditions, in a hydrogen atmosphere, under normal pressure to pressurized conditions , Methanol, ethanol, 2-propanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, ethyl acetate, acetic acid, water, or the like alone or in a mixed solvent to produce compound [I-2- 4] can be obtained.
- a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, platinum carbon, Raney nickel
- Step 5 Compound [I-2-5] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [I-2-4] in the same manner as in Step 7 of Production Method I-1. it can.
- Step 2 Compound [I-3-2] can be obtained by deprotecting R 11b of Compound [I-3-1] in the same manner as in Step 4 of Production Method I-2.
- Step 3 Compound [I-3-3] can be obtained by reacting compound [I-3-2] with a glycine derivative represented by H 2 NC (R 4 ) (R 5 ) COOH.
- the compound [I-3-2] is treated under the conditions of room temperature to warming hexane, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol.
- the compound [I-3-3] can be obtained by reaction with a sodium salt of a glycine derivative. .
- R 3 in [I-4-2] and [I-4-3] is the one finally defined by appropriately converting the substituent, even in the case of a substituent other than the defined one. (All other symbols are as described above.)
- Step 3 Compound [I-4-3] can be obtained by deprotecting R 11b of Compound [I-4-2] in the same manner as in Step 4 of Production Method I-2.
- Step 4 In the same manner as in Step 3 of production method I-3, glycine derivative represented by compound [I-4-3] and H 2 NC (R 4 ) (R 5 ) COOH, or a metal species thereof Compound [I-4-4] can be obtained by reacting a salt of
- Step 1 Compound [I-5-1] can be obtained by introducing substituent R 3 into compound [I-1-10] according to a conventional method.
- R 3 is a chloro group
- the compound [I-1-10] is converted into n-butyllithium, lithium hexamethyldisilazide, sodium bis (trimethylsilyl) amide, potassium hexamethyldisilazide, lithium under low temperature conditions.
- step process I-2 of the fourth step and the same method by a hydroxyl-protecting group R 11b of compound [I-5-2] is deprotected to give a compound [I-5-3] Can do.
- Step 4 In the same manner as in Step 3 of production method I-3, a glycine derivative represented by compound [I-5-3] and H 2 NC (R 4 ) (R 5 ) COOH, or a metal species thereof, Compound [I-5-4] can be obtained by reacting a salt of
- R 16a is an acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, etc.
- R 16b and R 16c are carboxyl-protecting groups such as methyl, ethyl, benzyl and tert-butyl groups
- X 16a is a fluorine atom, chlorine atom, bromine atom, iodine A leaving atom such as a halogen atom such as an atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc., and other symbols are as described above.
- [1-6-4] performing R 2 even if the substituents other than those defined as appropriate substituent conversion of [1-6-10] from And by finally may if those defined.)
- Step 1 In the same manner as in Step 3 of production method I-1, compound [I-6-2] is obtained by introducing a hydroxyl group protected with protecting group R 16a into compound [I-6-1]. be able to.
- Step 2 In the same manner as in Step 1 of production method I-1, compound [I-6-3] is converted into compound [I-6-2] by introducing a carboxyl group protected with a protecting group R 16b . Obtainable.
- Step 3 In the same manner as in Step 1 of production method I-2, compound [I-6-4] is obtained by introducing substituent R 2 or a precursor thereof into compound [I-6-3]. Can do.
- Step 4 In the same manner as in Step 4 of production method I-1, compound [I-6-5] can be obtained from compound [I-6-4].
- Step 5 Compound [I-6-6] can be obtained from compound [I-6-5] in the same manner as in Production Method I-1, Step 5.
- Step 6 In the same manner as in Step 6 of production method I-1, compound [I-6-7] can be obtained from compound [I-6-6].
- Seventh Step Compound [I-6-8] can be obtained by deprotecting the protective group for the carboxyl group of compound [I-6-7] in the same manner as in Step 7 of production method I-1. .
- Step 9 In the same manner as in Step 4 of production method I-2, compound [I-6-10] can be obtained by deprotecting the hydroxyl-protecting group R 16a of compound [I-6-9]. it can.
- Step 10 In the same manner as in Step 7 of production method I-1, compound [I-6-11] can be obtained by deprotecting the protecting group of the carboxyl group of compound [I-6-10]. .
- R 17a is a protecting group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group or a tert-butyl group
- X 17a is a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and represents a leaving group such as p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc.
- Step 1 Compound [I-7-1] is cooled to hexane, ethyl acetate, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol under low to warm conditions. , Cyanamide in the presence of an organometallic reagent such as nickel (II) acetylacetonate in a single or mixed solvent such as 2-propanol, dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, water, etc. To give compound [I-7-2].
- organometallic reagent such as nickel (II) acetylacetonate
- a single or mixed solvent such as 2-propanol, dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2-pyrrolidone, acetonit
- Step 2 Compound [I-7-3] can be obtained by converting the hydroxyl group of compound [I-7-2] to a leaving group according to a conventional method.
- the leaving group X 17a is a chlorine atom
- the compound [I-7-2] is converted to hexane, ethyl acetate, acetone, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran under low temperature to warm conditions. 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide, N, N-dimethylformamide, 2-pyrrolidone, acetonitrile, etc.
- Compound [I-7-3] is cooled under low temperature to warming conditions with ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, Compound [I-7] is reacted with N, N-dimethylformamide dialkylacetal in a single or mixed solvent such as dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like, and further reacted with hydroxylamine or its hydrochloride. -4] can be obtained.
- Step 4 Compound [I-7-4] is dissolved in hexane, ethyl acetate, acetone, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N, under low to high temperature conditions.
- dehydration reaction using polyphosphoric acid, thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, acetic anhydride, acetyl chloride, trifluoroacetic anhydride, etc. alone or in a mixed solvent such as N-dimethylformamide and acetonitrile.
- Compound [I-7-5] can be obtained.
- R 18a is a hydroxyl group such as acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, etc.
- R 18b represents a protecting group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, or a tert-butyl group, and other symbols are as described above.
- Step 1 Compound [I-8-1] is prepared by introducing substituent R 2 or a precursor thereof into Compound [I-7-5] according to a conventional method in the same manner as in Production Method I-2, Step 1. ] Can be obtained.
- Step 2 Compound [I-8-2] can be obtained by introducing a hydroxyl group protected with a protecting group represented by R 18a into compound [I-8-1].
- a hydroxyl group protected with a methyl group is introduced, the compound [I-8-1] is converted to hexane, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4 under low temperature to warm conditions.
- Step 3 Compound [I-8-3] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [I-8-2] in the same manner as in Step 7 of Production Method I-1. it can.
- Step 4 Condensation of compound [I-8-3] with a glycine derivative represented by H 2 NC (R 4 ) (R 5 ) COOR 18b in the same manner as in Step 3 of production method I-2 Can give compound [I-8-4].
- Step 5 Compound [I-8-5] can be obtained by deprotecting hydroxyl-protecting group R 18a and carboxyl-protecting group R 18b of compound [I-8-4] according to a conventional method.
- the compound [I-8-4] is converted to p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride under room temperature to warming conditions, Boron trifluoride-diethyl ether complex, boron trichloride, boron tribromide, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like in the presence of hexane, ethyl acetate, acetone, chloroform, Methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-d
- R 19a is a protecting group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, or a tert-butyl group, and R 19b forms a salt with carboxylic acid or phenol such as lithium, sodium, or calcium) (The other symbols are as described above.)
- Step 1 Compound [I-9-1] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [I-8-1] in the same manner as in Step 7 of Production Method I-1. it can.
- Step 3 Compound [I-9-3] can be obtained by reacting compound [I-9-2] with a base.
- a base for example, when R 19b is sodium, dimethyl sulfoxide, N, N-dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, Compound [I-9-3] can be obtained by reacting with sodium hydroxide alone or in a mixed solvent such as ethanol, 2-methoxyethanol, 2-ethoxyethanol and water.
- Step 4 Compound [I-9-3] is subjected to dimethyl sulfoxide, N, N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene under low to warm conditions.
- Compound [I-9-4] can be obtained by reacting an acid such as sulfuric acid.
- R 21a is a hydroxyl group such as benzyl group, acetyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, etc.
- R 21b represents a protecting group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, or a tert-butyl group, and other symbols are as described above. [II-1- 8] to [II-1-9] R 2 may be finally defined even if it is a substituent other than those defined, by appropriately performing substituent conversion.
- Compound [II-1-1] is subjected to low temperature to warming conditions under conditions of p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, hydrogen chloride, Hydrogen bromide, phosphoric acid, sulfuric acid, sulfamic acid, acetic acid, trifluoroacetic acid, etc., in the presence of hexane, chloroform, methylene chloride, ethyl acetate, methanol, ethanol, 2-propanol, toluene, 1,4-dioxane, tetrahydrofuran , 1,2-dimethoxyethane, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, water or the like alone or in a mixed solvent to react with 2,5-hexanedione to give compound [II-
- Second Step By introducing a hydroxyl group protected with a protecting group represented by R 21a into compound [II-1-2] in the same manner as in the third step of production method I-1, compound [II-1 -3] can be obtained.
- Compound [II-1-3] is heated under low temperature to warming conditions in the presence of a base such as triethylamine, potassium tert-butoxide, potassium carbonate, sodium hydride, lithium diisopropylamide, and hydroxylammonium chloride, methanol, ethanol,
- a base such as triethylamine, potassium tert-butoxide, potassium carbonate, sodium hydride, lithium diisopropylamide, and hydroxylammonium chloride, methanol, ethanol
- Compound [II-1-4] can be obtained by stirring in 2-propanol, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, water or the like alone or in a mixed solvent.
- Step 4 Compound [II-1-4] is stirred at room temperature or under conditions of ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl.
- Step 5 Compound [II-1-6] can be obtained by introducing a carboxyl group into compound [II-1-5] in the same manner as in Production Method I-1, Step 1.
- Step 6 Compound [II-1-7] can be obtained by introducing protective group R 21b into the carboxyl group of compound [II-1-6] according to a conventional method.
- R 21b is an ethyl group
- the compound [II-1-6] is subjected to hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-
- Compound [II-1-7] can be obtained by reacting with N, N-dimethylformamide diethyl acetal alone or in a mixed solvent such as dimethoxyethane, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like.
- Step 7 Compound [II-1-8] can be obtained by introducing substituent R 2 or a precursor thereof into compound [II-1-7] according to a conventional method.
- the compound [II-1-7] is subjected to [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, tetrakis (tri Palladium catalyst such as phenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, palladium acetate-triphenylphosphine, potassium acetate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, triethylamine, diisopropylethylamine Hexane, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, 1,2-dimethoxyethane,
- Step 8 Compound [II-1-9] is obtained by deprotecting the hydroxyl-protecting group R 21a of Compound [II-1-8] in the same manner as in Step 4 of Production Method I-2. Can do.
- R 31a and R 31d are each a protecting group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, and R 31b and R 31c are a benzyloxycarbonyl group, a tert-butoxy group, and the like.
- a protecting group for an amino group such as a carbonyl group or a benzyl group wherein X 31a and X 31b are each a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group And represents a leaving group such as a trifluoromethanesulfonyloxy group, and other symbols are as described above.
- Step 1 Compound [III-1-1] obtained by deprotecting R 11b of compound [I-1-4] in the same manner as in Step 4 of production method I-2 is eliminated according to a conventional method.
- the compound [III-1-2] can be obtained.
- X 31b is a bromine atom
- the compound [III-1] is subjected to hexane, chloroform, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, etc. under low to warm conditions.
- the compound [III-1-2] can be obtained by reacting with bromine or N-bromosuccinimide alone or in a mixed solvent.
- Step 2 Compound [III-1-3] can be obtained by introducing R 31b into compound [III-1-2] according to a conventional method.
- R 31b is a benzyl group, ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, water, etc., alone or in combination
- compound [III-1-2] with benzyl chloride or benzyl bromide in a solvent in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride, cesium carbonate or the like, compound [III-1 -3] can be obtained.
- a base such as potassium carbonate, potassium tert-butoxide, sodium hydride, cesium carbonate or the like
- Step 3 and Step 4 After deprotecting R 31a of the compound [III-1-3] in the same manner as in Step 7 of Production Method I-1, after converting to acid chloride according to a conventional method, H 2 NC (R 4 ) (R 5 ) COOR 31d alone or in a mixed solvent such as hexane, chloroform, methylene chloride, ethyl acetate, toluene, tetrahydrofuran under the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc.
- a mixed solvent such as hexane, chloroform, methylene chloride, ethyl acetate, toluene, tetrahydrofuran under the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc.
- Step 5 Compound [III-1-7] can be obtained from compound [III-1-6] in the same manner as in Production Method I-2, Step 1.
- Step 6 Compound [III-1-8] can be obtained by deprotecting R 31b of Compound [III-1-7] in the same manner as in Step 4 of Production Method I-2.
- Step 7 Compound [III-1-9] can be obtained by deprotecting amino-protecting group R 31c of compound [III-1-8] according to a conventional method.
- R 31c is a tert-butoxycarbonyl group, hexane, chloroform, methylene chloride, acetic acid in the presence of an acid such as hydrogen chloride, sulfuric acid, hydrogen bromide, phosphoric acid, acetic acid, trifluoroacetic acid under low temperature to room temperature conditions.
- Compound [III-1-9] can be obtained by stirring in ethyl acetate, toluene, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, water or the like alone or in a mixed solvent.
- Step 8 Compound [III-1-10] can be obtained from compound [III-1-9] in the same manner as in Production Method I-1, Step 5.
- Step 9 Compound [III-1-11] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [III-1-10] in the same manner as in Step 7 of Production Method I-1. it can.
- R 32a represents a protecting group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, or a tert-butyl group, and other symbols are as described above.
- Step 1 Compound [III-2-1] can be obtained from Compound [I-6-5] in the same manner as in Production Method I-1, Step 5.
- Step 2 Compound [III-2-2] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [III-2-1] in the same manner as in Step 7 of Production Method I-1. it can.
- Step 4 Compound [III-2-4] can be obtained by deprotecting R 16a of compound [III-2-3] in the same manner as in Step 4 of production method I-2.
- Step 5 Compound [III-2-5] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [III-2-4] in the same manner as in Step 7 of Production Method I-1. it can.
- R 41a is an acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, etc.
- R 41b is a protective group for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, or a tert-butyl group
- X 41a and X 41b are a chlorine atom, a bromine atom, and an iodine atom, respectively.
- halogen atoms such as p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyl group and methanesulfonyl group.
- Step 1 Compound [IV-1-2] can be obtained by converting leaving group X 41a of compound [IV-1-1] into a formyl group according to a conventional method.
- Compound [IV-1-1] is mixed with n-butyllithium, sec-butyllithium, lithium diisopropyl in a single or mixed solvent of hexane, benzene, toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane and the like under low temperature conditions.
- Second Step and Third Step Compound [IV-1-2] is heated at room temperature to warming conditions, ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol. , Dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, etc., alone or in a mixed solvent, reacted with hydrazine having a leaving group X 41b , and further added with a base such as morpholine, piperidine, pyrrolidine, and the like, and stirred. [IV-1-4] can be obtained.
- Step 4 Compound [IV-1-5] can be obtained from compound [IV-1-4] in the same manner as in Step 1 of production method 1-1.
- Step 5 Compound [IV-1-6] can be obtained by condensing glycine derivative with Compound [IV-1-5] in the same manner as in Step 3 of Production Method I-2.
- Step 6 Compound [IV-1-7] can be obtained by deprotecting R 41a of compound [IV-1-6] in the same manner as in Step 4 of production method I-2.
- Step 7 Compound [IV-1-8] can be obtained by deprotecting the protecting group of the carboxyl group of Compound [IV-1-7] in the same manner as in Step 7 of Production Method I-1. it can.
- R 1 is a hydrogen atom.
- R 1 is the above-described substituent other than a hydrogen atom
- N, N-dimethylformamide substituted with a desired substituent is substituted in place of N, N-dimethylformamide in the first step.
- the second and subsequent steps may be used in the same manner as described in the present production method.
- Step 1-1 The compound obtained in Step 1-1 (234 g) and tetrahydrofuran (1200 ml) were mixed, and boron trifluoride-diethyl ether complex (8 ml) was added. Subsequently, tert-butyl 2,2,2-trichloroacetimidate (361 ml) was added dropwise under ice cooling. A saturated aqueous sodium bicarbonate solution (1200 ml) and water (1200 ml) were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (1200 ml). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
- Step 1-8 The compound obtained in Step 1-8 (45 g) and 1,4-dioxane (450 ml) were mixed, and 4N aqueous sodium hydroxide solution (116 ml) was added at room temperature. After stirring at 100 ° C. for 17 hours, the reaction solution was concentrated under reduced pressure. Water (450 ml) was added thereto, neutralized with 6N hydrochloric acid (77 ml) under ice-cooling, and the precipitated solid was collected by filtration to obtain the compound (43 g) described in the above scheme.
- step 2-1 The compound (3.84 g) obtained in step 2-1 was mixed with toluene (29 ml) and ethyl acetate (9.5 ml), and stirred at room temperature with methanesulfonic acid (2.34 ml) and ethyl acetate (2. 34 ml) was added dropwise over 10 minutes. After stirring at room temperature for 3 hours, ethyl acetate (9.5 ml) was added to the reaction mixture, and the solid was collected by filtration to obtain the compound described in the above scheme (4.94 g, 98%).
- the title compound (2) is obtained by hydrolyzing the compound (2.28 g) obtained in Step 2-5 in the same manner as in Step 1-12, and converting the obtained compound to hydrochloride according to a conventional method. .16 g) was obtained.
- Step 2-2 the protecting group of the carboxyl group of the compound (53.7 g) obtained in Step 3-1 was deprotected, and the carboxylic acid compound was mixed with methanesulfonic acid (290 mol%). (69.8 g, 80%).
- the compound described in the above scheme was obtained as a mixture (42.8 g, 99%) with methanesulfonic acid (50 mol%) from this mixture by the same treatment as in Step 2-3.
- Step 4-3 The compound obtained in Step 4-3 (0.020 g) and 2-methoxyethanol (2 ml) were mixed, and glycine sodium salt (0.030 g) was added. After stirring at 130 ° C. for 1.5 hours, the mixture was cooled to room temperature, and 1N hydrochloric acid (0.34 ml) and water (10 ml) were added to the reaction mixture and stirred. The precipitate was collected by filtration and dried under reduced pressure. To the solid obtained were added ethyl acetate (1 ml) and 4N hydrochloric acid-ethyl acetate (0.1 ml), and the mixture was stirred at room temperature for 20 minutes. The solid was collected by filtration to give the title compound (0.052 mg, 67%).
- Step 6-2 The compound obtained in Step 6-2 (70 mg) and trifluoroacetic acid (1 ml) were mixed and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture and concentrated under reduced pressure. 4N Hydrochloric acid-ethyl acetate (1 ml) was added to the concentrated residue and stirred. Further, hexane (3 ml) was added and stirred, and the solid was collected by filtration to obtain the compound described in the above scheme (50 mg, 83%).
- Step 8-2 The compound obtained in Step 8-2 (58.4 g), hydroxylammonium chloride (233 g), ethanol (600 ml) and water (350 ml) were mixed. Triethylamine (46 ml) was added dropwise to the mixture at room temperature, ethanol (100 ml) was added, and the mixture was heated to reflux at a bath temperature of 95 ° C. for 89 hours. The reaction mixture was ice-cooled, and 50% aqueous sodium hydroxide solution (96 ml), 8N aqueous sodium hydroxide solution (134 ml), and saturated aqueous sodium hydrogen carbonate solution (50 ml) were sequentially added.
- Step 8-3 The compound obtained in Step 8-3 (7.25 g), N, N-dimethylformamide (11 ml) and N, N-dimethylformamide dimethyl acetal (11 ml) were mixed, and the mixture was heated and stirred at 130 ° C. for 15 minutes. After stirring at room temperature for 20 minutes, methanol (58 ml) and pyridine (4.2 ml) were added to the residue obtained by concentration under reduced pressure, and hydroxylamine-O-sulfonic acid (4.1 g) was added under ice cooling. After stirring overnight at room temperature, water (29 ml) and saturated aqueous sodium hydrogen carbonate solution (58 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
- Trifluoroacetic acid 180 ml was added to the compound (610 mg) obtained in Step 9-2 under ice cooling, and the mixture was stirred at room temperature for 2 hours. Chloroform (6 ml) was added to the reaction solution, diluted and concentrated under reduced pressure. Chloroform (6 ml) was again added to the residue. Thionyl chloride (0.18 ml) and N, N-dimethylformamide (1 drop) were added and heated at 70 ° C. for 30 minutes. The obtained solution was concentrated under reduced pressure to obtain the compound described in the above scheme (540 mg, 98%).
- Trimethyl orthoformate (0.41 ml) was added to the compound obtained in Step 9-7 (41 mg) and heated at 100 ° C. for 30 minutes.
- the reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform (1 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 3 hr.
- the reaction mixture was concentrated under reduced pressure, 4N hydrochloric acid dioxane solution (1 ml) was added to the residue, and the mixture was stirred at room temperature for 30 min.
- the residue obtained by concentrating the reaction solution under reduced pressure was slurried with water to obtain the title compound (29 mg, 89%).
- the title compound was obtained by subjecting the obtained compound to deprotection of the protecting group for hydroxyl group and deprotection of the protecting group for carboxyl group by the above-described method, and further converted into hydrochloride according to a conventional method.
- a toluene (4 ml) solution of the compound (1 g) obtained in Step 11-1 was added dropwise to n-butyllithium (1.54 mol / l hexane solution 25 ml) at ⁇ 78 ° C. over 7 minutes.
- the reaction solution was stirred at ⁇ 78 ° C. for 50 minutes, and then a solution of N, N-dimethylformamide (0.352 ml) in toluene (4 ml) was added dropwise.
- the reaction mixture was further stirred at ⁇ 78 ° C. for 1 hour, water (6 ml) was added at ⁇ 10 ° C., and the mixture was stirred at room temperature for 2 hours.
- Step 11-2 The compound obtained in Step 11-2 (637 mg), methanol (6.4 ml) and tosyl hydrazide (574 mg) were mixed and heated to reflux for 10 minutes.
- the reaction mixture was concentrated under reduced pressure, morpholine (6.4 ml) was added, and the mixture was heated to reflux for 30 min.
- the reaction mixture was concentrated under reduced pressure, and ethyl acetate (12 ml), 2M aqueous sodium carbonate solution (6 ml) and water (5 ml) were added. Further, tetrahydrofuran (6 ml) was added. After separation, the aqueous layer was extracted twice with ethyl acetate (5 ml), and the organic layers were combined and washed with saturated brine (10 ml).
- Step 116-1 The compound obtained in Step 116-1 (30 g), phosphorus oxychloride (150 ml) and N, N-diisopropylethylamine (30 ml) were mixed and stirred at room temperature for 3 days.
- the reaction mixture was concentrated and azeotroped three times with toluene.
- methanol (30 ml) and water (150 ml) were added, and the mixture was stirred at room temperature for 1 hour, and the resulting solid was collected by filtration.
- methanol (50 ml) was added and stirred at room temperature for 1 hour, and then the solid was collected by filtration to form primary crystals.
- Step 116-2 The compound obtained in Step 116-2 (2.2 g) and 2-propanol (31 ml) were mixed, and N, N-dimethylformamide dimethyl acetal (2.9 ml) was added. The mixture was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, hydroxylamine hydrochloride (1.4 g) was added, and the mixture was stirred at room temperature for 30. The reaction mixture was concentrated to about half volume, and water (40 ml) and 2-propanol (6.6 ml) were added. This mixture was stirred at room temperature for 30 minutes, and the resulting solid was collected by filtration to obtain the compound described in the above scheme (2.2 g, 84%).
- Step 116-8 The compound obtained in Step 116-8 (0.19 g) and water (0.63 ml) were mixed and heated to 50 ° C., and acetone (0.78 ml) and 6N hydrochloric acid (0.2 ml) were added. For 1 hour. After stirring for 1 hour under ice cooling, the compound described in the above scheme (0.11 g, 80%) was obtained by filtering the solid.
- Step 117-1 The compound obtained in Step 117-1 (0.043 g) and methanol (0.22 ml) were mixed, and 28% sodium methoxide methanol solution (0.014 ml) was added. The mixture was stirred at room temperature for 4 hours. After adding water (0.22 ml) and stirring at room temperature for 1 hour, 1N hydrochloric acid (0.16 ml) was added to the reaction solution, and the resulting solid was collected by filtration to obtain the compound (0.026 g, 66%).
- Step 117-2 The compound obtained in Step 117-2 (0.025 g) and N, N-dimethylformamide (0.50 ml) were mixed, and 1-hydroxybenzotriazole monohydrate (0.016 g) and glycine-tert-butyl were mixed. Ester (0.015 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.020 g) were added. The mixture was stirred at room temperature for 1.5 hours.
- the compound described in the above-mentioned scheme (0.033 g, 94%) was obtained by filtering a solid produced by adding a 5% aqueous sodium hydrogen carbonate solution and water to the reaction solution under ice cooling.
- Step 117-4 The compound obtained in Step 117-4 (0.100 g) and methyl ethyl ketone (1.0 ml) were mixed and heated to 80 ° C. To this solution was added heptane (1.0 ml) and stirred at room temperature overnight. The solid was collected by filtration to give the title compound (0.089 g, 89%).
- Examples 12 to 115 and Examples 118 to 118 shown in the following Tables 3 to 24 are carried out in the same manner as in Examples 1 to 11, Example 116 or 117, and using other conventional methods as necessary. 122 compounds were prepared.
- Examples of the preparation of the present invention include the following preparations. However, the present invention is not limited by these formulation examples.
- Formulation Example 1 Manufacture of capsules 1) 30 mg of the compound of Example 1 2) Microcrystalline cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
- Formulation Example 2 (Manufacture of tablets) 1) 10 g of the compound of Example 1 2) Lactose 50g 3) Corn starch 15g 4) Carmellose calcium 44g 5) Magnesium stearate 1g The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained.
- Test Example 1 Measurement of human PHD inhibitory activity i) Expression and purification of human PHD2 Human PHD2 was expressed in insect cells (Sf9 cells). A FLAG-tag was inserted at the N-terminal of the translation region of the human PHD2 registration sequence (NM_022051), and then introduced into the pVL1393 vector to confirm the sequence. The vector and baculovirus were co-expressed in Sf9, and a human PHD2-expressing baculovirus was isolated in Sf9. Using this virus, human PHD2-expressing cells were prepared. After culturing the cells at 27 ° C. for 72 hours, a cell lysis solution containing various protease inhibitors was added and disrupted by sonication.
- the cell lysate was bound to a column packed with ANTI-FLAG M2 Affinity Gel Freezer Safe (SIGMA). After washing, N-terminal FLAG-tag-added human PHD2 was eluted and collected. The purified product was confirmed to be human PHD2 enzyme by Western-Blotting method using anti-FLAG antibody and anti-PHD2 antibody.
- SIGMA ANTI-FLAG M2 Affinity Gel Freezer Safe
- VHL / Elongin B / Elongin C VBC complex VBC complex (VHL / Elongin B / Elongin C) was expressed in E. coli (BL21 (DE3)). GST-fusion is inserted into the translation region N-terminus of the human VHL registration sequence (NM_000551), and FLAG-tag is inserted into the translation region N-terminus of the human Elongin B registration sequence (NM_20713), and then introduced into the pETDuet-1 vector. The sequence was confirmed. A His-tag was inserted into the N terminus of the translation region of the human Elongin C registration sequence (NM_005648) and then introduced into the pRSFDuet-1 vector to confirm the sequence.
- the Escherichia coli was cultured at 37 ° C. in a medium containing IPTG.
- the collected E. coli was disrupted by sonication, bound to a column packed with Ni-NTA superflow (QIAGEN), and eluted after washing and collected.
- the eluate was bound to a column packed with Glutathione Sepharose 4B and eluted after washing and collected.
- the purified product was confirmed to be human VHL / human Elongin B and human Elongin C by Western-Blotting method using anti-GST antibody / anti-FLAG antibody and anti-His antibody.
- the human PHD2 enzyme activity was determined by measuring hydroxylation of proline residues contained in a peptide using TR-FRET (Time) using a 19-residue partial peptide based on the sequence of HIF-1 ⁇ as a substrate. -Measured by Resolved Fluorescence Resonance Energy Transfer) method.
- the enzyme and substrate are diluted with 50 mM Tris-HCl buffer (pH 7.5) containing 50 ⁇ M iron sulfate, 120 mM NaCl, 0.1% BSA, 0.1 mM ascorbic acid, 10 ⁇ M 2-oxoglutarate, 0.2 mM CHAPS.
- test compound was diluted with dimethyl sulfoxide (DMSO).
- Test compound and substrate solution were added to a 96 well plate.
- the reaction was started by adding human PHD2 enzyme solution to the reaction system (final concentration 1 nM). After incubation at 25 ° C. for 30 minutes, a stop solution containing EDTA is added, a VBC complex solution containing europium (Eu) and Xlent is added and bound, and the amount of hydroxylated proline residue is measured by time-resolved fluorescence. Quantified by the method.
- the time-resolved fluorescence of each well was measured, and the human PHD inhibitory activity (%) of the test compound in each well was calculated based on the values of the wells to which no enzyme was added and the test compound was not added.
- the human PHD inhibitory activity of each compound is shown in the following Tables 25 to 29 as human PHD inhibitory activity (%) at IC 50 ( ⁇ M) or 30 ⁇ M. In these tables, values represented only by numerical values indicate IC 50 ( ⁇ M), and values including% indicate human PHD inhibitory activity (%) at 30 ⁇ M.
- Test Example 2 Human EPO Production Inducing Activity The test compound induction activity for human EPO production was measured using Hep3B (ATCC), a liver-derived cell line established from humans. Hep3B cells were cultured in Eagle-MEM medium containing 10% fetal bovine serum, and the test compound was diluted with dimethyl sulfoxide (DMSO). Hep3B cells were cultured in 96-well plates, and test compounds were added at various concentrations after 24 hours. After incubation at 37 ° C. for 24 hours, the culture supernatant was collected. The concentration of human EPO produced in the culture supernatant was measured using a human EPO-ELISA kit (StemCell Technologies, 01630) according to the manufacturer's instructions.
- DMSO dimethyl sulfoxide
- the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof has human PHD inhibitory activity and human EPO production inducing activity.
- the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, promotes the production of EPO by stabilizing the HIF by inhibiting the binding of HIF and PHD by the PHD inhibitory activity. Can do. For this reason, the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof can be an effective drug for the prevention or treatment of various diseases and pathologies (disorders) caused by reduced production of EPO, and treatment of anemia Can be used effectively.
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Abstract
Description
更に、経口投与可能なESAとなれば、腎性貧血に限らず、種々の原因で起こる貧血に対しても治療の幅が広がる可能性が期待される。
PHDを阻害し、HIFを安定化することにより、改善が期待される疾病としては、虚血性心疾患(狭心症、心筋梗塞等)、虚血性脳血管障害(脳梗塞、脳塞栓症、一過性脳虚血発作等)、慢性腎不全(虚血性腎症、尿細管間質性障害等)、糖尿病合併症(糖尿病性創傷等)、認知障害(認知症、アルツハイマー病、パーキンソン病、ハンチントン病等)等があげられる。
従って、本発明は、プロリル水酸化酵素(PHD)阻害作用を有する薬剤を提供することを課題とする。また、本発明は、EPO産生誘導能を有する薬剤を提供することを課題とする。
より詳しくは、本発明は下記に示す通りである。
[1]下記一般式[I]で表される化合物(以下、「本発明化合物」ともいう)又はその医薬上許容される塩、或いはその溶媒和物:
部分構造式:
R1は、
(1)水素原子、
(2)C1-6アルキル基、
(3)C6-14アリール基、
(4)C3-8シクロアルキル基、
(5)C6-14アリール-C1-6アルキル基、又は、
(6)C3-8シクロアルキル-C1-6アルキル基であり;
R2は、
(1)水素原子、
(2)C1-10アルキル基、
(3)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC6-14アリール基、
(4)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC3-8シクロアルキル基、
(5)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC3-8シクロアルケニル基、
(6)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいヘテロアリール基(ここで、該ヘテロアリールは、炭素原子の他に、窒素原子、酸素原子、及び、硫黄原子から選ばれる1乃至6個のヘテロ原子を有する)、
(7)C6-14アリール-C1-6アルキル基(該C6-14アリールは、下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は、
(8)C3-8シクロアルキル-C1-6アルキル基(該C3-8シクロアルキルは、下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)であり;
R3は、
(1)水素原子、
(2)ハロゲン原子、
(3)C1-6アルキル基、
(4)C6-14アリール基、
(5)C3-8シクロアルキル基、又は、
(6)C6-14アリール-C1-6アルキル基であり;
R4及びR5は、それぞれ独立して、
(1)水素原子、又は、
(2)C1-6アルキル基である。
グループB:
(a)ハロゲン原子、
(b)C1-6アルキル基、
(c)C3-8シクロアルキル基、
(d)シアノ基、及び
(e)ハロ-C1-6アルキル基。];
[2]部分構造式:
[3]部分構造式:
[4]部分構造式:
[5]部分構造式:
[6]R4及びR5がともに水素原子である、上記[1]乃至[5]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物;
[7]R3が水素原子である、上記[1]乃至[5]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物;
[8]R1が水素原子である、上記[1]乃至[5]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物;
[9]R2が
(1)C1-10アルキル基、
(2)上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC6-14アリール基、
(3)C6-14アリール-C1-6アルキル基(該C6-14アリールは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は、
(4)C3-8シクロアルキル-C1-6アルキル基(該C3-8シクロアルキルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)である、上記[1]乃至[5]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物;
[10]R4及びR5がともに水素原子である、上記[2]に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物;
[11]R3が水素原子である、上記[10]に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物;
[12]R1が水素原子である、上記[11]に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物;
[13]R2が
(1)C1-10アルキル基、又は、
(2)C6-14アリール-C1-6アルキル基(該C6-14アリールは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)
である、上記[12]に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物:
[14]下記一般式[I-1]で表される化合物又はその医薬上許容される塩、或いはその溶媒和物:
部分構造式:
R11は、
(1)水素原子、
(2)C1-6アルキル基、
(3)フェニル基、
(4)C3-8シクロアルキル基、
(5)フェニル-C1-6アルキル基、又は、
(6)C3-8シクロアルキル-C1-6アルキル基であり;
R21は、
(1)水素原子、
(2)C1-10アルキル基、
(3)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいフェニル基、
(4)C3-8シクロアルキル基、
(5)C3-8シクロアルケニル基、
(6)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいチエニル基、
(7)フェニル-C1-6アルキル基(該フェニルは、下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は、
(8)C3-8シクロアルキル-C1-6アルキル基であり;
R31は、
(1)水素原子、
(2)ハロゲン原子、
(3)C1-6アルキル基、
(4)フェニル基、
(5)C3-8シクロアルキル基、又は、
(6)フェニル-C1-6アルキル基であり;
R41及びR51は、それぞれ独立して、
(1)水素原子、又は、
(2)C1-6アルキル基である。
グループB:
(a)ハロゲン原子、
(b)C1-6アルキル基、
(c)C3-8シクロアルキル基、
(d)シアノ基、及び
(e)ハロ-C1-6アルキル基。];
[15]下記式:
[16]下記式:
[17]下記式:
[18]下記式:
[19]下記式:
[20]下記式:
[21]下記式:
[22]下記式:
[23]下記式:
[24]下記式:
[25]下記式:
[26]上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物、及び医薬上許容される担体を含有する医薬組成物(以下、「本発明医薬組成物」ともいう);
[27]上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有するプロリル水酸化酵素阻害剤;
[28]上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有するエリスロポエチン産生誘導剤;
[29]上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有する貧血治療剤;
[30]上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有する腎性貧血治療剤;
[31]プロリル水酸化酵素阻害剤を製造するための、上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用;
[32]エリスロポエチン産生誘導剤を製造するための、上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用;
[33]貧血治療剤を製造するための、上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用;
[34]腎性貧血治療剤を製造するための、上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用;
[35]有効量の上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、プロリル水酸化酵素の阻害方法;
[36]有効量の上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、エリスロポエチン産生の誘導方法;
[37]有効量の上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、貧血の治療方法。
[38]有効量の上記[1]乃至[25]のいずれかに記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、腎性貧血の治療方法。
[39]上記[26]に記載の医薬組成物、及び当該医薬組成物を貧血及び腎性貧血より選ばれる疾患の治療又は予防の用途に使用することができる、或いは使用すべきであることを記載した当該医薬組成物に関する記載物を含む、商業パッケージ;
[40]上記[26]に記載の医薬組成物、及び当該医薬組成物を貧血及び腎性貧血より選ばれる疾患の治療又は予防の用途に使用することができる、或いは使用すべきであることを記載した当該医薬組成物に関する記載物を含む、キット。
(a)上記定義の「ハロゲン原子」、
(b)上記定義の「C1-6アルキル基」、
(c)上記定義の「C3-8シクロアルキル基」、
(d)シアノ基、及び
(e)上記定義の「ハロ-C1-6アルキル基」。
該部分構造式として好ましくは、
該部分構造式として、より好ましくは、
(1)水素原子、
(2)C1-6アルキル基、
(3)C6-14アリール基、
(4)C3-8シクロアルキル基、
(5)C6-14アリール-C1-6アルキル基、又は、
(6)C3-8シクロアルキル-C1-6アルキル基、を示す。
R1として好ましくは、
(1)水素原子、
(2)C1-3アルキル基(例、メチル)、
(3)C6-14アリール基(例、フェニル)、
(4)C3-5シクロアルキル基(例、シクロプロピル)、
(5)C6-14アリール(例、フェニル)-C1-3アルキル(好ましくは直鎖のC1-3アルキル、例、エチル)基、及び、
(6)C3-8シクロアルキル(例、シクロヘキシル)-C1-3アルキル(例、エチル)基、等である。
R1としてより好ましくは、水素原子である。
(1)水素原子、
(2)C1-10アルキル基、
(3)上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC6-14アリール基、
(4)上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC3-8シクロアルキル基、
(5)上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC3-8シクロアルケニル基、
(6)上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいヘテロアリール基(ここで、該ヘテロアリールは、炭素原子の他に、窒素原子、酸素原子及び硫黄原子から選ばれる1乃至6個のヘテロ原子を有する)、
(7)C6-14アリール-C1-6アルキル基(該C6-14アリールは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は
(8)C3-8シクロアルキル-C1-6アルキル基(該C3-8シクロアルキルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)を示す。
R2として好ましくは、
(1)水素原子、
(2)C1-10アルキル基、
(3)上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC6-14アリール基、
(4)C3-8シクロアルキル基(例、シクロペンチル、シクロヘキシル、シクロヘプチル)、
(5)C3-8シクロアルケニル基(例、シクロヘキセニル)、
(6)上記グループB
(例、(a)ハロゲン原子(例、塩素原子)、及び
(b)C1-6アルキル基(例、メチル))
から選ばれる同一又は異なった1乃至5個(例、1個)の置換基で置換されてもよいヘテロアリール基(好ましくは単環のヘテロアリール基、例、チエニル)
(ここで、該ヘテロアリールは、炭素原子の他に、窒素原子、酸素原子及び硫黄原子(例、硫黄原子)から選ばれる1乃至6個(例、1乃至4個)のヘテロ原子を有する)、
(7)C6-14アリール-C1-6アルキル基(該C6-14アリールは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、及び
(8)C3-8シクロアルキル-C1-3アルキル基(該C3-8シクロアルキルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、である。
R2としてより好ましくは、
(1)C1-10アルキル基(例、エチル、プロピル、イソプロピル、ブチル、イソブチル、ペンチル、イソペンチル、tert-ペンチル、ヘキシル、1-エチルプロピル、2-エチルブチル、3,3-ジメチルブチル、3,3-ジメチルペンチル)、
(2)上記グループB
(例、(a)ハロゲン原子(例、塩素原子、フッ素原子)、
(b)C1-3アルキル基(例、メチル)、
(c)C3-5シクロアルキル基(例、シクロプロピル)、
(d)シアノ基、及び
(e)ハロ-C1-3アルキル基(例、トリフルオロメチル))
から選ばれる同一又は異なった1乃至5個(例、1乃至3個)の置換基で置換されてもよいC6-14アリール基(例、フェニル)、
(3)C6-14アリール(例、フェニル)-C1-6アルキル(好ましくは直鎖のC1-6アルキル、例、メチル、エチル、プロピル)基
(該C6-14アリールは、上記グループB
(例、(a)ハロゲン原子(例、塩素原子、フッ素原子)、
(b)C3-8シクロアルキル基(例、シクロプロピル)、及び
(c)ハロ-C1-3アルキル基(例、トリフルオロメチル))
から選ばれる同一又は異なった1乃至5個(例、1乃至3個)の置換基で置換されてもよい)、及び
(4)C3-8シクロアルキル(例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル)-C1-3アルキル(例、メチル、エチル)基
(該C3-8シクロアルキルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、である。
R2として更に好ましくは、
(1)C1-6アルキル基(例、ブチル、ペンチル、1-エチルプロピル)、
(2)(a)ハロゲン原子(例、塩素原子、フッ素原子)、
(b)C1-3アルキル基(例、メチル)、
(c)C3-5シクロアルキル基(例、シクロプロピル)、及び
(d)ハロ-C1-3アルキル基(例、トリフルオロメチル)
から選ばれる同一又は異なった1乃至3個の置換基で置換されてもよいフェニル、
(3)フェニルエチル、
(4)シクロペンチルエチル、である。
R2として特に好ましくは、ブチル、フェニルエチル、4-フルオロ-3-トリフルオロメチルフェニルである。
(1)C1-10アルキル基、又は、
(2)C6-14アリール-C1-6アルキル基(該C6-14アリールは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)
である。
(1)水素原子、
(2)ハロゲン原子、
(3)C1-6アルキル基、
(4)C6-14アリール基、
(5)C3-8シクロアルキル基、又は、
(6)C6-14アリール-C1-6アルキル基、を示す。
R3として好ましくは、
(1)水素原子、
(2)ハロゲン原子(例、塩素原子)、
(3)C1-6アルキル基(例、エチル、ペンチル)、
(4)C6-14アリール基(例、フェニル)、
(5)C6-14アリール(例、フェニル)-C1-6アルキル(好ましくは直鎖のC1-6アルキル、例、エチル)基、である。
R3としてより好ましくは、水素原子である。
(1)水素原子、又は、
(2)C1-6アルキル基を示す。
R4及びR5として好ましくは、それぞれ独立して、
(1)水素原子、又は、
(2)C1-3アルキル基(例、メチル)である。
R4及びR5としてより好ましくは、ともに水素原子である。
部分構造式:
R1aが、
(1)水素原子、
(2)C1-3アルキル基(例、メチル)、
(3)C6-14アリール基(例、フェニル)、
(4)C3-5シクロアルキル基(例、シクロプロピル)、
(5)C6-14アリール(例、フェニル)-C1-3アルキル(好ましくは直鎖のC1-3アルキル、例、エチル)基、又は、
(6)C3-8シクロアルキル(例、シクロヘキシル)-C1-3アルキル(例、エチル)基;
R2aが、
(1)水素原子、
(2)C1-10アルキル基、
(3)上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC6-14アリール基、
(4)C3-8シクロアルキル基(例、シクロペンチル、シクロヘキシル、シクロヘプチル)、
(5)C3-8シクロアルケニル基(例、シクロヘキセニル)、
(6)上記グループB
(例、(a)ハロゲン原子(例、塩素原子)、及び
(b)C1-6アルキル基(例、メチル))
から選ばれる同一又は異なった1乃至5個(例、1個)の置換基で置換されてもよいヘテロアリール基(好ましくは単環のヘテロアリール基、例、チエニル)
(ここで、該ヘテロアリールは、炭素原子の他に、窒素原子、酸素原子及び硫黄原子(例、硫黄原子)から選ばれる1乃至6個(例、1乃至4個)のヘテロ原子を有する)、
(7)C6-14アリール-C1-6アルキル基(該C6-14アリールは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は
(8)C3-8シクロアルキル-C1-3アルキル基(該C3-8シクロアルキルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい);
R3aが、
(1)水素原子、
(2)ハロゲン原子(例、塩素原子)、
(3)C1-6アルキル基(例、エチル、ペンチル)、
(4)C6-14アリール基(例、フェニル)、又は
(5)C6-14アリール(例、フェニル)-C1-6アルキル(好ましくは直鎖のC1-6アルキル、例、エチル)基;及び
R4a及びR5aが、それぞれ独立して、
(1)水素原子、又は、
(2)C1-3アルキル基(例、メチル)]
で表される化合物が、より好ましい。
R1aが、水素原子;
R2aが、
(1)C1-10アルキル基(例、エチル、プロピル、イソプロピル、ブチル、イソブチル、ペンチル、イソペンチル、tert-ペンチル、ヘキシル、1-エチルプロピル、2-エチルブチル、3,3-ジメチルブチル、3,3-ジメチルペンチル)、
(2)上記グループB
(例、(a)ハロゲン原子(例、塩素原子、フッ素原子)、
(b)C1-3アルキル基(例、メチル)、
(c)C3-5シクロアルキル基(例、シクロプロピル)、
(d)シアノ基、及び
(e)ハロ-C1-3アルキル基(例、トリフルオロメチル))
から選ばれる同一又は異なった1乃至5個(例、1乃至3個)の置換基で置換されてもよいC6-14アリール基(例、フェニル)、
(3)C6-14アリール(例、フェニル)-C1-6アルキル(好ましくは直鎖のC1-6アルキル、例、メチル、エチル、プロピル)基
(該C6-14アリールは、上記グループB
(例、(a)ハロゲン原子(例、塩素原子、フッ素原子)、
(b)C3-8シクロアルキル基(例、シクロプロピル)、及び
(c)ハロ-C1-6アルキル基(例、トリフルオロメチル))
から選ばれる同一又は異なった1乃至5個(例、1乃至3個)の置換基で置換されてもよい)、又は
(4)C3-8シクロアルキル(例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル)-C1-3アルキル(例、メチル、エチル)基
(該C3-8シクロアルキルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい);
R3aが、水素原子;及び
R4a及びR5aが、ともに水素原子;
である化合物が、更に好ましい。
部分構造式:
R11は、
(1)水素原子、
(2)C1-6アルキル基(例、メチル)、
(3)フェニル基、
(4)C3-8シクロアルキル基(例、シクロプロピル)、
(5)フェニル-C1-6アルキル基、又は、
(6)C3-8シクロアルキル-C1-6アルキル基であり;
R21は、
(1)水素原子、
(2)C1-10アルキル基(例、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、n-ペンチル、n-ヘキシル、1-エチルプロピル、3-メチルブチル、2,2-ジメチルプロピル、3,3-ジメチルブチル、2-エチルブチル、3,3-ジメチルペンチル)、
(3)上記グループBから選ばれる同一又は異なった1乃至5個の置換基(例、フッ素原子、塩素原子、メチル、シアノ、シクロプロピル、トリフルオロメチル)で置換されてもよいフェニル基、
(4)C3-8シクロアルキル基(例、シクロペンチル、シクロヘキシル、シクロヘプチル)、
(5)C3-8シクロアルケニル基(例、シクロヘキセニル)、
(6)上記グループBから選ばれる同一又は異なった1乃至5個の置換基(例、塩素原子、メチル)で置換されてもよいチエニル基、
(7)フェニル-C1-6アルキル基(例、フェニルメチル、フェニルエチル、フェニルプロピル)(該フェニルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基(例、フッ素原子、塩素原子、シクロプロピル、トリフルオロメチル)で置換されてもよい)、又は、
(8)C3-8シクロアルキル-C1-6アルキル基(例、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、シクロプロピルエチル、シクロブチルエチル、シクロペンチルエチル、シクロヘキシルエチル)、であり;
R31は、
(1)水素原子、
(2)ハロゲン原子(例、塩素原子)、
(3)C1-6アルキル基(例、エチル、n-ペンチル)、
(4)フェニル基、
(5)C3-8シクロアルキル基、又は、
(6)フェニル-C1-6アルキル基(例、フェニルエチル)であり;
R41及びR51は、それぞれ独立して、
(1)水素原子、又は、
(2)C1-6アルキル基(例、メチル)である。]
で表される化合物が好ましい。
R11が、
(1)水素原子、
(2)C1-6アルキル基(例、メチル)、
(3)フェニル基、又は
(4)C3-8シクロアルキル基(例、シクロプロピル)であり;
R21が、
(1)水素原子、
(2)C1-10アルキル基(例、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、n-ペンチル、n-ヘキシル、1-エチルプロピル、3-メチルブチル、2,2-ジメチルプロピル、3,3-ジメチルブチル、2-エチルブチル、3,3-ジメチルペンチル)、
(3)上記グループBから選ばれる同一又は異なった1乃至5個の置換基(例、フッ素原子、塩素原子、メチル、シアノ、シクロプロピル、トリフルオロメチル)で置換されてもよいフェニル基、
(4)C3-8シクロアルキル基(例、シクロペンチル、シクロヘキシル、シクロヘプチル)、
(5)C3-8シクロアルケニル基(例、シクロヘキセニル)、
(6)上記グループBから選ばれる同一又は異なった1乃至5個の置換基(例、塩素原子、メチル)で置換されてもよいチエニル基、
(7)フェニル-C1-6アルキル基(例、フェニルメチル、フェニルエチル、フェニルプロピル)(該フェニルは、上記グループBから選ばれる同一又は異なった1乃至5個の置換基(例、フッ素原子、塩素原子、シクロプロピル、トリフルオロメチル)で置換されてもよい)、又は、
(8)C3-8シクロアルキル-C1-6アルキル基(例、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、シクロプロピルエチル、シクロブチルエチル、シクロペンチルエチル、シクロヘキシルエチル)であり;
R31が、
(1)水素原子、
(2)ハロゲン原子(例、塩素原子)、
(3)C1-6アルキル基(例、エチル、n-ペンチル)、
(4)フェニル基、又は、
(6)フェニル-C1-6アルキル基(例、フェニルエチル)であり;
R41及びR51が、それぞれ独立して、
(1)水素原子、又は、
(2)C1-6アルキル基(例、メチル)である、
化合物が好ましく、
R11が、水素原子、メチル、フェニル、又はシクロプロピルであり;
R21が、水素原子;エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、n-ペンチル、n-ヘキシル、1-エチルプロピル、3-メチルブチル、2,2-ジメチルプロピル、3,3-ジメチルブチル、2-エチルブチル、3,3-ジメチルペンチル;フッ素原子、塩素原子、メチル、シアノ、シクロプロピルおよびトリフルオロメチルから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいフェニル;シクロペンチル、シクロヘキシル、シクロヘプチル;シクロヘキセニル;塩素原子およびメチルから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいチエニル;フェニルメチル、フェニルエチル、フェニルプロピル(該フェニルは、フッ素原子、塩素原子、シクロプロピルおよびトリフルオロメチルから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい);シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、シクロプロピルエチル、シクロブチルエチル、シクロペンチルエチル、又はシクロヘキシルエチルであり;
R31が、水素原子、塩素原子、エチル、n-ペンチル、フェニル、又はフェニルエチルであり;
R41及びR51が、それぞれ独立して、水素原子、又はメチルである、
化合物がより好ましい。
無機酸との塩として、例えば、塩酸、硝酸、硫酸、リン酸、臭化水素酸等との塩が挙げられる。
有機酸との塩として、例えば、シュウ酸、マレイン酸、クエン酸、フマル酸、乳酸、リンゴ酸、コハク酸、酒石酸、酢酸、トリフルオロ酢酸、グルコン酸、アスコルビン酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等との塩が挙げられる。
無機塩基との塩として、例えば、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩等が挙げられる。
有機塩基との塩として、例えば、メチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、エチレンジアミン、トリス(ヒドロキシメチル)メチルアミン、ジシクロヘキシルアミン、N,N’-ジベンジルエチレンジアミン、グアニジン、ピリジン、ピコリン、コリン、シンコニン、メグルミン等との塩が挙げられる。
アミノ酸との塩として、例えば、リジン、アルギニン、アスパラギン酸、グルタミン酸等との塩が挙げられる。
公知の方法に従って、一般式[I]で表される化合物と、無機塩基、有機塩基、無機酸、有機酸、又はアミノ酸とを反応させることにより、各々の塩を得ることができる。
公知の方法に従って、本発明化合物又はその医薬上許容される塩の溶媒和物を得ることができる。
また、本発明化合物又はその医薬上許容される塩、或いはその溶媒和物は、同位元素(例えば、3H、14C、35S等)で標識されていてもよい。
修飾部位としては本発明化合物中の水酸基、カルボキシル基、アミノ基などの反応性の高い官能基が挙げられる。
カルボキシル基の修飾基として具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、tert-ブチル基、ピバロイルオキシメチル基、カルボキシメチル基、ジメチルアミノメチル基、1-(アセチルオキシ)エチル基、1-(エトキシカルボニルオキシ)エチル基、1-(イソプロピルオキシカルボニルオキシ)エチル基、1-(シクロヘキシルオキシカルボニルオキシ)エチル基、(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル基、ベンジル基、フェニル基、o-トリル基、モルホリノエチル基、N,N-ジエチルカルバモイルメチル基、フタリジル基等が挙げられる。
アミノ基の修飾基として具体的には、tert-ブチル基、ドコサノイル基、ピバロイルメチルオキシ基、アラニル基、ヘキシルカルバモイル基、ペンチルカルバモイル基、3-メチルチオ-1-(アセチルアミノ)プロピルカルボニル基、1-スルホ-1-(3-エトキシ-4-ヒドロキシフェニル)メチル基、(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル基、(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシカルボニル基、テトラヒドロフラニル基、ピロリジルメチル基等が挙げられる。
EPOの産生低下に起因する各種疾患や病態(障害)としては、貧血等が挙げられる。
一般的に、貧血としては、骨髄での造血異常による貧血、鉄、ビタミンB12又は葉酸の欠乏による貧血、事故や手術施行時の出血、慢性炎症(自己免疫疾患、悪性腫瘍、慢性感染症、形質細胞異常症等)に伴う貧血、内分泌疾患(甲状腺機能低下症、多腺性自己免疫症候群、IA型糖尿病、不正子宮出血等)に伴う貧血、慢性心不全に伴う貧血、潰瘍に伴う貧血、肝疾患に伴う貧血、老人性貧血、薬剤性貧血、腎性貧血(腎不全に伴う貧血)、化学療法に伴う貧血等があげられる。
また、PHDを阻害し、HIFを安定化することにより、改善が期待される疾病としては、虚血性心疾患(狭心症、心筋梗塞等)、虚血性脳血管障害(脳梗塞、脳塞栓症、一過性脳虚血発作等)、慢性腎不全(虚血性腎症、尿細管間質性障害等)、糖尿病合併症(糖尿病性創傷等)、認知障害(認知症、アルツハイマー病、パーキンソン病、ハンチントン病等)等があげられる。
本発明のプロリル水酸化酵素(PHD)阻害剤およびEPO産生誘導剤は、好ましくは、貧血治療剤、さらに好ましくは腎性貧血の治療剤として使用される。
上記一般式[I]で表される化合物又はその医薬上許容される塩、或いはその溶媒和物、及び併用薬剤の投与時期は限定されず、これらを投与対象に対し、配合剤として投与してもよいし、両製剤を同時に又は一定の間隔をおいて投与してもよい。また、本発明医薬組成物及び併用薬剤とからなるキットであることを特徴とする医薬として用いてもよい。併用薬剤の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、疾患、症状、剤形、投与ルート、投与時間、組み合わせ等により適宜選択することができる。併用薬剤の投与形態は、特に限定されず、本発明化合物又はその医薬上許容される塩、或いはその溶媒和物と併用薬剤とが組み合わされていればよい。
併用薬剤としては、例えば、貧血の治療剤及び/又は予防剤等が挙げられ、本発明の化合物とを組み合わせて用いることができる。
「貧血の治療剤及び/又は予防剤」としては、例えば、クエン酸第一鉄、硫酸鉄等が挙げられる。
以下の製造方法において、「室温」とは1~40℃を意味する。
化合物[I-1-1]を常法に従い、メタル化を行い、その後二酸化炭素を用いて、カルボキシル基を導入することにより、化合物[I-1-2]を得ることができる。メタル化については、低温条件下、ヘキサン、ベンゼン、トルエン、テトラヒドロフラン、ジエチルエーテル、1,4-ジオキサン等の単独又は混合溶媒中、n-ブチルリチウム、sec-ブチルリチウム、リチウムジイソプロピルアミド、リチウムビス(トリメチルシリル)アミド、ナトリウムビス(トリメチルシリル)アミド、カリウムビス(トリメチルシリル)アミド、リチウムアミド、ナトリウムアミド等の有機金属試薬と反応させてメタル化を行い、その後、二酸化炭素と反応させることにより、化合物[I-1-2]を得ることができる。
化合物[I-1-2] のカルボキシル基に、常法に従い、保護基を導入することにより、化合物[I-1-3]を得ることができる。例えば、保護基がtert-ブチル基の場合は、低温乃至加温条件下、p-トルエンスルホン酸、メタンスルホン酸、三フッ化ホウ素、三塩化ホウ素、三臭化ホウ素、三塩化アルミニウム、塩化水素、臭化水素、リン酸、硫酸、酢酸、トリフルオロ酢酸等の酸存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、tert-ブチル 2,2,2-トリクロロアセトイミダートと反応させることにより、化合物[I-1-3]を得ることができる。
化合物[I-1-3]に、常法に従い、R11bで表される保護基で保護された水酸基を導入することにより、化合物[I-1-4]を得ることができる。例えば、ベンジル基で保護された水酸基を導入する場合、化合物[I-1-3]を、低温乃至加温条件下、トリエチルアミン、カリウムtert-ブトキシド、炭酸カリウム、水素化ナトリウム、n-ブチルリチウム、リチウムジイソプロピルアミド等の塩基の存在下、ヘキサン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン、トルエン等の単独又は混合溶媒中、ベンジルアルコールと反応させることにより、化合物[I-1-4]を得ることができる。
化合物[I-1-4]を、低温乃至加温条件下、クロロホルム、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、水等の単独又は混合溶媒中、ヒドラジン一水和物と反応させることにより化合物[I-1-5]を得ることができる。
化合物[I-1-5]を、低温乃至加温条件下、p-トルエンスルホン酸、メタンスルホン酸、三フッ化ホウ素、三塩化ホウ素、三臭化ホウ素、塩化水素、臭化水素、リン酸、硫酸等の酸存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒又は無溶媒において、オルトギ酸トリメチル、オルトギ酸トリエチル等のオルトエステル化合物またはギ酸と反応させることにより化合物[I-1-6]を得ることができる。
化合物[I-1-6]を、室温乃至加温条件下、水酸化ナトリウム、モルホリン、ピペリジン、ピロリジン等の塩基の存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、1,2-ジメトキシエタン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、アセトニトリル等の単独又は混合溶媒中、環内転位反応を行うことにより、化合物[I-1-7]を得ることができる。
化合物[I-1-7]のカルボキシル基の保護基を常法に従い、脱保護することにより、化合物[I-1-8]を得ることができる。例えば、R11aがtert-ブチル基の場合、低温乃至加温条件下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、1,2-ジメトキシエタン、1,4-ジオキサン、テトラヒドロフラン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、アセトニトリル、水等の単独又は混合溶媒中、p-トルエンスルホン酸、メタンスルホン酸、三フッ化ホウ素、三塩化ホウ素、三臭化ホウ素、三塩化アルミニウム、塩化水素、臭化水素、リン酸、硫酸、酢酸、トリフルオロ酢酸等の酸と反応させることにより化合物[I-1-8]を得ることができる。R11aがメチル基、エチル基やtert-ブチル基の場合は、化合物[I-1-7]を低温乃至加温条件下、水酸化ナトリウム、水酸化カリウム、炭酸カリウム、炭酸ナトリウム、水酸化リチウム等の塩基存在下、メタノール、エタノール、2-プロパノール、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン、N,N-ジメチルホルムアミド、アセトニトリル等の溶媒と水との混合溶媒中、加水分解することにより、化合物[I-1-8]を得ることができる。
化合物[I-1-8] のカルボキシル基に常法に従い、保護基を導入することにより、化合物[I-1-9]を得ることができる。例えば、保護基がエチル基の場合は低温乃至加温条件下、クロロホルム、塩化メチレン、酢酸エチル、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、化合物[I-1-8]をN,N-ジメチルホルムアミドジエチルアセタールと反応させることにより、化合物[I-1-9]を得ることができる。
なお、第7工程及び第8工程は省略することもできる。その場合、R11a=R11cである。
化合物[I-1-9]のピリジン環上に常法に従い、脱離基を導入することにより、化合物[I-1-10]を得ることができる。ジ置換体化合物[I-1-11]が得られることもある。脱離基がヨウ素原子の場合、低温条件下、ヘキサン、トルエン、1,2-ジメトキシエタン、ジエチルエーテル、1,4-ジオキサン、テトラヒドロフラン等の単独又は混合溶媒中、n-ブチルリチウム、sec-ブチルリチウム、リチウムジイソプロピルアミド、リチウムビス(トリメチルシリル)アミド、ナトリウムビス(トリメチルシリル)アミド、カリウムビス(トリメチルシリル)アミド、リチウムアミド、ナトリウムアミド等の有機金属試薬と反応させてメタル化を行い、その後ヨウ素と反応させることにより、化合物[I-1―10]および化合物[I-1-11]を得ることができる。
化合物[I-1-10]に置換基R2もしくはその前駆体を、常法に従い導入することにより、化合物[I-2-1]を得ることができる。例えばR2がブチル基の場合、化合物[I-1-10]を室温乃至加温条件下、[1,1-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド、テトラキス(トリフェニルホスフィン)パラジウム、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド、酢酸パラジウム-トリフェニルホスフィン等のパラジウム触媒及び酢酸カリウム、炭酸カリウム、炭酸水素カリウム、炭酸水素ナトリウム、リン酸カリウム、トリエチルアミン、ジイソプロピルエチルアミン、リン酸水素ナトリウム、炭酸セシウム等の塩基の存在下、必要に応じて炭酸銀、硝酸銀、酸化銀(I)などの銀塩を加えて、ヘキサン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、アセトニトリル、1,2-ジメトキシエタン、テトラヒドロフラン、1,4-ジオキサン、トルエン、水等の単独又は混合溶媒中、ブチルボロン酸と反応させることにより、化合物[I-2-1]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物[I-2-1]のカルボキシル基の保護基を脱保護することにより、化合物[I-2-2]を得ることができる。
化合物[I-2-2]に、常法に従い、H2NC(R4)(R5)COOR12aで表されるグリシン誘導体を縮合することにより、化合物[I-2-3]を得ることができる。例えば、低温乃至加温条件下、化合物[I-2-2]を、ジシクロヘキシルカルボジイミド、1,1’―カルボニルジイミダゾール、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド又はその塩、ジフェニルホスホリルアジド等の縮合剤及び必要に応じてN-ヒドロキシスクシンイミド、1-ヒドロキシベンゾトリアゾール、ジメチルアミノピリジン等の存在下、必要に応じて炭酸カリウム、炭酸水素ナトリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、モルホリン、ピリジン等の塩基を加えて、N,N-ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、クロロホルム、酢酸エチル、塩化メチレン、トルエン等の溶媒中、H2NC(R4)(R5)COOR12aで表されるグリシン誘導体と縮合することにより化合物[I-2-3]を得ることができる。
化合物[I-2-3]の水酸基の保護基R11bを常法に従い、脱保護することにより、化合物[I-2-4]を得ることができる。例えば、R11bがベンジル基の場合、室温乃至加熱条件下、水素雰囲気下、常圧乃至加圧条件下、パラジウム炭素、水酸化パラジウム、酸化白金、白金炭素、ラネーニッケル等の触媒の存在下、ヘキサン、メタノール、エタノール、2-プロパノール、テトラヒドロフラン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、酢酸エチル、酢酸、水等の単独又は混合溶媒中で水素化することにより化合物[I-2-4]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物 [I-2-4]のカルボキシル基の保護基を脱保護することにより、化合物[I-2-5]を得ることができる。
製法I-2の第1工程と同様の方法で、化合物[I-1-11]に置換基R2とR3もしくはその前駆体を導入することにより、化合物[I-3-1]を得ることができる。例えば、R2およびR3の前駆体として、アルケニル基を導入する場合、製法I-2の第1工程と同様の方法で、化合物[I-1-11]とアルケニルボロン酸を反応させることにより、化合物[I-3-1]を得ることができる。
製法I-2の第4工程と同様の方法で、化合物[I-3-1]のR11bを脱保護することにより、化合物[I-3-2]を得ることができる。
化合物[I-3-2]に、H2NC(R4)(R5)COOHで表されるグリシン誘導体を反応させることにより、化合物[I-3-3]を得ることができる。例えば、化合物[I-3-2]を、室温乃至加温条件下、ヘキサン、クロロホルム、塩化メチレン、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、2-メトキシエタノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、水等の単独又は混合溶媒中、グリシン誘導体のナトリウム塩と反応させることにより化合物[I-3-3]を得ることができる。
化合物[I-1-11]を低温乃至加温条件下、[1,1-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド、テトラキス(トリフェニルホスフィン)パラジウム、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド、酢酸パラジウム-トリフェニルホスフィン等のパラジウム触媒及び水素化トリn-ブチルすず等の還元剤の存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、ベンゼン、トルエン、1,2-ジメトキシエタン、1,4-ジオキサン、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、水等の単独又は混合溶媒中、攪拌することにより、化合物[I-4-1]を得ることができる。
製法I-2の第1工程と同様の方法で、化合物[I-4-1]のX11bを、R3もしくはその前駆体で置換することにより、化合物[I-4-2]を得ることができる。
製法I-2の第4工程と同様の方法で、化合物[I-4-2]のR11bを脱保護することにより、化合物[I-4-3]を得ることができる。
製法I-3の第3工程と同様の方法で、化合物[I-4-3]とH2NC(R4)(R5)COOHで表されるグリシン誘導体、またはその金属種との塩を反応させることにより、化合物[I-4-4]を得ることができる。
化合物[I-1-10]に常法に従い、置換基R3を導入することにより、化合物[I-5-1]を得ることができる。例えば、R3がクロロ基の場合、化合物[I-1-10]を低温条件下、n-ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムビス(トリメチルシリル)アミド、カリウムヘキサメチルジシラジド、リチウムジイソプロピルアミド、tert-ブトキシド等の有機金属試薬存在下、ヘキサン、ベンゼン、トルエン、テトラヒドロフラン、ジエチルエーテル、1,4-ジオキサン等の単独又は混合溶媒中、ヘキサクロロエタン等のクロロ化剤と反応させることにより、化合物[I-5-1]を得ることができる。
製法I-2の第1工程と同様の方法で、化合物[I-5-1]の置換基X11bを、置換基R2もしくはその前駆体で置換することにより、化合物[I-5-2]を得ることができる。
製法I-2の第4工程と同様の方法で、化合物[I-5-2]の水酸基の保護基R11bを脱保護することにより、化合物[I-5-3]を得ることができる。
製法I-3の第3工程と同様の方法で、化合物[I-5-3]とH2NC(R4)(R5)COOHで表されるグリシン誘導体、またはその金属種との塩を反応させることにより、化合物[I-5-4]を得ることができる。
製法I-1の第3工程と同様にして、化合物[I-6-1]に保護基R16aで保護された水酸基を導入することにより、化合物[I-6-2]を得ることができる。
製法I-1の第1工程と同様にして、化合物[I-6-2]に保護基R16bで保護されたカルボキシル基を導入することにより、化合物[I-6-3]を得ることができる。
製法I-2の第1工程と同様にして、化合物[I-6-3]に置換基R2もしくはその前駆体を導入することにより、化合物[I-6-4]を得ることができる。
製法I-1の第4工程と同様にして、化合物[I-6-4]より、化合物[I-6-5]を得ることができる。
製法I-1の第5工程と同様にして、化合物[I-6-5]より、化合物[I-6-6]を得ることができる。
製法I-1の第6工程と同様にして、化合物[I-6-6]より、化合物[I-6-7]を得ることができる。
製法I-1の第7工程と同様にして、化合物[I-6-7]のカルボキシル基の保護基を脱保護することにより、化合物[I-6-8]を得ることができる。
製法I-2の第3工程と同様にして、化合物[I-6-8]にH2NC(R4)(R5)COOR16cで表されるグリシン誘導体を縮合することにより、化合物[I-6-9]を得ることができる。
製法I-2の第4工程と同様にして、化合物[I-6-9]の水酸基の保護基R16aを脱保護することにより、化合物[I-6-10]を得ることができる。
製法I-1の第7工程と同様にして、化合物[I-6-10] のカルボキシル基の保護基を脱保護することにより、化合物[I-6-11]を得ることができる。
化合物[I-7-1]を、低温乃至加温条件下、ヘキサン、酢酸エチル、クロロホルム、塩化メチレン、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、N-メチル-2-ピロリドン、アセトニトリル、水等の単独又は混合溶媒中、ニッケル(II)アセチルアセトナート等の有機金属試薬存在下、シアナミドと反応させることにより化合物[I-7-2]を得ることができる。
化合物[I-7-2] の水酸基を常法に従い、脱離基へと変換することにより化合物[I-7-3]を得ることができる。例えば脱離基X17aが塩素原子の場合、化合物[I-7-2]を、低温乃至加温条件下、ヘキサン、酢酸エチル、アセトン、クロロホルム、塩化メチレン、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、2-ピロリドン、アセトニトリル等の単独又は混合溶媒中又は無溶媒下、必要に応じて、トリエチルアミン、ピリジン、4-(ジメチルアミノ)ピリジン、N-メチルモルホリン、ジイソプロピルエチルアミン、テトラメチルエチレンジアミン等の塩基および必要に応じてN,N-ジメチルホルムアミドの存在下、塩化チオニル、オキザリルクロリド、トリホスゲン、五塩化リン、オキシ塩化リン等を用いて塩素化することにより、化合物[I-7-3]を得ることができる。
化合物[I-7-3]を、低温乃至加温条件下、酢酸エチル、クロロホルム、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、N,N-ジメチルホルムアミドジアルキルアセタールと反応させた後、さらにヒドロキシルアミンあるいはその塩酸塩と反応させることにより化合物[I-7-4]を得ることができる。
化合物[I-7-4]を、低温乃至高温条件下、ヘキサン、酢酸エチル、アセトン、クロロホルム、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、ポリリン酸、塩化チオニル、オキシ塩化リン、p-トルエンスルホニルクロリド、無水酢酸、塩化アセチル、トリフルオロ酢酸無水物等を用いて脱水反応させることにより化合物[I-7-5]を得ることができる。
製法I-2の第1工程と同様の方法で、化合物[I-7-5]に置換基R2もしくはその前駆体を、常法に従い導入することにより化合物[I-8-1]を得ることができる。
化合物[I-8-1]に、R18aで表される保護基で保護された水酸基を導入することにより、化合物[I-8-2]を得ることができる。例えば、メチル基で保護された水酸基を導入する場合、化合物[I-8-1]を、低温乃至加温条件下、ヘキサン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン、トルエン、メタノール、水等の単独又は混合溶媒中、ナトリウムメトキシドと反応させるか、低温乃至加温条件下、メタノール単独又はヘキサン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン、トルエン等との混合溶媒中、トリエチルアミン、カリウムtert-ブトキシド、ナトリウムメトキシド、炭酸カリウム、水素化ナトリウム、n-ブチルリチウム、リチウムジイソプロピルアミド等の塩基と反応させることにより化合物[I-8-2]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物[I-8-2] のカルボキシル基の保護基を脱保護することにより、化合物[I-8-3]を得ることができる。
製法I-2の第3工程と同様の方法で、化合物[I-8-3]に、H2NC(R4)(R5)COOR18bで表されるグリシン誘導体を縮合することにより化合物[I-8-4]を得ることができる。
化合物[I-8-4]の水酸基の保護基R18aとカルボキシル基の保護基R18bとを常法に従い、脱保護することにより化合物[I-8-5]を得ることができる。例えば、R18aがメチル基でR18bがtert-ブチル基の場合、化合物[I-8-4]を、室温乃至加温条件下、p-トルエンスルホン酸、メタンスルホン酸、三フッ化ホウ素、三フッ化ホウ素-ジエチルエーテル錯体、三塩化ホウ素、三臭化ホウ素、塩化水素、臭化水素、リン酸、硫酸、酢酸、トリフルオロ酢酸等の酸存在下、ヘキサン、酢酸エチル、アセトン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、1,2-ジメトキシエタン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、イソプロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、アセトニトリル、酢酸、水等の単独又は混合溶媒中、攪拌することにより化合物[I-8-5]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物[I-8-1] のカルボキシル基の保護基を脱保護することにより、化合物[I-9-1]を得ることができる。
製法I-2の第3工程と同様の方法で、化合物[I-9-1] とH2NC(R4)(R5)COOR19aで表されるグリシン誘導体を縮合することにより、化合物[I-9-2]を得ることができる。
化合物[I-9-2] に、塩基を反応させることにより、化合物[I-9-3]を得ることができる。例えば、R19bがナトリウムの場合、室温乃至加温条件下、ジメチルスルホキシド、N,N-ジメチルホルムアミド、ジメチルアセトアミド、アセトニトリル、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン、トルエン、メタノール、エタノール、2-メトキシエタノール、2-エトキシエタノール、水等の単独又は混合溶媒中、水酸化ナトリウムと反応させることにより、化合物[I-9-3]を得ることができる。
化合物[I-9-3] に、低温乃至加温条件下、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトン、アセトニトリル、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタン、トルエン、メタノール、エタノール、2-メトキシエタノール、2-エトキシエタノール、水等の単独又は混合溶媒中、酢酸、p-トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、塩化水素、臭化水素、リン酸、硫酸等の酸を反応させることにより、化合物[I-9-4]を得ることができる。
化合物[II-1-1]を低温乃至加温条件下、p-トルエンスルホン酸、メタンスルホン酸、三フッ化ホウ素、三塩化ホウ素、三臭化ホウ素、三塩化アルミニウム、塩化水素、臭化水素、リン酸、硫酸、スルファミン酸、酢酸、トリフルオロ酢酸等の酸存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、メタノール、エタノール、2-プロパノール、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、水等の単独又は混合溶媒中、2,5-ヘキサンジオンと反応させることにより、化合物[II-1-2]を得ることができる。
製法I-1の第3工程と同様の方法で、化合物[II-1-2]にR21aで表される保護基で保護された水酸基を導入することにより、化合物[II-1-3]を得ることができる。
化合物[II-1-3]を低温乃至加温条件下、トリエチルアミン、カリウムtert-ブトキシド、炭酸カリウム、水素化ナトリウム、リチウムジイソプロピルアミド等の塩基および塩化ヒドロキシルアンモニウム存在下、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、水等の単独又は混合溶媒中、攪拌することにより化合物[II-1-4]を得ることができる。
化合物[II-1-4]を室温乃至加温条件下、酢酸エチル、クロロホルム、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、N,N-ジメチルホルムアミドジメチルアセタールと反応させて得られる化合物を、低温乃至高温条件下、ヘキサン、酢酸エチル、アセトン、クロロホルム、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、2-プロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、トリエチルアミン、ジイソプロピルエチルアミン、モルホリン、ピリジン等の塩基存在下、ヒドロキシルアミンあるいはその塩と反応させた後にポリリン酸と反応させるか、ヒドロキシルアミン-O-スルホン酸と反応させることにより化合物[II-1-5]を得ることができる。
製法I-1の第1工程と同様の方法で、化合物[II-1-5]にカルボキシル基を導入することにより、化合物[II-1-6]を得ることができる。
化合物[II-1-6]のカルボキシル基に常法に従い、保護基R21bを導入することにより、化合物[II-1-7]を得ることができる。例えば、R21bがエチル基の場合、化合物[II-1-6]を室温乃至加温条件下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、N,N-ジメチルホルムアミドジエチルアセタールと反応させることにより、化合物[II-1-7]を得ることができる。
化合物[II-1-7]に常法に従い、置換基R2もしくはその前駆体を導入することにより、化合物[II-1-8]を得ることができる。例えば、tert-ブチルアセチレン基を導入する場合、化合物[II-1-7]を室温乃至加温条件下、[1,1-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド、テトラキス(トリフェニルホスフィン)パラジウム、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド、酢酸パラジウム-トリフェニルホスフィン等のパラジウム触媒、酢酸カリウム、炭酸カリウム、炭酸水素カリウム、炭酸水素ナトリウム、リン酸カリウム、トリエチルアミン、ジイソプロピルエチルアミン、リン酸水素ナトリウム、炭酸セシウム等の塩基およびヨウ化銅の存在下、ヘキサン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、アセトニトリル、1,2-ジメトキシエタン、テトラヒドロフラン、1,4-ジオキサン、トルエン、水等の単独又は混合溶媒中、tert-ブチルアセチレンと反応させることにより、化合物[II-1-8]を得ることができる。
製法I-2の第4工程と同様の方法で、化合物[II-1-8]の水酸基の保護基R21aを脱保護することにより、化合物[II-1-9]を得ることができる。
製法I-3の第3工程と同様の方法で、化合物[II-1-9]から、化合物[II-1-10]を得ることができる。
なお、本製法ではR1が水素原子の場合の製造方法について記載した。R1が前述の置換基であって、水素原子以外のものの場合は、第4工程において、N,N-ジメチルホルムアミドジメチルアセタールに代えて、所望の置換基で置換された、N,N-ジメチルホルムアミドジメチルアセタールを用い、第5工程以降は本製造方法に記載の方法と同様の方法で行えばよい。
化合物[I-1-4]のR11bを製法I-2の第4工程と同様の方法で脱保護することにより得られる化合物[III-1-1]に常法に従い、脱離基X31bを導入することにより、化合物[III-1-2]を得ることができる。例えば、X31bが臭素原子の場合、化合物[III-1-1]を低温乃至加温条件下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、テトラヒドロフラン、1,4-ジオキサン、アセトニトリル、水等の単独又は混合溶媒中、臭素やN-ブロモスクシンイミドと反応させることにより、化合物[III-1-2]を得ることができる。
化合物[III-1-2]に常法に従い、R31bを導入することにより、化合物[III-1-3]を得ることができる。例えば、R31bがベンジル基の場合、酢酸エチル、クロロホルム、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル、水等の単独又は混合溶媒中、炭酸カリウム、カリウムtert-ブトキシド、水素化ナトリウム、炭酸セシウム等の塩基の存在下、化合物[III-1-2]と塩化ベンジルや臭化ベンジルを反応させることにより、化合物[III-1-3]を得ることができる。
化合物[III-1-3]のR31aを製法I-1の第7工程と同様の方法で脱保護した後、常法に従い、酸クロライドとした後、低温乃至加温条件下、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等の塩基存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、テトラヒドロフラン等の単独又は混合溶媒中、H2NC(R4)(R5)COOR31dで表されるグリシン誘導体と反応させて化合物[III-1-4]とし、さらにこのものを、低温乃至加温条件下、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等の塩基存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、テトラヒドロフラン、1,4-ジオキサン等の単独又は混合溶媒中、化合物[III-1-5]と反応させることにより、[III-1-6]を得ることができる。
製法I-2の第1工程と同様の方法で、化合物[III-1-6]から、化合物[III-1-7]を得ることができる。
製法I-2の第4工程と同様の方法で、化合物[III-1-7]のR31bを脱保護することにより、化合物[III-1-8]を得ることができる。
化合物[III-1-8]のアミノ基の保護基R31cを常法に従い、脱保護することにより、化合物[III-1-9]を得ることができる。例えば、R31cがtert-ブトキシカルボニル基の場合、低温乃至室温条件下、塩化水素、硫酸、臭化水素、リン酸、酢酸、トリフルオロ酢酸などの酸存在下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、メタノール、エタノール、2-プロパノール、テトラヒドロフラン、1,4-ジオキサン、アセトニトリル、水等の単独又は混合溶媒中、攪拌することにより、化合物[III-1-9]を得ることができる。
製法I-1の第5工程と同様の方法で、化合物[III-1-9]から、化合物[III-1-10]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物[III-1-10]のカルボキシル基の保護基を脱保護することにより、化合物[III-1-11]を得ることができる。
製法I-1の第5工程と同様の方法で化合物[I-6-5]より化合物[III-2-1]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物[III-2-1]のカルボキシル基の保護基を脱保護することにより、化合物[III-2-2]を得ることができる。
製法I-2の第3工程と同様の方法で、化合物[III-2-2]にH2NC(R4)(R5)COOR32aで表されるグリシン誘導体を縮合させることにより、化合物[III-2-3]を得ることができる。
製法I-2の第4工程と同様の方法で、化合物[III-2-3]のR16aを脱保護することにより、化合物[III-2-4]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物[III-2-4]のカルボキシル基の保護基を脱保護することにより、化合物[III-2-5]を得ることができる。
化合物[IV-1-1]の脱離基X41aを常法に従い、ホルミル基に変換することにより、化合物[IV-1-2]を得ることができる。化合物[IV-1-1]を、低温条件下、ヘキサン、ベンゼン、トルエン、テトラヒドロフラン、ジエチルエーテル、1,4-ジオキサン等の単独又は混合溶媒中、n-ブチルリチウム、sec-ブチルリチウム、リチウムジイソプロピルアミド、リチウムビス(トリメチルシリル)アミド、ナトリウムビス(トリメチルシリル)アミド、カリウムビス(トリメチルシリル)アミド、リチウムアミド、ナトリウムアミド等の有機金属試薬と反応させ、さらにN,N-ジメチルホルムアミドと反応させることにより、化合物[IV-1-2]を得ることができる。
化合物[IV-1-2]を室温乃至加温条件下、酢酸エチル、クロロホルム、トルエン、1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン、メタノール、エタノール、イソプロパノール、ジメチルスルホキシド、N,N-ジメチルホルムアミド、アセトニトリル等の単独又は混合溶媒中、脱離基X41bを有するヒドラジンと反応させ、さらに、モルホリン、ピペリジン、ピロリジン等塩基を加えて攪拌することにより、化合物[IV-1-4]を得ることができる。
製法I-1の第1工程と同様の方法で化合物[IV-1-4]から、化合物[IV-1-5]を得ることができる。
製法I-2の第3工程と同様の方法で、化合物[IV-1-5]にグリシン誘導体を縮合することにより、化合物[IV-1-6]を得ることができる。
製法I-2の第4工程と同様の方法で、化合物[IV-1-6]のR41aを脱保護することにより、化合物[IV-1-7]を得ることができる。
製法I-1の第7工程と同様の方法で、化合物[IV-1-7]のカルボキシル基の保護基を脱保護することにより、化合物[IV-1-8]を得ることができる。
なお、本製法ではR1が水素原子の場合の製造方法について記載した。R1が前述の置換基であって、水素原子以外のものの場合は、第1工程において、N,N-ジメチルホルムアミドに代えて、所望の置換基で置換された、N,N-ジメチルホルムアミドを用い、第2工程以降は本製造方法に記載の方法と同様の方法で行えばよい。
{[5-(4-フルオロ-3-トリフルオロメチルフェニル)-7-ヒドロキシ[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル]アミノ}酢酸 塩酸塩の製造
1H-NMR (DMSO-D6) δ: 7.74 (1H, d, J = 5.6 Hz), 8.47 (1H, d, J = 5.6 Hz), 14.53 (1H, br s).
1H-NMR (CDCl3) δ: 1.63 (9H, s), 7.31 (1H, d, J = 5.2 Hz), 8.31 (1H, d, J = 5.2 Hz).
1H-NMR (CDCl3) δ: 1.55 (9H, s), 5.17 (2H, s), 6.83 (1H, d, J = 6.0 Hz), 7.32-7.42 (5H, m), 8.24 (1H, d, J = 6.0 Hz).
1H-NMR (CDCl3) δ: 1.42 (9H, s), 3.98 (2H, br s), 5.09 (2H, s), 6.32 (1H, d, J= 5.6 Hz), 7.28-7.45 (5H, m), 7.96 (1H, br s), 8.08 (1H, d, J = 5.6 Hz).
1H-NMR (DMSO-D6) δ: 1.49 (9H, s), 5.36 (2H, s), 7.22 (1H, d, J = 7.6 Hz), 7.32-7.50 (5H, m), 8.62 (1H, d, J = 7.6 Hz), 9.13 (1H, s).
1H-NMR (CDCl3) δ: 1.59 (9H, s), 5.28 (2H, s), 6.85 (1H, d, J = 7.6 Hz), 7.33-7.46 (5H, m), 8.29 (1H, s), 8.50 (1H, d, J= 7.6 Hz).
1H-NMR (DMSO-D6) δ: 1.46 (9H, s), 5.39 (2H, s), 7.33-7.51 (5H, m), 7.87 (1H, s), 8.43 (1H, s).
1H-NMR (CDCl3) δ: 1.61 (9H, s), 5.33 (2H, s), 6.88 (1H, s), 7.35-7.48 (6H, m), 8.04 (1H, dd, J= 6.7, 2.1 Hz), 8.11-8.15 (1H, m), 8.31 (1H, s).
1H-NMR (DMSO-D6) δ: 5.51 (2H, s), 7.34-7.38 (1H, m), 7.41-7.45 (2H, m), 7.50-7.52 (2H, m), 7.63 (1H, s), 7.80 (1H, dd, J = 10.5, 8.9 Hz), 8.40-8.48 (2H, m), 8.48 (1H, s).
1H-NMR (CDCl3) δ: 1.33 (3H, t, J = 7.1 Hz), 4.28 (2H, q, J= 7.1 Hz), 4.35 (2H, d, J = 4.8 Hz), 5.47 (2H, s), 6.95 (1H, s), 7.32-7.43 (4H, m), 7.54 (2H, d, J = 7.3 Hz), 8.01 (1H, dd, J = 6.4, 2.0 Hz), 8.10-8.14 (1H, m), 8.31 (1H, s), 9.72 (1H, t, J = 4.8 Hz).
1H-NMR (CDCl3) δ: 1.34 (3H, t, J = 7.3 Hz), 4.30 (2H, q, J= 7.3 Hz), 4.33 (2H, d, J = 5.2 Hz), 6.87 (1H, s), 7.41 (1H, dd, J= 9.7, 8.9 Hz), 8.16-8.20 (1H, m), 8.24 (1H, dd, J = 6.9, 2.4 Hz), 8.26 (1H, s), 10.15 (1H, t, J = 5.2 Hz), 14.13 (1H, s).
1H-NMR (DMSO-D6) δ:4.24 (2H, d, J = 5.6 Hz), 7.30 (1H, s), 7.77 (1H, dd, J = 10.5, 9.3 Hz), 8.36-8.40 (1H, m), 8.47 (1H, d, J = 6.9 Hz), 8.60 (1H, s), 9.97 (1H, br s), 14.38 (1H, br s).
また、得られた化合物を、常法に従い、塩酸塩とすることで実施例1の化合物とした。
1H-NMR (DMSO-D6) δ: 4.25 (d, 2H, J = 5.6 Hz), 7.31 (s, 1H), 7.73-7.82 (m, 1H), 8.34-8.43 (m, 1H), 8.43-8.51 (m, 1H), 8.61 (s, 1H), 9.99 (t, 1H, J = 5.6 Hz).
[(7-ヒドロキシ-5-フェネチル[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸 塩酸塩の製造
1H-NMR (DMSO-D6) δ: 1.48 (9H, s), 5.42 (2H, s), 7.36 (1H, tt, J = 7.1, 1.8 Hz),7.40-7.45 (2H, m), 7.48 (2H, dt, J = 7.0, 1.9 Hz), 7.51-7.58 (3H, m), 7.72 (2H,dd, J= 7.7, 1.6 Hz), 7.78 (1H, s), 8.49 (1H, s).
1H-NMR (DMSO-D6) δ: 2.38 (6H, s), 5.48 (2H, s), 7.37 (1H, tt, J = 7.2, 1.7 Hz),7.41-7.45 (2H, m), 7.48-7.52 (2H, m), 7.53-7.62 (3H, m), 7.71-7.75 (2H, m), 7.86 (1H, s), 8.67 (1H, s).
1H-NMR (DMSO-D6) δ: 5.45 (2H, s), 7.36 (1H, tt, J = 7.4, 2.1 Hz), 7.43 (2H, t, J = 7.3 Hz), 7.49 (2H, d, J = 7.5 Hz), 7.52-7.60 (3H, m), 7.72 (2H, dd, J = 6.7,1.9 Hz), 7.78 (1H, s), 8.51 (1H, s), 13.59 (1H, s).
1H-NMR (DMSO-D6) δ: 1.21 (3H, t, J = 7.1 Hz), 4.10 (2H, d, J= 5.7 Hz), 4.13 (2H, q, J = 7.5 Hz), 5.44 (2H, s), 7.34 (1H, tt, J= 7.2, 1.7 Hz), 7.38-7.43 (2H, m), 7.52-7.58 (5H, m), 7.71-7.74 (2H, m), 7.75 (1H, s), 8.52 (1H, s), 9.18 (1H, t,J= 5.8 Hz).
1H-NMR (DMSO-D6) δ: 1.23 (3H, t, J = 7.2 Hz), 3.12 (2H, t, J= 7.8 Hz), 3.41 (2H, t, J = 7.9 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.29 (2H, d, J = 5.7 Hz), 6.82 (1H, s), 7.18-7.32 (5H, m), 8.58 (1H, s), 9.87 (1H, t, J = 5.6 Hz), 14.12 (1H, s).
1H-NMR (DMSO-D6) δ: 3.12 (t, 2H, J = 7.8 Hz), 3.41 (t, 2H, J = 7.8 Hz), 4.21 (d, 2H, J = 5.6 Hz), 6.81 (s, 1H), 7.14-7.33 (m, 5H), 8.60 (s, 1H), 9.85 (t, 1H, J= 5.6 Hz).
[(5-ブチル-7-ヒドロキシ[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸 塩酸塩の製造
1H-NMR (DMSO-D6) δ: 0.91 (t, 3H, J = 7.7 Hz), 1.28-1.39 (m, 2H), 1.48 (s, 9H), 1.71-1.81 (m, 2H), 3.11 (t, 2H, J = 7.7 Hz), 5.38 (s, 2H), 7.23 (s, 1H), 7.32-7.51 (m, 5H), 8.39 (s, 1H).
1H-NMR (DMSO-D6) δ: 0.91 (t, 3H, J = 7.7 Hz), 1.29-1.40 (m, 2H), 1.71-1.80 (m, 2H), 2.34 (s, 1.5H), 3.14 (t, 2H, J = 7.7 Hz), 5.47 (s, 2H), 7.32-7.45 (m, 4H),7.48-7.53 (m, 2H), 8.73 (s, 1H).
1H-NMR (CDCl3) δ: 0.94 (t, 3H, J = 7.5 Hz), 1.31 (t, 3H, J= 7.1 Hz), 1.34-1.43 (m, 2H), 1.70-1.79 (m, 2H), 3.11 (t, 2H, J = 7.5 Hz), 4.26 (q, 2H, J = 7.1 Hz), 4.33 (d, 2H, J = 5.2 Hz), 5.41 (s, 2H), 6.69 (s, 1H), 7.29-7.55 (m, 5H), 8.28 (s, 1H), 9.77 (t, 1H, J = 5.2 Hz).
1H-NMR (DMSO-D6) δ: 0.93 (t, 3H, J = 7.5 Hz), 1.22 (t, 3H, J= 7.3 Hz), 1.33-1.44 (m, 2H), 1.71-1.81 (m, 2H), 3.09 (t, 2H, J = 7.5 Hz), 4.16 (q, 2H, J = 7.3 Hz), 4.29 (d, 2H, J = 5.6 Hz), 6.85 (s, 1H), 8.54 (s, 1H), 9.88 (br s, 1H), 14.14 (s, 1H).
1H-NMR (DMSO-D6) δ: 0.93 (t, 3H, J = 7.5 Hz), 1.33-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J = 7.5 Hz), 4.20 (d, 2H, J = 5.2 Hz), 6.85 (s, 1H), 8.55 (s, 1H), 9.84 (br s, 1H), 14.26 (br s, 1H).
1H-NMR (DMSO-D6) δ: 0.93 (t, 3H, J = 7.5 Hz), 1.34-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J = 7.5 Hz), 4.21 (d, 2H, J = 5.6 Hz), 6.86 (s, 1H), 8.57 (s, 1H), 9.83 (t, 1H, J = 5.6 Hz).
[(5,6-ジエチル-7-ヒドロキシ[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸 塩酸塩の製造
1H-NMR (CDCl3) δ: 1.38 (t, 3H, J = 7.1 Hz), 4.50 (q, 2H, J= 7.1 Hz), 5.22 (s, 2H), 7.36-7.56 (m, 5H), 8.33 (s, 1H).
1H-NMR (CDCl3) δ: 1.38 (t, 3H, J= 7.1 Hz), 4.50 (q, 2H, J = 7.1 Hz), 5.09 (s, 2H), 5.73 (dd, 1H, J= 17.7, 1.4 Hz), 5.76 (dd, 1H, J= 11.5, 1.4 Hz), 6.05 (dd, 1H, J=11.5, 1.4 Hz), 6.77 (dd, 1H, J = 17.7, 11.7 Hz), 6.87 (dd, 1H, J = 17.7, 1.2Hz), 7.14 (dd, 1H, J = 17.7, 11.5 Hz), 7.35-7.44 (m, 5H), 8.37 (s, 1H).
1H-NMR (CDCl3) δ: 1.23 (t, 3H, J= 7.5 Hz), 1.36 (t, 3H, J = 7.5 Hz), 1.52 (t, 3H, J = 7.3 Hz), 2.78 (q, 2H, J = 7.5 Hz), 3.25 (q, 2H, J = 7.5 Hz), 4.64 (q, 2H,J = 7.3 Hz), 8.26 (s, 1H), 13.10 (s, 1H).
1H-NMR (DMSO-D6) δ: 1.15 (t, 3H, J = 7.5 Hz), 1.29 (t, 3H, J = 7.5 Hz), 2.72 (q, 2H, J = 7.5 Hz), 3.20 (q, 2H, J = 7.6 Hz), 4.21 (d, 2H, J = 5.6 Hz), 8.52 (s, 1H), 9.95 (t, 1H, J = 5.6 Hz).
[(7-ヒドロキシ-6-フェネチル[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸 塩酸塩の製造
1H-NMR (CDCl3) δ: 1.39 (t, 3H, J = 7.2 Hz), 4.51 (q, 2H, J= 7.2 Hz), 5.23 (s, 2H), 7.36-7.56 (m, 5H), 8.31 (s, 1H), 8.99 (s, 1H).
1H-NMR (CDCl3) δ: 1.43 (t, 3H, J = 7.1 Hz), 4.54 (q, 2H, J= 7.1 Hz), 5.17 (s, 2H), 7.13 (d, 1H, J= 9.3 Hz), 7.29-7.45 (m, 11H), 8.34 (s, 1H), 8.80 (s, 1H).
1H-NMR (CDCl3) δ: 1.54 (t, 3H, J = 7.2 Hz), 3.00 (s, 4H), 4.66 (q, 2H, J = 7.2 Hz), 7.16-7.31 (m, 5H), 8.20 (s, 1H), 8.23 (s, 1H), 13.17 (s, 1H).
1H-NMR (DMSO-D6) δ: 2.93 (s, 4H), 4.22 (d, 2H, J = 5.7 Hz), 7.19 (tt, 1H, J = 7.1, 1.8 Hz), 7.23-7.31 (m, 4H), 8.50 (s, 1H), 8.78 (s, 1H), 9.97 (s, 1H).
[(5-ブチル-6-クロロ-7-ヒドロキシ[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸 塩酸塩の製造
1H-NMR (DMSO-D6) δ: 0.94 (3H, t, J = 7.5 Hz), 1.28 (3H, t, J= 7.1 Hz), 1.37-1.47 (2H, m), 1.68-1.75 (2H, m), 3.32-3.37 (2H, m), 4.37 (2H, q, J = 7.1 Hz), 5.19 (2H, s), 7.37-7.52 (5H, m), 8.57 (1H, s).
1H-NMR (DMSO-D6) δ: 0.92 (3H, t, J = 7.3 Hz), 1.31 (3H, t, J= 7.1 Hz), 1.37-1.45 (2H, m), 1.62-1.69 (2H, m), 3.17 (2H, t, J = 7.7 Hz), 4.35 (2H, q, J = 7.1 Hz), 8.69 (1H, s).
1H-NMR (DMSO-D6) δ: 0.93 (t, 3H, J = 7.3 Hz), 1.36-1.47 (m, 2H), 1.64-1.72 (m, 2H), 3.15-3.28 (m, 2H), 4.15 (d, 2H, J = 2.8 Hz), 8.74 (br s, 1H), 10.20 (br s, 1H).
[(7-ヒドロキシ-2-メチル-5-フェネチル[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸 塩酸塩の製造
1H-NMR (CDCl3) δ: 5.11 (s, 2H), 6.86 (s, 2H), 7.36-7.46 (m, 5H).
1H-NMR (CDCl3) δ: 1.53 (s, 9H), 5.11 (s, 2H), 6.86 (s, 1H), 7.32-7.46 (m, 5H).
1H-NMR (CDCl3) δ: 1.55 (s, 9H), 5.21 (s, 2H), 6.87 (s, 1H), 7.01 (d, 1H, J = 15.9 Hz), 7.30-7.44 (m, 8H), 7.56 (d, 2H, J = 7.1 Hz), 7.65 (d, 1H, J = 16.1 Hz).
1H-NMR (CDCl3) δ: 1.55 (s, 9H), 3.02 (br s, 4H), 5.05 (s, 2H), 6.55 (s, 1H), 7.16-7.41 (m, 10H).
1H-NMR (CDCl3) δ: 1.39 (s, 9H), 2.92 (t, 2H, J = 8.2 Hz), 3.03 (t, 2H, J = 8.2 Hz), 4.05 (br s, 2H), 5.00 (s, 2H), 6.10 (s, 1H), 7.16-7.43 (m, 10H), 8.10 (s, 1H).
1H-NMR (CD3OD) δ: 1.51 (9H, s), 2.93 (3H, s), 3.06 (2H, t, J = 7.6 Hz), 3.52 (2H, t, J = 7.6 Hz), 5.16 (2H, s), 6.72 (1H, s), 7.14-7.48 (10H, m).
1H-NMR (CD3OD) δ: 1.49 (9H, s), 2.52 (3H, s), 3.13 (2H, t, J = 7.6 Hz), 3.42 (2H, t, J = 7.7 Hz), 5.16 (2H, s), 6.83 (1H, s), 7.15-7.19 (3H, m), 7.24-7.28 (2H,m), 7.32-7.44 (5H, m).
本工程で得られた化合物を、実施例1の工程1-10から工程1-12と同様の方法で処理し、得られた化合物を常法を用いて塩酸塩とすることにより、表題化合物を得た。
1H-NMR (DMSO-D6) δ: 2.52 (s, 3H), 3.10 (t, 2H, J = 7.8 Hz), 3.35 (t, 2H, J = 7.8 Hz), 4.19 (d, 2H, J = 5.7 Hz), 6.69 (s, 1H), 7.18-7.31 (m, 5H), 9.81 (t, 1H, J= 5.5 Hz).
{[8-(3,3-ジメチル-ブチル)-6-ヒドロキシ[1,2,4]トリアゾロ[1,5-a]ピリジン-5-カルボニル]アミノ}酢酸 塩酸塩の製造
1H-NMR (CDCl3) δ: 2.00 (6H, s), 5.92 (2H, s), 8.22 (1H, d, J = 2.4 Hz), 8.63 (1H, d, J = 2.4 Hz).
1H-NMR (CDCl3) δ: 1.99 (6H, s), 5.15 (2H, s), 5.89 (2H, s), 7.37-7.48 (5H, m), 7.64 (1H, d, J = 2.8 Hz), 8.31 (1H, d, J= 2.8 Hz).
1H-NMR (CDCl3) δ: 4.60 (2H, br s), 5.00 (2H, s), 7.31-7.40 (5H, m), 7.41 (1H, d, J= 2.8 Hz), 7.83 (1H, d, J = 2.8 Hz).
1H-NMR (CDCl3) δ: 5.09 (s, 2H), 7.36-7.45 (m, 5H), 7.66 (d, 1H, J = 2.0 Hz), 8.19 (d, 1H, J = 2.0 Hz), 8.29 (s, 1H).
1H-NMR (DMSO-D6) δ: 5.33 (s, 2H), 7.31-7.49 (m, 5H), 8.37 (s, 1H), 8.56 (s, 1H).
1H-NMR (CDCl3) δ: 1.39 (t, 3H, J = 7.1 Hz), 4.53 (q, 2H, J= 7.1 Hz), 5.21 (s, 2H), 7.35-7.43 (m, 5H), 7.72 (s, 1H), 8.38 (s, 1H).
本工程で得られた化合物から、実施例4の工程4-4と同様の方法により、表題化合物を得た。
1H-NMR δ: 0.98 (s, 9H), 1.57-1.66 (m, 2H), 2.89-2.99 (m, 2H), 4.25 (d, 2H, J = 5.4 Hz), 7.42 (s, 1H), 8.64 (s, 1H), 10.42 (t, 1H, J = 5.4 Hz), 13.28 (s, 1H).
[(7-ヒドロキシ-6-フェニル[1,2,4]トリアゾロ[4,3-a]ピリジン-8-カルボニル)アミノ]酢酸の製造
1H-NMR (CDCl3) δ: 1.66 (9H, s), 8.39 (1H, s), 12.77 (1H, s).
1H-NMR (CDCl3) δ: 1.58 (9H, s), 5.21 (2H, s), 7.19-7.21 (2H, m), 7.37-7.46 (3H,m), 7.76 (1H, s).
1H-NMR (CDCl3) δ: 1.30 (9H, s), 1.48 (9H, s), 4.05 (2H, d, J = 5.5 Hz), 5.24 (2H, s), 6.27 (1H, s), 7.14 (2H, t, J = 4.1 Hz), 7.34-7.41 (3H, m), 7.47 (1H, s), 11.50 (1H, t, J = 5.4 Hz), 11.83 (1H, s).
1H-NMR (CDCl3) δ: 1.31 (9H, s), 1.48 (9H, s), 4.06 (2H, d, J = 5.5 Hz), 5.30 (2H, s), 6.16 (1H, s), 7.17 (2H, d, J = 7.4 Hz), 7.18 (1H, s), 7.28-7.40 (6H, m), 7.43-7.46 (2H, m), 11.79 (1H, s), 11.85 (1H, t, J = 5.4 Hz).
1H-NMR (CDCl3) δ: 1.45 (9H, s), 1.49 (9H, s), 4.15 (2H, s), 7.06-7.29 (8H, m), 10.40 (1H, s), 10.95 (1H, s).
1H-NMR (CD3OD) δ: 1.49 (9H, s), 4.04 (2H, s), 7.36-7.47 (5H, m), 7.57 (1H, s).
1H-NMR (DMSO-D6) δ: 4.06 (2H, d, J = 5.5 Hz), 7.39-7.46 (3H, m), 7.60 (2H, dd, J = 8.3, 1.4 Hz), 8.39 (1H, s), 8.86 (1H, s), 10.50 (1H, t, J = 5.7 Hz), 12.59 (1H, s), 13.75 (1H, s).
[(7-ヒドロキシ[1,2,4]トリアゾロ[4,3-a]ピリジン-8-カルボニル)アミノ]酢酸 塩酸塩の製造
1H-NMR (DMSO-D6) δ: 5.60 (s, 2H), 7.35-7.55 (m, 5H), 7.69 (d, 1H, J = 7.7 Hz), 9.03 (d, 1H, J = 7.7 Hz), 9.48 (s, 1H).
1H-NMR (CDCl3) δ: 1.51 (s, 9H), 4.23 (d, 2H, J = 5.6 Hz), 5.35 (s, 2H), 6.81 (d, 1H, J = 7.7 Hz), 7.26-7.51 (m, 5H), 8.10 (d, 1H, J = 7.7 Hz), 8.67 (s, 1H), 9.66 (br s, 1H).
1H-NMR (DMSO-D6) δ: 4.07 (s, 2H), 6.65 (d, 1H, J = 7.7 Hz), 8.32 (d, 1H, J = 7.7 Hz), 8.99 (s, 1H), 10.09 (s, 1H).
[(6-ヒドロキシ[1,2,3]トリアゾロ[1,5-a]ピリジン-7-カルボニル)アミノ]酢酸の製造
1H-NMR (CDCl3) δ: 5.09 (s, 2H), 7.15 (dd, 1H, J = 8.1, 3.2 Hz), 7.33-7.38 (m, 1H), 7.36 (d, 1H, J = 8.1 Hz), 7.40-7.41 (m, 4H), 8.13 (d, 1H, J= 3.2 Hz).
1H-NMR (CDCl3) δ: 5.21 (s, 2H), 7.35-7.45 (m, 6H), 7.95 (d, 1H, J = 8.9 Hz), 8.51 (d, 1H, J = 2.8 Hz), 9.99 (s, 1H).
1H-NMR (CDCl3) δ: 5.12 (s, 2H), 7.11 (dd, 1H, J = 9.7, 2.0 Hz), 7.36-7.47 (m, 5H), 7.61 (dd, 1H, J = 9.7, 0.8 Hz), 7.99 (d, 1H, J = 0.8 Hz), 8.34 (d, 1H, J = 2.0 Hz).
1H-NMR (CDCl3) δ: 3.80 (s, 3H), 4.38 (d, 2H, J = 5.2 Hz), 5.32 (s, 2H), 7.24 (d, 1H, J = 9.7 Hz), 7.31-7.41 (m, 3H), 7.46-7.49 (m, 2H), 7.75 (d, 1H, J= 9.7 Hz), 8.11 (s, 1H), 8.79 (br s, 1H).
1H-NMR (CDCl3) δ: 3.83 (s, 3H), 4.37 (d, 2H, J = 6.0 Hz), 7.17 (d, 1H, J = 9.7 Hz), 7.80 (d, 1H, J = 9.7 Hz), 8.12 (s, 1H), 10.57 (br s, 1H), 13.56 (s, 1H).
得られた化合物を、既出の方法により、カルボキシル基の脱保護を行うことにより、表題化合物を得た。
1H-NMR (DMSO-D6) δ: 4.28 (d, 2H, J = 5.2 Hz), 7.31 (d, 1H, J = 9.7 Hz), 8.20 (d, 1H, J = 9.7 Hz), 8.39 (s, 1H), 10.36 (t, 1H, J = 5.2 Hz), 13.82 (s, 1H).
[(7-ヒドロキシ-5-フェネチル[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸の製造
1H-NMR (DMSO-D6) δ: 3.80 (s, 3H), 4.92 (s, 1H), 7.20 (s, 2H), 10.29 (s, 1H), 11.51 (s, 1H).
1H-NMR (DMSO-D6) δ: 3.84 (s, 3H), 6.84 (s, 1H), 7.16 (br s, 2H).
1H-NMR (DMSO-D6) δ: 3.92 (s, 3H), 7.37 (s, 1H), 7.85 (d, 1H, J = 9.5 Hz), 10.12 (d, 1H, J = 9.5 Hz), 10.83 (s, 1H).
1H-NMR (DMSO-D6) δ: 3.99 (s, 3H), 7.92 (s, 1H), 8.71 (s, 1H).
1H-NMR (CDCl3) δ: 3.17 (t, 2H, J = 7.8 Hz), 3.48 (t, 2H, J = 7.8 Hz), 4.08 (s, 3H), 6.84 (s, 1H), 7.18-7.28 (m, 5H), 8.42 (s, 1H).
1H-NMR (DMSO-D6) δ: 3.13 (t, 2H, J = 7.8 Hz), 3.45 (t, 2H, J = 7.8 Hz), 7.23-7.31 (m, 5H), 8.65 (s, 1H), 14.19 (s, 1H).
1H-NMR (CDCl3) δ: 3.18 (t, 2H, J = 7.8 Hz), 3.48 (t, 2H, J = 7.8 Hz), 3.81 (s, 3H), 4.34 (d, 2H, J = 5.2 Hz), 6.92 (s, 1H), 7.15-7.33 (m, 5H), 8.42 (s, 1H) , 9.90 (s, 1H).
1H-NMR (DMSO-D6) δ: 2.99-3.11 (m, 4H), 3.58 (d, 2H, J = 4.4 Hz), 6.01 (s, 1H), 7.20-7.27 (m, 5H), 7.86 (s, 1H), 11.23 (t, 1H, J = 4.4 Hz).
1H-NMR (DMSO-D6) δ: 3.12 (t, 2H, J = 7.9 Hz), 3.40 (t, 3H, J = 7.9 Hz), 4.22 (d, 2H, J = 5.2 Hz), 6.79 (s, 1H), 7.21-7.29 (m, 5H), 8.58 (s, 1H), 9.84 (t, 1H, J= 5.2 Hz), 12.97 (s, 1H), 14.22 (s, 1H).
1H-NMR (DMSO-D6) δ: 3.12 (t, 2H, J = 7.9 Hz), 3.40 (t, 3H, J = 7.9 Hz), 4.22 (d, 2H, J = 5.2 Hz), 6.79 (s, 1H), 7.21-7.29 (m, 5H), 8.58 (s, 1H), 9.84 (t, 1H, J= 5.2 Hz), 12.97 (s, 1H), 14.22 (s, 1H).
[(5-ブチル-7-ヒドロキシ[1,2,4]トリアゾロ[1,5-a]ピリジン-8-カルボニル)アミノ]酢酸の製造
1H-NMR (CDCl3) δ: 1.00 (t, 3H, J = 7.4 Hz), 1.45-1.53 (m, 2H), 1.79-1.87 (m, 2H), 3.18 (t, 2H, J= 7.9 Hz), 4.08 (s, 3H), 6.92 (s, 1H), 8.38 (s, 1H).
1H-NMR (CDCl3) δ: 1.01 (t, 3H, J = 7.3 Hz), 1.46-1.57 (m, 2H), 1.82-1.90 (m, 2H), 3.21 (t, 2H, J= 7.9 Hz), 4.15 (s, 3H), 6.77 (s, 1H), 8.28 (s, 1H).
1H-NMR (CDCl3) δ: 1.00 (t, 4H, J = 7.3 Hz), 1.51 (s, 9H), 1.80-1.90 (m, 2H), 3.18 (t, 2H, J = 7.9 Hz), 4.21 (d, 2H, J = 5.2 Hz), 6.72 (s, 1H), 8.29 (s, 1H), 9.72 (t, 1H, J= 4.2 Hz).
1H-NMR (DMSO-D6) δ: 0.93 (t, 3H, J = 7.5 Hz), 1.33-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J= 7.5 Hz), 4.20 (d, 2H, J = 5.2 Hz), 6.85 (s, 1H), 8.55 (s, 1H), 9.84 (br s, 1H), 14.26 (br s, 1H).
1H-NMR (DMSO-D6) δ: 0.93 (t, 3H, J = 7.5 Hz), 1.33-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J= 7.5 Hz), 4.20 (d, 2H, J = 5.2 Hz), 6.85 (s, 1H), 8.55 (s, 1H), 9.84 (br s, 1H), 14.26 (br s, 1H).
製剤例1(カプセルの製造)
1)実施例1の化合物 30mg
2)微結晶セルロース 10mg
3)乳糖 19mg
4)ステアリン酸マグネシウム 1mg
1)、2)、3)及び4)を混合して、ゼラチンカプセルに充填する。
1)実施例1の化合物 10g
2)乳糖 50g
3)トウモロコシデンプン 15g
4)カルメロースカルシウム 44g
5)ステアリン酸マグネシウム 1g
1)、2)、3)の全量及び30gの4)を水で練合し、真空乾燥後、整粒を行う。この整粒末に14gの4)及び1gの5)を混合し、打錠機により打錠する。このようにして、1錠あたり実施例1の化合物10mgを含有する錠剤1000錠を得る。
i)ヒトPHD2の発現・精製
ヒトPHD2の発現は、昆虫細胞(Sf9細胞)にて行った。ヒトPHD2登録配列(NM_022051)の翻訳領域N末端にFLAG-tagを挿入してからpVL1393ベクターに導入し、配列を確認した。該ベクターおよびバキュロウィルスをSf9に共発現し、Sf9にてヒトPHD2発現バキュロウィルスを単離した。このウィルスを用いて、ヒトPHD2発現細胞を調製した。細胞を27℃で72時間培養後、各種プロテアーゼ阻害剤を含んだ細胞溶解用液を加え、超音波処理(Sonication)により破砕した。ANTI-FLAG M2 Affinity Gel Freezer Safe(SIGMA)を充填したカラムに該細胞溶解液を結合させ、洗浄後、N末端FLAG-tag付加ヒトPHD2を溶出させて回収した。抗FLAG抗体及び抗PHD2抗体を用いたWestern-Blotting法にて、精製物がヒトPHD2酵素であることを確認した。
VBC complex(VHL/Elongin B/Elongin C)の発現は、大腸菌(BL21(DE3))にて行った。ヒトVHL登録配列(NM_000551)の翻訳領域N末端にはGST-fusionを、ヒトElongin B登録配列(NM_207013)の翻訳領域N末端にはFLAG-tagを挿入してからpETDuet-1ベクターに導入し、配列を確認した。ヒトElongin C登録配列(NM_005648)の翻訳領域N末端にはHis-tagを挿入してからpRSFDuet-1ベクターに導入し、配列を確認した。これらの発現ベクターを大腸菌(BL21(DE3))に遺伝子導入後、大腸菌を37℃でIPTG含有培地で培養した。回収した大腸菌を超音波処理(Sonication)により破砕した後、Ni-NTA superflow(QIAGEN)を充填したカラムに結合させ、洗浄後に溶出させて回収した。溶出液をGlutathione Sepharose 4Bを充填したカラムに結合させ、洗浄後に溶出させて回収した。抗GST抗体・抗FLAG抗体及び抗His抗体を用いたWestern-Blotting法にて、精製物がヒトVHL・ヒトElongin B及びヒトElongin Cであることを確認した。
前記ii)で得たVBC complexを用いて、HIF-1αの配列を基にした19残基のBiotin標識部分ペプチド(HIF-1α-C19)又は同配列でプロリン残基を水酸化させたBiotin標識部分ペプチド(HIF-1α-C19(Hyp))を結合させたStreptavidin Coated Plateに対する結合活性を測定した。検出は抗GST抗体を用いたELISA法にて行い、VBC complexが、水酸化されたHIF-1α部分ペプチドに対してのみ結合することを確認した。
ヒトPHD2酵素活性は、HIF-1αの配列を基にした19残基の部分ペプチドを基質として、ペプチド中に含まれるプロリン残基の水酸化をTR-FRET(Time-Resolved Fluorescence Resonance Energy Transfer)法にて測定した。
酵素及び基質は、50μM 硫酸鉄、120mM NaCl、0.1% BSA、0.1mM アスコルビン酸、10μM 2-オキソグルタル酸、0.2mM CHAPSを含む50mM トリス-塩酸緩衝液(pH7.5)で希釈し、試験化合物はジメチルスルホキシド(DMSO)で希釈した。
試験化合物及び基質溶液を96ウェルプレートに添加した。反応は、ヒトPHD2酵素溶液を反応系に添加(終濃度1nM)することにより開始した。25℃で30分間インキュベーションした後、EDTAを含む停止液を添加し、ユーロピウム(Eu)及びXlentを含むVBC complex溶液を添加・結合させて、水酸化されたプロリン残基の量を時間分解蛍光測定法により定量した。各ウェルの時間分解蛍光を測定し、各ウェルの試験化合物のヒトPHD阻害活性(%)を、酵素無添加ウェル及び試験化合物無添加ウェルの値に基づいて計算した。各化合物のヒトPHD阻害活性を、IC50(μM)又は30μMのときのヒトPHD阻害活性(%)として、以下の表25乃至29に示す。これらの表において、数値のみで表された値はIC50(μM)を示し、%を含めて表された値は30μMのときのヒトPHD阻害活性(%)を示す。
ヒトEPO産生に対する試験化合物の誘導活性は、ヒトから樹立された肝臓由来の細胞株であるHep3B(ATCC)を用いて測定した。
Hep3B細胞は、10%ウシ胎児血清を含むEagle-MEM培地で培養し、試験化合物はジメチルスルホキシド(DMSO)で希釈した。
Hep3B細胞を96ウェルプレートにて培養し、24時間後に試験化合物を各濃度で添加した。37℃で24時間インキュベーションした後、培養上清を回収した。培養上清中に産生されたヒトEPO濃度は、ヒトEPO-ELISAキット(StemCell Technologies社製,01630)を用いて、製造業者の説明に従って測定し、試験化合物のヒトEPO産生誘導活性(%)は、この条件で最大に産生された際の値及び試験化合物無添加の値に基づいて計算した。各化合物のヒトEPO産生誘導活性を、EC50(μM)又は30μMのときのヒトEPO産生誘導活性(%)として、以下の表30乃至34に示す。これらの表において、数値のみで表された値はEC50(μM)を示し、%を含めて表された値は30μMのときのヒトEPO産生誘導活性(%)を示す。
このため、本発明化合物又はその医薬上許容される塩、或いはその溶媒和物は、EPOの産生低下に起因する各種疾患や病態(障害)の予防若しくは治療に有効な薬剤となり得、貧血の治療に有効に使用することができる。
Claims (40)
- 下記一般式[I]で表される化合物又はその医薬上許容される塩、或いはその溶媒和物:
[式中、
部分構造式:
は、下記式:
で表される基のいずれかであり;
R1は、
(1)水素原子、
(2)C1-6アルキル基、
(3)C6-14アリール基、
(4)C3-8シクロアルキル基、
(5)C6-14アリール-C1-6アルキル基、又は、
(6)C3-8シクロアルキル-C1-6アルキル基であり;
R2は、
(1)水素原子、
(2)C1-10アルキル基、
(3)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC6-14アリール基、
(4)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC3-8シクロアルキル基、
(5)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC3-8シクロアルケニル基、
(6)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいヘテロアリール基(ここで、該ヘテロアリールは、炭素原子の他に、窒素原子、酸素原子、及び、硫黄原子から選ばれる1乃至6個のヘテロ原子を有する)、
(7)C6-14アリール-C1-6アルキル基(該C6-14アリールは、下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は、
(8)C3-8シクロアルキル-C1-6アルキル基(該C3-8シクロアルキルは、下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)であり;
R3は、
(1)水素原子、
(2)ハロゲン原子、
(3)C1-6アルキル基、
(4)C6-14アリール基、
(5)C3-8シクロアルキル基、又は、
(6)C6-14アリール-C1-6アルキル基であり;
R4及びR5は、それぞれ独立して、
(1)水素原子、又は、
(2)C1-6アルキル基である。
グループB:
(a)ハロゲン原子、
(b)C1-6アルキル基、
(c)C3-8シクロアルキル基、
(d)シアノ基、及び
(e)ハロ-C1-6アルキル基。]。 - R4及びR5がともに水素原子である、請求項1乃至5のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。
- R3が水素原子である、請求項1乃至5のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。
- R1が水素原子である、請求項1乃至5のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。
- R2が
(1)C1-10アルキル基、
(2)前記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいC6-14アリール基、
(3)C6-14アリール-C1-6アルキル基(該C6-14アリールは、前記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は、
(4)C3-8シクロアルキル-C1-6アルキル基(該C3-8シクロアルキルは、前記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)
である、請求項1乃至5のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。 - R4及びR5がともに水素原子である、請求項2に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。
- R3が水素原子である、請求項10に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。
- R1が水素原子である、請求項11に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。
- R2が
(1)C1-10アルキル基、又は、
(2)C6-14アリール-C1-6アルキル基(該C6-14アリールは、前記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)
である、請求項12に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物。 - 下記一般式[I-1]で表される化合物又はその医薬上許容される塩、或いはその溶媒和物:
[式中、
部分構造式:
は、下記式:
で表される基のいずれかであり;
R11は、
(1)水素原子、
(2)C1-6アルキル基、
(3)フェニル基、
(4)C3-8シクロアルキル基、
(5)フェニル-C1-6アルキル基、又は、
(6)C3-8シクロアルキル-C1-6アルキル基であり;
R21は、
(1)水素原子、
(2)C1-10アルキル基、
(3)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいフェニル基、
(4)C3-8シクロアルキル基、
(5)C3-8シクロアルケニル基、
(6)下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよいチエニル基、
(7)フェニル-C1-6アルキル基(該フェニルは、下記グループBから選ばれる同一又は異なった1乃至5個の置換基で置換されてもよい)、又は、
(8)C3-8シクロアルキル-C1-6アルキル基であり;
R31は、
(1)水素原子、
(2)ハロゲン原子、
(3)C1-6アルキル基、
(4)フェニル基、
(5)C3-8シクロアルキル基、又は、
(6)フェニル-C1-6アルキル基であり;
R41及びR51は、それぞれ独立して、
(1)水素原子、又は、
(2)C1-6アルキル基である。
グループB:
(a)ハロゲン原子、
(b)C1-6アルキル基、
(c)C3-8シクロアルキル基、
(d)シアノ基、及び
(e)ハロ-C1-6アルキル基。]。 - 請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物、及び医薬上許容される担体を含有する医薬組成物。
- 請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有するプロリル水酸化酵素阻害剤。
- 請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有するエリスロポエチン産生誘導剤。
- 請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有する貧血治療剤。
- 請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を含有する腎性貧血治療剤。
- プロリル水酸化酵素阻害剤を製造するための、請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用。
- エリスロポエチン産生誘導剤を製造するための、請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用。
- 貧血治療剤を製造するための、請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用。
- 腎性貧血治療剤を製造するための、請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物の使用。
- 有効量の請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、プロリル水酸化酵素の阻害方法。
- 有効量の請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、エリスロポエチン産生の誘導方法。
- 有効量の請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、貧血の治療方法。
- 有効量の請求項1乃至25のいずれか1項に記載の化合物又はその医薬上許容される塩、或いはその溶媒和物を哺乳動物に投与することを含む、腎性貧血の治療方法。
- 請求項26に記載の医薬組成物、及び当該医薬組成物を貧血及び腎性貧血より選ばれる疾患の治療又は予防の用途に使用することができる、或いは使用すべきであることを記載した当該医薬組成物に関する記載物を含む、商業パッケージ。
- 請求項26に記載の医薬組成物、及び当該医薬組成物を貧血及び腎性貧血より選ばれる疾患の治療又は予防の用途に使用することができる、或いは使用すべきであることを記載した当該医薬組成物に関する記載物を含む、キット。
Priority Applications (26)
Application Number | Priority Date | Filing Date | Title |
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RSP20140406 RS53499B1 (en) | 2009-07-17 | 2010-07-16 | TRIAZOLOPYRIDINE COMPOUND AND ITS ACTION AS A PROLYL HYDROXYLASE INHIBITOR AND ERITROPOETIN MANUFACTURER |
KR1020197029507A KR20190117807A (ko) | 2009-07-17 | 2010-07-16 | 트리아졸로피리딘 화합물, 그리고 그 프롤릴 수산화효소 저해제 및 에리트로포이에틴 생성 유도제로서의 작용 |
KR1020187010331A KR20180042443A (ko) | 2009-07-17 | 2010-07-16 | 트리아졸로피리딘 화합물, 그리고 그 프롤릴 수산화효소 저해제 및 에리트로포이에틴 생성 유도제로서의 작용 |
AU2010271732A AU2010271732B2 (en) | 2009-07-17 | 2010-07-16 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
MX2012000766A MX2012000766A (es) | 2009-07-17 | 2010-07-16 | Compuestos triazolopiridina, y su accion como inhibidor de prolil hidroxilasa e inductor de la produccion de eritropoyetina. |
SG2012003570A SG178049A1 (en) | 2009-07-17 | 2010-07-16 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
DK10799914.6T DK2455381T5 (en) | 2009-07-17 | 2010-07-16 | Triazolopyridinforbindelse and its effect as an inhibitor of prolyl hydroxylase and induce erythropoietin production by |
KR1020177003353A KR101850661B1 (ko) | 2009-07-17 | 2010-07-16 | 트리아졸로피리딘 화합물, 그리고 그 프롤릴 수산화효소 저해제 및 에리트로포이에틴 생성 유도제로서의 작용 |
KR1020217012148A KR20210048589A (ko) | 2009-07-17 | 2010-07-16 | 트리아졸로피리딘 화합물, 그리고 그 프롤릴 수산화효소 저해제 및 에리트로포이에틴 생성 유도제로서의 작용 |
SI201030682T SI2455381T1 (sl) | 2009-07-17 | 2010-07-16 | Triazolopiridinova spojina in njeno delovanje kot zaviralec prolil-hidroksilaze in induktor produkcije eritropoietina |
EP10799914.6A EP2455381B9 (en) | 2009-07-17 | 2010-07-16 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
CA2768505A CA2768505C (en) | 2009-07-17 | 2010-07-16 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
PL10799914T PL2455381T3 (pl) | 2009-07-17 | 2010-07-16 | Triazolopirydynowy związek i jego działanie jako inhibitora hydroksylazy prolinowej i środka indukującego wytwarzanie erytropoetyny |
ES10799914.6T ES2477968T3 (es) | 2009-07-17 | 2010-07-16 | Compuesto de triazolopiridina, y acción del mismo como inhibidor de prolil-hidroxilasa e inductor de la producción de eritropoyetina |
KR1020237040564A KR20230165366A (ko) | 2009-07-17 | 2010-07-16 | 트리아졸로피리딘 화합물, 그리고 그 프롤릴 수산화효소 저해제 및 에리트로포이에틴 생성 유도제로서의 작용 |
RU2012105467/04A RU2538963C2 (ru) | 2009-07-17 | 2010-07-16 | Триазолопиридиновое соединение и его действие в качестве ингибитора пролилгидроксилазы и индуктора выработки эритропоэтина |
BR112012001157A BR112012001157A2 (pt) | 2009-07-17 | 2010-07-16 | compostos de triazolopiridina, e ação do mesmo como inibidor de prolil hidroxilase e indutor de produção de eritropoetina |
NZ598242A NZ598242A (en) | 2009-07-17 | 2010-07-16 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
KR1020127004258A KR101706803B1 (ko) | 2009-07-17 | 2010-07-16 | 트리아졸로피리딘 화합물, 그리고 그 프롤릴 수산화효소 저해제 및 에리트로포이에틴 생성 유도제로서의 작용 |
MEP-2014-82A ME01858B (me) | 2009-07-17 | 2010-07-16 | Jedinjenje triazolopiridina i njegovo dejstvo kao inhibitora prolil hidroksilaze i induktora proizvodnje eritropoetina |
CN201080032238.2A CN102471337B (zh) | 2009-07-17 | 2010-07-16 | 三唑并吡啶化合物及其作为脯氨酰基羟化酶抑制剂和红细胞生成素产生诱导剂的作用 |
EP19188636.5A EP3594213A1 (en) | 2009-07-17 | 2010-07-16 | Triazolopyridine compounds and action thereof as prolyl hydroxylase inhibitors and erythropoietin production inducers |
IL217541A IL217541A (en) | 2009-07-17 | 2012-01-15 | Triazolopyridine compounds, preparations containing them and their uses |
HK12109057.7A HK1168346A1 (en) | 2009-07-17 | 2012-09-14 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
HRP20140705AT HRP20140705T1 (hr) | 2009-07-17 | 2014-07-22 | Spoj triazolopiridina i njegovo djelovanje kao inhibitora prolil hidroksilaze i induktora proizvodnje eritropoetina |
SM201500122T SMT201500122B (it) | 2009-07-17 | 2015-05-22 | Composto di triazolopiridina e sua azione come inibitore di prolilidrossilasi e induttore della produzione di eritropoientina |
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JP2009169565 | 2009-07-17 | ||
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US27312709P | 2009-07-30 | 2009-07-30 | |
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US (3) | US8283465B2 (ja) |
EP (3) | EP2746282A1 (ja) |
JP (9) | JP5021797B2 (ja) |
KR (4) | KR101706803B1 (ja) |
CN (1) | CN102471337B (ja) |
AR (1) | AR077417A1 (ja) |
AU (1) | AU2010271732B2 (ja) |
BR (1) | BR112012001157A2 (ja) |
CA (1) | CA2768505C (ja) |
CO (1) | CO6430426A2 (ja) |
DK (1) | DK2455381T5 (ja) |
ES (1) | ES2477968T3 (ja) |
HK (1) | HK1168346A1 (ja) |
HR (1) | HRP20140705T1 (ja) |
IL (1) | IL217541A (ja) |
ME (1) | ME01858B (ja) |
MX (1) | MX2012000766A (ja) |
MY (1) | MY160814A (ja) |
NZ (1) | NZ598242A (ja) |
PE (1) | PE20120629A1 (ja) |
PL (1) | PL2455381T3 (ja) |
PT (1) | PT2455381E (ja) |
RS (1) | RS53499B1 (ja) |
RU (1) | RU2538963C2 (ja) |
SG (1) | SG178049A1 (ja) |
SI (1) | SI2455381T1 (ja) |
SM (1) | SMT201500122B (ja) |
TW (1) | TWI485150B (ja) |
WO (1) | WO2011007856A1 (ja) |
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WO2014102818A1 (en) | 2012-12-24 | 2014-07-03 | Cadila Healthcare Limited | Novel quinolone derivatives |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11302257A (ja) * | 1997-10-20 | 1999-11-02 | Hoechst Marion Roussel Deutsche Gmbh | 置換イソキノリン−3−カルボキサミド、その製法および薬剤としてのその使用 |
WO2007103905A2 (en) * | 2006-03-07 | 2007-09-13 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
WO2007136990A2 (en) * | 2006-05-16 | 2007-11-29 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
WO2007150011A2 (en) * | 2006-06-23 | 2007-12-27 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
WO2008089052A2 (en) * | 2007-01-12 | 2008-07-24 | Smithkline Beecham Corporation | N-substituted glycine derivatives: hydroxylase inhibitors |
WO2008130600A2 (en) * | 2007-04-18 | 2008-10-30 | Amgen Inc. | Quinolones and azaquinolones that inhibit prolyl hydroxylase |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6355653B1 (en) * | 1999-09-06 | 2002-03-12 | Hoffmann-La Roche Inc. | Amino-triazolopyridine derivatives |
US6514989B1 (en) * | 2001-07-20 | 2003-02-04 | Hoffmann-La Roche Inc. | Aromatic and heteroaromatic substituted 1,2,4-triazolo pyridine derivatives |
EP1435952A1 (en) * | 2001-10-08 | 2004-07-14 | F. Hoffmann-La Roche Ag | 8-amino- 1,2,4]triazolo 1,5-a]pyridine-6-carboxylic acid amide |
JP2007501844A (ja) | 2003-08-08 | 2007-02-01 | トランス テック ファーマ,インコーポレイテッド | アリール及びヘテロアリール化合物、組成物並びに使用方法 |
KR100854864B1 (ko) * | 2004-08-05 | 2008-08-28 | 에프. 호프만-라 로슈 아게 | 인돌, 인다졸 또는 인돌린 유도체 |
FR2889383A1 (fr) * | 2005-08-01 | 2007-02-02 | France Telecom | Procede et dispositif de detection pour systeme mimo, systeme mimo, programme et support d'information |
CN101506149B (zh) * | 2006-06-26 | 2012-11-14 | 华纳奇考特有限责任公司 | 脯氨酰羟化酶抑制剂及使用方法 |
AU2007272009A1 (en) | 2006-07-12 | 2008-01-17 | Syngenta Limited | Triazolopyridine derivatives as herbicides |
CA2685219C (en) | 2007-05-04 | 2012-06-19 | Amgen Inc. | Diazaquinolones that inhibit prolyl hydroxylase activity |
US20110028463A1 (en) | 2007-07-03 | 2011-02-03 | Astellas Pharma Inc. | Amide compounds |
JP2011505367A (ja) * | 2007-11-30 | 2011-02-24 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | プロリルヒドロキシラーゼ阻害剤 |
EP2227770A4 (en) * | 2007-11-30 | 2011-11-09 | Glaxosmithkline Llc | PROLYLHYDROXYLASEINHIBITOREN |
WO2009126624A1 (en) * | 2008-04-11 | 2009-10-15 | Bristol-Myers Squibb Company | Triazolo compounds useful as dgat1 inhibitors |
US20110039895A1 (en) | 2008-04-30 | 2011-02-17 | Glaxo Smith Kline LLC., a corporation | Prolyl hydroxylase inhibitors |
CN102112475A (zh) | 2008-05-29 | 2011-06-29 | 西特里斯药业公司 | 作为沉默调节蛋白调节剂的咪唑并吡啶和相关的类似物 |
BRPI0922452A2 (pt) | 2008-12-19 | 2015-12-15 | Leo Pharma As | composto, composição farmacêutica, uso em um composto, e método para prevenir, tratar ou melhorar doenças ou condições dérmicas, ou distúrbios de ferimento cutâneo agudos ou crônicos. |
PT2455381E (pt) * | 2009-07-17 | 2014-06-24 | Japan Tobacco Inc | Composto de triazolopiridina e sua acção como inibidor da prolil-hidroxilase e indutor da produção de eritropoietina |
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2018
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- 2020-04-20 JP JP2020074508A patent/JP2020111612A/ja not_active Ceased
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2022
- 2022-06-29 JP JP2022104161A patent/JP2022126843A/ja not_active Ceased
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2024
- 2024-04-24 JP JP2024070200A patent/JP2024091878A/ja active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11302257A (ja) * | 1997-10-20 | 1999-11-02 | Hoechst Marion Roussel Deutsche Gmbh | 置換イソキノリン−3−カルボキサミド、その製法および薬剤としてのその使用 |
WO2007103905A2 (en) * | 2006-03-07 | 2007-09-13 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
WO2007136990A2 (en) * | 2006-05-16 | 2007-11-29 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
WO2007150011A2 (en) * | 2006-06-23 | 2007-12-27 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
WO2008089052A2 (en) * | 2007-01-12 | 2008-07-24 | Smithkline Beecham Corporation | N-substituted glycine derivatives: hydroxylase inhibitors |
WO2008130600A2 (en) * | 2007-04-18 | 2008-10-30 | Amgen Inc. | Quinolones and azaquinolones that inhibit prolyl hydroxylase |
Cited By (19)
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WO2011090127A1 (ja) * | 2010-01-21 | 2011-07-28 | 石原産業株式会社 | トリアゾロピリジン誘導体又はその塩、それらの製造方法及びそれらを含有する有害生物防除剤 |
WO2014102818A1 (en) | 2012-12-24 | 2014-07-03 | Cadila Healthcare Limited | Novel quinolone derivatives |
RU2534804C1 (ru) * | 2013-08-05 | 2014-12-10 | Общество С Ограниченной Ответственностью "Ньювак" (Ооо "Ньювак") | ЗАМЕЩЕННЫЕ [1,2,4]ТРИАЗОЛО[4,3-a]ПИРИДИНЫ, ПРОЯВЛЯЮЩИЕ СВОЙСТВА АНТАГОНИСТОВ АДЕНОЗИНОВЫХ А2А РЕЦЕПТОРОВ, И ИХ ПРИМЕНЕНИЕ |
WO2015020565A1 (ru) * | 2013-08-05 | 2015-02-12 | Общество С Ограниченной Ответственностью "Ньювак" (Ооо "Ньювак") | Замещенные [1,2,4]триазоло[4,3-a]пиридины, проявляющие свойства антогонистов аденозиновых а2а рецепторов, и их применение |
WO2016190420A1 (ja) * | 2015-05-28 | 2016-12-01 | 日本たばこ産業株式会社 | 糖尿病性腎症を治療又は予防する方法 |
KR20180011124A (ko) | 2015-05-28 | 2018-01-31 | 니뽄 다바코 산교 가부시키가이샤 | 당뇨병성 신증을 치료 또는 예방하는 방법 |
JPWO2016190420A1 (ja) * | 2015-05-28 | 2018-03-15 | 日本たばこ産業株式会社 | 糖尿病性腎症を治療又は予防する方法 |
KR102473897B1 (ko) | 2015-05-28 | 2022-12-06 | 니뽄 다바코 산교 가부시키가이샤 | 당뇨병성 신증을 치료 또는 예방하는 방법 |
AU2017364725B2 (en) * | 2016-11-25 | 2021-04-01 | Japan Tobacco Inc. | Method for producing triazolopyridine compound |
KR20190085004A (ko) | 2016-11-25 | 2019-07-17 | 니뽄 다바코 산교 가부시키가이샤 | 트리아졸로피리딘 화합물의 제조 방법 |
JPWO2018097254A1 (ja) * | 2016-11-25 | 2019-10-17 | 日本たばこ産業株式会社 | トリアゾロピリジン化合物の製造方法 |
JP2020073474A (ja) * | 2016-11-25 | 2020-05-14 | 日本たばこ産業株式会社 | トリアゾロピリジン化合物の製造方法 |
WO2018097254A1 (ja) | 2016-11-25 | 2018-05-31 | 日本たばこ産業株式会社 | トリアゾロピリジン化合物の製造方法 |
WO2018205928A1 (zh) | 2017-05-09 | 2018-11-15 | 杭州安道药业有限公司 | 吲哚嗪衍生物及其在医药上的应用 |
US11021478B2 (en) | 2017-05-09 | 2021-06-01 | Kind Pharmaceutical | Indolizine derivatives and their application in medicine |
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US11970495B2 (en) | 2017-05-09 | 2024-04-30 | Kind Pharmaceutical | Indolizine derivatives and their application in medicine |
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