JP4612414B2 - 3’−[(2z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4h−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン) - Google Patents
3’−[(2z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4h−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン) Download PDFInfo
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- JP4612414B2 JP4612414B2 JP2004506532A JP2004506532A JP4612414B2 JP 4612414 B2 JP4612414 B2 JP 4612414B2 JP 2004506532 A JP2004506532 A JP 2004506532A JP 2004506532 A JP2004506532 A JP 2004506532A JP 4612414 B2 JP4612414 B2 JP 4612414B2
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- pharmaceutical composition
- thrombocytopenia
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- compound
- hydrazino
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 title claims description 24
- SVOQIEJWJCQGDQ-UHFFFAOYSA-N 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid Chemical compound CC1=C(C=C(C=C1)N2C(=O)C(=C(N2)C)N=NC3=CC=CC(=C3O)C4=CC(=CC=C4)C(=O)O)C SVOQIEJWJCQGDQ-UHFFFAOYSA-N 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 15
- -1 3,4-Dimethylphenyl Chemical group 0.000 claims description 13
- 206010043554 thrombocytopenia Diseases 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 230000001737 promoting effect Effects 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- PYTBSUAIKFVNEG-UHFFFAOYSA-N C(O)CN.C(O)CN.C1(=CC(=CC=C1)C(=O)O)C1=CC=CC=C1 Chemical compound C(O)CN.C(O)CN.C1(=CC(=CC=C1)C(=O)O)C1=CC=CC=C1 PYTBSUAIKFVNEG-UHFFFAOYSA-N 0.000 claims description 3
- 241000282412 Homo Species 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229940126062 Compound A Drugs 0.000 claims description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 4
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims 2
- 210000004027 cell Anatomy 0.000 claims 2
- 238000000338 in vitro Methods 0.000 claims 2
- 230000035800 maturation Effects 0.000 claims 2
- 210000003593 megakaryocyte Anatomy 0.000 claims 2
- 210000000130 stem cell Anatomy 0.000 claims 2
- 230000000638 stimulation Effects 0.000 claims 2
- 238000002054 transplantation Methods 0.000 claims 2
- ZJWUEJOPKFYFQD-UHFFFAOYSA-N 2-hydroxy-3-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1O ZJWUEJOPKFYFQD-UHFFFAOYSA-N 0.000 claims 1
- 206010065553 Bone marrow failure Diseases 0.000 claims 1
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- 230000003213 activating effect Effects 0.000 claims 1
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- 210000004369 blood Anatomy 0.000 claims 1
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- 229940126214 compound 3 Drugs 0.000 claims 1
- 210000004700 fetal blood Anatomy 0.000 claims 1
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- 210000004185 liver Anatomy 0.000 claims 1
- 208000019423 liver disease Diseases 0.000 claims 1
- 230000005976 liver dysfunction Effects 0.000 claims 1
- 244000005700 microbiome Species 0.000 claims 1
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
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- 102100034195 Thrombopoietin Human genes 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000000556 agonist Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
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- 239000003826 tablet Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000002169 ethanolamines Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- OCZVWZVTEQXRPI-UHFFFAOYSA-N 3-(2-hydroxyphenyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C(=CC=CC=2)O)=C1 OCZVWZVTEQXRPI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PLILLUUXAVKBPY-SBIAVEDLSA-N NCCO.NCCO.CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 Chemical compound NCCO.NCCO.CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 PLILLUUXAVKBPY-SBIAVEDLSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011928 denatured alcohol Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
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- 230000000699 topical effect Effects 0.000 description 2
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- XNLWJFYYOIRPIO-UHFFFAOYSA-N 3-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1 XNLWJFYYOIRPIO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LNHIVMIJIIYELO-XVKSGSRPSA-N CC=1C=C(C=CC1C)N1N=C(/C(/C1=O)=N/NC=1C(=C(C=CC1)C1=CC(=CC=C1)C(=O)O)O)C.C(O)CN.C(O)CN.C1(=CC(=CC=C1)C(=O)O)C1=CC=CC=C1 Chemical compound CC=1C=C(C=CC1C)N1N=C(/C(/C1=O)=N/NC=1C(=C(C=CC1)C1=CC(=CC=C1)C(=O)O)O)C.C(O)CN.C(O)CN.C1(=CC(=CC=C1)C(=O)O)C1=CC=CC=C1 LNHIVMIJIIYELO-XVKSGSRPSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
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- 239000000356 contaminant Substances 0.000 description 1
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- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸は、国際出願日2001年5月24日および国際公開日2001年11月29日を有する国際特許出願PCT/US01/16863において、TPO受容体のアゴニストとして、特に、血小板産生促進において有用であるとして、その医薬上許容される塩、水和物、溶媒和物およびエステルとともに開示され、特許請求されている。その全開示を参照により本明細書に一体化させる。国際特許出願PCT/US01/16863は、そこに開示された化合物の塩の形態を特に開示していない。
3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)の調製
δ 2.21 (s, 3H), 2.26 (s, 3H), 2.31 (s, 3H), 2.85 (m, 4H), 3.57 (t, 4H), 7.07 (m), 7.14 (s), 7.18 (d, 重複した3H), 7.61 (t), 7.63 (dd, 重複した2H), ~7.7 (m, 重複した2H), 7.79 (d),~7.8 (br. s, 重複した2H), 7.96 (d, 2H), 8.13 (s, 1H), 13.8 (br. s, 測定不能, TFA共鳴と重なる)ならびにTHF 1.76 (m) および 3.60 (エタノールアミンシグナルと重複) に関するシグナル(1.05重量%)ならびにエタノール 1.06 (t) および 3.44 (q) に関するシグナル(1.3重量%)
IR Data (Nujol mull)
1636, 1506, 1466, 1378, 1348, 1294, 1273, 1255, 1228, 1194, 1127, 1118, 1066, 1015, 767, 747 cm-1
3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)の調製
窒素雰囲気下、室温において、粗オレンジ色固体である8gの3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸を、室温において、500mlの丸底3つ首フラスコ中のTHF(240ml)に溶解した。エタノールアミン(2.2ml,2モル当量)を、シリンジにより5分間かけて添加した。得られた暗赤色懸濁液を室温で1.5時間撹拌し、ろ過により固体を単離し、THF(16mlx2)で洗浄し、減圧オーブン中、50℃で一晩乾燥させて10.37gの標記化合物を得た(NMRによれば残存溶媒、すなわち2.4重量%のTHFのせいで定量的収率よりも多かった、他のNMRは実施例1と同様)。
3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)の調製
窒素雰囲気下、室温において、粗オレンジ色固体である8gの3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸を、エタノール(800ml)に懸濁した。エタノールアミン(2.2ml,2モル当量)を、シリンジにより5分間かけて添加した。得られた暗赤色懸濁液を室温で45分間撹拌し、ろ過により固体を単離し、エタノール(10mlx2)で洗浄し、減圧オーブン中、50℃で一晩乾燥させて9.83g(収率96%)の標記化合物を得た。NMRは実施例1と同様であり、エタノール含量は1.3重量%であったが、THFは存在しなかった。
3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)の調製
3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸(259.0g)を、室温において、THF(4660ml)中で撹拌して完全に溶解させた。溶液をろ過し、さらなるTHF(520ml)を、フィルターを通して流してリアクターを洗浄した(一緒にした濾液=溶液1)。
相対溶解度
遊離酸の3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸(化合物A)およびビス−(モノエタノールアミン)塩(化合物B)の溶解度を、3種の異なる系:水、0.1% HClおよびメタノール中で測定した。データを下表1にまとめる。
錠剤組成物
ラクトース、微細結晶セルロース、デンプングリコール酸ナトリウム、ステアリン酸マグネシウムおよび3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を、下表2に示す割合で混和する。次いで、混和物を圧縮して錠剤にする。
注射可能非経口組成物
3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を投与するための注射可能形態を、1.0mlの通常セイライン中で5.0mgの化合物を撹拌することにより製造する。
Claims (23)
- 化合物3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)および医薬上許容される担体または希釈剤を含む医薬組成物。
- 請求項1記載の化合物を含む、ヒトを包含する哺乳動物の血小板減少症の治療のための医薬組成物。
- 哺乳動物がヒトである請求項3記載の医薬組成物。
- 請求項1記載の化合物を含む、ヒトを包含する哺乳動物において血小板産生を促進するための医薬組成物。
- 哺乳動物がヒトである請求項5記載の医薬組成物。
- 経口投与用の請求項3記載の医薬組成物。
- 非経口投与用の請求項3記載の医薬組成物。
- 請求項1記載の化合物を含む、対象においてTPO受容体を作動させるための医薬組成物。
- 医薬上許容される担体または希釈剤ならびに有効量の請求項1記載の化合物を含有する医薬組成物の製造方法であって、請求項1記載の化合物を医薬上許容される担体または希釈剤と混合することを含む方法。
- 請求項1記載の化合物を含む、ドナーから得られる血小板の産生を促進するための医薬組成物であって、血小板フェレーシス、輸血または血小板提供の前にかかるドナーに投与するための医薬組成物。
- 請求項1記載の化合物を含む、インビトロまたはエクスビボで巨核球成熟および/または血小板産生の刺激を促進するための医薬組成物であって、TPO受容体を発現する細胞の培地に添加するための医薬組成物。
- 請求項1記載の化合物を含む、インビトロまたはエクスビボで巨核球成熟および/または血小板産生の刺激を促進するための医薬組成物であって、幹細胞、骨髄細胞、臍帯血細胞または末梢血細胞の培地に添加するための医薬組成物。
- 該血小板減少症が化学療法または放射線療法により引き起こされる骨髄抑制によるものである、請求項3記載の医薬組成物。
- 該血小板減少症が器官移植によるものである、請求項3記載の医薬組成物。
- 該血小板減少症が骨髄、幹細胞、または肝臓の移植によるものである、請求項3記載の医薬組成物。
- 該血小板減少症が突発性血小板減少性紫斑病(ITP)によるものである、請求項3記載の医薬組成物。
- 該血小板減少症が骨髄形成異常症候群(MDS)、再生不能性貧血または白血病によるものである、請求項3記載の医薬組成物。
- 該血小板減少症がウイルス、真菌、微生物または寄生虫の感染によるものである、請求項3記載の医薬組成物。
- 該血小板減少症が肝臓の機能不全によるものである、請求項3記載の医薬組成物。
- 該血小板減少症が外科的処置によるものである、請求項3記載の医薬組成物。
- 該血小板減少症が抗ウイルス剤または抗生物質での処置によるものである、請求項3記載の医薬組成物。
- 下記工程:
i)3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸を適切な有機溶媒に溶解して溶液を得て;
ii)2当量またはそれ以上のエタノールアミンを該溶液に添加し;次いで、
iii)調製された化合物を単離する
を含む、請求項1の化合物の製造方法。
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