JP6353620B1 - 固体形態のプラジエノライドピリジン化合物及び使用の方法 - Google Patents
固体形態のプラジエノライドピリジン化合物及び使用の方法 Download PDFInfo
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- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
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- 239000012160 loading buffer Substances 0.000 description 1
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- 201000010453 lymph node cancer Diseases 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
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- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
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- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940074355 nitric acid Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
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- 230000009437 off-target effect Effects 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 125000004269 oxiran-2-yl group Chemical group [H]C1([H])OC1([H])* 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
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- 239000013557 residual solvent Substances 0.000 description 1
- 239000003161 ribonuclease inhibitor Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000037423 splicing regulation Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
を有するプラジエノライドピリジン化合物及び医薬上許容しうるその塩(集約的に「式Iの化合物」)から選択される少なくとも1つの実体の新規固体形態を提供する。
により代表されうる。
a)骨髄異形成症候群(MDS):例えば、「SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications」、Damm F.ら、Leukemia、2011、1〜4頁;「Frequent pathway mutations in splicing machinery in myelodysplasia」、Yoshida K.ら、Nature、2011年、478巻、64〜69頁;「Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms」、Malcovati L.ら、Blood、2011年、118、24、6239〜6246頁;「Mutations in the spliceosome machinery, a novel and ubiquitous pathway 20 in leukemogenesis」、Makishimaら、Blood、2012年、119巻、3203〜3210頁;「Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts」、Pappaemannuil,E.ら、New England J. Med.2011年、DOI 10.1056/NEJMoa1103283を参照されたい。
b)慢性リンパ性白血病(CLL):例えば、「Defects in the spliceosomal machinery: a new pathway of leukaemogenesis」、Maciejewski, J.P.、Padgett,R.A.、Br.J.Haematology、2012、1〜9頁;「Mutations in the SF3B1 splicing factor in chronic lymphocytic leukemia: associations with progression and fludarabine−refractoriness」、Rossiら、Blood、2011年、118巻、6904〜6908頁;「Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia」、Quesadaら、Nature Genetics、2011年、44巻、47〜52頁を参照されたい。
c)慢性骨髄単球性白血病(CMML):例えば、Yoshidaら、Nature 2011;30「Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia」、Kar S.A.ら、Haematologia、2012、DOI:10.3324/haematol.2012.064048;DeBoeverら、「Transcriptome sequencing reveals potential mechanism of cryptic 3’ splice site selection in SF3B1−mutated cancers」、PLOS Computational Biology、2013、DOI:10.1371/journal.pcbi.1004105を参照されたい。
d)急性骨髄性白血病(AML):例えば、Malcovatiら、Blood 2011;Yoshidaら、Nature 2011を参照されたい。
e)乳がん:例えば、「Whole genome analysis informs breast cancer response to aromatase inhibition」、Ellisら、Nature、2012年、486巻、353〜360頁;DeBoeverら、「Transcriptome sequencing reveals potential mechanism of cryptic 3’ splice site selection in SF3B1−mutated cancers」、PLOS Computational Biology、2013、DOI:10.1371/journal.pcbi.1004105;Maguireら、「SF3B1 mutations constitute a novel therapeutic target in breast cancer」、J Pathol 2015、235巻、571〜580頁を参照されたい。
f)ブドウ膜黒色腫:例えば、「SF3B1 mutations are associated with alternative splicing in uveal melanoma」、Furneyら、Cancer Disc. 2013、10巻、1122〜1129頁;DeBoeverら、「Transcriptome sequencing reveals potential mechanism of cryptic 3’ splice site selection in SF3B1−mutated cancers」、PLOS Computational Biology、2013、DOI:10.1371/journal.pcbi.1004105を参照されたい。
g)子宮内膜がん:例えば、Tefferiら、「Myelodysplastic syndromes」。N Engl J Med.2009;361巻:1872〜85頁を参照されたい。
h)胃がん:例えば、Int J Cancer. 2013 Jul;133(1):260〜5頁、「Mutational analysis of splicing machinery genes SF3B1,U2AF1 and SRSF2 in myelodysplasia and other common tumors」。 Jeらを参照されたい。
i)卵巣がん:例えば、Int J Cancer.2013 Jul;133(1):260〜5頁、「Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors」。Jeらを参照されたい。
j)胆管がん、例えば胆管細胞がん及び膵臓がん:例えば、Biankinら、「Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes」、Nature 2012、491巻、399〜405頁を参照されたい。
k)肺がん:例えば、「Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia」、Quesadaら、Nature Genetics 44巻、47〜52頁(2012年);Scottら、「Acquired mutations that affect pre−mRNA splicing in hematologic malignancies and solid tumors」、JNCI 105、20、1540〜1549頁を参照されたい。
MeOH:メタノール
DMF:ジメチルホルムアミド
KHMDS:カリウムビス(トリメチルシリル)アミド
LCMS:液体クロマトグラフィー−質量分光測定装置
TBS Cl:tert−ブチルジメチルシリルクロリド
THF:テトラヒドロフラン
TLC:薄層クロマトグラフィー
移動相:A(H2O中の0.1%ギ酸)及びB(アセトニトリル中の0.1%ギ酸)。
勾配:1.8分でB 5%→95%。
カラム:AcquityBEH C18カラム(1.7um、2.1×50mm)。
7日間及び14日間25℃で保存
7日間及び14日間40℃/75%RH(開放)で保存
7日間及び14日間60℃で保存
それらの条件下で、有意な崩壊は、それらの条件下で観察されるものはなく、14日間40℃/75%RH(開放)で保存した試料のXRPD及びTGA−DSC分析は、結晶性に変化を示さなかった。
Ti>/=Tzの濃度について、[(Ti−Tz)/(C−Tz)]×100
Ti<Tzの濃度について、[(Ti−Tz)/Tz]×100。
*時間ゼロ(Tz)、対照成長(C)、及び化合物の存在下での試験成長(Ti)
成長阻害率/生存率を、化合物濃度に対してプロットし、Emaxを決定した。
Panc 05.04細胞:膵臓がん細胞、突然変異体SF3B1細胞株(SF3B1におけるQ699H及びK700E突然変異)
WiDr細胞:結腸がん細胞(野生型SF3B1)
WiDr−R細胞:結腸がん細胞(E7107に耐性である化学的に誘発されているSF3B1突然変異体(R1074H突然変異))
Claims (7)
- (2S,3S,6S,7R,10R,E)−7,10−ジヒドロキシ−3,7−ジメチル−12−オキソ−2−((R,2E,4E)−6−(ピリジン−2−イル)へプタ−2,4−ジエン−2−イル)オキサシクロドデカ−4−エン−6−イル4−メチルピペラジン−1−カルボキシレート(「化合物1」)の結晶形1を調製するための方法であって、
(a)化合物1と第1の溶媒とを混ぜ合わせて混合物を得ること、
(b)前記混合物を加熱すること、
(c)前記混合物にN−ヘプタンを添加すること、
(d)前記混合物を冷却すること、及び
(e)化合物1の結晶形1を単離すること、
を含み、
前記第1の溶媒は、酢酸エチル及びメチルtert−ブチルエーテルから選択され、
化合物1の結晶形1は、5.9±0.2、7.7±0.2、12.8±0.2、15.3±0.2、18.2±0.2、19.3±0.2、21.2±0.2、23.6±0.2及び25.8±0.2°2θにあるピークから選択された少なくとも5つのピークを有するXRPDディフラクトグラムを有する、方法。 - (2S,3S,6S,7R,10R,E)−7,10−ジヒドロキシ−3,7−ジメチル−12−オキソ−2−((R,2E,4E)−6−(ピリジン−2−イル)へプタ−2,4−ジエン−2−イル)オキサシクロドデカ−4−エン−6−イル4−メチルピペラジン−1−カルボキシレート(「化合物1」)の結晶形1を調製するための方法であって、
(a)化合物1とメチルtert−ブチルエーテルとを混ぜ合わせて第1の混合物を得ること、
(b)前記第1の混合物からメチルtert−ブチルエーテルを除去して化合物1を単離すること、
(c)化合物1と第1の溶媒とを混ぜ合わせて第2の混合物を得ること、
(d)前記第2の混合物を加熱すること、
(e)前記第2の混合物にN−ヘプタンを添加すること、
(f)前記第2の混合物を冷却すること、及び
(g)化合物1の結晶形1を単離すること、
を含み、
前記第1の溶媒は、酢酸エチル及びメチルtert−ブチルエーテルから選択され、
化合物1の結晶形1は、5.9±0.2、7.7±0.2、12.8±0.2、15.3±0.2、18.2±0.2、19.3±0.2、21.2±0.2、23.6±0.2及び25.8±0.2°2θにあるピークから選択された少なくとも5つのピークを有するXRPDディフラクトグラムを有する、方法。 - 前記第1の溶媒が、酢酸エチルである、請求項1又は2に記載の方法。
- 前記第1の溶媒が、メチルtert−ブチルエーテルである、請求項1又は2に記載の方法。
- 前記混合物又は第2の混合物が、50〜53℃又は65℃に加熱される、請求項1〜4のいずれか一項に記載の方法。
- (2S,3S,6S,7R,10R,E)−7,10−ジヒドロキシ−3,7−ジメチル−12−オキソ−2−((R,2E,4E)−6−(ピリジン−2−イル)へプタ−2,4−ジエン−2−イル)オキサシクロドデカ−4−エン−6−イル4−メチルピペラジン−1−カルボキシレート(「化合物1」)の結晶形1を調製するための方法であって、
(a)化合物1と少なくとも1つの第1の溶媒とを混ぜ合わせて混合物を得ること、
(b)前記混合物を加熱すること、及び
(c)前記少なくとも1つの第1の溶媒を蒸発させること、
を含み、
前記少なくとも1つの第1の溶媒が、トルエン、アセトン、酢酸エチル及びメチルtert−ブチルエーテル/ジクロロメタンの9:1(v/v)混合物から選択され、
化合物1の結晶形1は、5.9±0.2、7.7±0.2、12.8±0.2、15.3±0.2、18.2±0.2、19.3±0.2、21.2±0.2、23.6±0.2及び25.8±0.2°2θにあるピークから選択された少なくとも5つのピークを有するXRPDディフラクトグラムを有する、方法。 - 前記少なくとも1つの第1の溶媒が、メチルtert−ブチルエーテル/ジクロロメタンの9:1(v/v)混合物である、請求項6に記載の方法。
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