JP5666651B2 - 糖尿病の治療用sglt2阻害剤としてのアミノ酸を有する(1s)−1,5−アンヒドロ−1−c−(3−((フェニル)メチル)フェニル)−d−グルシトール誘導体の結晶性溶媒和物および複合体 - Google Patents
糖尿病の治療用sglt2阻害剤としてのアミノ酸を有する(1s)−1,5−アンヒドロ−1−c−(3−((フェニル)メチル)フェニル)−d−グルシトール誘導体の結晶性溶媒和物および複合体 Download PDFInfo
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- 230000000407 monoamine reuptake Effects 0.000 description 1
- 229940126403 monoamine reuptake inhibitor Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- WGESLFUSXZBFQF-UHFFFAOYSA-N n-methyl-n-prop-2-enylprop-2-en-1-amine Chemical class C=CCN(C)CC=C WGESLFUSXZBFQF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 1
- 108060005714 orexin Proteins 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229950008492 pentopril Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 210000002824 peroxisome Anatomy 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920000371 poly(diallyldimethylammonium chloride) polymer Polymers 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000030558 renal glucose absorption Effects 0.000 description 1
- 208000007278 renal glycosuria Diseases 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- IMNTVVOUWFPRSB-JWQCQUIFSA-N sch-48461 Chemical compound C1=CC(OC)=CC=C1[C@H]1N(C=2C=CC(OC)=CC=2)C(=O)[C@@H]1CCCC1=CC=CC=C1 IMNTVVOUWFPRSB-JWQCQUIFSA-N 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 1
- 229960002578 sitaxentan Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 description 1
- 229950004704 tesaglitazar Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000004457 water analysis Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
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Description
式I:
化合物Iの結晶構造、例えば
SC−3型である(S)−プロピレングリコール((S)−PG)構造Ia:
SB−2型であるエチレングリコール構造Ie:
以下:
3型であるL−プロリンを有する1:2結晶性複合体構造Ih:
2型であるL−フェニルアラニンを有する1:1結晶性複合体構造Ik:
本明細書で定義される、化合物I、化合物Ia、化合物Ib、化合物Ih、化合物Ii、化合物Ijおよび化合物Ik、および化合物IIの結晶構造を用いた糖尿病および関連疾患の治療方法に関する。
構造:
このような結晶構造の製造方法、およびこのような結晶構造を用いた結晶性化合物Ia (S)−PGの製造方法もまた提供される。
構造:
ジメタノール溶媒和物Igの製造方法、およびIgを用いた結晶性化合物Ia (S)−PGの製造方法もまた提供される。
適宜、冷却して、(S)−プロピレングリコール結晶SC−3型(Ia)の種晶を上記溶液に加え、エチレングリコール二水和物SB−1型(Id)の結晶を回収する段階を含むことを特徴とする方法が提供される。
好ましくは加熱することで化合物Iをエチレングリコール水溶液に溶解し;
適宜、冷却して、モノEtOH二水和物結晶SA−1型(Ic)の種晶を上記溶液に加え;および
エチレングリコール二水和物SB−2型(Ie)の結晶を回収する段階を含むことを特徴とする方法が提供される。
R1、R2およびR2aは独立して、水素、OH、OR5、アルキル、−OCHF2、−OCF3、−SR5aまたはハロゲンであり;
R3およびR4は独立して、水素、OH、OR5b、アルキル、アルケニル、アルキニル、シクロアルキル、CF3、−OCHF2、−OCF3、ハロゲン、−CONR6R6a、−CO2R5c、−CO2H、−COR6b、−CH(OH)R6c、−CH(OR5d)R6d、−CN、−NHCOR5e、−NHSO2R5f、−NHSO2アリール、−SR5g、−SOR5h、−SO2R5i、−SO2アリール、またはN、O、S、SO、および/またはSO2である1もしくは4個のヘテロ原子を環内に含んでいてもよい5、6もしくは7員ヘテロ環であるか、またはR3およびR4は、それらに結合する炭素と共に、N、O、S、SO、および/またはSO2である1〜4個のヘテロ原子を環内に含んでいてもよい閉環型(annelated)5、6もしくは7員炭素環もしくはヘテロ環を形成し;
R5、R5a、R5b、R5c、R5d、R5e、R5f、R5g、R5hおよびR5iは独立して、アルキルであり;並びに
R6、R6a、R6b、R6cおよびR5dは独立して、水素、アルキル、アリール、アルキルアリールまたはシクロアルキルであるか、あるいはR6およびR6aは、それらに結合する窒素と共に、N、O、S、SO、および/またはSO2である1〜4個のヘテロ原子を環内に含んでいてもよい閉環型5、6もしくは7員ヘテロ環を形成する]
の化合物の結晶構造に関する。
R1、R2およびR2aは独立して、水素、OH、OR5、アルキル、−OCHF2、−OCF3、−SR5aまたはハロゲンであり;
R3およびR4は独立して、水素、OH、OR5b、アルキル、アルケニル、アルキニル、シクロアルキル、CF3、−OCHF2、−OCF3、ハロゲン、−CONR6R6a、−CO2R5c、−CO2H、−COR6b、−CH(OH)R6c、−CH(OR5d)R6d、−CN、−NHCOR5e、−NHSO2R5f、−NHSO2アリール、−SR5g、−SOR5h、−SO2R5i、−SO2アリール、またはN、O、S、SO、および/またはSO2である1〜4個のヘテロ原子を環内に含んでいてもよい5、6もしくは7員ヘテロ環であるか、またはR3およびR4は、それらに結合する炭素と共に、N、O、S、SO、および/またはSO2である1〜4個のヘテロ原子を環内に含んでいてもよい閉環型5、6もしくは7員炭素環もしくはヘテロ環を形成し;
R5、R5a、R5b、R5c、R5d、R5e、R5f、R5g、R5hおよびR5iは独立して、アルキルであり;並びに
R6、R6a、R6b、R6cおよびR5dは独立して、水素、アルキル、アリール、アルキルアリールまたはシクロアルキルであるか、あるいはR6およびR6aは、それらに結合する窒素と共に、N、O、S、SO、および/またはSO2である1〜4個のヘテロ原子を環内に含んでいてもよい閉環型5、6もしくは7員ヘテロ環を形成する]
の化合物の結晶構造に関する。
の化合物C(例えば、ここで、R3またはR4はアルケニルまたはアルキニルであり、それはすべて、2003年12月23日に出願された米国特許出願第10/745,075号、実施例17〜20に記載された方法を用いて製造されうる)を用意し、
化合物Cを、不活性雰囲気下および高温で、アルコール溶媒(例えばメタノール)、および塩基水溶液(例えば水酸化ナトリウム)、および水(必要であれば)で処理して、構造:
本発明は、新規物質として、化合物Iの結晶構造の少なくとも一部を提供する。
本発明の結晶構造は様々な方法によって製造されうるが、それには、例えば、適当な溶媒からの結晶化または再結晶化、昇華、融解からの成長、固体以外から固体への状態変換、超臨界流体からの結晶化、および噴射スプレーが含まれる。溶媒混合物からの結晶構造の結晶化または再結晶化のための技術には、例えば、溶媒の蒸発、溶媒混合物の温度の低下、分子および/または塩の過飽和溶媒混合物への種晶の付加、溶媒混合物の凍結乾燥、および溶媒混合物への貧溶媒(counter solvents)の付加が含まれる。ハイスループット結晶化技術は、多形を含む結晶構造の製造に用いられうる。
反応式II
反応式III
反応式IV
(1)化合物Eをリチウム化(Lithiation)してリチウム化中間体Gを生成する工程、および
(2)リチウム化中間体Gを化合物Dとカップリングさせる工程
が含まれる。
反応式IVA
反応式V
反応式VI
反応式VIII
結晶構造の製造
実施例1
(S)−プロピレングリコール((S)−PG)構造−SC−3型−式Iaの製造
1HPLC:カラム:YMC ODS−A(C−18) S3,4.6×50mm。溶媒A:0.2% H3PO4水溶液。溶媒B:90%CH3CN/10%H2O 最初の%B=0、最後の%B=100 グラジエント時間 8分;保持時間 3分。積分(Integration)停止時間 11.0分。流速2.5ml/分。UV波長220nm。
2相分離の前にNaOHを用いて中和を行い、生成物の混入を防いだ。中和せずに製造した(S)−PG構造は、わずかに塩基性であった[水中で超音波処理した懸濁液のpH 8.3(〜20mg/ml)]。
3HPLC法:移動相A:0.05% TFAのH2O溶液。移動相B:0.05% TFAのCAN溶液。カラム:YMC Hydrosphere 4.6×150(3μ)。グラジエント:45分かけて30〜90%B、5分保持;30%Bに戻し、10分間 再平衡化。波長:220nm。注入容積:10μl。温度:周囲
(S)−プロピレングリコール((S)−PG)構造−SC−3型−式Ia
化合物A(20g)を、周囲の温度および圧力で反応器に入れた。メタノール(30mL)およびNaOH(3N、49.75mL)を反応器に加え、反応混合物を80℃または還流するまで加熱し、反応の完了<0.5APのために約2〜3時間保持した。バッチを20℃に冷却し、濃HClまたは1N 酢酸(〜1mL/gmの投入が必要)を用いてpH6.0〜7.5に中和した。
生成物を反応混合物から酢酸イソプロピル(100mL)中に抽出し、水相を分離し、伝導度<10mS(〜4mL/gmを投入)まで有機層を水で洗浄した。水相を分離した。
(S)−(+)−1,2 プロパンジオール(2.8g、1.05当量)を反応混合物に加えた。バッチに化合物Iの種晶(0.1g)を加えた。シクロヘキサン(160mL)を加え、バッチを室温〜5℃に冷却した。単離の少なくとも1時間前に、バッチを室温〜5℃で攪拌した。
それぞれの単離したケーキを、容量で50/50の酢酸イソプロピル/シクロヘキサン混合物で洗浄した。ケーキを真空オーブン中、十分な減圧下、30℃で乾燥した。(KF=3.6%〜4.1%の場合、ケーキは乾燥している)。
収率=84%(但し、補正されていない)
典型的な純度=99.81AP
典型的なPG含量=15.1〜15.8%(GCによる)
(R)−プロピレングリコール構造−Ibの製造
モノEtOH二水和物(エタノールまたはEtOH構造)−SA−1型−式Icの製造
エチレングリコール構造 SB−1およびSB−2型(それぞれ式IdおよびIe)の製造
1H NMR (400 MHz, DMSO) δ 1.29 (t, 3H, J = 6.98 Hz, -CH3) 3.15 (m, 4H,), 3.33 (bs, 6H, -CH2), 3.42 (m, 3H), 3.6 (bdd, J = 11.4 Hz, 1H), 3.9 (bm, 5H, H-1, -2CH2), 4.43 (t, 1H, J = 7.4 Hz, OH), 4.86 (d, 1H, J = 2.4, OH), 4.95 (q, 1H, -OH), 6.82 (d, 2H, J = 11.47 Hz, Ar-H), 7.8 (d, 2H, J = 11.4 Hz, Ar-H), 7.22 (dd, 1H, J = 2.5 Hz, J = 11.4 Hz, Ar-H), 7.35 (t, 2H, J= 10.96, Ar-H; 13C NMR (400 MHz, DMSO) δ 12.49, 59.16, 60.61, 60.69, 68.10, 72.51, 76.11, 78.51, 79.02, 112.09, 125.16, 126.47, 127.38, 128.61, 129.02, 129.73, 135.62, 137.48, 154.70.
(S)−PG溶媒和物SC−3型Iaの製造
結晶性MeOH溶媒和物Igの製造
種晶を用いた、精製されていない化合物Bの80/20 メタノール/トルエン溶液からの結晶性ジMeOH溶媒和物Igの製造
化合物B(6g、HPLC AP 約80%)を80/20 メタノール/トルエン(15mL)に溶解した。
種晶を用いた、精製されていない化合物Bのメタノール/トルエン/ヘプタン溶液からの結晶性ジMeOH溶媒和物Igの製造
化合物B(2.5g、91.5%)を、磁気攪拌子を有するシンチレーションバイアルに加えた。
種晶を用いた、化合物Bのトルエン/酢酸エチル溶液からの結晶性1,4−ブチンジオール溶媒和物Ifの製造
1,4−ブチンジオール溶媒和物を、酢酸アルキル(例えば酢酸エチル、酢酸プロピルもしくは酢酸ブチル)、アルコール(例えばイソプロパノール、ブタノール)または水中でも結晶化してもよい。酢酸アルキル中で結晶化する場合、トルエンおよびヘプタンは貧溶媒として作用する。
化合物Bの酢酸ブチル/ヘプタン溶液からの結晶性1,4−ブチンジオール溶媒和物Ifの製造
化合物B(0.5g、91重量%)を、60℃で酢酸ブチル(3.5mL)+ヘプタン(3.5mL)に溶解した。2−ブチン−1,4−ジオール(1.5当量)を加え、混合物を室温に冷却した。生じたスラリーを12時間攪拌し、濾過し、1:1 酢酸ブチル:ヘプタン(1mL)で洗浄し、50℃で減圧乾燥して、1,4−ブチンジオール溶媒和物Ifの結晶を得た。効力=85.1%。収率=90%。
L−プロリンを有する1:2結晶性複合体−構造Ih,3型の製造
L−プロリンを有する1:1結晶性複合体−構造Ii,6型の製造
L−プロリン化合物I半水和物−構造Ijの結晶性H.5−2型の製造
L−フェニルアラニンを有する1:1結晶性複合体−構造Ik,2型の製造
E/THF/トルエン(2.74ml/分)およびQ(すなわち、n−BuLiのヘキサン溶液、0.41ml/分)の2つのフィード(feed)を、ジャケット付きスタティックミキサー5(−30℃)を通して混合した。
(a)カップリング反応の開始する前、および
(b)反応混合物をMSA−MeOH反応器内に集めた後
に、サンプルを取った。
リチウム化のストリームと混合する前に、D/トルエンの供給(2.96ml/分)を熱交換器で予冷した。
カップリング反応のストリーム24を、MSAおよびメタノールまたはHCl/MeOHを含む500mL反応器25に、<−10℃で攪拌しながら供給した。
2−ブチン−1,4−ジオール(J)のトルエン/EtOAc溶液を用いてBを結晶化して、Ifの結晶を得た。
下記およびここで特許請求された結晶構造と同等の結晶構造は、試験条件、純度、装置および当業者に知られている他の共通の変数(variable)に依存して、妥当な範囲内の誤差で、同一ではないが、類似の分析特性を示しうる。
粉末X線回折パターンが、用いられる測定条件に依存する測定誤差とともに得られうることは、当業者に認識されている。特に、粉末X線回折パターンにおける強度が、用いられる測定条件に依存して変動しうることは、一般に知られている。相対的な強度もまた、実験条件に依存して変化しうることがさらに理解されるべきであり、したがって、強度の正確な順番は考慮されるべきではない。また、通常の粉末X線回折パターンについての回折角の測定誤差は、典型的には約5%またはそれ以下であり、このような測定誤差の程度は、前述の回折角に付属するものとして考慮されるべきである。その結果、本発明の結晶構造は、本明細書で開示される添付図面に図示される粉末X線回折パターンと完全に同一なX線回折パターンを提供する結晶構造に限らないことは理解されるべきである。添付図面に開示されるものと実質的に同一な粉末X線回折パターンを提供するいずれの結晶構造も、本発明の範囲内に入る。粉末X線回折パターンの実質的同一性を確かめる能力は、当業者の範囲内にある。
約200mgをフィリップス粉末X線回折(PXRD)サンプルホルダーの中に詰めた。サンプルをフィリップスMPDユニット(45KV、40mA、Cu Kα1)に移した。データを室温で2〜32の2θの範囲で収集した(連続走査モード、走査速度0.03度/秒、オートダイバージェンス(auto divergence)および散乱防止スリット(anti scatter slit)、受光スリット(receiving slit):0.2mm、サンプルスピナー(sample spinner):ON)。
表1
選択されたPXRDピーク(2θ±0.2°)
(S)−PG(Ia)、(R)−PG(Ib)、1,4−ブチンジオール溶媒和物Ifおよびジメタノール溶媒和物Igの構造を、固体NMR法で評価した。
(S)−プロピレングリコール溶媒和物IaについてのプロトンNMRピーク位置
1H NMR (400 MHz, d6-DMSO) δ 1.00 (d, 3H, J = 6.25 Hz, PG-CH3), 1.29 (t, 3H, J = 6.98 Hz, -CH2CH3), 3.0-3.30 (m, 4H, H2, H3, H4, H-5), 3.43 (m, 1H, H-6a), 3.53 (m, 1H), 3.69 (bdd, H, J = 4.4 Hz, H-6b), 3.9-4.1 (m, 5H, H-1, -CH2, -CH2), 4.38 (d, 1H, J = 4.5 Hz, OH), 4.44 (dt, 2H, J = 2.2 Hz, J = 5.7 Hz), 4.82 (d, 1H, J = 5.7 Hz, -OH), 4.94 and 4.95 (2d, 2H, 2-OH), 6.82 (d, 2H, J = 8.6 Hz, Ar-H), 7.09 (d, 2H, J = 8.6 Hz, Ar-H), 7.22 (dd, 1H, J = 1.97 Hz, 8.25 Hz, Ar-H), 7.31 (bd, 1H, 1.9 Hz, Ar-H), 7.36 (d, 1H, J = 8.2 Hz, Ar-H).
表2
TMS(テトラメチルシラン)に対するSSNMRピーク位置/δ(ppm)
1,4−ブチンジオール溶媒和物IfについてのプロトンNMRピーク位置
1H NMR (400 MHz, CDCl3) δ 1.33 (t, 3H, J = 7.1 Hz, -CH3), 2.90 (s, 2H, -CH2), 3.39 (s, 9H, -OCH3), 3.4-3.65 (m, 3H), 3.81 (bm, 2H), 3.91 (q, 2H, J =7.1 Hz, -CH2), 3.97 (m, 1H), 6.73 (d, 1H, J=8.6 Hz, Ar-H), 7.02 (d, 2H, J = 8.4 Hz, Ar-H), 7.25 (s, 2H, Ar-H), 7.34 (s, 1H, Ar-H); 13 C (CDCl3) δ 14,78, 38.43, 49.14, 50.57, 61.84, 63.34, 69.98, 72.53, 74.63, 100.95, 114.36, (2), 126.64, 129.19, 129.59, 129.71, 131.38, 134.30, 136.61, 138.50, 157.27. 融点103.08℃.
ジメタノール溶媒和物IgについてのプロトンNMRピーク位置
1H NMR (400 MHz, DMSO-D6) δ 1.26 (t, 3H, J = 7.1 Hz, -CH3), 2.38-2.54 (m, 1H), 2.5 (s, 2H, -CH2), 3.2 (m, 1H), 3.35 (m, 3H, -OCH3), 3.16-3.39 (m, 1H, H-6), 3.41-3.42 (m, 1H, H-6), 3.9 (q, 2H, J=7.2 Hz, CH2), 4.05 (d, 4H, -CH2), 4.52 (t, 1H), 4.75 (m, 2H), 4.95 (d, 2H), 5.23 (t, 2H), 6.82 (d, 2H, J =8.6 Hz, Ar-H), 7.07 (d, 2H, J = 8.6 Hz, Ar-H) 7.4 (s, 2H, Ar-H), 7.50 (s, 1H, Ar-H); 13 C (CDCl3) δ 14.69, 48.28, 49.02, 60.81, 62.84, 70.05, 74.02, 76.81, 83.97, 100.64, 114.23, 127.40, 128.2, 129.44, 131.2, 131.4, 132.45, 137.38, 138.57, 156.84. C26H33ClO9について計算された元素分析: 計算値 C 59.48, H6.34, Cl 6.75; 実測値 C 59.35, H5.97, Cl 6.19.
熱重量分析(TGA)実験を、ティー・エイ・インスツルメント(登録商標)モデルQ500において行った。サンプル(約10〜30mg)を、あらかじめ風袋を量った白金皿に置いた。サンプルの重量を正確に測定し、装置によって1000分の1ミリグラムまで記録した。窒素ガスを用いて100mL/分で炉(furnace)をパージした。10℃/分の加熱速度で、室温と300℃の間でデータを収集した。
(S)−PG Ia、(R)−PG Ib、1,4−ブチンジオール溶媒和物If、ジメタノール溶媒和物Ig、1:2 L−プロリンIh、1:1 L−プロリンIiおよび1:1 L−プロリン半水和物Ij構造の固体の熱挙動を、示差走査熱量測定(DSC)によって調査した。(S)−PG Iaおよび(R)−PG Ib構造についてのDSC曲線を、それぞれ図7および8に示す。1,4−ブチンジオール溶媒和物Ifおよびジメタノール溶媒和物Ig構造についてのDSC曲線を、それぞれ図11および12に示す。1:2 L−プロリン複合体Ih、1:1 L−プロリン複合体Iiおよび1:1 L−プロリン半水和物Ij構造についてのDSC曲線を、それぞれ図19、20および21に示す。
(S)−PG Ia構造について、並びに1,4−ブチンジオール溶媒和物If、ジメタノール溶媒和物Ig、1:2 L−プロリンIh、1:1 L−プロリンIiおよび1:1 L−プロリン半水和物Ij構造についての単結晶が得られ、X線回折によって調査した。
表3
(S)−PG(Ia)についての単位格子データ
Z’=非対称単位(asymmetric unit)あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(residual index)(I>2σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表5
エタノールSA−1(Ic)についての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>3σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表6
T=−50℃でのSA−1型についての部分原子座標(fractional atomic coordinate)
表7
EG−SB−1(Id)についての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>3σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表9
EG−SB−2(Ie)についての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>3σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表11
1,4−ブチンジオール溶媒和物Ifについての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>2σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表12
T=25℃での1,4−ブチンジオール溶媒和物Ifについての部分原子座標の表
*結晶構造中の2−ブチン−1,4−ジオール溶媒のディスオーダー(disorder)のため、原子占有因子(Atomic occupancy factor)は0.5である。
表13
ジメタノール溶媒和物Igについての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>2σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表14
T=−50℃でのジメタノール溶媒和物Igについての部分原子座標の表
*結晶構造中のメタノール溶媒のディスオーダーのため、原子占有因子は0.5である
表15
1:2 L−プロリン複合体(Ih)についての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>3σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表16
1:1 L−プロリン複合体(Ii)についての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>3σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表17
L−プロリンを有する化合物I複合体半水和物H.5−2型についての単位格子データ
Z’=非対称単位あたりの薬物分子の数
Vm=V(単位格子)/(格子あたりのZ薬物分子)
R=残差因子(I>2σ(I))
Dcalc=計算された結晶の密度
SG=空間群
表18
T=−40℃でのL−プロリンを有する化合物Ij 1:1複合体半水和物H.5−2型についての部分原子座標の表
A.有用性
本発明の化合物は、哺乳類の腸および腎臓に見られるナトリウム依存性グルコース輸送体の阻害剤として活性を有する。好ましくは、本発明の化合物は腎臓のSGLT2活性の選択的阻害剤であり、それゆえ、SGLT2活性に関連する疾患または障害の治療に用いられうる。
本発明は、単独または医薬担体もしくは希釈剤と併用して、式Iの化合物、例えば(S)−PG(SC−3型、Ia)、(R)−PG(SD−3型、Ib)、SA−1(Ic)、SB−1(Id)、SB−2(Ie)、1:2 L−プロリン複合体3型(Ih)、1:1 L−プロリン複合体6型(Ii)、1:1 L−プロリン半水和物複合体H.5−2型(Ij)、および1:1.3 L−フェニルアラニン複合体2型(Ik)の治療上の有効量を活性成分として含む医薬組成物をその範囲内に含む。適宜、本発明の化合物は、個々の治療剤として利用されるか、または一つ以上の他の治療剤と併用して利用されうる。
Claims (12)
- 室温で、3.9±0.1、8.0±0.1、8.7±0.1、15.3±0.1、15.6±0.1、17.2±0.1、19.2±0.1、19.9±0.1および20.3±0.1からなる群から選択される2θ値(CuKα λ=1.5418Å)を含む粉末X線回折パターンの特徴を有する、請求項1の結晶。
- 零点でのTMSに対して400MHz分光計で決定される、15.8、17.6、39.0、60.9、63.2、67.4、69.7、77.3、79.2、79.8、113.3、123.6、129.0、130.4、132.0、135.6、139.2および157.9ppmでピーク位置を有する固体13C NMRスペクトルを有する請求項1または2の結晶。
- 純粋な形態である、請求項1〜5のいずれかの結晶。
- 請求項1〜6のいずれかの結晶の有効量および医薬的に許容される担体もしくは希釈剤を含む医薬組成物。
- 請求項1〜6のいずれかの結晶を含む、哺乳類における、糖尿病、インスリン耐性、高血糖、高インスリン血症、脂肪酸もしくはグリセロールの血中濃度の上昇、高脂血症、脂質代謝異常、肥満症、高トリグリセリド血症、または糖尿病合併症の治療剤。
- 該還元剤がトリエチルシランであり、該活性化基がBF3OEt2またはBF3・2CH3OOHである、請求項10の方法。
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JP2016172758A (ja) * | 2006-06-28 | 2016-09-29 | アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag | 糖尿病の治療用sglt2阻害剤としてのアミノ酸を有する(1s)−1,5−アンヒドロ−1−c−(3−((フェニル)メチル)フェニル)−d−グルシトール誘導体の結晶性溶媒和物および複合体 |
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