JP2021535103A - グリコシダーゼ阻害剤として有用なピペラジン誘導体のコハク酸付加塩及びフマル酸付加塩 - Google Patents
グリコシダーゼ阻害剤として有用なピペラジン誘導体のコハク酸付加塩及びフマル酸付加塩 Download PDFInfo
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
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Abstract
Description
のピペラジン誘導体は、医薬成分として有用であり、グリコシダーゼ阻害剤として高い活性を示す。類似した化合物は、例えば、PCT/EP2015/069598に開示されている。
Yは、H又はCH3を表し;
Tは、N又はCHを表し;
Xは、以下のスルホキシイミン基のうちの1つを表し:
S(O)(NR3’)CH3、S(O)(NR3’)CH2CH3、S(O)(NR3’)CH2CH2OH、S(O)(NR3’)CH2CH2OCH3、NS(O)(R3’)CH3、NS(O)(R3’)CH2CH3、NS(O)(R3’)CH2CH2OH、又は、NS(O)(R3’)CH2CH2OCH3;
そして、
R3’は、Hを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基(ここで、1〜3のCH2基は、SO2、CO、Oから選択される基で置き換えられることができ、そしてここで、1〜5個の水素原子は、F、Cl、Br又はIで置き換えられることができる)を表す〕
の化合物との酸付加塩、並びに、その立体異性体、固体形態(例えば、溶媒和物及び多形形態)に関する。
の化合物の酸付加塩及びその固体形態(例えば、溶媒和物及び多形形態)に関する。
の化合物の酸付加塩及びその固体形態(例えば、溶媒和物及び多形形態)に関する。
の群から選択される〕の化合物の酸付加塩に関する。
(a) 式(I)の化合物及びコハク酸又はフマル酸を、適切な溶媒又は溶媒混合物に懸濁又は溶解させ;
(b) 工程(a)で得られた混合物を、約30℃〜選択された溶媒の沸点付近の温度、好ましくは、約50℃〜約100℃の温度、最も好ましくは、約60℃、約70℃又は約80℃に加熱し、そして、その混合物を室温まで冷却させ;
(c) 場合により、工程(b)を数回繰り返し;
(d) このようにして得られた固体を分離し、乾燥させる。
本発明の酸付加塩の好ましい形態は、薬物として使用するのに十分な特性を示す。特に、そのような好ましい化合物は、高い固体状態安定性、肝臓ミクロソームの存在下での高い安定性、高い酸化安定性及び適切な浸透性を示す。さらに好ましい本発明の化合物は、強力な生物学的活性、例えば、脳抽出物で測定される総タンパク質のO−GlcNAc化レベルによって、薬物としての適合性を示す。そのようなパラメータを測定するための関連する試験は、当業者には知られており、例えば、固体状態安定性(Waterman K.C.(2007) Pharm Res 24(4);780−790)、肝臓ミクロソーム存在下での安定性(Obach R.S.(1999) Drug Metab Dispos 27(11);1350−135)及び浸透性(例えば、Caco−2 permeability assay,Calcagno A.M.(2006) Mol Pharm 3(1);87−93)である。OGA阻害アッセイにおける高い効力及び上記特性のうちの1以上を示す本発明の化合物は、本明細書で挙げられた適応症に関する薬物として特に適している。
Ac(アセチル)、aq(水性)、h(時間)、g(グラム)、L(リットル)、mg(ミリグラム)、MHz(メガヘルツ)、μM(マイクロモル濃度)、min(分)、mm(ミリメートル)、mmol(ミリモル)、mM(ミリモル濃度)、m.p.(融点)、equiv(当量)、mL(ミリリットル)、μL(マイクロリットル)、ACN(アセトニトリル)、AcOH(酢酸)、BINAP(2,2’−ビス(ジスフェニルホスフィノ)−1,1’−ビナフタレン)、BOC(tert−ブトキシ−カルボニル)、CBZ(カルボベンゾキシ)、CDCl3(重クロロホルム)、CD3OD(重メタノール)、CH3CN(アセトニトリル)、c−hex(シクロヘキサン)、DCC(ジシクロヘキシルカルボジイミド)、DCM(ジクロロメタン)、dppf(1,1’−ビス(ジフェニルホスフィノ)フェロセン)、DIC(ジイソプロピルカルボジイミド)、DIEA(ジイソプロピルエチル−アミン)、DMF(ジメチルホルムアミド)、DMSO(ジメチルスルホキシド)、DMSO−d6(重ジメチルスルホキシド)、EDC(1−(3−ジメチル−アミノ−プロピル)−3−エチルカルボジイミド)、ESI(エレクトロスプレーイオン化)、EtOAc(酢酸エチル)、Et2O(ジエチルエーテル)、EtOH(エタノール)、FMOC(フルオレニルメチルオキシカルボニル)、HATU(ジメチルアミノ−([1,2,3]トリアゾロ[4,5−b]ピリジン−3−イルオキシ)−メチレン]−ジメチル−アンモニウムヘキサフルオロホスフェート)、HPLC(高性能液体クロマトグラフィー)、i−PrOH(2−プロパノール)、K2CO3(炭酸カリウム)、LC(液体クロマトグラフィー)、MD Autoprep(質量分離Autoprep)、MeOH(メタノール)、MgSO4(硫酸マグネシウム)、MS(質量分析)、MTBE(メチルtert−ブチルエーテル)、Mtr.(4−メトキシ−2,3,6−トリメチルベンゼンスルホニル)、MW(マイクロ波)、NBS(N−ブロモスクシンイミド)、NaHCO3(重炭酸ナトリウム)、NaBH4(水素化ホウ素ナトリウム)、NMM(N−メチルモルホリン)、NMR(核磁気共鳴)、POA(フェノキシアセテート)、Py(ピリジン)、PyBOP(登録商標)(ベンゾトリアゾール−1−イル−オキシ−トリス−ピロリジノ−ホスホニウムヘキサフルオロホスフェート)、RT(室温)、Rt(保持時間)、SFC(超臨界流体クロマトグラフィー)、SPE(固相抽出)、T3P(プロピルホスホン酸無水物)、TBAF(テトラ−n−ブチルアンモニウムフルオリド)、TBTU(2−(1−H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムテトラフルオロボレート)、TEA(トリエチルアミン)、TFA(トリフルオロ酢酸)、THF(テトラヒドロフラン)、TLC(薄層クロマトグラフィー)、UV(紫外線)。
化合物の調製
式(I)に従う化合物は、液相及び固相の両方の化学プロトコル又は混合液相及び固相プロトコルを用いて、容易に入手可能な出発物質から幾つかの合成アプローチによって調製することができる。合成経路の例は、実施例において以下に記載されている。報告されている全ての収率は、最適化されていない収率である。別途示されていない限り、ラセミ混合物として得られる式(I)及び関連する式の化合物は、分離して、エナンチオマー的に富化された混合物又は純粋なエナンチオマーを提供することができる。
機器名:Agilent Technologies 1290 infinity 11;
方法A:方法:A−H2O中0.1%TFA、B−ACN中0.1%TFA;流速:2.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm)、+veモード;
方法B:方法:A−H2O中10mM NH4HCO3、B−ACN;流速:1.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm)、+veモード;
方法C:方法:A−H2O中0.1%HCOOH、B−ACN;流速:1.5mL/分;カラム:ZORBAX Eclipse XDB−C18(50×4.6mm、3.5μm)、+veモード。
機器名:Agilent 1200 Series instruments;以下のように、UV検出による%を使用(maxplot);
方法A:方法:A−H2O中0.1%TFA、B−ACN中0.1%TFA;流速:2.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm);
方法B:方法:A−H2O中10mM NH4HCO3、B−ACN;流速:1.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm)。
機器名:Agilent 1260 infiinity II;
方法A:移動相:n−ヘキサン:EtOH(60:40)の中の0.1%DEA;流速:1.0mL/分;カラム:Chiralcell OD−H(250×4.6mm、5μm)。
機器名:THAR−SFC 80、及び、THAR−SFC 200(分析的)
CO2と共溶媒の間の比率は、60:40〜80:20の範囲である;
方法A:移動相:IPA中20mMアンモニア、流速:4mL/分;カラム:Chiralpak ADH(250×4.6mm、5μm);
方法B:移動相:メタノール20mMアンモニア、流速:10mL/分;カラム:YMC Cellulose C(250×4.6mm、5μm);
方法C:移動相:IPA中20mMアンモニア、流速:4mL/分;カラム:Lux A1(250×4.6mm、5μm);
方法D:移動相:MeOH中20mMアンモニア、流速:4mL/分;カラム:Chiralpak ADH(250×4.6mm、5μm);
方法E:移動相:IPA、流速:3mL/分;カラム:Lux A1(250×4.6mm、5μm)。
方法A:A−H2O中0.1%TFA、B−MeOH又はCAN;カラム:Sunfire C8(19×250mm、5μm)、又は、Sunfire C18(30×250mm、10μm);
方法B:A−H2O中10mM NH4HCO3、B−MeOH又はACN、カラム:Sunfire C8(19×250mm、5μm)、又は、Sunfire C18(30×250mm、10μm)。
機器名:THAR−SFC 80、THAR−SFC 200、及び、PIC SFC 10−150
CO2と共溶媒の間の比率は、60:40〜80:20の範囲である;
方法A:移動相:IPA中20mMアンモニア;流速:3mL/分;カラム:Chiralpak ADH(250×30mm、5μm);
方法B:移動相:メタノール中20mMアンモニア;流速:5mL/分;カラム:YMC Cellulose C(250×30mm、5μm);
方法C:移動相:IPA中20mMアンモニア;流速:5mL/分;カラム:Lux A1(250×30mm、5μm);
方法D:移動相:MeOH中20mMアンモニア;流速:4mL/分;カラム:Chiralpak ADH(250×30mm、5μm);
方法E:移動相:IPA、流速:100mL/分;カラム:Phenomenex Lux Amylose−1(250×30mm、5μm)。
機器名:Autopol VI(供給元:Rudolph Research Analytical, Hackettstown, NJ, USA)。
LCMS: (方法 A) 288.0 (M+H), Rt. 3.8 分, 71.1% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 2H), 2.98 (s, 3H). LCMS: (方法 A) 177.0 (M+H), Rt. 0.7 分, 99.9% (Max). HPLC: (方法 B) Rt. 2.04 分, 99.8% (Max). キラル SFC: (方法 E) Rt 2.1 分,100% (Max).
段階1で単離された最初に溶出した化合物(0.5g、2.8mmol)のDCM(5mL)中の攪拌溶液に、トリフルオロアセトアミド(0.64g、5.66mmol)、MgO(0.45g、11.3mmol)、Rh2(OAc)4(0.062g、0.14mmol)及びPhI(OAc)2(1.36g、4.20mmol)を添加し、反応混合物を室温で一晩撹拌した。反応が完了したことをTLCでモニターした。次いで、反応混合物をセライトを通して濾過し、DCMで洗浄した。有機層を減圧下で濃縮し、得られた粗物質をフラッシュクロマトグラフィー(Biotage Isolera、溶離液:石油エーテル中25−28%EtOAc)で精製して、中間体11が得られた。収率:86%(0.69g、白色の固体)。
1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 2H), 3.12-3.08 (m, 2H), 1.26-1.22 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 2H), 3.31 (q, J = 8.6 Hz, 2H), 1.11 (t, J = 8.6 Hz, 3H). LCMS: (方法 A) 191.2 (M+H), Rt. 1.3 分, 98.7% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 2H), 2.68 (t, J = 9.2 Hz, 2H), 1.81-1.54 (m, 2H), 1.14-0.90 (m, 3H). LCMS: (方法 A) 189 (M+H), Rt. 3.7 分, 94.5 (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 2H), 3.19-3.00 (m, 2H), 1.75-1.53 (m, 2H), 0.97 (t, J = 6.0 Hz, 3H).
1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 2H), 3.19-3.00 (m, 2H), 1.75-1.53 (m, 2H), 0.97 (t, J = 6.0 Hz, 3H).
1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 2.8 Hz, 1H), 7.79-7.76 (m, 1H), 7.46-7.44 (m, 1H), 2.54 (s, 3H). LCMS: (方法 A) 160.2 (M+H), Rt. 2.3 分, 95.4% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 3.2 Hz, 1H), 8.20-8.16 (m, 1H), 7.76 (s, 1H), 2.89 (s, 3H). LCMS: (方法 A) 176.2 (M+H), Rt. 1.4 分, 96.3% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.48-8.46 (m, 1H), 7.96-7.93 (m, 1H), 3.91 (s, 3H). LCMS: (方法 B) 190.9 (M−CF3CO), Rt. 2.6 分, 96.4% (Max).
1H NMR (400 MHz, DMSO-d6): δ 7.25-7.23 (m, 2H), 6.96-6.93 (m, 2H), 3.58-3.57 (m, 4H), 3.12-3.09 (m, 4H), 2.42 (s, 3H), 1.50 (s, 9H). LCMS: (方法 A) 309.2 (M+H), Rt. 4.3 分, 98.7% (Max).
1H NMR (400 MHz, DMSO-d6): δ 7.5 (m, 2H), 7.22-7.16 (m, 2H), 7.06-6.93 (m, 2H), 3.02-2.99 (m, 4H), 2.51-2.38 (m, 4H), 2.38 (s, 3H).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.65 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.50 (dd, J = 8.2, 1.2 Hz, 1H), 4.22 (s, 1H), 3.85-3.83 (m, 4H), 3.68 (d, J = 6.4 Hz, 1H), 3.06 (d, J = 0.8 Hz, 3H), 2.52-2.32 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 403.3 (M+H), Rt. 1.8 分, 97.5% (Max). HPLC: (方法 A) Rt. 1.9 分, 95.9% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.58 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.51-7.49 (m, 1H), 4.22 (s, 1H), 3.85-3.83 (m, 4H), 3.67 (d, J = 6.8 Hz, 1H), 3.12 (t, J = 7.6 Hz, 2H), 2.49-2.39 (m, 4H), 1.40 (d, J = 6.40 Hz, 3H), 1.07 (t, J = 7.20 Hz, 3H). LCMS: (方法 A) 417.3 (M+H), Rt. 2.2 分, 99.6% (Max). HPLC: (方法 A) Rt. 2.0 分, 97.1% (Max).
1H NMR (400 MHz, DMSO-d6) : δ 9.39 (s, 1H), 8.59 (s, 2H), 8.13 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.22 (s, 1H), 3.85-3.83 (m, 4H), 3.68 (d, J = 6.0 Hz, 1H), 3.17-3.08 (m, 2H), 2.53-2.44 (m, 4H), 1.57-1.51 (m, 2H), 1.41 (d, J = 6.40 Hz, 3H), 0.88 (t, J = 7.20 Hz, 3H). LCMS: (方法 A) 431.3 (M+H), Rt. 2.4 分, 97.2% (Max). HPLC: (方法 A) Rt. 2.2 分, 97.6% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.55 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.50 (dd, J = 8.2, 1.2 Hz, 1H), 3.86-3.70 (m, 4H), 3.69-3.65 (m, 1H), 3.10 (s, 3H), 2.56-2.51 (m, 2H), 2.50-2.32 (m, 5H), 1.41 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 416.8 (M+H), Rt. 1.94 分, 98.9% (Max). HPLC: (方法 A) Rt. 1.9 分, 99.7% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.85 (dd, J = 9.2, 2.4 Hz, 1H), 7.49 (dd, J = 6.8, 1.6 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 4.02 (s, 1H), 3.67-3.62 (m, 5H), 3.00 (s, 3H), 2.67-2.33 (m, 4H), 1.41 (d, J = 6.40 Hz, 3H). LCMS: (方法 A) 402.0 (M+H), Rt. 1.8 分, 97.7% (Max). HPLC: (方法 A) Rt. 1.8 分, 97.6% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.65 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.50 (dd, J = 8.2, 1.2 Hz, 1H), 3.85-3.83 (m, 4H), 3.68 (q, J = 6.4 Hz, 1H), 3.33-3.30 (m, 2H), 3.06 (s, 3H), 2.44-2.33 (m, 4H), 1.41 (d, J = 6.80 Hz, 3H) 1.08 (t, J = 6.4 Hz, 3H). LCMS: (方法 A) 431.3 (M+H), Rt. 2.1 分, 99.7% (Max). HPLC: (方法 A) Rt. 1.9 分, 95.9% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 2H), 8.12 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 4.11-4.10 (m, 4H), 3.85 (q, J = 6.8 Hz, 1H), 3.18-3.09 (m, 4H), 2.52-2.33 (m, 4H), 1.42 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 7.2 Hz, 6H). LCMS: (方法 A) 445.0 (M+H), Rt. 2.2 分, 96.5% (Max). HPLC: (方法 A) Rt. 2.3 分, 97.4% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.59 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.50 (dd, J = 8.4, 1.2 Hz, 1H), 3.85-3.82 (m, 4H), 3.68 (d, J = 6.4 Hz, 1H), 3.18 (s, 3H), 3.12 (s, 3H), 2.95-2.82 (m, 2H), 2.50-2.33 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 460.9 (M+H), Rt. 2.1 分, 99.1% (Max). HPLC: (方法 A) Rt. 2.1 分, 99.1% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.37 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 3.64-3.57 (m, 5H), 3.05 (s, 3H), 2.44-2.41 (m, 7H), 1.42 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 415.8 (M +H), Rt. 1.9 分, 97.5% (Max). HPLC: (方法 A) Rt. 2.1 分, 97.3% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.42 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 3.69-3.64 (m, 5H), 2.40-2.33 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 406.2 (M +H), Rt. 3.0 分, 99.9% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.03-8.01 (m, 3H), 7.51-7.49 (m, 1H), 3.64-3.59 (m, 4H), 3.37-3.36 (m, 1H), 3.18 (s, 6H), 2.42-2.34 (m, 4H), 1.42 (d, J = 8.0 Hz, 3H). LCMS: (方法 A) 417.0 (M+H), Rt. 2.1 分, 98.5% (Max). HPLC: (方法 A) Rt. 2.1 分, 98.8 (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 9.2 Hz, 2H), 3.68-3.66 (m, 1H), 3.34-3.30 (m, 4H), 2.37 (s, 3H), 2.68-2.34 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 369.9 (M +H), Rt. 2.3 分, 83.3% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 9.2 Hz, 2H), 3.68-3.66 (m, 1H), 3.34-3.30 (m, 4H), 2.65 (s, 3H), 2.68-2.34 (m, 4H), 1.42 (d, J = 6.80 Hz, 3H). LCMS: (方法 A) 386.5 (M +H), Rt. 1.7 分, 83.3% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 9.2 Hz, 2H), 3.89 (s, 1H), 3.68-3.66 (m, 1H), 3.34-3.30 (m, 4H), 2.97 (s, 3H), 2.68-2.34 (m, 4H), 1.42 (d, J = 6.80 Hz, 3H). LCMS: (方法 A) 401.0 (M +H), Rt. 1.9 分, 98.2% (Max). HPLC: (方法 A) Rt. 1.8 分, 96.9% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.65 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.51-7.49 (m, 1H), 4.24 (s, 1H), 3.86-3.83 (m, 4H), 3.69-3.67 (m, 1H), 3.07 (s, 3H), 2.54-2.39 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 402.8 (M+H), Rt. 1.8 分, 99.7% (Max). HPLC: (方法 A) Rt. 1.8 分, 99.8% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.65 (s, 2H), 8.13 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51-7.49 (m, 1H), 4.24 (s, 1H), 3.86-3.83 (m, 4H), 3.69-3.67 (m, 1H), 3.07 (s, 3H), 2.54-2.39 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 403.3 (M +H), Rt. 1.8 分, 99.6% (Max). HPLC: (方法 A) Rt. 1.8 分, 99.2% (Max). キラル SFC: (方法 B) Rt 9.3 分, 99.9% (Max). [α]25 D = -107.69, c 0.104 (MeOH).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (t, J = 2.0 Hz, 1H), 8.65 (t, J = 2.0 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.24 (s, 1H), 3.84-3.82 (m, 4H), 3.68 (d, J = 6.4 Hz, 1H), 3.07 (s, 3H), 2.51-2.34 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 403.3 (M+H), Rt. 1.8 分, 93.9% (Max). HPLC: (方法 A) Rt. 1.9 分, 94.5% (Max). キラル SFC: (方法 B) Rt 10.2 分, 98.8% (Max). [α]25 D = -18.64, c 0.103 (MeOH).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.55 (s, 2H), 8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 1.6, 8.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.71-3.66 (m, 1H), 3.11 (s, 3H), 2.56-2.42 (m, 7H), 1.41 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 417.0 (M+H), Rt. 1.9 分, 98.1% (Max). HPLC: (方法 A) Rt. 1.9 分, 98.5% (Max).
中間体6(0.47g、1.46mmol)のACN(2.0mL,)中の攪拌溶液に、TEA(0.88mL、5.8mmol)及び中間体12(464mg、1.6mmol)を添加し、反応混合物を室温で30分間撹拌した。反応が完了したことをTLCでモニターし、次いで、反応混合物を減圧下で濃縮した。得られた粗物質をフラッシュクロマトグラフィー(Biotage Isolera、石油エーテル中60−80%EtOAc)で精製して、標題化合物が得られた。収率:44%(320mg、白色の固体)。
1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.75 (s, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.89 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H), 3.70 (d, J = 6.8 Hz, 1H), 2.58-2.43 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 268.0 (M+H), Rt. 1.9 分, 92.8% (Max). HPLC: (方法 A) Rt. 3.8 分, 96.1% (Max).
段階1の生成物(310mg、0.62mmol)のMeOH(2mL)とDCM(1mL)中の攪拌溶液に、K2CO3(200mg、1.0mmol)を添加し、1時間撹拌した。反応が完了したことをTLCでモニターし、次いで、反応混合物を減圧下で濃縮した。得られた粗物質をフラッシュクロマトグラフィー(Biotage Isolera、勾配:DCM中3−4%メタノール)で精製して、標題化合物が得られた。収率:84%(210g、白色の固体)。
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.64 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.49 (dd, J = 8.2, 1.2 Hz, 1H), 4.23 (s, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.06 (s, 3H), 2.54-2.41 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 403.1 (M+H), Rt. 1.6 分, 99.9% (Max). HPLC: (方法 A) Rt. 1.9 分, 99.7% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.75 (s, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.89 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H), 3.70 (d, J = 6.8 Hz, 1H), 2.58-2.43 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 403.1.0 (M+H), Rt. 1.9 分, 92.8% (Max). HPLC: (方法 A) Rt. 3.8 分, 96.1% (Max).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.64 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.49 (dd, J = 8.2, 1.2 Hz, 1H), 4.23 (s, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.06 (s, 3H), 2.54-2.41 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 403.1 (M+H), Rt. 1.6 分, 99.9% (Max). HPLC: (方法 A) Rt. 1.9 分, 99.7% (Max).
1H NMR: (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.65 (s, 2H), 8.12 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.23 (s, 1H), 3.84 (d, J = 4.4 Hz, 4H), 3.67 (d, J = 6.4 Hz, 1H), 3.06 (s, 3H), 2.44-2.40 (m, 2H), 1.41 (d, J = 6.40 Hz, 3H). LCMS: (方法 A) 403.1 (M+H), Rt 1.6 分, 99.3% (Max). HPLC: (方法 A) Rt 1.8 分, 98.9% (Max). キラル SFC: (方法 B) Rt. 8.1 分, 100% (Max).
1H NMR: (400 MHz, DMSO-d6): δ 9.39 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 1.6 Hz, 2H), 8.13 (q, J = 1.6 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.25 (s, 1H), 3.85 (m, 4H), 3.69 (d, J = 6.8 Hz, 1H), 3.08 (s, 3H), 2.45-2.34 (m, 2H),1.42 (d, J = 6.40 Hz, 3H). LCMS: (方法 A) 403.1 (M+H), Rt 1.6 分, 99.7% (Max). HPLC: (方法 A), Rt 1.9 分, 99.5% (Max). キラル SFC: (方法 B) Rt. 9.33 分, 100% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.23 (s, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.63 (d, J = 6.8 Hz, 1H), 3.06 (s, 3H), 2.60 (s, 3H), 2.43-2.39 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 417.3 (M+H), Rt. 2.1 分, 97.3% (Max). HPLC: (方法 A) Rt. 2.2 分, 97.1% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 4.22 (s, 1H), 3.83 (t, J = 4.4 Hz, 4H), 3.65-3.60 (m, 1H), 3.17-3.08 (m, 2H), 2.78 (s, 3H), 2.52-2.32 (m, 4H), 1.38 (d, J = 6.4 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H). LCMS: (方法 A) 431.3 (M+H), Rt. 2.5 分, 98.2% (Max). HPLC: (方法 A) Rt. 2.2 分, 98.3% (Max).
1H NMR (400 MHz, DMSO-d6) : δ 8.59 (s, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.22 (s, 1H), 3.85-3.83 (m, 4H), 3.66-3.61 (m, 1H), 3.12-3.08 (m, 2H), 2.79 (s, 3H), 2.49-2.39 (m, 2H), 1.57-1.51 (m, 2H), 1.39 (d, J = 6.40 Hz, 3H), 0.88 (t, J = 7.20 Hz, 3H). LCMS: (方法 A) 445.2 (M+H), Rt. 2.2 分, 99.7% (Max). HPLC: (方法 A) Rt 2.4 分, 99.7% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.85-3.84 (m, 4H), 3.64-3.62 (m, 1H), 3.10 (s, 3H), 2.78 (s, 3H), 2.54-2.53 (m, 2H), 2.46 (s, 3H), 2.44-2.42 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 430.8 (M+H), Rt. 2.2 分, 98.7% (Max). HPLC: (方法 A) Rt. 2.1 分, 99.3% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.86-7.84 (m, 2H), 7.38 (dd, J = 8.0, 1.2 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 4.02 (s, 1H), 3.63-3.59 (m, 5H), 3.00 (s, 3H), 2.78 (s, 3H), 2.54-2.49 (m, 2H), 2.43-2.37 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 415.8 (M +H), Rt. 2.1 分, 99.0% (Max). HPLC: (方法 A) Rt. 2.1 分, 99.2% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.76-7.73 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 3.63-3.58 (m, 5H), 3.04 (s, 3H), 2.79 (s, 3H), 2.51-2.48 (m, 2H), 2.44 (s, 3H), 2.44-2.40 (m, 2H), 1.39 (d, J = 6.80 Hz, 3H). LCMS: (方法 A) 429.8 (M+H), Rt. 2.2 分, 96.2% (Max). HPLC: (方法 A) Rt. 2.1 分, 99.6% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.39 (dd, J = 8.2, 1.2 Hz, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.63 (d, J = 6.4 Hz, 1H), 3.10 (s, 3H), 2.84-2.73 (m, 5H), 2.55-2.39 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H), 1.03 (t, J = 7.20 Hz, 3H). LCMS: (方法 A) 445.0 (M+H), Rt. 2.3 分, 91.3% (Max). HPLC: (方法 A) Rt. 2.2 分, 92.0% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.39 (dd, J = 8.2, 1.2 Hz, 1H), 3.84 (t, J = 5.2 Hz, 4H), 3.63 (d, J = 6.8 Hz, 1H), 3.15-3.08 (m, 4H), 2.79 (s, 3H), 2.50-2.33 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 459.0 (M+H), Rt. 2.4 分, 99.3% (Max). HPLC: (方法 A) Rt. 2.5 分, 99.3% (Max).
段階1: 2−メチル−5−(1−(4−(4−(メチルチオ)フェニル)ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
1H NMR (400 MHz, DMSO-d6): δ 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 9.2 Hz, 2H), 3.68-3.66 (m, 1H), 3.34-3.30 (m, 4H), 2.96 (s, 3H ) 2.37 (s, 3H), 2.68-2.34 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 384.3 (M+H), Rt. 2.3 分, 83.3% (Max).
1H NMR (400 MHz, DMSO-d6): δ 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 9.2 Hz, 2H), 3.68-3.66 (m, 1H), 3.34-3.30 (m, 4H), 2.97 (s, 3H), 2.65 (s, 3H), 2.68-2.34 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 400.3 (M+H), Rt. 1.7 分, 83.3% (Max).
1H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.86 (s, 1H), 3.61 (d, J = 6.4 Hz, 1H), 3.34-3.28 (m, 4H), 2.97 (s, 3H), 2.80 (s, 3H), 2.59-2.46 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 415.2 (M+H), Rt. 2.2 分, 96.5% (Max). HPLC: (方法 A) Rt. 2.2 分, 96.0% (Max).
(A)注射用バイアル: 100gの本発明による活性成分及び5gのリン酸水素二ナトリウムの3Lの2回蒸留水中の溶液を、2N塩酸を用いてpH6.5に調節し、滅菌濾過し、注射用バイアルに移し入れ、無菌条件下で凍結乾燥させ、そして、無菌条件下で密閉した。各注射用バイアルは、5mgの活性成分を含んでいた。
X線粉末回折(XRPD)
約5〜10mgのサンプルを、XRPDゼロバックグラウンド単一斜め切断シリカサンプルホルダー上で穏やかに圧縮した。次いで、サンプルを「Philips X−Pert PRO」回折計に装入し、以下の実験条件を用いて分析した。
発生装置電圧: 40kV
管電流: 40mA
波長α1: 1.5406Å
波長α2: 1.5444Å
開始角度[2θ]: 5
終了角度[2θ]: 50
連続走査
サンプルを、ラマンスペクトルについて、以下の条件を使用して「Nicolet Almega DXR Dispersive Raman Microscope」によって分析した:
露光時間: 1.0秒
取得数: 10
分光器開口部: 50μmピンホール
格子: 600ライン/mm
レーザー: He−Ne 633nm 100%パワー
化合物を7mg/mLの濃度で重水素化DMSOに溶解させた。1H NMRスペクトルは、「Bruker Avance 400」(Bruker, Coventry, UK)によって得た。FIDファイルは、NMRソフトウェア「MestReNova V8.0」で処理した。化学シフト及びピークの積分を解析した。
約5mgのサンプルをセラミック製るつぼの中に正確に秤量し、それを周囲温度の「Perkin−Elmer STA 6000 TGA/DTA」分析装置のチャンバーの中に入れた。次いで、サンプルを10℃/分の速度で、典型的には30℃から300℃の温度まで加熱し、その間に、重量の変化及びDTAシグナルをモニターした。使用したパージガスは、20cm3/分の流速の窒素であった。
約10mgのサンプルをワイヤーメッシュの蒸気収着バランスパンに入れ、「IgaSorp」蒸気収着バランス(Hiden Analytical Instruments)にロードした。次いで、サンプルを、それ以上の重量変化が記録されなくなるまで、湿度0%の環境を維持することによって乾燥させた。次いで、サンプルを10%RH増分で0−90%RHの傾斜プロフィールに付し、平衡化が達成されるまで(99%段階完了)各段階でサンプルを維持した。平衡に達したら、当該装置内の%RHを次の段階まで上昇させ、そして、平衡化手順を繰り返した。収着サイクルの完了後、当該サンプルを同じ手順を使用して乾燥させた。吸着/脱着サイクルは、通常、最初のサイクルでサンプルが変化した場合、2回目を繰り返した。次いで、収着/脱着サイクル中の重量変化をモニターし、それによって、サンプルの吸湿性を測定した。
コハク酸塩を調製する好ましい方法は、以下のとおりであった:
実施例35の化合物(3.0g)及びコハク酸(0.97g)を量って20mL容ガラス製バイアルの中に入れ、物理的固体混合物にエタノール(10mL)を加えた。得られた懸濁液を透明な溶液が得られるまで加熱し、次いで、それを40℃と周囲温度の間で18時間にわたって一晩温度サイクルに付した。この間に結晶が沈澱し、蓄積した。追加のエタノール(2mL)を加えて駆り集め、生成物を周囲温度で濾過し、エタノール(2×5mL)で洗浄し、真空オーブンの中で50℃で24時間乾燥させて恒量にした(収量3.1g)。
コハク酸塩を量ってガラス製バイアルの中に入れ、水を100μLずつ1mLまで加え、その後、0.5mLずつ加えた。コハク酸塩は溶解度が高く、0.8 mLの水に完全に溶解した(>12.5mg/mL)。
・ XRPDパターンは、図1に示されている;
・ NMRデータは、化学量論的な単塩と一致した(図2);
・ STAは、約125.5℃で開始する溶融に至るまで重量損失を示さなかった。サンプルは、水和も溶媒和もされていなかった(図3);
・ GVSは、サンプルがわずかに吸湿性であり、1.8%から80%RHまでの可逆的な重量増加を示した;
・ 10mg/200μLで水にスラリー化させた後、XRPDに変化はなかった;
・ IPA/水の中にスラリー化させた後、X線パターンに変化はなかった;
・ この塩は、視覚的に約12.5mg/mLと推定される非常に良好な水溶性を示した;
・ 水和物を形成する傾向の証拠はない;
・ これら観察を組み合わせることによって、実施例35の化合物のコハク酸塩がさらなる研究及び開発のための適切な候補となるであろう。
実施例35の化合物(300mg)を、固体を溶解させるためにエタノール(2mL)中で温めた。その温かい溶液にフマル酸(95mg)を加え、混合物を効率的に撹拌した。追加のエタノール(1mL)を添加した。最初は透明な溶液が観察されたが、混合物が周囲温度に冷却されるにつれて固体が徐々に沈澱した。得られた懸濁液を40℃と周囲温度の間で一晩(18〜24時間)温度サイクルに付した。生成物を濾過し、エタノール(2×1mL)で洗浄し、真空オーブンの中で45℃で乾燥させて恒量にした(収量350mg、91%)。
フマル酸塩を量ってガラス製バイアルの中に入れ、水を100μLずつ1mLまで加え、その後、0.5mLずつ加えた。フマル酸塩は、3mLの水に完全に溶解した(>3.3mg/mL)。
・ XRPDパターンは、図4に示されている。多形形態は、見られなかった;
・ NMRデータは、化学量論的な単塩と一致した(図5);
・ STAは、約169℃で開始する溶融に至るまで重量損失を示さなかった。サンプルは、水和も溶媒和もされていなかった(図6);
・ GVSは、サンプルがわずかに吸湿性であり、2.1%から80%RHまでの可逆的な限界重量増加を示した;
・ 10mg/200μLで水にスラリー化させた後、XRPDに変化はなかった;
・ IPA/水の中にスラリー化させた後、X線パターンに変化はなかった;
・ フマル酸塩の水溶性は、約3.3mg/mLと測定された。
比較実施例C06−1: 実施例35の化合物のコハク酸塩形態2の調製
実施例C02で調製した実施例35のコハク酸塩(200mg)(形態1)を、2−プロパノール(2mL)に懸濁させ、加熱して溶解させた。2−プロパノール又はテトラヒドロフランからのゆっくりとした結晶化の後に得られた少量の結晶を前記温かい溶液に加え、混合物を周囲温度に冷却するにつれて結晶が沈澱した。過剰の溶媒を窒素流下で蒸発させ、生成物を真空下50℃で約24時間さらに乾燥させて、恒量にした。
・ NMRデータは、化学量論的な単塩と一致した(図8);
・ GVSは、サンプルがわずかに吸湿性であり、1.25%から80%RHまでの可逆的な重量増加を示した。さらにまた、GVS後に得られたX線パターンで明らかな形態1に、部分的な変換があった。このことは、形態2の熱力学的不安定性を示している;
・ エタノール、2−プロパノール/水(90/10)、2−プロパノール及びテトラヒドロフランの中にそれぞれの塩の形態1及び形態2を含むスラリーは、全て、周囲温度及び40℃で、形態1に完全に変換した。このことも、形態2の熱力学的不安定性を示している
・ 従って、形態2は、医薬品開発に関する現在の規制要件を満たしていない。
実施例35の化合物(300mg)をアセトン(3mL)の中で温めて、固体を溶解させた。その温かい溶液に、濃塩酸を2倍に希釈することで調製した塩酸(5.825M、135μL)を加え、よく混合させた。油状物が最初に分離し、それをスパチュラを使用して引っかいた結果、生成物が5〜10分以内に固化した。得られた懸濁液を40℃と周囲温度の間で一晩(18〜24時間)温度サイクルに付した。生成物を濾過し、アセトン(2×1mL)で洗浄し、真空オーブンの中で45℃で乾燥させて恒量にした(収量194mg、57%)。
・ XRPDパターンは、図9に示されている;
・ STAは、50℃と150℃の間で約3.6%の重量減少を示した。これは、当該塩の水和バージョンに関する理論値と一致した(図10);
・ GVSは、さらにまた、サンプルが明らかに吸湿性であり、3.6%から70%RHまで及び4%から80%RHまでの可逆的な重量増加を示した;
・ 塩は、水にスラリー化させた後、油状物質に変わった;
・ 上記で記載した負の特性のため、この塩酸塩は医薬品開発に関する現在の規制要件を満たしていない。
実施例35の化合物(300mg)をアセトン(2mL)の中で加熱還流した。固体は完全には溶解しなかったが、その温かい混合物に安息香酸(100mg)を加え、追加のアセトン(1mL)を加えた。混合物を再び加熱還流して、透明な溶液が得られた。この溶液を40℃と周囲温度の間で一晩(18時間)温度サイクルに付したが、透明なままであった。約半分の体積の溶媒を蒸発させ、固体を約24時間かけて分離させた。生成物を濾過し、アセトン(2×1mL)で洗浄し、真空オーブンの中で45℃で乾燥させて恒量にした(収量290mg、74%)。
・ XRPDパターンは、図11に示されている;
・ NMRデータは、化学量論的なモノ塩と一致した(図12);
・ 水の中及びIPA/水の中にスラリー化させた後、XRPDが変化し、このことは、この塩の多形形態が熱力学的に安定ではなく、従って、医薬品開発には適していないことを示している。
実施例35の化合物(300mg)をアセトン(3mL)の中で温めて、固体を溶解させた。その温かい混合物にメタンスルホン酸(27μ)を加え、その結果、油状凝集物が最初に形成された。混合物を約1分間超音波処理に付し、一部の固体が分離したように見えた。混合物を40℃と周囲温度との間で一晩(18時間)温度サイクルに付し、そして、約半分の体積の溶媒を蒸発させた。固体生成物が得られ、それを濾過し、真空オーブンの中で45℃で乾燥させて恒量にした(収量95mg)。
・ 生成物のX線パターンは、親遊離塩基とアモルファス塩の混合物と一致しており、このことは、メシル酸塩を固体形態として再現可能に分離することができないことを示している。従って、実施例35のメシル酸塩は、医薬品開発には適していない。
遊離塩基実施例35(10mg)を量ってガラス製バイアルの中に入れ、水を100μLずつ1mLまで加え、その後、0.5mLずつ加えた。溶解度は、短時間平衡化した後で視覚的に評価した。当該遊離塩基は、8mLの水に溶解し得ることを全く示さなかった(<<1.25mg/mL)。
Claims (15)
- コハク酸又はフマル酸と、式(I)
Yは、H又はCH3を表し;
Tは、N又はCHを表し;
Xは、以下のスルホキシイミン基のうちの1つを表し:
S(O)(NR3’)CH3、S(O)(NR3’)CH2CH3、S(O)(NR3’)CH2CH2OH、又は、S(O)(NR3’)CH2CH2OCH3、NS(O)(R3’)CH3、NS(O)(R3’)CH2CH3、NS(O)(R3’)CH2CH2OH、又は、NS(O)(R3’)CH2CH2OCH3;そして、
R3’は、Hを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基(ここで、1〜3のCH2基は、SO2、CO及びOから選択される基で置き換えられることができ、そしてここで、1〜5個の水素原子は、F、Cl、Br又はIで置き換えられてもよい)を表す〕
の化合物との酸付加塩、並びに、その立体異性体及び固体形態。 - 式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)、式(If)、式(Ig)、式(Ih)、式(Ii)、式(Ij)、式(Ik)、式(IL)、式(I1a)、式(I1b)、式(I2a)、式(I2b)、式(I3a)、式(I3b)、式(I1)、式(I2)又は式(I3)の化合物と酸とのモル比が1:1である、請求項1〜5のいずれか1項に記載のコハク酸付加塩又はフマル酸付加塩。
- 図1に示されている特徴的なX線粉末回折パターンを有する固体形態である、請求項5に記載の化合物(Ia)、化合物(Ib)、化合物(Ic)、化合物(Id)のうちの1つのモノコハク酸塩。
- 図4に示されている特徴的なX線粉末回折パターンを有する固体形態である、請求項5に記載の化合物(Ia)、化合物(Ib)、化合物(Ic)、化合物(Id)のうちの1つのモノフマル酸塩。
- コハク酸又はフマル酸と式(I)の化合物又はそれらの立体異性体との酸付加塩を調製する方法であって、以下の工程:
(a) 式(I)の選択された化合物及びそれぞれの酸を適切な溶媒又は溶媒混合物に懸濁又は溶解させ;
(b) 工程(a)で得られた混合物を、約30℃〜選択された溶媒又は溶媒混合物の沸点付近の温度に加熱し、そして、混合物を室温まで冷却させ;
(c) 場合により、工程(b)を数回繰り返し;
(d) このようにして得られた固体を分離し、乾燥させる;
工程を含む、方法。 - 請求項1〜8のいずれか1項に記載のコハク酸付加塩又はフマル酸付加塩を含む、固体経口投与形態。
- 医薬として使用するための、請求項1〜8のいずれか1項に記載のコハク酸付加塩又はフマル酸付加塩。
- 神経変性疾患、糖尿病、癌、心血管疾患及び脳卒中からなる群から選択される症状を治療する方法において使用するための、請求項1〜8のいずれか1項に記載のコハク酸付加塩又はフマル酸付加塩。
- 請求項12に記載の症状の治療において使用するための請求項1〜8のいずれか1項に記載のコハク酸付加塩又はフマル酸付加塩であって、前記症状が、1以上のタウオパシー及びアルツハイマー病、認知症、筋萎縮性側索硬化症(ALS)、認知障害を伴う筋萎縮性側索硬化症(ALSci)、嗜銀顆粒病、行動異常型前頭側頭型認知症(BvFTD)、ブルーイト病(Bluit disease)、慢性外傷性脳症、大脳皮質基底核変性症(CBP)、ボクサー認知症、石灰化を伴うびまん性神経原線維変化病、ダウン症候群、家族性英国型認知症、家族性デンマーク型認知症、染色体17と関連したパーキンソニズムを伴う前頭側頭認知症(FTDP−17)、前頭側頭葉変性症(FTLD)、神経節膠腫、神経節細胞腫、ゲルストマン・シュトロイスラー・シャインカー病、球状グリアタウオパシー(Globular glia tauopathy)、グアドループパーキンソニズム、ハレルフォルデン・スパッツ病(脳内の鉄蓄積1型を伴う神経変性)、鉛脳症、リポフスチン沈着症、髄膜血管腫症、多系統萎縮症、筋強直性ジストロフィー、ニーマン・ピック病(C型)、淡蒼球・橋脳・黒質変性症(Pallido−ponto−nigral degeneration)、グアムのパーキンソン認知症症候群、ピック病(PiD)、パーキンソン病認知症、脳炎後パーキンソニズム(PEP)、原発性進行性失語、プリオン病(クロイツフェルト・ヤコブ病(CJD)を包含する)、進行性非流暢性失語、変異型クロイツフェルト・ヤコブ病(vCJD)、致死性家族性不眠症、クールー病、進行性超皮質性グリオーシス(Progressive supercortical gliosis)、進行性核上麻痺(PSP)、意味性認知症、スティール・リチャードソン・オルスゼフスキー症候群、亜急性硬化性全脳炎、神経原線維型老年認知症、結節硬化症、ハンチントン病及びパーキンソン病の群から選択され、好ましくは、1以上のタウオパシー及びアルツハイマー病の群から選択される、前記コハク酸付加塩又はフマル酸付加塩。
- タウオパシーを治療する方法であって、そのような治療を必要とする哺乳動物に請求項1〜8のいずれか1項に記載の酸付加塩が投与される、前記方法。
- グリコシダーゼを阻害する方法であって、グリコシダーゼを発現する系を、グリコシダーゼが阻害されるように、インビトロ条件下で、請求項1〜8のいずれか1項に記載の酸付加塩と接触させる、前記方法。
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