JP2022551393A - ピリミジン化合物及びその調製方法 - Google Patents
ピリミジン化合物及びその調製方法 Download PDFInfo
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- JP2022551393A JP2022551393A JP2022515459A JP2022515459A JP2022551393A JP 2022551393 A JP2022551393 A JP 2022551393A JP 2022515459 A JP2022515459 A JP 2022515459A JP 2022515459 A JP2022515459 A JP 2022515459A JP 2022551393 A JP2022551393 A JP 2022551393A
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 75
- 201000010099 disease Diseases 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
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- 239000001257 hydrogen Substances 0.000 claims description 17
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- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
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- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 3
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
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- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
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- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 40
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- 235000002639 sodium chloride Nutrition 0.000 description 29
- 239000012074 organic phase Substances 0.000 description 27
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- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 26
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
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Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
QはC3-C10シクロアルキル、3-10員複素環式基、C6-C10アリール、5-10員ヘテロアリールから選ばれ、前記C3-C10シクロアルキル、3-10員複素環式基、C6-C10アリール、5-10員ヘテロアリールは任意選択的にm個のR1によって置換され、mは0~9の整数から選ばれ、
それぞれのR1は独立して水素、ハロゲン、-CN、-OH、-SH、-NO2、C1-C10アルキル、C3-C10シクロアルキル、C1-C10アルコキシから選ばれ、
X、Yはそれぞれ独立して-N=、-C(R2)=から選ばれ、
Zは-O-、-S-、-N(R3)-から選ばれ、
nは0~3の整数から選ばれ、
M1、M2、M3、M4、M5はそれぞれ独立して-N=、-N(R4)-、-C(R5)=から選ばれ、且つM1、M2、M3、M4、M5のうちの少なくとも1つは-N=又は-N(R4)-から選ばれ、且つM1、M2、M3、M4、M5のうちの少なくとも1つは-C(R5)=であり、
R2とR5はそれぞれ独立して水素、ハロゲン、-CN、-OH、-SH、C1-C3アルキルから選ばれ、
R3とR4はそれぞれ独立して水素、C1-C3アルキルから選ばれ、
且つ前記化合物は以下の化合物又はそのエナンチオマー、立体異性体を含まない。
Qはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、アゼチジニル、ピロリジニル、テトラヒドロフランリル、ピペリジニル、ピペラジニル、モルホリニル、フェニル、インデニル、ナフタレン、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、テトラゾリル、フラニル、チエニル、チアゾリル、オキサゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、ベンズイミダゾリル、インドール又はキノリニルから選ばれ、
mは0、1、2又は3であり、
M1、M2、M3はいずれも-N=又は-N(R4)-から選ばれ、M4、M5はいずれも-C(R5)=である。
任意選択的に、Qがインデニルである場合、前記インデニルは任意選択的に0、1又は2つのR1によって置換されることができ、
任意選択的に、Xが-N=である場合、Yは-C(R2)=であり、又はXが-C(R2)=である場合、Yは-N=であり、
任意選択的に、Zは-O-、-S-、-N(R3)-から選ばれ、Zが-N(R3)-である場合、R3は水素、C1-C3アルキルであり、
特に明記しない限り、本願の明細書及び特許請求の範囲に記載される基と用語の定義には、例としての定義、例示的な定義、好ましい定義、表に記載される定義、実施例における具体的な化合物の定義等が含まれ、互いに任意に組み合わせ及び結合することができる。このように組み合わせ及び結合した基の定義及び化合物構造は、本願の明細書に記載される範囲に属する。
本発明の具体的な例によれば、本発明に記載の式(I)に示される化合物、又はその薬学的に許容される塩、互変異性体、立体異性体、水和物、溶媒和物又はプロドラッグは、ATX酵素に対して有意な阻害効果がある。
DIPEA:DIEAと書くこともでき、ジイソプロピルエチルアミン、即ちN,N-ジイソプロピルエチルアミン
DMF:N,N-ジメチルホルムアミド
Et3N:トリエチルアミン
MeOH:メタノール
N:同等の濃度、例えば2N塩酸は2mol/L塩酸溶液を意味する
NADPH:還元型補酵素II
NaH:水素ナトリウム、水素化ナトリウム
NMM:N-メチルモルホリン、別名N-メチルモルフォリン
NMP:N-メチルピロリドン
SFC:超臨界流体クロマトグラフィー
T3P:プロピルホスフェート三環系無水物、即ち2,4,6-トリプロピル-1,3,5,2,4,6-トリオキサトリホスフィン-2,4,6-トリオキシド又は1-プロパンリン酸無水物
THF:テトラヒドロフラン
TMSN3:アジドトリメチルシラン
IC50:半分発育阻害濃度、最大阻害効果の半分に達する濃度を意味する。
対照化合物は特許出願WO2014110000A1を参照して合成した。
対照化合物2は特許文献WO2014139882A1を参照して合成した。
2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-カルボン酸(中間体A)
2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid(中間体A)
LC-MS m/z:256.2[M+H]+
4-(((1H-1,2,3-トリアゾール-4-イル)メトキシ)メチル)ピペリジン塩酸塩(中間体B)
4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidine hydrochloride(中間体B)
tert-butyl 4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate
tert-butyl 4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate
LC-MS,M/Z:297.1[M+H]+
4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidine hydrochloride
LC-MS,M/Z:197.1[M+H]+
(4-(((2H-1,2,3-トリアゾール-4-イル)メトキシ)メチル)ピペリジン-1-イル)(2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-1)
(4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone
tert-butyl4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate
4-((prop-2-yn-1-yloxy)methyl)piperidine hydrochloride
2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid
LC-MS,M/Z(ESI):256.2(M+H)。
(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(4-((prop-2-yn-1-yloxy)methyl)piperidin-1-yl)methanone
LC-MS,M/Z(ESI):391.4(M+1)。
(4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone
1H NMR (400 MHz, DMSO-d6):δ8.37 (s, 2H), 7.96 (d, 1H), 7.82(s, 1H), 7.25-7.10 (m, 4H), 4.75-4.60 (m, 1H), 4.54 (s, 2H), 4.05 (m, 2H), 3.32-3.20 (m, 4H), 2.97-2.85 (m, 4H), 1.83 (m, 1H), 1.75-1.60 (m, 2H), 1.2-1.05(m, 2H).
LC-MS,M/Z(ESI):434.4(M+1)。
(4-((1-(2H-1,2,3-トリアゾール-4-イル)エトキシ)メチル)ピペリジン-1-イル)(2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-2)
(4-((1-(2H-1,2,3-triazol-4-yl)ethoxy)methyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-2)
tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate(I-2B)
tert-butyl 4-((but-3-yn-2-yloxy)methyl)piperidine-1-carboxylate (I-2C)
4-((but-3-yn-2-yloxy)methyl)piperidine hydrochloride(I-2D)
(4-((but-3-yn-2-yloxy)methyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (I-2E)
LC-MS m/z:405.51[M+H]+
(4-((1-(2H-1,2,3-triazol-4-yl)ethoxy)methyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-2)
1H NMR (400 MHz,DMSO-d6) δ8.33 (s, 2H), 7.92~7.93 (d, 1H), 7.74(s, 1H), 7.16~7.19(m, 2H), 7.09~7.13(m, 2H), 4.56~4.64(m, 2H), 3.09~3.25(m, 5H), 2.85~2.90(q, 4H), 1.63~1.74(m, 3H), 1.38~1.40(d, 3H),1.03~1.12(m, 3H)。
LC-MS m/z:448.54[M+H]+
(4-(1-((1H-1,2,3-トリアゾール-4-イル)メトキシ)エチル)ピペリジン-1-イル)(2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-3)
(4-(1-((1H-1,2,3-triazol-4-yl)methoxy)ethyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-3)
tert-butyl 4-(1-(prop-2-yn-1-yloxy)ethyl)piperidine-1-carboxylate(012B)
4-(1-(prop-2-yn-1-yloxy)ethyl)piperidine hydrochloride(I-3C)
(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(4-(1-(prop-2-yn-1-yloxy)ethyl)piperidin-1-yl)methanone(I-3D)
LC-MS m/z:405.51[M+H]+
(4-(1-((1H-1,2,3-triazol-4-yl)methoxy)ethyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-3)
1H NMR (400 MHz, DMSO-d6) δ8.33 (s , 2H), 7.92~7.93 (d、1H), 7.77(s, 1H), 7.16~7.19(m, 2H), 7.10~7.13(m, 2H), 4.57~4.66(m,,2H), 4.42~4.46(d, 2H), 3.31~3.30(q, 4H), 2.85~2.91(q, 3H), 1.53~1.75(m, 4H),1.05~1.30(m, 6H)。
LC-MS m/z:448.54[M+H]+
(4-(((1H-1,2,3-トリアゾール-4-イル)メトキシ)メチル)-3-メチルピペリジン-1-イル)(2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-4)
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-3-methylpiperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-4)
tert-butyl 3-methyl-4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate(I-4B)
tert-butyl-4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-3-methylpiperidine-1-carboxylate(I-4C)
4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-3-methylpiperidine hydrochloride
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-3-methylpiperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(I-4)
1H NMR (400 MHz, DMSO-d6):δ 8.33 (s, 2H), 7.94~7.92 (d, 1H), 7.80(s, 1H), 7.21~7.18(m, 2H), 7.14~7.11(m, 2H), 4.65~4.48(m, 3H), 3.28~3.20(m, 2H), 2.99~2.86(m, 3H), 2.43~2.37(m, 1H), 2.01~1.89(m, 2H), 1.43~1.32(m, 3H), 121~1.20(m, 1H), 0.94~0.93(d, 3H), 0.71~0.70(d, 2H)。
LC-MS,M/Z:448.3[M+H]+。
(4-(((1H-1,2,3-トリアゾール-4-イル)メトキシ)メチル)-2-メチルピペリジン-1-イル)(2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-5)
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-2-methylpiperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-5)
benzyl (Z)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate(I-5B)
benzyl 4-formyl-2-methylpiperidine-1-carboxylate(I-5C)
benzyl 4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate(I-5D)
benzyl 2-methyl-4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate(I-5E)
benzyl 4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-2-methylpiperidine-1-carboxylate(I-5F)
4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-2-methylpiperidine(I-5G)
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-2-methylpiperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(I-5)
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 2H), 7.93~7.91(d, 1H), 7.80(s, 1H), 7.21~7.17 (m, 2H), 7.14~7.10(m, 2H), 4.67~4.58(m, 1H), 4.51(s, 2H), 3.29~3.20(m, 7H), 2.92~2.86(dd, 2H), 2.03(s, 1H), 1.68~1.53(dd, 2H), 1.38~1.04(m, 5H)。
LC-MS,M/Z:448.3[M+H]+。
(4-(((1H-1,2,3-トリアゾール-4-イル)メトキシ)メチル)-3-フルオロピペリジン-1-イル)(2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-6)
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-3-fluoropiperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-6)
tert-butyl 3-fluoro-4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate(I-6B)
3-fluoro-4-((prop-2-yn-1-yloxy)methyl)piperidine hydrochloride(I-6C)
(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(3-fluoro-4-((prop-2-yn-1-yloxy)methyl)piperidin-1-yl)methanone(I-6D)
LC-MS,M/Z:409.3[M+H]+。
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)-3-fluoropiperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(I-6)
1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 2H), 8.02~8.00 (d, 1H), 7.84(s, 1H), 7.24~7.20(m, 2H), 7.17~7.13(m, 2H), 4.88(s, 0.5H), 4.76(s, 0.5H), 4.69~4.64(m, 1H), 4.58(s, 2H), 3.48~3.44(t, 4H), 3.29~3.23(m, 4H), 2.95~2.89(dd, 2H), 2.16~2.00(m, 1H), 1.59~1.55(m, 1H), 1.42~1.35(m, 1H)。
LC-MS,M/Z:452.3[M+H]+。
(4-(((1H-1,2,3-トリアゾール-4-イル)メトキシ)メチル)ピペリジン-1-イル)(2-((5-フルオロ-2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-7)
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-7)
(E)-5-fluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one
LC-MS,M/Z:180.1[M+H]+。
5-fluoro-2,3-dihydro-1H-inden-2-amine(I-7C)
LC-MS,M/Z:152.2[M+H]+。
2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid
LC-MS,M/Z:274.2[M+H]+。
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(I-7)
1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 2H), 7.98~7.96(d、1H)、7.81 (bs、1H), 7.23~7.20(m, 1H), 7.06~7.03(dd, 1H), 6.97~6.92(m, 1H), 4.71~4.62(m, 1H), 4.53(s, 2H), 3.29~3.18(m, 6H), 2.94~2.83(m, 4H), 1.86~1.79(m, 1H), 1.70~1.67(d, 2H), 1.23~1.07(m, 2H)。
LC-MS,M/Z:452.4[M+H]+。
(4-(((1H-1,2,3-トリアゾール-4-イル)メトキシ)メチル)ピペリジン-1-イル)(2-((5,6-ジフルオロ-2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-8)
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone
2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid(I-8B)
(4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(I-8)
LC-MS,M/Z:470.3[M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2H), 7.94 (s, 1H), 7.22 (s, 2H), 4.72-4.62 (m, 3H), 3.99 (b, 1H), 3.18 (m, 4H), 2.85(m, 4H), 1.75-1.61 (m, 3H), 1.16-1.10 (m, 4H).
(6-((1H-1,2,3-トリアゾール-4-イル)メトキシ)-2-アザスピロ[3.3]ヘプタン-2-イル)(2-((2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-9)
(6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone
tert-butyl 6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate
tert-butyl 6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptane-2-carboxylate
6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptane hydrochloride
(6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone
1H NMR (400 MHz, DMSO-d6):δ8.53~8.49(d, 2H), 8.09~8.07(d, 1H), 7.78(s, 1H), 7.19~7.16(m, 2H), 7.13~7.10(m, 2H), 4.67~4.59(m, 1H), 4.40(s, 3H), 4.34~4.29(d, 1H), 3.97~3.91(m, 3H), 3.29~3.19(dd, 2H), 2.90~2.85(dd, 2H), 2.47~2.41(m,2H), 2.04~1.99(m, 2H).
LC-MS,M/Z (ESI):432.4(M+H)。
(6-((1H-1,2,3-トリアゾール-4-イル)メトキシ)-2-アザスピロ[3.3]ヘプタン-2-イル)(2-((5-フルオロ-2,3-ジヒドロ-1H-インデン-2-イル)アミノ)ピリミジン-5-イル)メタノン(目標化合物I-10)
(6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptan-2-yl)(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(目標化合物I-10)
tert-butyl 6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate(I-10B)
tert-butyl 6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptane-2-carboxylate(I-10C)
6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptane hydrochloride(I-10D)
(6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]heptan-2-yl)(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone(I-10)
1H NMR (400 MHz, DMSO-d6) δ 8.56~8.53 (d, 2H), 8.15~8.13(d, 1H), 7.81(bs, 1H), 7.25~7.21(m, 1H), 7.07~7.04 (m, 1H), 6.99~6.94(m, 1H), 4.73~4.64(m, 1H), 4.44(s, 2H), 4.38~4.33(d, 2H),4.06~3.96(m, 3H), 3.30~3.20(m, 2H), 2.95~2.84(m, 2H), 2.48~2.45(m, 2H), 2.08~2.00(m, 2H)。
LC-MS,M/Z:450.4[M+H]+。
試験例1:Autotaxin(ATX)酵素活性阻害試験
Autotaxin酵素に対する阻害活性は、Autotaxin Inhibitor Screening Assay Kit(Cayman、700580)で検出した。まず、測定対象化合物をDMSO溶媒中で10mMのストック溶液に調製し、次に、DMSO勾配で8濃度ポイントに希釈し、その後、キットにより提供されたAutotaxin Assay buffer(1×)で8濃度ポイントを19×の化合物作業液(DMSOの含有量が1.9%である)に希釈した。Autotaxin Assay Reagent(10×)を取り出してAutotaxin Assay Buffer(1×)を使用して10倍希釈した。Autotaxin Substrateを取り出して、1.2mLのAutotaxin Assay Buffer(1×)を加えて溶解し、均一に混合した後室温で静置した。96ウェルプレートでは、各濃度ポイントの各ウェルに、それぞれ150μLのAutotaxin Assay Buffer(1×)、10μLの希釈した19×の化合物作業液、10μLのAutotaxin Assay Reagent(1×)、20μLの溶解したAutotaxin Substrateを加えて、均一に混合し、37℃の恒温振とう機で、暗所で30minインキュベートし、96ウェルプレートを取出し、マイクロプレートリーダーでOD405を読み取り、実験結果をGraphPad Prismソフトウェアに入力し、フィッティング計算によって各化合物のIC50を取得した。
健康なボランティアから全血を採取し、ヘパリンを使用して抗凝固し、採血管を3000 rpmで10分間遠心分離し、後で使用するために血漿を-80℃で保存した。
阻害率(%)=100-(異なる濃度の化合物グループ-ブランクグループ)/(陽性グループ-ブランクグループ)*100
化合物の異なる濃度の阻害率に従って、化合物のヒト血漿におけるATX酵素活性に対する阻害IC50値を計算した。
ラット全血を採取し、ヘパリンを使用して抗凝固し、採血管を3000rpmで15分間遠心分離し、後で使用するために血漿を氷上に置いた。
阻害率(%)=100-(異なる濃度の化合物グループ-ブランクグループ)/(陽性グループ-ブランクグループ)*100
化合物の異なる濃度の阻害率に従って、化合物のヒト血漿におけるATX酵素活性に対する阻害IC50値を計算した。
ヒト肝ミクロソームの安定性試験では、化合物とヒト肝ミクロソームの体外での共同インキュベートを検出した。まず、測定対象化合物をDMSO溶媒中で10mMのストック溶液に調製し、その後、アセトニトリルを使用して化合物を0.5mMまで希釈した。PBSを使用してヒト肝ミクロソーム(Corning)をミクロソーム/緩衝液溶液に希釈し、該溶液を使用して0.5mMの化合物を作業溶液に希釈し、作業溶液中の化合物濃度は1.5μMであり、ヒト肝ミクロソームの濃度は0.75mg/mlであった。ディープウェルプレートを取り、各ウェルに30μLの作業溶液を加え、次に、15μLの予熱された6mMのNADPH溶液を加えて反応を開始し、37℃でインキュベートした。0、5、15、30、45分のインキュベートで、135 μLのアセトニトリルを対応するウェルに加えて反応を停止した。最後の45分の時点でアセトニトリルで反応を停止した後、ディープウェルプレートを10分間(600rpm/min)ボルテックスして振動し、次に15分間遠心分離した。遠心分離後、上清を取り、精製水を1:1で加えた後、LC-MS/MS検出を実行し、各時点での化合物のピーク面積と内部標準ピーク面積の比率を取得し、5、15、30、45分での化合物のピーク面積比と0分でのピーク面積比を比較し、各時点での化合物の残りのパーセンテージを計算し、Excelを使用してT1/2を計算した。
全自動電気生理学的パッチクランプQPatchを使用して化合物のhERGに対する阻害効果を検出した。本試験で使用される細胞は、hERG cDNAをトランスフェクトし、hERGチャネルを安定して発現するCHO細胞株(デンマークSophion Bioscience会社製)であり、細胞世代数はP24であった。細胞は、Ham’s F12培地、10%(v/v)不活化のウシ胎児血清、100μg/mlのハイグロマイシンB、100μg/mlのGeneticinを含む培地で(すべてInvitrogen社製)培養された。CHO hERG細胞は、上記培養液を含む培養皿で成長し、37℃で、5%CO2を含む培養箱で培養された。
ラット薬物動態試験において、180-240gの雄性SDラット3匹を使用し、一晩絶食させ、10mg/kgを強制経口投与した。投与前、投与後15、30分、及び1、2、4、8、24時間後に採血した。血液サンプルを8000回転/分、4℃で、6分間遠心分離し、血漿を収集し、-20℃で保存した。各時点の血漿を取り、内部標準を含む3-5倍量のアセトニトリル溶液を加えて混合し、1分間ボルテックスして混合し、13000回転/分、4℃で、10分間遠心分離し、上清液を取って3倍量の水を加えて混合し、適切な量の混合液を取り、LC-MS/MS分析を行った。主な薬物動態パラメータをWinNonlin 7.0ソフトウェア非コンパートメントモデルによって分析した。
マウス薬物動態試験において、20-25gの雄性CD-1マウスを使用し、一晩絶食させ、10mg/kgを強制経口投与した。投与前、投与後15、30分、及び1、2、4、8、24時間後に採血した。血液サンプルを8000回転/分、4℃で、6分間遠心分離し、血漿を収集し、-20℃で保存した。各時点の血漿を取り、内部標準を含む3-5倍量のアセトニトリル溶液を加えて混合し、1分間ボルテックスして混合し、13000回転/分、4℃で、10分間遠心分離し、上清液を取って3倍量の水を加えて混合し、適切な量の混合液を取り、LC-MS/MS分析を行った。主な薬物動態パラメータをWinNonlin 7.0ソフトウェア非コンパートメントモデルによって分析した。
犬の薬物動態試験において、8-10kgの雄性ビーグル犬を3匹使用し、一晩絶食させ、5mg/kg強制経口投与した。それ以外、操作はラット薬物動態試験と同様である。
pH7.4のリン酸塩緩衝液(PBS)、pH5.8のFeSSIF溶液(タウロコール酸ナトリウム10mM、レシチン2mM、水酸化ナトリウム81.65mM、塩化ナトリウム125.5mM、オレイン酸ナトリウム0.8mM、モノオレイン酸グリセロール5mM、マレイン酸55.02mMを含む)、pH1.6のFaSSGF溶液(1L溶液には、タウロコール酸ナトリウム80μM、レシチン20μM、ペプシン0.1g、塩化ナトリウム34.2mMが含まれる)を調製した。
Claims (20)
- 式(I)に示される化合物、又は式(I)に示される化合物の互変異性体、立体異性体、水和物、溶媒和物、薬学的に許容される塩又はプロドラッグであり、
それぞれのR1は独立して水素、ハロゲン、-CN、-OH、-SH、-NO2、C1-C10アルキル、C3-C10シクロアルキル、C1-C10アルコキシから選ばれ、
X、Yはそれぞれ独立して-N=、-C(R2)=から選ばれ、
Zは-O-、-S-、-N(R3)-から選ばれ、
M1、M2、M3、M4、M5はそれぞれ独立して-N=、-N(R4)-、-C(R5)=から選ばれ、且つM1、M2、M3、M4、M5のうちの少なくとも1つは-N=又は-N(R4)-から選ばれ、且つM1、M2、M3、M4、M5のうちの少なくとも1つは-C(R5)=であり、
R2とR5はそれぞれ独立して水素、ハロゲン、-CN、-OH、-SH、C1-C3アルキルから選ばれ、
R3とR4はそれぞれ独立して水素、C1-C3アルキルから選ばれ、
且つ前記化合物は以下の化合物又はそのエナンチオマー、立体異性体を含まない、
- 式(I)に示される化合物において、
Qはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、アゼチジニル、ピロリジニル、テトラヒドロフランリル、ピペリジニル、ピペラジニル、モルホリニル、フェニル、インデニル、ナフタレン、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、テトラゾリル、フラニル、チエニル、チアゾリル、オキサゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、ベンズイミダゾリル、インドール又はキノリニルから選ばれ、
mは0、1、2又は3であり、
M1、M2、M3はいずれも-N=又は-N(R4)-から選ばれ、M4、M5はいずれも-C(R5)=である、ことを特徴とする請求項1に記載の化合物。 - 有効用量の、請求項1~7のいずれか一項に記載の化合物を含む、ことを特徴とする薬物組成物。
- 請求項1~7のいずれか一項に記載の化合物、その立体異性体、水和物、溶媒和物、薬学的に許容される塩又はプロドラッグの、ATX関連疾患を治療するための薬物の調製における使用。
- 前記ATX関連疾患は、癌、代謝疾患、腎臓病、肝疾患、線維症疾患、間質性肺疾患、増殖性疾患、炎症性疾患、疼痛、自己免疫疾患、呼吸器系疾患、心血管疾患、神経変性疾患、皮膚病学障碍及び/又は異常な血管新生関連疾患から選ばれる、請求項9に記載の使用。
- 前記ATX関連疾患は、間質性肺疾患、肺線維症、肝線維症、及び腎臓線維症から選ばれ、好ましくは、前記ATX関連疾患は特発性肺線維症である、請求項9に記載の使用。
- 前記ATX関連疾患は代謝疾患であり、好ましくは、II型糖尿病、及び非アルコール性脂肪性肝炎から選ばれる、請求項9に記載の使用。
- 前記ATX関連疾患は神経因性疼痛、及び炎症性疼痛から選ばれ、好ましくは、前記ATX関連疾患は変形性関節症関連の疼痛である、請求項9に記載の使用。
- 前記ATX関連疾患は癌である、請求項9に記載の使用。
- ATX関連疾患を患う患者に請求項8に記載の薬物組成物を投与することを含む、ことを特徴とするATX関連疾患を治療する方法。
- 前記ATX関連疾患は、癌、代謝疾患、腎臓病、肝疾患、線維症疾患、間質性肺疾患、増殖性疾患、炎症性疾患、疼痛、自己免疫疾患、呼吸器系疾患、心血管疾患、神経変性疾患、皮膚病学障碍及び/又は異常な血管新生関連疾患から選ばれる、ことを特徴とする請求項15に記載のATX関連疾患を治療する方法。
- 前記ATX関連疾患は間質性肺疾患、肺線維症、肝線維症、及び腎臓線維症から選ばれ、好ましくは、前記ATX関連疾患は特発性肺線維症である、ことを特徴とする請求項15に記載のATX関連疾患を治療する方法。
- 前記ATX関連疾患は代謝疾患であり、好ましくは、II型糖尿病、及び非アルコール性脂肪性肝炎から選ばれる、ことを特徴とする請求項15に記載のATX関連疾患を治療する方法。
- 前記ATX関連疾患は神経因性疼痛、及び炎症性疼痛から選ばれ、好ましくは、前記ATX関連疾患は変形性関節症関連の疼痛である、ことを特徴とする請求項15に記載のATX関連疾患を治療する方法。
- 前記ATX関連疾患は癌である、ことを特徴とする請求項15に記載のATX関連疾患を治療する方法。
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