JP2005225896A - プロテインキナーゼc阻害剤 - Google Patents
プロテインキナーゼc阻害剤 Download PDFInfo
- Publication number
- JP2005225896A JP2005225896A JP2005135900A JP2005135900A JP2005225896A JP 2005225896 A JP2005225896 A JP 2005225896A JP 2005135900 A JP2005135900 A JP 2005135900A JP 2005135900 A JP2005135900 A JP 2005135900A JP 2005225896 A JP2005225896 A JP 2005225896A
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- Prior art keywords
- mmol
- added
- methyl
- indol
- protein kinase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 229940123924 Protein kinase C inhibitor Drugs 0.000 title description 12
- 239000003881 protein kinase C inhibitor Substances 0.000 title description 12
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
- -1 monoalkylaminoalkyl Chemical group 0.000 claims description 71
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000004480 active ingredient Substances 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
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- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 108010044467 Isoenzymes Proteins 0.000 abstract description 72
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- 206010012601 diabetes mellitus Diseases 0.000 abstract description 16
- 108010024526 Protein Kinase C beta Proteins 0.000 abstract description 12
- 102000015766 Protein Kinase C beta Human genes 0.000 abstract description 12
- 239000003112 inhibitor Substances 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 6
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- 238000002844 melting Methods 0.000 description 24
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
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- RQEDXUKWSYJDPG-UHFFFAOYSA-N 1-piperidin-4-ylindole Chemical compound C1CNCCC1N1C2=CC=CC=C2C=C1 RQEDXUKWSYJDPG-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 9
- 239000012156 elution solvent Substances 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 125000004442 acylamino group Chemical group 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- 244000309464 bull Species 0.000 description 7
- 239000002808 molecular sieve Substances 0.000 description 7
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
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- 238000003556 assay Methods 0.000 description 6
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- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
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- 238000000746 purification Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 102000009310 vitamin D receptors Human genes 0.000 description 1
- 108050000156 vitamin D receptors Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 125000000969 xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 description 1
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Abstract
【解決手段】 β−1およびβ−2アイソザイム選択的阻害剤として、糖尿病とその合併症に関連する病的状態、およびβ−1およびβ−2アイソザイムの上昇に関連する他の病的状態を治療する上で治療学的に有用な化合物を得る。
【選択図】なし
Description
で示される基であり、
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、もしくはCF3であるか、またはR1およびR2は、一緒になって−(CH2)r−X−CH2−を形成することができ、
R3は水素またはCH3COであり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、
XはCHR8またはNR8であり、
R8は(CH2)sR9であり、
R9は水素、ヒドロキシ、アルコキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アジド、アシルアミノ、アルコキシカルボニル、シアノ、アミジノ、またはアミノカルボニルであり、
nは1、2、3、4、5、または6であり、
rは1、2、または3であり、
sは0、1、2、または3である]
で示される化合物の医薬的有効量を、そのような治療を必要とする哺乳動物に投与することを特徴とするプロテインキナーゼCβ−1およびβ−2アイソザイムを選択的に阻害する方法を提供するものである。
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、またはCF3であり、R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、R12は水素、アルキル、ハロアルキル、シクロアルキル、アセチル、アリール、−CH(アリール)2、アミノ、モノアルキルアミノ、ジアルキルアミノ、グアニジノ、−C(=N(アルコキシカルボニル))NH(アルコキシカルボニル)、アミジノ、ヒドロキシ、カルボキシ、アルコキシカルボニル、またはヘテロサイクリル基であり、
pおよびqは独立して1、2、3、または4であり、
sは0、1、2、または3であり、
tは1または2であり、uは0または1である]、
式III:
R2'は、水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、またはCF3であり、
R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、XはCR8R9であり、
R8は(CH2)sR10であり、
R9は(CH2)sR11であり、
R10およびR11は、独立してヒドロキシ、アルコキシ、カルボキシ、アシルオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アジド、アシルアミノ、アルコキシカルボニル、シアノ、アミジノ、またはアミノカルボニルであり、
rは1、2、または3であり、
sは0、1、2、または3である]、および
式IV:
R1'は水素、C1−C4アルキル、シクロプロピルメチル、アミノアルキル、モノアルキルアミノアルキル、またはジアルキルアミノアルキルであり、
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(0)C1−C3アルキル、またはCF3であり、R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(0)C1−C3アルキルであり、nは1、2、3、4、5、または6である]。
R1'は水素、C1−C4アルキル、アミノアルキル、モノアルキルアミノアルキル、またはジアルキルアミノアルキルであり、
R2は水素またはメチルである]、および
式Ib:
XはCR8R9またはNR8であり、
R8は(CH2)sR10であり、
R9は(CH2)sR11であり、
R10およびR11は、独立して水素、ヒドロキシ、モノアルキルアミノ、またはジアルキルアミノであり、
rは1、または2であり、
sは1である]。
R1'は水素またはC1−C4アルキルであり、
R12は水素またはC1−C4アルキルである]
で示される化合物である。
工程1
1)エステラーゼもしくはリパーゼによって開裂させることができるエステルもしくはアミド誘導体、
2)特異的または非特異的プロテアーゼによって認識可能なペプチド、あるいは3)プロドラッグ形もしくは修飾されたプロドラッグ形が膜選択性を介して作用部位に蓄積される誘導体、またはこれら1)〜3)のあらゆる組み合せ。適切なプロドラッグ誘導体を選択し、製造するための一般的方法は、例えば、H.Bundgaardの、Design of Profrugs(1985)に記載されている。
PKC酵素アッセイ
PKC酵素=α、βI、βII、γ、δ、ε、η、およびζ。
20mM HEPES緩衝液(Sigma,St.Louis,Missouri)(pH7.5)中、酵素活性を最大に活性化するのに十分なジアシルグリセロール(Avanti Polar Lipids)および120μg/mLのホスファチジルセリン(Avanti Polar Lipids)からなる小胞、α、βI、βII、およびγ酵素のみのアッセイ用として940μM塩化カルシウム(Sigma,St.Louis,Missouri)、全ての酵素について1mM EGTA、10mM塩化マグネシウム(Sigma,St.Louis,Missouri)、および30μM(γ−32P)ATP(DuPont)。全ての酵素についてヒストンHL型(Worthington)またはミエリン塩基性蛋白のいずれかを基質として使用した。プロテインキナーゼC酵素を加えてアッセイを開始し、30℃で10分間インキュベーションした後、冷トリクロロ酢酸(Amresco)0.5mL、次いで1mg/mLのウシ血清アルブミン(Sigma,St.Louis,Missouri)100μLを加えてアッセイを止めた。TOMTECTM濾過システムを用いてガラス線維フィルターで減圧濾過することによって沈降物を回収し、βシンチレーションカウンターでカウントすることによって定量した。
製造例2
2−(1−(1−N(H)−ピペリジン−4−イル)−インドール−3−イル)−酢酸エチルエステル
製造例3
1−(1−エチル−ピペリジン−4−イル)−1H−インドール
製造例4
1−[(1−N−シクロプロピルメチル)−ピペリジン−4−イル]−インドール
製造例5
1−N−[1−N−(3−クロロプロピル)−ピペリジン−4−イル]−インドール
製造例6
[3−(4−インドール−1−イル−ピペリジン−1−イル)−プロピル]− ジメチルアミン
製造例7
1−ベンゾイル−4−(1−インドリル)−ピペリジン
製造例8
1−t−ブトキシカルボニル−4−(1−インドリル)−ピペリジン
製造例9
4−(1−インドリル)−ピペリジン
製造例10
6,7,8,9−テトラヒドロピリド[1,2−a]インドール−8,8−ジカルボン酸ジエチルエーテル
製造例11
1−(1−メチル−ピペリジン−4−イル)−インドール
製造例12
4−(インドール−1−イル)−ピペリジン−1−カルボン酸エチルエステル
製造例13
1−N−(1−N−(シクロプロピルメチル)−ピペリジン−4−イル)−インドール
製造例14
製造例15
1−N−[1−N−(2,2,2−トリフルオロ−エチル)−ピペリジン−4−イル]−インドール
製造例16
1−N−(1−N−(トリフルオロアセチル)ピペリジン−4−イル)−インドール
製造例17
1−N−[1−N−(2,2,3,3,4,4,4−ヘプタフルオロ−ブチル)−ピペリジン−4−イル]−インドール
製造例18
1−N−[1−N−2,2,3,3,4,4,4−ヘプタフルオロ)ブチルアミド−ピペリジン−4−イル]−インドール
製造例19
[t−ブトキシカルボニルイミノ−(4−インドール−1−イル−ピペリジン−1−イル)−メチル]−カルバミン酸t−ブチルエステル
製造例20
1−N−(1−メチル−ピペリジン−4−イル)メチレン)−インドール
製造例21
4−(インドール−1−イル)メチレン−ピペリジン−1−カルボン酸エチルエステル
製造例22
2−(インドール−1−イル)ブチロラクトン
インドール(9g、78mモル)の氷冷乾燥DMF(80mL)溶液を、油を含まない水素化ナトリウム(2.25g、94mモル)で処理した。1時間後、2−ブロモブチロラクトン(14.6mL、78mモル)の乾燥THF(20mL)溶液を滴加した。周囲温度で一夜撹拌した後、混合物を砕いた氷に注ぎ、酢酸エチル(3×)で抽出し、乾燥して留去した。残留物を、ヘキサン/酢酸エチルグラジエント(9:1〜7:3)を用いるシリカゲルフラッシュクロマトグラフィーで精製した。溶離溶媒を留去して帯黄色油状物8g(理論値の52%)を得た。
製造例23
2−(インドール−1−イル)−ブタン−1,4−ジオール
製造例24
1,4−(ビス)メタンスルホニルオキシ−2−(インドール−1−イル)−ブタン
製造例25
1,4−ジイオド−2−インドール−1−イル−ブタン
製造例26
1−N−(1−ベンジル−ピロリジン−3−イル)−インドール
製造例27
1−N−(1−ベンズヒドリル−アゼチジン−3−イル)−インドール
2−[2−(1−ベンズヒドリル)−アゼチジン−3−イル)−2−アミノ)−フェニル]−エタノール(3.1g、0.01モル)の乾燥塩化メチレン(100mL)溶液を−5℃に冷却し、少量に分けたピロジニウムジクロメート(PDC)(9.3g)で処理した。混合物を徐々に周囲温度とし、さらにPDC(9.3g)を加えた。1時間後、混合物を乾燥シリカゲル層に通して濾過し、次いで黄色油状の溶離液(0.85g)を留去して塩化メチレンチエチルエーテルですすぎ、これをさらに精製することなく使用した(理論値の25%)。MS
製造例28
1−N−(1−N(ベンズヒドリル)−アゼチジン−3−イル)−2−(エタン−2−オール)−アナリン
乾燥トルエン(150mL)中のメタンスルホン酸 1−ベンズヒドリル−アゼチジン−3−イル エステル(14g、44.2mモル)、2−(エタン−2−オール)−アナリン(14g、44.2mモル)、および無水炭酸カリウムの(2.8g、50mモル)の混合物を4時間還流した。トルエンを留去して残留物を水と塩化メチレンに分配した。有機相を乾燥し、留去し、残る油状物をヘキサン/アセトングラジエント(90:10〜85:15)で溶離するシリカゲルカラムクロマトグラフィーで精製した。溶離溶媒を留去して無色油状物6g(理論値の44%)を得た。MS
製造例29
メタンスルホン酸 1−ベンズヒドリル−アゼチジン−3−イル エステル
1−ベンズヒドリル−アゼチジン−3−オール(50g、0.208モル)の乾燥ピリジン(500mL)溶液を5℃に冷却した。メタンスルホニルクロリド(16.2mL、0.208モル)を30分間かけて加えた。混合物を徐々に(12時間)周囲温度とし、さらに2時間撹拌し続けた。溶媒を、40〜50℃で減圧除去した。残留物を塩化メチレンに再溶解し、水洗(2×)して乾燥した。粗製物質をt−ブチルメチルエーテル/石油エーテル(15:85)溶液でトリチュレートして精製された生成物の結晶(53g、収率80%)を得た。融点:85〜87℃。MS
製造例30
メチル−2−デオキシ−5−O−トシル−D−リボース
メチル−2−デオキシ−5−D−リボース(8g、54mモル)をピリジン(60mL)に溶解した。この溶液にトシルクロリド(10.86g、57mモル)を、0℃で1時間かけて加えた。室温で14時間後、この溶液を濃縮し、氷水(250mL)で反応を止め、酢酸エチルで抽出した。抽出物を飽和NaHCO3および水で洗浄し、乾燥し、次いで濾過して濃縮した。残留物(13.6g、収量83.5%)を直接用いた。NMR
製造例31
メチル−5−アジド−2.5 ジデオキシ−D−リボース
メチル−2−デオキシ−5−O−トシル−D−リボース(13.6g、45mモル)のDMF(250mL)溶液にアジ化ナトリウム(4.4g、67mモル)を加えた。混合物を4時間還流し、次いで室温に冷却し、氷水(1.5mL)で反応を止めて酢酸エチルで抽出した。抽出物を水洗し、乾燥し、濃縮して油状物(6.2g、収率86%)を得た。NMR
製造例32
メチル−3−O−アセチル−5−アジド−2.5 ジデオキシ−D−リボース
無水酢酸(25mL)を、メチル−5−アジド−2.5−ジデオキシ−D−リボース(6.2g、38mモル)のピリジン(100mL)溶液に加えた。室温で4時間後、混合物を減圧下で濃縮した。残留物(6g)をヘキサンエチルアセテート(8:2)で溶離するフラッシュクロマトグラフィーで精製した。溶離する溶媒を留去し、油状の生成物(4.9g、収率60%)を得た。NMR
製造例33
3−O−アセチル−5−アジド−2,5−ジデオキシ−D−リボシルアセテート
製造例34
8,8−ビス(アセトキシメチレン)−6,7,8,9−テトラヒドロピリド[1,2−a]インドール
3−(1−[2−(5−アセトアミド−2,5−ジデオキシ−α−D−
リボピラノシル)ヒドロキシエチル]−3−インドリル)−4−
(1−メチル−3−インドリル)−1H−ピロール−2,5−ジオン
αアノマー 1H−NMR(CDCl3):1.9(3H,s,NAc)、2.2(2H,m,H−2ab)、3.8(2H,m,CH2)、3.85(3H,s,NCH3)、4.2(2H,m,CH2)、5.05(1H,d,H−1)、6.7−7.8(10H,インドール H)、8.4(1H,s,NH)。
質量分析。
1H−NMR(CDCl3、250MHz) δ 2.02−2.26(6H,m)、3.06(2H,m)、3.64(2H,s)、3.84(3H,2)、4.24(1H,m)、6.68(1H,m)、6.81(2H,m)、7.11(3H,m)、7.28(7H,m)、7.69(1H,s)、7.85(1H,s)、8.50(1H,bs)。
質量分析:515[M++H]、計算値 514 FW。
全収量:鮮やかな橙色の結晶210mg(理論値の16%)。
融点:238−245℃。
1H−NMR(CDCl3、250MHz) δ 1.49(18H,s)、2.02(2H,m)、2.02(4H,m)、3.09(2H,m)、3.86(3H,s)、5.29(3H,m)、6.66(2H,m)、6.91(1H,m)、7.16−7.36(5H,m)、7.48(1H,s)、7.75(1H,s)、10.18(1H,bs)。
質量分析:667[M++H]、計算値 666 FW。
1H−NMR(CDCl3、250MHz) δ 1.48(9H,s)、1.74(2H,m)、2.02(2H,m)、2.87(2H,m)、3.85(3H,s)、4.29(3H,m)、6.69(2H,d)、6.88(1H,t)、7.07−7.36(5H,m)、7.51(1H,s)、7.68(1H,s)、7.75(1H,bs)。
1H−NMR(CDCl3、250MHz) δ 1.49(9H,m)、1.79(2H,m)、2.02(2H,m)、2.88(2H,m)、4.27(3H,m)、6.74(1H,m)、6.85(2H,m)、7.07−7.35(5H,m)、7.59(1H,s)、7.62(1H,s)、7.74(1H,s)、8.67(1H,bs)。
質量分析:510[M+]、計算値 510 FW。
収率:理論値の11%。
融点:>250℃。
1H−NMR(DMSO−d6):1.9および2.3(2H,m,H−2'ab)、3.7(2H,m,CH2)、3.85(3H,s,NCH3)、3.9(3H,s,NCH3)、4.4(2H,m,CH2)、4.6−5.0(4H,m,糖 H)、6.6−7.9(10H,m,インドール H)、10.9(1H,s,NH)。
3−(1−[4−(2,5−ジデオキシ−5−アジド−α−D−
リボフラノシル)ヒドロキシブチル]−3−インドリル)−4−
(1−メチル−3−インドリル)−1H−ピロール−2,5−ジオン
および
3−(1−[4−(2,5−ジデオキシ−5−アジド−β−D−
リボフラノシル)ヒドロキシ−ブチル]−3−インドリル)−4−(1−メチル−
3−インドリル)−1H−ピロール−2,5−ジオン−ピロール−2,5−ジオン
αアノマー 1H−NMR(CDCl3):1.6(2H,m,CH3)、1.9(2H,m,CH2)、2.1(2H,m,H−2'ab)、3.7(2H,m,CH2)、3.8(3H,s,NCH3)、4.2(2H,m,CH2)、5.2(1H,d,H−1')、6.7−7.9(10H,インドール H)。
βアノマー 1H−NMR(CDCl3):1.6(2H,m,CH2)、1.9(2H,m,CH2)、2.1(m,1H−2'a)、2.2(1H,m,H−2'b)、3.8(2H,m,CH2)、3.9(3H,s,NCH3)、4.2(2H,m,CH2)、5.15(1H,d,H−1')、6.7−7.8(10H,インドール H)。
αアノマーの収量:320mg(30%)。
βアノマーの収量:410mg(39%)。
βアノマー 1H−NMR(CDCl3):1.6(2H,m,CH2)、1.9(2H,m,CH2)、2.1(m,1H,H−2'b)、2.2(1H,m,H−2'a)、3.8(2H,m,CH3)、3.85(3H,s,NCH3)、4.2(2H,m,CH3)、5.2(1H,d,H−1')、6.7−7.7(10H,インドール H)、8.5(1H,s,NH)。
3−(1−[2−(5−アセトアミド−2,5−ジデオキシ−β−D−
リボフラノシル)ヒドロキシエチル]−3−インドリル)−4−
(1−メチル−3−インドリル)−1H−ピロール−2,5−ジオン
βアノマー 1H−NMR(CDCl3):1.8(3H,s,NAc)、2.0(1H,m,H−2b)、2.2(m,1H,H−2a)、3.7(2H,m,CH2)、3.8(3H,s,NMe)、4.2(2H,m,CH2)、600(1H,d,H−1)、6.7−7.7(10H,インドール H)、9.1(1H,s,NH)。
融点:>293℃。
融点:247−252℃。
融点:>250℃。
融点:>250℃。
収量:赤色の粉末100mg(収率 6%)。
全収量:41.6g(理論値の54%)。
融点:316−318℃。
収量:70g(理論値の92%)。
融点:280−282℃。
実施例 44
3−[1−(1−カルボキシアミジン−ピペリジン−4−
イル)インドール−3−イル]−4−(1−メチル−インドール−3−
イル)−1−ピロール−2,5−ジオン
融点:>210℃(分解)。
収量:鮮やかな橙色の結晶160mg(理論値の49%)。
融点:>250℃。
3−{1−[1−(2,2,3,3,4,4,4−ヘプタフルオロ−
ブチル)ピペリジン−4−イル]インドール−3−イル}−4−
(1−メチル−インドール−3−イル)−1H−ピロール−2,5−ジオン
収量:鮮やかな橙色の結晶260mg(理論値の38%)。
融点:231−234℃。
収量:鮮やかな橙色の結晶210mg(理論値の25%)。
融点:228℃(分解)。
融点:104−106℃。
収量:理論値の6%。
質量分析:500(M+)、341、303、276、159、91(100%)。
収量:理論値の3%。
融点:102−105℃。
製剤例 1
量(mg/カプセル剤)
活性成分 250
デンプン,乾燥 200
ステアリン酸マグネシウム 10
合 計 460mg
上記成分を混合して、硬ゼラチンカプセルに460mg量を充填する。
製剤例 2
量(mg/錠剤)
活性成分 250
セルロース,微晶質 400
二酸化ケイ素,フュームド 10
ステアリン酸 5
合 計 665mg
各成分を混合し、圧縮して、各々の重量が665mgである錠剤を成形する。
製剤例 3
量(重量%)
活性成分 0.25
エタノール 29.75
プロペラント 22(クロロジフルオロメタン) 70.00
合 計 100.00
活性成分をエタノールと混合する。その混合物をプロペラント 22の一部に加え、−30℃まで冷却して、充填装置へ移す。次いで、必要量をステンレススチール製の容器に入れ、残りのプロペラントで希釈する。次いで、バルブ装置を容器に取り付ける。
製剤例 4
量(mg/錠剤)
活性成分 60mg
デンプン 45mg
微晶質セルロース 35mg
ポリビニルピロリドン(10%水溶液として) 4mg
カルボキシメチルデンプンナトリウム 4.5mg
ステアリン酸マグネシウム 0.5mg
タルク 1mg
合 計 150mg
活性成分、デンプンおよびセルロースを米国No.45メッシュの篩にかけて、完全に混合する。その結果得られた粉末とポリビニルピロリドン溶液とを混合した後、これを米国No.14メッシュの篩にかける。このようにして製造した顆粒を50℃で乾燥し、米国No.18メッシュの篩にかける。次いで、あらかじめ米国No.60メッシュの篩にかけておいたカルボキシメチルデンプンナトリウム、ステアリン酸マグネシウム、およびタルクを顆粒に加え、混合した後、打錠機で圧縮して、各々の重量が150mgである錠剤を得る。
製剤例 5
量(mg/カプセル剤)
活性成分 80mg
デンプン 59mg
微晶質セルロース 59mg
ステアリン酸マグネシウム 2mg
合 計 200mg
活性成分、セルロース、デンプンおよびステアリン酸マグネシウムを混合し、米国No.45メッシュの篩にかけて、硬ゼラチンカプセルに200mg量を充填する。
製剤例 6
量(mg/坐剤)
活性成分 225mg
飽和脂肪酸グリセリド 2,000mg
合 計 2,225mg
活性成分を米国No.60メッシュの篩にかけ、あらかじめ必要最小限の熱を用いて溶融しておいた飽和脂肪酸グリセリドに懸濁させる。次いで、その混合物を容量2gの坐薬型に注入して放冷する。
製剤例 7
量
活性成分 50mg
カルボキシメチルセルロースナトリウム 50mg
シロップ 1.25ml
安息香酸溶液 0.10ml
香料 適 量
着色料 適 量
精製水を加えて5.0mlとする
薬物を米国No.45メッシュの篩にかけ、カルボキシメチルセルロースナトリウムおよびシロップと混合して、滑らかなペーストとする。安息香酸溶液、香料、および着色料を少量の水で希釈して、撹拌しながら加える。次いで、十分水を加え、所望の容量とする。
製剤例 8
量
活性成分 250mg
等張生理食塩水 1000mg
先の成分の溶液を1分間につき約1mlの速度で処置を必要とする患者に静脈内投与する。
Claims (3)
- 式:
R1'は水素、C1−C4アルキル、シクロプロピルメチル、アミノアルキル、モノアルキルアミノアルキル、またはジアルキルアミノアルキルであり、
R2およびR2'は、独立して水素、アルキル、アルコキシアルキル、ヒドロキシアルキル、C1−C3アルキルチオ、S(O)C1−C3アルキル、またはCF3であり、
R3は水素またはCH3CO−であり、
R4、R4'、R5、R5'、R6、R6'、R7、およびR7'は、独立して水素、ハロゲン、アルキル、ヒドロキシ、アルコキシ、−COO(C1−C3アルキル)、CF3、ニトロ、アミノ、アセチルアミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルチオ、C1−C3アルキルチオ、またはS(O)C1−C3アルキルであり、nは1、2、3、4、5、または6である]
で示される化合物またはその医薬的に許容される塩もしくは溶媒和物。 - 医薬として使用する請求項1に記載の化合物。
- 活性成分である請求項1に記載の化合物を、1またはそれ以上の医薬的に許容される担体、賦形剤もしくは希釈剤と一緒に含有する医薬製剤。
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-
1994
- 1994-12-14 PT PT95904892T patent/PT817627E/pt unknown
- 1994-12-14 EP EP04102054A patent/EP1449529B1/en not_active Expired - Lifetime
- 1994-12-14 WO PCT/US1994/014313 patent/WO1995017182A1/en active IP Right Grant
- 1994-12-14 DK DK95904892T patent/DK0817627T3/da active
- 1994-12-14 EP EP95904892A patent/EP0817627B1/en not_active Expired - Lifetime
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- 1994-12-14 AU AU13398/95A patent/AU1339895A/en not_active Abandoned
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1995
- 1995-05-25 US US08/450,320 patent/US5661173A/en not_active Expired - Lifetime
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CA2179650A1 (en) | 1995-06-29 |
EP1449529A1 (en) | 2004-08-25 |
EP1449529B1 (en) | 2010-01-27 |
WO1995017182A1 (en) | 1995-06-29 |
ATE290378T1 (de) | 2005-03-15 |
JP4369397B2 (ja) | 2009-11-18 |
JP2005225895A (ja) | 2005-08-25 |
JP3998261B2 (ja) | 2007-10-24 |
PT817627E (pt) | 2005-07-29 |
JPH09507066A (ja) | 1997-07-15 |
JP4365803B2 (ja) | 2009-11-18 |
US5668152A (en) | 1997-09-16 |
US5672618A (en) | 1997-09-30 |
AU1339895A (en) | 1995-07-10 |
EP0817627A1 (en) | 1998-01-14 |
JP2006316068A (ja) | 2006-11-24 |
DK0817627T3 (da) | 2005-06-06 |
EP0817627A4 (en) | 2002-07-17 |
JP4490400B2 (ja) | 2010-06-23 |
US5661173A (en) | 1997-08-26 |
DE69434294D1 (de) | 2005-04-14 |
DE69434294T2 (de) | 2005-12-29 |
SI0817627T1 (ja) | 2005-08-31 |
ATE456367T1 (de) | 2010-02-15 |
ES2236702T3 (es) | 2005-07-16 |
HK1008183A1 (en) | 1999-05-07 |
CA2179650C (en) | 2007-10-30 |
EP0817627B1 (en) | 2005-03-09 |
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