JP5107058B2 - 鎮痛活性および/または免疫賦活活性を有する3−ヘテロ環−3−ヒドロキシ−2−アミノプロピオン酸アミドおよび関連化合物 - Google Patents
鎮痛活性および/または免疫賦活活性を有する3−ヘテロ環−3−ヒドロキシ−2−アミノプロピオン酸アミドおよび関連化合物 Download PDFInfo
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- JP5107058B2 JP5107058B2 JP2007553193A JP2007553193A JP5107058B2 JP 5107058 B2 JP5107058 B2 JP 5107058B2 JP 2007553193 A JP2007553193 A JP 2007553193A JP 2007553193 A JP2007553193 A JP 2007553193A JP 5107058 B2 JP5107058 B2 JP 5107058B2
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- UYNCFCUHRNOSCN-GMAHTHKFSA-N n-[(1s,2s)-1-hydroxy-3-morpholin-4-yl-1-phenylpropan-2-yl]decanamide Chemical compound C([C@H](NC(=O)CCCCCCCCC)[C@@H](O)C=1C=CC=CC=1)N1CCOCC1 UYNCFCUHRNOSCN-GMAHTHKFSA-N 0.000 description 1
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- 229940053973 novocaine Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- JOCYRIINDHNKNL-UHFFFAOYSA-N propanal;dihydrochloride Chemical compound Cl.Cl.CCC=O JOCYRIINDHNKNL-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical class 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
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Classifications
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- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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Description
で表される化合物および該化合物の全ての製薬的に許容される塩に関する。
本発明の新規な化合物は、哺乳動物において、鎮痛活性および/または免疫賦活活性を有する。背景技術に記載した化合物のいくつかは、当技術分野においては、それ自体が既知であるが、本発明の発明者らによって、哺乳動物において鎮痛効果も示すことが発見された。本発明の発明者らの知る限りにおいては、これらの既知の化合物の鎮痛活性または免疫賦活性の生物学的活性は、今回発見されるまでは知られていなかった。
本発明の化合物を薬学的有効量で投与することができる。通常、そのような投与量は、所望の治療効果を達成するために必要とする最少の用量である。慢性疼痛の治療においては、この量は、およそ、疼痛によって生じる不快感を低減させるのに必要とする量であろう。一般に、ヒト成人では、そのような用量は、0.1〜5000mg/日の範囲であり、より好ましくは、1〜3000mg/日の範囲であり、さらにより好ましくは、10〜1000mg/日の範囲である。しかし、所与の症例において投与する化合物の実際の量は、疼痛の重症度、患者の年齢および体重、患者の全身状態、疼痛の原因、ならびに投与経路など、関連する状況を考慮して医師が決定するものとする。
本発明の化合物を以下の実験例に記載する合成方法、または本開示に照らせば当業者には容易に明らかになるであろう、以下に記載する実験的方法の変法を利用して合成することができる。より具体的には、本発明の各化合物の合成は、R4がHである具体的な化合物について記載する。当業者は、R4が、1〜6炭素のアルキルであるかまたはR5が1〜6炭素のアルキルであるCO−R5である化合物が、それぞれアルキル化またはアシル化等の当分野に周知の製造方法によって容易に製造することができることを容易に理解する。また、当業者は、ヒドロキシ基のアルキル化またはアシル化を実施するにあたり、アミノ基等の他の基が保護に必要であり得ること、この保護基を後に当分野で周知の方法によって脱離することができることを容易に理解する。ある場合においては、ヒドロキシ基のアルキル化またはアシル化を、本発明の化合物に導く合成の過程における中間体に対して行うことができる。
Advance 300分光計(Bruker製)を用いて、室温で1H NMRスペクトルを記録した。Waters 2525ポンプ、Waters 2696フォトダイオードアレイ検出器およびXTerraカラム(特許第186000482号、5μm、C18、4.5×50mm)を備えるWaters Autopurification Systemを使用して、逆相高速液体クロマトグラフィー(HPLC)によって、化合物を分析した。使用したHPLC法では、7分間で、溶媒Bの濃度を5%から100%に変化させた。溶媒Aは、0.05%TFAを有する水であり、溶媒Bは、0.05%TFAを有するCH3CNであった(方法A)。
Buchi B−545型融点測定装置を用いて、融点を測定したが、補正はしなかった。反応生成物を単離するために、回転式真空蒸発器を使用して溶媒を蒸発させて除去した。水浴の温度は、40℃以下とした。
本発明の化合物を一般的な意味では直下に、さらにより詳細には本出願の実験例の項に記載する合成法を利用することによって、または本開示に照らせば当業者には容易に明らかになるであろう、以下に記載する一般的なおよび実験例の方法の変法によって合成することができる。
化合物19の調製
2−イソシアノ−1−(ピロリジン−1−イル)エタノン、BLE 04098
イソシアノ酢酸メチル(96%、工業用グレード、5.0g、47.8mmol)に、冷却(0℃)および撹拌しながら、ピロリジン(6.5mL、78mmol)をゆっくり添加した。混合物を引き続き冷却しながら、1.5時間撹拌し、次いで、濃縮した。得られた油をCH2Cl2:ヘキサンから、2回にわたり共蒸発させて、残留しているピロリジンを除去した。2−イソシアノ−1−(ピロリジン−1−イル)エタノン、BLE 04098を黄色の固体(6.85g、収率98%)として得た後、精製せずに、次の工程で使用した。
1H-NMR (CDCl3,δ): 1.81-2.08 (m, 4H, 2xCH2), 3.35-3.45 (m, 2H, -NCH2), 3.50-3.60 (m, 2H, -NCH2), 4.23 (s, 2H, CH2CO).
メタノール(10mL)中に水酸化カリウム(0.55g、9.80mmol)を含む溶液に、冷却(0℃)および撹拌しながら、3−ピリジンカルボキサルデヒド(1.03mL、10.84mmol)および2−イソシアノ−1−(ピロリジン−1−イル)エタノン、BLE 04098(1.50g、10.86mmol)の混合物を添加した。溶液を0℃で3時間撹拌し、次いで、濃縮した。残滓を酢酸エチル(100mL)と水とに分配した。有機層を2回のさらなる酢酸エチル抽出液(100mL、2回)と合わせ、塩化ナトリウム水溶液で洗浄、MgSO4上で乾燥、ろ過後、蒸発させた。濃縮により粗生成物を得、これをシリカ上のカラムクロマトグラフィー(CH2Cl2:MeOH=98:2)によって精製して、トランス−(4,5−ジヒドロ−5−(ピリジン−3−イル)オキサゾール−4−イル)(ピロリジン−1−イル)メタノン、BLE 04110Bを淡黄色の固体(0.95g、収率39%)として得た。
1H-NMR (CDCl3,δ): 1.78-2.10 (m, 4H, 2xCH2), 3.40-3.61 (m, 3H, CH2N), 3.90-4.04 (m, 1H, CH2N), 4.59 (dd, 1H, J=7.7 Hz, J=2.2 Hz, CH-N), 6.21 (d, 1H, J=7.7 Hz, CH-O), 7.04 (d, 1H, J=2.2 Hz, O-CH=N), 7.33 (m, 1H, ArH), 7.64 (m, 1H, ArH), 8.59 (d, 2H, J=2.8 Hz, ArH).
13C-NMR (CDCl3,δ): 24.2, 26.0, 46.4, 46.6, 75.7, 79.3, 123.7, 133.5, 135.3, 147.6, 149.9, 155.2, 166.2.
化合物19をピリジン−4−カルバルデヒド(1.88mL、19.76mmol)、メタノール(18mL)中のKOH(1.01g、18mmol)および2−イソシアノ−1−(ピロリジン−1−イル)エタノン、BLE 04098(2.73g、19.76mmol)を用いて、方法Bにしたがって調製した。残滓を酢酸エチル(200mL)と水(150mL)とに分配した。有機層をさらなる酢酸エチル抽出液(150mL、2回)と合わせ、塩化ナトリウム水溶液で洗浄(150mL、2回)、MgSO4上で乾燥、ろ過後、蒸発させた。トランス−(4,5−ジヒドロ−5−(ピリジン−4−イル)オキサゾール−4−イル)(ピロリジン−1−イル)メタノン、化合物19を白色の固体(4.32g、収率98%)として得た。
Rf:0.65(MeOH:CH2Cl2=10:90)
1H-NMR (CDCl3,δ): 1.78-2.06 (m, 4H, 2xCH2), 3.44-3.60 (m, 3H, CH2N), 3.90-4.01 (m, 1H, CH2N), 4.52 (dd, 1H, J=7.9 Hz, J=2.2 Hz, CH-N), 6.19 (d, J=7.9 Hz, 1H, CH-O), 7.03 (d, 1H, J=2.2 Hz, N=CH-O), 7.24 (dd, 2H, J=4.5 Hz, J=1.5 Hz, ArH), 8.61 (dd, 2H, J=4.5 Hz, J=1.5 Hz, ArH).
一般的方法C:DL−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−3−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩、化合物20の調製による例示
メタノール(10mL)中のトランス−(4,5−ジヒドロ−5−(ピリジン−3−イル)オキサゾール−4−イル)(ピロリジン−1−イル)メタノン、BLE 04110B(0.932g、3.80mmol)に、37%塩酸(1.2mL)を添加した。混合物を2.25時間加熱(50℃)した後、反応混合物を濃縮し、粗生成物を酢酸エチルと共に、2回にわたり共蒸発させた。酢酸エチルと共に粉砕し、ろ過および乾燥後、DL−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−3−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩、化合物20を白色の固体(1.10g、収率94%)として得た。
1H-NMR (CD3OD,δ): 1.65-2.00 (m, 4H, 2xCH2), 2.82-3.11 (m, 1H, -CH2N), 3.30-3.57 (m, 2H, CH2N), 3.57-3.77 (m, 1H, CH2N), 4.54 (d, 1H, J=5.3 Hz, CH-N), 5.38 (d, 1H, J=5.3 Hz, CH-O), 8.15 (dd, 1H, J=7.6 Hz, J=5.0 Hz, ArH), 8.68 (d, 1H, J=7.6 Hz, ArH), 8.89 (d, 1H, J=7.6 Hz, ArH), 8.96 (s, 1H, ArH).
13C-NMR (CD3OD,δ): 24.9, 26.9, 47.7, 48.2, 58.1, 69.6, 128.7, 141.5, 141.6, 143.1, 146.5, 165.4.
化合物22をトランス−(4,5−ジヒドロ−5−(ピリジン−4−イル)オキサゾール−4−イル)(ピロリジン−1−イル)メタノン、化合物19(0.750g、3.07mmol)、37%塩酸(1.0mL)およびメタノール(10mL)を用いて、方法Eにしたがって調製した。50℃で3.0時間加熱した後、精査して、DL−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩、化合物22を白色の固体(0.935g、収率99%)として得た。
1H-NMR (CD3OD,δ): 1.75-2.03 (m, 4H, 2xCH2), 2.93-3.08 (m, 1H, CHN), 3.32-3.75 (m, 3H, 2xCH2), 4.54 (d, 1H, J=5.9 Hz, CH-N), 5.40 (d, 1H, J=5.9 Hz, CH-O), 8.21 (d, 2H, J=5.8 Hz, ArH), 8.94 (d, 2H, J=5.8 Hz, ArH).
MS−ESI m/z(%rel.int.):236.1([MH]+,17)、219(25)、148(100)
HPLC:方法A、検出UV 254nm、化合物22 RT=0.8分、ピーク面積 96.3%
CH2Cl2(12mL)中のDL−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩(化合物22)(0.60g,1.77mmol)の懸濁液に、TEA(0.739mL,5.32mmol)を加え、反応混合物を10分間攪拌し、氷浴中攪拌を続けながら冷却した。Boc−アミノヘキサン酸(0.451g,1.951mmol)およびBOP(1.05g,1.95mmol)の溶液をCH2Cl2中で予め調製し、5分間かけて滴加した。0℃にて反応混合物を2時間、室温で16時間攪拌した。揮発性成分を蒸発させた後,残留物をEtOAcに溶解し、NaH2PO4(pH7.2)、飽和NaHCO3で洗浄し、Na2SO4で乾燥させた。得られた白色の固体をEtOAc中10%EtOAcを用いるシリカゲルカラムクロマトグラフィーで精製してtert−ブチル5−(DL−トレオ−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イルカルバモイル)ペンチルカルバメートEBE06102(0.41g,52%の収率)を白色の固体として得た。
Rf:0.10(EtOAc:MeOH=90:10).
1H−NMR:(CDCl3,δ):1.10−1.12(m,2H,CH2),1.35−1.55(m,11H,(CH3)3&CH2),1.72−1.92(m,4H,CH2),2.05−2.22(m,2H,CH2),2.40(d,2H,J=9.3Hz,CH2),3.05(q,2H,J=6.6Hz,CH2),3.20−3.28(m,1H,NCH2),3.32−3.50(m,2H,NCH2),3.62−3.72(m,1H,NCH2),4.79(bs,1H,NH),4.97(dd,1H,J=8.7,4.1Hz,NCH),5.07(d,1H,J=4.1Hz,OCH),5.40(bs,1H,NH),6.74(d,1H,J=8.4Hz,OH),7.35(d,2H,J=6.0Hz,ArH),8.56(d,2H,J=6.0Hz,ArH).
13C−NMR(CDCl3,δ):24.0,25.0,26.1,28.4,29.6,35.9,36.9,40.3,46.1,46.9,54.9,72.9,79.0,121.3,148.8,149.6,156.1,169.0,173.2.
MS−ESIm/z(%rel.Int.):449.1([MH]+,20).
HPLC:方法A,検出UV254nm,EBE06102RT=4.1min,ピーク面積99.9%.
MeOH(1mL)中の5−(DL−トレオ−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イルカルバモイル)ペンチルカルバメートEBE06102(0.370g,0.824mmol)の溶液に、EtOAc(10mL)中のHCl(4.2M)の溶液を加えた。反応混合物を室温で2に時間攪拌し、揮発性成分を蒸発させて粗製の褐色の油状物EBE06104(0.221g,63%粗製収率)を得、これを精製せずに次の工程で用いた。CH2Cl2(5mL)中のEBE06104(0.221g,0.522mmol)の懸濁液に、トリエチルアミン(0.217mL,1.57mmol)を加え、反応混合物を10分間攪拌し、攪拌を続けながら氷浴中で冷却した。ビオチン(0.14g,0.574mmol)およびBOP(0.309g,0.574mmol)の溶液をCH2Cl2(1mL)中で予め調製し、5分間かけて滴加した。混合物を0℃で2時間、室温で16時間攪拌した。反応混合物を蒸発乾燥し、NaH2PO4とn−ブタノールの間に分離した。n−ブタノール相を飽和Na2CO3で洗浄し、蒸発乾燥した。所望の生成物をカラムクロマトグラフィー(EtOAc:MeOH:NH4OH=70:28:2)を用いて精製し、化合物50(1:1の比率のジアステレオ異性体の混合物,0.160g,53%の収率)を白色の固体として得た。
Rf:0.2(EtOAc:MeOH:NH4OH=70:28:2).
1H−NMR(CDCl3,δ):1.17−1.32(m,2H),1.40−1.60(m,4H),1.60−1.90(m,6H),1.90−2.10(m,4H),2.15−2.30(m,4H),2.74(d,1H,J=12.6Hz),2.91(dd,J=4.8Hz,12.8Hz),2.95−3.10(m,1H),3.10−3.45(m,4H),3.60−3.72(m,1H),4.34(dd,1HJ=4.4HzJ=7.5Hz),4.50−4.58(m,1H),4.85−4.95(m,1H),5.02−5.08(m,1H),6.12(s,1H),6.50−6.15(m,1H),6.68(s,1H),7.36(m,2H),7.67(q,1H,J=8.12Hz),8.55(d,2H,J=5.8Hz).
MS−ESIm/z(%rel.Int.):575.3([MH]+,70).
HPLC:方法A,検出UV254nm,化合物50RT=3.61min,ピーク面積97.2%.
トランス−(4,5−ジヒドロ−5−(2−メトキシピリジン−3−イル)オキサゾール−4−イル)(ピロリジン−1−イル)メタノン、BAL01014
BAL01014は、方法Dにしたがい、2−メトキシ−3−ピリジンカルボキシアルデヒド(0.64ml,5.43mmol)、メタノール(5mL)中のKOH(0.305mg,5.43mmol)および2−イソシアノ−1−(ピロリジン−1−イル)エタノンBLE04098(0.75g,5.43mmol)を用いて製造した。処理の後、トランス−(4,5−ジヒドロ−5−(2−メトキシピリジン−3−イル)オキサゾール−4−イル)(ピロリジン−1−イル)メタノンBAL01014(0.74mg,50%の収率)を白色の固体として得た。
Rf:0.25(EtOAc).
1HNMR(CDCl3,δ):1.82−2.10(m,4H,2xCH2),3.40−3.62(m,3H,CH2N),3.80−3.90(m,3H,CH2N),3.93(s,3H,OMe),4.61(dd,1H,J=7Hz,J=2Hz,CH−N),6.14(d,1H,J=7Hz,CH−O),6.90(dd,1H,J=7.3Hz,J=5Hz,ArH),7.02(d,1H,J=2Hz,OCH=N),7.60(dd,1H,J=7.3Hz,J=1.7Hz,ArH),8.13(dd,1H,J=5Hz,J=1.8Hz,ArH).
13C−NMR(CDCl3,δ):24.3,26.1,46.3,46.6,53.5,73.5,78.1,116.8,122.2,135.2,146.5,155.3,160.5および167.4.
MS−ESIm/z(%rel.Int.):276.1([MH]+,42).
HPLC:方法A,検出UV254nm,BAL01014RT=3.63min,ピーク面積97.2%.
トランス−(4,5−ジヒドロ−5−(2−メトキシピリジン−3−イル)オキサゾール−4−イル)(ピロリジン−1−イル)メタノン、BAL 01014(0.684g、2.487mmol)をメタノール(10mL)に溶解した。塩酸溶液(37%、0.6mL)を室温で注射器を介して添加した。混合物を還流しながら、22時間撹拌した。残滓を濃縮した後、EtOAcと共に粉砕し、ろ過して、淡黄色の固体である、3−(DL−トレオ−2−アミノ−1−ヒドロキシ−3−オキソ−3−ピロリジン−1−イル−プロピル)−1H−ピリジン−2−オン塩酸塩、化合物49を得た(136mg、収率19.0%)。
1H NMR (CD3OD,δ): 1.82-2.09 (m, 4H, 2xCH2), 3.35-3.80 (m, 4H, 2xCH2N), 4.63 (s, 1H, CH-N), 5.17 (s, 1H, CH-O), 6.56 (t, 1H, ArH) ), 7.5 (d, 1H, J=6.1 Hz, ArH), 7.86 (d, 1H, J=6.5 Hz, ArH).
13C-NMR (CD3OD,δ): 24.2, 26.0, 46.6, 46.6, 75.8, 79.7, 127.3, 127.5, 127.9, 129.4, 130.0, 132.3, 133.2, 148.1, 148.4, 155.3, 166.2.
MS−ESI m/z(%rel.Int.):252.1([MH]+,18)、163.0(100)
HPLC:方法A、検出UV 254nm、化合物49 RT=1.13分、ピーク面積 84.0%
(±)−トレオ−2−フタルイミド−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン塩酸塩、化合物300
(±)−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩化合物22(0.51g,1.64mmol)をK2CO3の1N水溶液20mLにより処理し、CH2Cl2:MeOH=90:10の混合物で抽出した(5x40mL)。溶液MgSO4で乾燥し、濾過し、蒸発させて化合物22の遊離塩基(0.323g,82.5%の収率)を白色の固体として得た。
10mL容の丸底フラスコ中、無水フタル酸(0.203mg,1.373mmol)を化合物22の遊離塩基(0.323g,1.37mmol)に加え、混合物を65℃から145℃に加熱し、145℃で5分間攪拌した。冷却後、イエローブラックのゴム状物質を粗製物として得た。この粗製物をカラムクロマトグラフィー(SiO2,EtOAc:MeOH=100:0〜90::10)により精製した。溶媒を留去した後、白色の固体(±)−トレオ−2−フタルイミド−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オンBLE04156A(0.15g,30%の収率)を白色の固体として得た。(±)−トレオ−2−フタルイミド−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オンBLE04156A(0.135g,0.37mmol)に、イソプロパノール(10mL)中のHClの0.1N溶液を加え、混合物を28℃でロータリーエバポレーター、次いで高真空ポンプにて蒸発乾燥させた。(±)−トレオ−2−フタルイミド−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン塩酸塩化合物300(0.147g,24.5%の収率)を白色の固体として得た。
1H−NMR(CD3OD,δ):1.60−1.90(m,4H,2xCH2),2.95−3.09(m,1H,CH2N),3.30−3.47(m,3H,CH2N),5.30(d,1H,J=7.9Hz,CH),5.82(d,1H,J=7.9Hz,CH),7.80(m,4H,ArH),8.25(d,2H,J=5.4Hz,ArH),8.81(d,2H,J=5.2Hz,ArH).
13C−NMR(CD3OD,δ):24.7,27.1,47.7,47.8,58.0,70.6,124.8(2xC),127.5(2xC),132.6(2xC),136.1(2xC),142.5(2xC),164.9,166.5,168.8.
MS−ESIm/z(%rel.Int.):366.0([MH]+,22),219.1(100),148.0(47).
HPLC:方法A,検出UV254nm,RT=3.88min,ピーク面積98.7%.
tert−ブチル5−((±)−トレオ−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イルカルバモイル)ペンチルカルバメート、化合物237
N−Boc−アミノヘキサン酸(342mg,1.48mmol)のTHF(10mL)溶液にn−メチルモルホリン(163μL,1.48mmol)を加えた。溶液を5分間攪拌し、−15℃に冷却し、イソブチルクロロホルメート(211μL,1.48mmol)を滴加することにより処理した。この溶液をステンレススチールカニューレを用いて−15℃のTHF(10mL)中の(±)−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩化合物22(500mg,1.48mmol)およびN−メチル−モルホリン(489mg,1.47mmol)の溶液に加えた。反応混合物を−15℃に0.5時間保った後、25℃にて2時間攪拌した。溶媒を蒸発させた後、残留物をEtOAcとH2Oの間に分配し、NaH2PO4、NaHCO3飽和水溶液で洗浄し、硫酸ナトリウムで乾燥し、0%〜10%[v/v]MeOH(EtOAc中)のグラジェントを用いるカラムクロマトグラフィー(SiO2)により精製してtert−ブチル5−((±)−トレオ−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イルカルバモイル)ペンチルカルバメート化合物237(455mg,69%の収率)を白色の固体として得た。
Rf:0.20(EtOAc:MeOH=90:10).
1H−NMR(CD3OD,δ):1.05−1.15(m,2H,CH2),1.35−1.55(m,13H,2×CH2+C(CH3)3),1.75−1.95(m,4H,2×CH2),2.00−2.20(m,2H,O=CCH2),3.05(q,2H,J=6.7Hz,n−CH2),3.20−3.35(m,1H,n−CH),3.38−3.50(m,2H,n−CH2),3.65−3.75(m,1H,n−CH),4.72(bs,1H,NH),4.98(dd,1H,J=8.8Hz,J=3.6Hz),5.08(d,1H,J=3.3Hz,OCH),5.23(bs,1H,OH),6.50(d,1H,J=8.7Hz,NH),7.35(d,2H,J=6.0Hz,ArH),8.58(d,2H,J=4.6Hz,J=1.4Hz,ArH).
MS−ESIm/z(%rel.Int.):449.2([MH]+,30),349.2(100).
HPLC:方法A,検出(254nm),RT=4.03min,ピーク面積99.9%
tert−ブチル5−((±)−トレオ−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イルカルバモイル)ペンチルカルバメート化合物237(81mg,0.181mmol)のCH2Cl2(8mL)溶液に0℃のTFA(2mL)を加え、0℃で2時間攪拌した。揮発性成分を蒸発させ残留物をMeOH中のAmberlite−400(OH-)懸濁液で処理した。濾過後、濾液を蒸発させて生成物をCH2Cl2:MeOH:NH4OH=10:5:0.4を用いるカラムクロマトグラフィー(SiO2)により単離して6−アミノ−N−((±)−トレオ−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イル)ヘキサンアミド化合物238(40mg,64%の収率)を白色の固体として得た。
Rf:0.30(CH2Cl2:MeOH:NH4OH=10:5:0.4).
1HNMR(CDCl3,δ):1.12−1.30(m,2H,CH2),1.30−1.50(m,2H,CH2),1.50−1.65(m,2H,CH2),1.65−1.95(m,4H,CH2),2.10−2.30(m,2H,CH2),2.55−2.70(t,2H,J=6.9Hz,CH2),3.10−3.20(m,2H,CH2),3.28−3.50(m,2H,CH2),3.60−3.70(m,1H,CH),4.95(dd,1H,J=5.1Hz,J=8.4Hz,O−CH),5.02(d,1H,J=5.0Hz,OH),7.11Hz(d,J=8.48Hz,1H,ArH),7.35(dd,2H,J=4.4Hz,J=1.5Hz,ArH),8.55(dd,J=1.5Hz,J=4.6Hz,2H,ArH).
13C NMR(CDCl3,δ):24.0,25.1,25.8,25.9,32.5,35.8,41.7,46.0,46.9,55.6,72.6,121.3(2×C),149.2,149.5(2×C),168.9,173.7
Boc−GABA−GABA−GABA−OH(354mg,0.95mmol)をCHCl3(40mL)中、Et3N(0.3mL,2.1mmol)およびHOBT(145mg,1.05mmol)と共に窒素下で4℃にて5分間攪拌した。EDC(205mg,1.05mmol)を加え、混合物を4℃にて15分間攪拌した。6−アミノ−N−((±)−トレオ−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イル)ヘキサンアミド(333mg,0.95mmol)のCHCl3(20mL)溶液を滴加し、混合物を窒素下、4℃にて2時間および室温で15時間攪拌した。ブライン(30mL)を加え、生成物をCH2Cl2(200mL)により抽出した。有機層を2N NaOHの溶液、ブラインで洗浄し、MgSO4で乾燥した。濾過後、溶液を蒸発させ、乾燥させて粗製の黄色の油(420mg)を得た。カラムクロマトグラフィー(SiO2,CH2Cl2:MeOH=85:15)による精製後、(±)−トレオ−{3−[3−(3−{5−[1−(ヒドロキシ−ピリジン−4−イル−メチル)−2−オキソ−2−ピロリジン−1−イル−エチルカルバモイル]−ペンチルカルバモイル}−プロピルカルバモイル)−プロピルカルバモイル]−プロピル}−カルバミン酸tert−ブチルエステルTTA08156(260mg,39%の収率)を淡黄色の油状物として得た。
Rf:0.20(CH2Cl2:MeOH=9:1).
1H−NMR(CDCl3,δ):1.17−1.25(m,2H,CH2),1.40−1.56(m,13H,2xCH2,3xCH3)1.73−1.85(m,10H,5xCH2),2.13−2.29(m,8H,4xCH2CO),2.40(s,1H,OH),3.09−3.67(m,12H,6xCH2−N),4.91(dd,1H,J=4.9Hz,J=8.5Hz,CH−N),5.05(d,1H,J=5.1Hz,CH−O),5.15(t,1H,J=5.8Hz,NH),7.01−7.04(m,1H,NH),7.14(t,1H,J=5.6Hz,NH),7.33(t,1H,J=5.6Hz,NH),7.37(d,2H,J=6.0Hz,ArH),8.55(d,2H,J=6.0Hz,ArH).
13C−NMR(CD3OD, δ):24.0,24.9,25.6,25.8,26.1,26.5,28.4(3xC),29.0,33.5,33.7,35.8,38.6,38.8,39.1,39.6,46.1,46.8,55.6,72.7,79.5,121.5(x2),149.1,149.5(x2),156.7,168.8,173.1,173.3,173.4,173.5.
MS−ESIm/z(%rel.Int.):704.3([MH]+,100).
HPLC:方法A,検出UV254nm,TTA08156RT=3.90min,ピーク面積99.0%.
(±)−トレオ−{3−[3−(3−{5−[1−(ヒドロキシ−ピリジン−4−イル−メチル)−2−オキソ−2−ピロリジン−1−イル−エチルカルバモイル]−ペンチルカルバモイル}−プロピルカルバモイル)−プロピルカルバモイル]−プロピル}−カルバミン酸tert−ブチルエステルTTA08156(260mg,0.37mmol)をMeOH(5mL)中、37%HCl(0.3mL,3.70mmol)と共に40℃にて15分間攪拌した。MeOHを蒸発させ残留物を真空乾燥させた。AmberliteIRA−400(Cl-)(6mL、8.4mmol)を水(2x10mL)、0.5N NaOH(3x20mL)、水(2x10mL)およびMeOH(3x10mL)で順次洗浄した。前に得られた残留物と洗浄したAmberliteをMeOH(30mL)中室温で5分間攪拌した。濾過後、MeOHを蒸発させてアミンを遊離塩基の形態で得た(210mg、94%の収率)。ビオチン(95mg、0.38mmole)をCHCl3/DMF(40mL/10mL)およびEt3N(0.11mL、0.77mmol)、HOBT(53mg、0.38mmol)の混合物に溶解し、EDC(75mg、0.38mmol)を加え、溶液を窒素下、室温で2時間攪拌した。CHCl3(10mL)中の前に得られたアミン(210mg,0.35mmol)を滴加し、混合物を窒素下室温で24時間攪拌した。ブライン(40mL)、2NNaOH(10mL)、CHCl3(50mL)を加え、生成物をCHCl3/DMF(50mL/10mL)でさらに3回抽出することにより抽出した。集めた有機層をブラインで洗浄し、MgSO4で乾燥し、濾過し、留去して粗製の黄色の油(160mg,52%の収率)を得た。粗製の油をカラムクロマトグラフィー(SiO2,CH2Cl2:MeOH:NH3=95:5:0.1〜85:15:0.3)により精製し、留去後6−(5−((3aR,6S,6aS)−ヘキサヒドロ−2−オキソ−1H−チエノ[3,4−d]イミダゾール−6−イル)−ペンタノイルアミノ)−ブチリルアミノ−ブチリルアミノ−ブチリルアミノ−N−((1R,2S)−&(1S,2R)−1−ヒドロキシ−3−オキソ−1−(ピリジン−4−イル)−3−(ピロリジン−1−イル)プロパン−2−イル)ヘキサンアミド(ジアステレオ異性体混合物比1:1)を淡黄色の油状物として得た(45mg,15%の収率).
Rf:0.30(CH2Cl2:MeOH:NH3=85:15:0.3).
1H−NMR(CD3OD,δ):1.26−1.82(m,22H,11xCH2),2.18−2.25(m,10H,5xCH2CO),2.70(d,1H,J=12.7Hz,CH2−S),2.92(dd,1H,J=4.8Hz,J=12.7Hz,CH2S),3.06−3.80(m,13H,6xCH2−N,CH−S),4.29(dd,1H,J=4.4Hz,J=7.8Hz,CH−N),4.48(dd,1H,J=4.9Hz,J=7.8Hz,CH−N),4.82(d,1H,J=6.4Hz,CH−N),5.01(d,1H,J=6.4Hz,CH−O),7.49(d,2H,J=5.5Hz,ArH),8.5(d,2H,J=4.6Hz,ArH).
13C−NMR(CD3OD,δ):25.0,26.5,26.8,(2xC),26.9(2xC),27.5,29.5,29.8,30.1,34.3,34.4(2xC),36.4,36.8,39.8,39.9,40.1,41.1,47.2,47.3,57.1,58.3,61.6,63.4,73.1,74.2,123.5(2xC),149.9(2xC),152.8,166.1,170.0,175.3,175.4(2xC),176.0,176.1.
MS−ESIm/z(%rel.Int.):830.2.([MH]+,85),219.1(100).
HPLC:方法A,検出UV254nm,RT=3.70min,ピーク面積99.8%.
(±)−トレオ−2−アミノ−3−ヒドロキシ−3−(ピペリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩、化合物302
(±)−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩化合物22(500mg,1.61mmol)を、水素雰囲気下、PtO2水和物(Pt含量79−84%,100mg)と共にAcOH(10mL)中、室温にて24時間攪拌した。セライト(登録商標)545にて濾過後、濾液を蒸発させ残留物を減圧下で乾燥させてベージュ色の固体(450mg,88.2%の収率)を得た。粗製物をMeOH(50mL)中Amberlite(Cl−)IRA−400(9mL,12.7mmol、予め0.5NNaOH次いで水およびMeOHで洗浄)と共に室温にて15分間攪拌した。混合物を濾過し、濾液を蒸発させ、遊離塩基の形態をカラムクロマトグラフィー(SiO2,CH2Cl2:MeOH:20%NH3(H2O中)=70:30:8)により精製して(±)−トレオ−2−アミノ−3−ヒドロキシ−3−(ピペリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オンTTA08144A(226mg,58%収率)を得た。MeOH中HCl処理して(±)−トレオ−2−アミノ−3−ヒドロキシ−3−(ピペリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩化合物302(190mg,28%の収率)を白色の固体として得た。
Rf:0.20(CH2Cl2:MeOH:20%NH3(H2O中)=70:30:8,遊離塩基).
1H−NMR(CD3OD,δ):1.57−2.00(m,9H,4xCH2&CH),2.94−3.08(m,2H,CH2−N),3.46−3.77(m,7H,3xCH2−N,CH−N),4.33(s,1H,CH−O).
13C−NMR(CD3OD, δ):22.5,23.4,24.1,24.7,35.2,42.2,42.5,45.4,45.5,52.0,69.8,164.6.
MS−ESIm/z(%rel.Int.):242.2([MH]+,45),129.1(100).
HPLC:方法A,検出UV214nm,RT=0.70min,ピーク面積98.0%.
方法D(CH2Cl2中):
+4℃の10mLのCH2Cl2中のDL−トレオ−2−アミノ−3−ヒドロキシ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−1−オン二塩酸塩化合物22(0.15g,0.49mmol)の攪拌した溶液にトリエチルアミン(200μL,1.45mmol)を加え、CH2Cl23mL中の酸クロリドをゆっくりと加えた。混合物を窒素下、室温にて一晩攪拌した後、CH2Cl2と1N炭酸ナトリウム水溶液との間に分配した。有機層を蒸発させ、得られた残留物をシリカのカラムクロマトグラフィー(EtOAc:MeOH=95:5)により精製した。0℃のMeOH中、ジエチルエーテル中の0.3MHClを加え、溶媒を留去し、アシル化化合物を乾燥して塩酸塩を得た。
化合物をベンジルクロロホルマート(91mg、0.53mmol)を用いて、方法Gにしたがって調製した。精査して、DL−トレオ−3−ヒドロキシ−1−オキソ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−2−イルカルバミン酸ベンジル塩酸塩、化合物58を白色の固体(90mg、収率46%)として得た。
Rf:0.38(MeOH:EtOAc=10:90)、遊離の塩基
1H-NMR (CD3OD,δ): 1.87-2.03 (m, 4H, 2xCH2), 3.40-3.48 (m, 2H, CH2N), 3.56-3.62 (m, 2H, CH2N), 4.85-5.04 (m, 3H, CH2O, CHO), 5.39 (d, 1H, J=2.8 Hz, NH), 7.26-7.36 (m, 5H, ArH), 8.12 (d, 2H, J=6.0 Hz, ArH), 8.69 (d, 2H, J=6.0 Hz, ArH).
13C-NMR (CD3OD,δ): 25.0, 27.0, 47.5, 48.0, 58.8, 67.9, 72.7, 126.6 (2xC), 129.1, 129.2, 129.5, 138.1, 141.9 (2xC), 158.1, 164.4, 169.2.
MS−ESI m/z(%rel.Int.):370.1([MH]+,15)、219.0(100)
HPLC:方法A、検出UV 254nm、化合物58 RT=4.10分、ピーク面積 99.8%
6℃のDMSO:DMF(2mL:0.2mL)混合物中のDL−トレオ−3−ヒドロキシ−1−オキソ−3−(ピリジン−4−イル)−1−(ピロリジン−1−イル)プロパン−2−イルカルバメート化合物58遊離塩基(0.10g,0.27mmol)の攪拌した溶液に、tert−BuOK(38mg,0.33mmol)および硫酸ジメチル(26μL,0.27mmol)をゆっくりと加えた。窒素下、室温で15時間混合物を攪拌し、氷水(5mL)、1M Na2CO3(2mL)および酢酸エチル(100mL)の間に分配した。有機相をブライン(20mL)で洗浄し、MgSO4で乾燥した。酢酸エチルを留去した後、粗製物を乾燥して粗製の遊離塩基を油として得た。0℃のMeOH中、ジエチルエーテル中0.3MHCl溶液を用いて塩酸塩を得た。ジエチルエーテル中で沈殿させて、トランス−3−メチル−5−ピリジン−4−イル−4−(ピロリジン−1−カルボニル)−オキサゾリジン−2−オン塩酸塩を淡黄色の固体(80mg,95%の収率)として得た。EtOAc:MeOH(10:1)中でさらに結晶化させて化合物70を白色の固体(16mg,20%の収率)として得た。
Rf:0.15(EtOAc:MeOH=95:5),遊離塩基.
1H−NMR(CD3OD,δ):1.90−2.10(m,4H,2xCH2),2.84(s,3H,CH3),3.47−3.70(m,4H,CH2N),4.82(m,1H,CH),5.89(m,1H,CH),8.17(m,2H,ArH),8.97(m,2H,ArH).
13C−NMR(CD3OD, δ):24.9,27.1,30.2,48.1,64.9,76.3,125.6(2xC),143.8(2xC),159.1,160.1,167.3.
MS−ESIm/z(%rel.Int.):276.1([MH]+,25),177.1(100).
HPLC:方法A,検出UV254nm,化合物70RT=2.00min,ピーク面積97.0%.
Claims (26)
- R4がHである請求項2記載の化合物。
- R4がHである請求項5記載の化合物。
- R4がHである請求項7記載の化合物。
- R4がHである請求項9記載の化合物。
- R4がHである請求項11記載の化合物。
- 鎮痛剤の製造のための請求項1記載の化合物の使用。
- 鎮痛剤の製造のための請求項2記載の化合物の使用。
- 鎮痛剤の製造のための請求項4記載の化合物の使用。
- 鎮痛剤の製造のための請求項5記載の化合物の使用。
- 鎮痛剤の製造のための請求項7記載の化合物の使用。
- 鎮痛剤の製造のための請求項9記載の化合物の使用。
- 鎮痛剤の製造のための請求項11記載の化合物の使用。
- 請求項1記載の化合物を有効成分とする鎮痛剤。
- 請求項2記載の化合物を有効成分とする鎮痛剤。
- 請求項4記載の化合物を有効成分とする鎮痛剤。
- 請求項5記載の化合物を有効成分とする鎮痛剤。
- 請求項7記載の化合物を有効成分とする鎮痛剤。
- 請求項9記載の化合物を有効成分とする鎮痛剤。
- 請求項11記載の化合物を有効成分とする鎮痛剤。
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JP2007553191A Expired - Fee Related JP5042040B2 (ja) | 2005-01-26 | 2006-01-25 | 鎮痛活性および/または免疫賦活活性を有する1−アリール−1−ヒドロキシ−2,3−ジアミノ−プロピルアミン、1−ヘテロアリール−1−ヒドロキシ−2,3−ジアミノ−プロピルアミンおよび関連化合物 |
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JP2012085676A Pending JP2012162546A (ja) | 2005-01-26 | 2012-04-04 | 鎮痛活性および/または免疫賦活活性を有する3−ヘテロアリール−3−ヒドロキシ−2−アミノ−プロピルアミンおよび関連化合物 |
JP2012085680A Pending JP2012162547A (ja) | 2005-01-26 | 2012-04-04 | 鎮痛活性および/または免疫賦活活性を有する3−アリール−3−ヒドロキシ−2−アミノ−プロピオン酸アミド、3−ヘテロアリール−3−ヒドロキシ−2−アミノ−プロピオン酸アミドおよび関連化合物 |
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JP2007553179A Expired - Fee Related JP5039564B2 (ja) | 2005-01-26 | 2006-01-25 | 鎮痛薬としての1−ベンジル−1−ヒドロキシ−2,3−ジアミノ−プロピルアミン、3−ベンジル−3−ヒドロキシ−2−アミノ−プロピオン酸アミドおよび関連化合物の使用方法 |
JP2007553191A Expired - Fee Related JP5042040B2 (ja) | 2005-01-26 | 2006-01-25 | 鎮痛活性および/または免疫賦活活性を有する1−アリール−1−ヒドロキシ−2,3−ジアミノ−プロピルアミン、1−ヘテロアリール−1−ヒドロキシ−2,3−ジアミノ−プロピルアミンおよび関連化合物 |
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