JP6163210B2 - 窒素含有モルフィナン誘導体およびその使用 - Google Patents
窒素含有モルフィナン誘導体およびその使用 Download PDFInfo
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- JP6163210B2 JP6163210B2 JP2015547159A JP2015547159A JP6163210B2 JP 6163210 B2 JP6163210 B2 JP 6163210B2 JP 2015547159 A JP2015547159 A JP 2015547159A JP 2015547159 A JP2015547159 A JP 2015547159A JP 6163210 B2 JP6163210 B2 JP 6163210B2
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- Prior art keywords
- alkyl
- halo
- group
- alkylamino
- alkoxy
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- -1 Nitrogen-containing morphinan derivatives Chemical class 0.000 title claims description 185
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 93
- 125000001424 substituent group Chemical group 0.000 claims description 81
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Classifications
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
Landscapes
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- Rheumatology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
R1は、水素、OH、ハロ、シアノ、カルボキシ、もしくはアミノカルボニルであるか、またはアルキル、アルケニル、アルキニル、アルコキシ、アルケニルオキシ、もしくはアルキニルオキシ(これらのうちのいずれかは、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されている)であるか、または−O−PG(式中、PGはヒドロキシル保護基である)であり、
R2は、
(a)水素もしくはカルボキサミドであるか、または
(b)アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、(シクロアルキル)アルキル、(シクロアルケニル)アルキル、(ヘテロシクロ)アルキル、アリールアルキル、ヘテロアリールアルキル、アルキルカルボニル、アルコキシカルボニル、(アリールアルコキシ)カルボニル、または(ヘテロアリールアルコキシ)カルボニルであり、これらのうちのいずれかは、ヒドロキシ、アルキル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されており、
R3は、水素、OH、もしくはハロであるか、またはアルコキシ、アルキルアミノ、もしくはジアルキルアミノ(これらのうちのいずれかは、ヒドロキシル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されている)であり、
R4は水素であるか、または
R3およびR4は一緒になって結合を形成し、
Zは、
a)水素、
b)(シクロアルキル)アルキル、
c)(シクロアルケニル)アルキル、
d)アリールアルキル、
e)ヘテロアリールアルキル、
f)(ヘテロシクロ)アルキル、
g)−アルキル−C(=O)NR5R6、
h)−アルキル−C(=O)OR7、
i)−C(=O)−アルキル−NR8R9、
j)−C(=O)−アルキル−OR10、および
k)シアノアルキル
からなる群から選択され、
前記シクロアルキル、アリール、ヘテロアリールおよびヘテロシクロ部分は、アルキル、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、
R5〜R10は、水素、アルキル、およびアリールからなる群からそれぞれ独立して選択され、前記アルキルおよびアリール基は、アルキル、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1または2つの置換基で場合によって置換されており、
各R11は、ヒドロキシ、アルキル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、およびアルコキシカルボニルからなる群から独立して選択され、
YはC=OまたはCH2である)
で表される化合物または薬学的に許容されるその塩もしくは溶媒和物である。
a)水素、
b)(シクロアルキル)(C1〜6)アルキル、
c)(シクロアルケニル)(C1〜6)アルキル、
d)アリール(C1〜6)アルキル、
e)ヘテロアリール(C1〜6)アルキル、
f)(ヘテロシクロ)(C1〜6)アルキル、
g)−(C1〜6)アルキル−C(=O)NR5R6、
h)−(C1〜6)アルキル−C(=O)OR7、
i)−C(=O)−(C1〜6)アルキル−NR8R9、
j)−C(=O)−(C1〜6)アルキル−OR10、および
k)シアノ(C1〜6)アルキル
からなる群から選択され、
このシクロアルキル、アリール、ヘテロアリールおよびヘテロシクロ部分が、C1〜6アルキル、ヒドロキシ、ハロ、ハロ(C1〜6)アルキル、アミノ、C1〜6アルキルアミノ、ジ(C1〜6)アルキルアミノ、カルボキシ、C1〜6アルコキシ、C1〜6アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、
R5〜R10が、水素、C1〜6アルキル、およびC6〜10アリールからなる群からそれぞれ独立して選択され、このアルキルおよびアリール基が、C1〜6アルキル、ヒドロキシ、ハロ、ハロ(C1〜6)アルキル、アミノ、C1〜6アルキルアミノ、ジ(C1〜6)アルキルアミノ、カルボキシ、C1〜6アルコキシ、C1〜6アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1または2つの置換基で場合によって置換されている、式I〜IXのうちのいずれか1つの化合物である。
a)水素、
b)(C3〜7シクロアルキル)(C1〜6)アルキル、
c)(C3〜7シクロアルケニル)(C1〜6)アルキル、
d)C6〜12アリール(C1〜6)アルキル、
e)(5〜10員のヘテロアリール)(C1〜6)アルキル、
f)(3〜10員のヘテロシクロ)(C1〜6)アルキル、
g)−(C1〜6)アルキル−C(=O)NR5R6、
h)−(C1〜6)アルキル−C(=O)OR7、
i)−C(=O)−(C1〜6)アルキル−NR8R9、
j)−C(=O)−(C1〜6)アルキル−OR10、および
k)−(CH2)1〜6−CN
からなる群から選択され、
このシクロアルキル、アリール、ヘテロアリールおよびヘテロシクロ部分が、C1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、C1〜4アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、
R5〜R10が、水素、C1〜4アルキル、およびフェニルからなる群からそれぞれ独立して選択され、このアルキルおよびフェニル基が、非置換であるか、またはC1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、C1〜4アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1もしくは2つの置換基で置換されている、式I〜IXのうちのいずれか1つの化合物である。
g)−(C1〜4)アルキル−C(=O)NR5R6、
h)−(C1〜4)アルキル−C(=O)OR7、
i)−C(=O)−(C1〜4)アルキル−NR8R9、および
j)−C(=O)−(C1〜4)アルキル−OR10
からなる群から選択され、
R5〜R10が、水素、C1〜4アルキル、およびフェニルからなる群からそれぞれ独立して選択され、このアルキルおよびフェニル基が非置換であるか、またはC1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、C1〜4アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1もしくは2つの置換基で置換されている、式I〜IXのうちのいずれか1つの化合物である。好ましくは、本発明のこの態様では、Zは、
g)−(C1〜2)アルキル−C(=O)NH2、
h)−(C1〜2)アルキル−C(=O)OR7、
i)−C(=O)−(C1〜2)アルキル−NR8R9、および
j)−C(=O)−(C1〜2)アルキル−OR10
からなる群から選択され、
R7、R8、R9、およびR10は、水素、メチル、またはエチルからなる群からそれぞれ独立して選択される。
で表される(シクロプロピル)メチルである、式Iの化合物、ならびに薬学的に許容されるその塩および溶媒和物である。
(a)適切なモルフィナンケトン、例えば、式XIIの化合物、
酸の存在下で、ジオールHO−CH2−(CH2)n−OH(式中、nは少なくとも1である)と反応させることによって、式XIVの化合物
(b)式XIVの化合物を、脱水剤と反応させることによって、式XVの化合物
(c)式XVの化合物を酸で処理することによって、式XVIの化合物
(d)式XVIの化合物を酸化させることによって、式XVIIの化合物
(e)式XVIIの化合物に還元的アミノ化を行うことによって、式XVIIIおよび式XIXの化合物
本発明の化合物は、本開示を考慮して当業者に公知の方法を使用して、または以下のスキームに示されている例示的方法により調製することができる。例えば、YがC=Oである式I〜XIの化合物は、以下のスキーム1に示されているように調製することができる。YがCH2である式I〜XIの化合物は、以下のスキーム2に示されているように調製することができる。合成の追加的方法は、以下に記述されている実施例において記載および例示されている。
μ−オピオイド受容体結合実験の手順:μ−オピオイド受容体に対する放射リガンド投与置換結合実験では、最終容量500μlの結合緩衝液(10mM MgCl2、1mM EDTA、5%DMSO、50mM HEPES、pH7.4)中の5mg膜タンパク質/穴と共に、0.3nM[3H]−ジプレノルフィン(Perkin Elmer、Shelton、CT)を使用した。反応は、非標識ナロキソンの不在下または増加濃度での非標識ナロキソンの存在下で行った。すべての反応は、96穴深底ポリプロピレンプレートの中で、室温で2時間行った。96穴組織ハーベスター(Perkin Elmer、Shelton、CT)を用いて0.5%ポリエチレンイミン中に予浸させておいた、96穴Unifilter GF/C濾過プレート(Perkin Elmer、Shelton、CT)への急速濾過により結合反応を終了させ、続いて500μlの氷冷した結合緩衝液で3回濾過洗浄を実施した。濾過プレートを、続いて50℃で2〜3時間乾燥させた。BetaScintシンチレーション反応混液(Perkin Elmer、Shelton、CT)を加え(50μl/穴)、Packard Top−Countを用いて、1分/穴の間、プレートをカウントした。GraphPad PRISM(商標)v.3.0以上(San Diego、Calif.)の、ワンサイト競合カーブフィッティング機能を用いて、またはワンサイト競合カーブフィッティング用の自社機能を用いて、データを解析した。
試験動物:各実験では、実験の開始時に体重が200〜260gのラットを用いる。これらのラットは、群で収容し、投薬より約16時間前に飼料を撤去する本発明の化合物の経口投与前を除いては、飼料および水を常時自由摂取させる。対照群は、本発明の化合物で治療したラットとの比較の役割を果たす。対照群には、本発明の化合物用の担体を投与する。対照群に投与した担体の量は、試験群に投与した担体と本発明の化合物の量と同じである。
足圧力アッセイを使用して、機械的痛覚過敏を評価することができる。このアッセイでは、C.Stein、「Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation:Alterations in Behavior and Nociceptive Thresholds」、Pharmacol.Biochem.and Behavior 31:451-455(1988年)に記載の通り、アナルゲシメーター(モデル7200、イタリアのUgo Basileから市販)を用いて、侵害性の機械的刺激に対する後足引っ込め閾値(PWT)を測定する。ラットを穏やかに拘束し、その後足を小さな丸いプラットフォーム上に置き、段階的な方式で後足の背側の表面に点状の圧力を加える。後足にかかる最大重量を250gに設定し、足の完全な引っ込みとしてエンドポイントを取る。各時間点で、各ラットに対して一度ずつPWTを測定し、影響のあった(同側、つまり傷と同じ側)後足のみを試験するか、または同側と反対側(非傷害の、つまり傷の反対側)の両方の後足を試験する。
本発明の化合物は、その活性により、ヒトのおよび獣医薬において好都合に有用である。上述のように、本発明の化合物は、それを必要とする患者において、ある状態を治療または予防するために有用である。本発明の化合物は、オピオイド受容体の調節を必要とする任意の患者に投与することができる。「患者」という用語は、本明細書で使用する場合、本発明の化合物の有利な作用を経験し得る任意の動物を指す。一番のこのような動物は、哺乳動物、例えば、ヒトおよび伴侶動物であるが、ただし、本発明は、これらに限定されることを意図していない。
(実施例)
(5R,10bR)−13−(シクロプロピルメチル)−9−メトキシ−3−(4−メトキシベンジル)−5,6−ジヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−2(3H)−オン(2)
(4aS,5R,10bS)−13−(シクロプロピルメチル)−9−メトキシ−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−2(3H)−オン(3)
2−((4aS,5R,10bS)−13−(シクロプロピルメチル)−9−ヒドロキシ−2−オキソ−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−3(2H)−イル)アセトアミド(4)
(4aS,5R,10bS)−13−(シクロプロピルメチル)−9−ヒドロキシ−3−(4−ヒドロキシベンジル)−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−2(3H)−オン(5)
(5R,10bR)−13−(シクロプロピルメチル)−9−ヒドロキシ−3−(4−ヒドロキシベンジル)−5,6−ジヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−2(3H)−オン(6)
(4aS,5R,10bS)−13−(シクロプロピルメチル)−9−ヒドロキシ−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−2(3H)−オン(7)
2−((4aS,5R,10bS)−13−(シクロプロピルメチル)−9−ヒドロキシ−2−オキソ−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−3(2H)−イル)酢酸(8)
1H NMR:δH (400 MHz, CD3OD): 6.80 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.3, 2.4 Hz, 1H), 3.81-3.75 (m, 1H), 3.75-3.67 (m, 1H), 3.67-3.60 (m, 1H), 3.60-3.55 (m, 4H), 2.89 (d, J = 18.1 Hz, 2H), 2.65 (dd, J = 18.8, 5.7 Hz, 1H), 2.45-2.15 (m, 4H), 2.01-1.84 (m, 4H), 1.62 (dt, J = 4.8, 18.8 Hz, 1H), 1.32 (t, J = 12.9 Hz, 2H), 0.92 (d, J = 9.8 Hz, 1H), 0.77-0.65 (m, 1H), 0.41-0.31 (m, 2H), 0.05- -0.05 (m, 2H).
LC/MS、m/z=385.2[M+H]+(計算値:385.50)。
1H NMR:δH (400 MHz, CD3OD): 6.81 (d, J = 8.3 Hz, 1H), 6.57-6.51 (m, 2H), 5.42 (dd, J = 4.8, 3.0 Hz, 1H), 3.91-3.85 (m, 1H), 3.83-3.66 (m, 3H), 3.58 (s, 3H), 3.52 (d, J = 5.7 Hz, 1H), 3.00 (d, J = 17.5 Hz, 1H), 2.74 (dd, J = 17.7, 6.1 Hz, 1H), 2.55 (dd, J = 12.5, 2.8 Hz, 1H), 2.36-2.27 (m, 2H), 2.27-2.12 (m, 4H), 2.09-1.97 (m, 2H), 1.18-1.06 (m, 1H), 0.77-0.66 (m, 1H), 0.37 (d, J = 7.7 Hz, 2H), 0.05- -0.05 (m, 2H).
LC/MS、m/z=367.2[M+H]+(計算値:367.48)。
1H NMR:δH (400 MHz, CD3OD): 6.77 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 10.0, 1.7 Hz, 1H), 6.54 (d, J = 2.6 Hz, 1H), 6.47 (dd, J = 8.5, 2.6 Hz, 1H), 5.60 (dd, J = 10.0, 2.8 Hz, 1H), 3.50 (s, 3H), 3.41 (t, J = 3.9 Hz, 1H), 3.02 (d, J = 16.0 Hz, 1H), 2.86-2.79 (m, 2H), 2.61-2.54 (m, 1H), 2.49-2.33 (m, 3H), 2.19 (dd, J = 12.7, 6.7 Hz, 1H), 1.90-1.78 (m, 2H), 1.35-1.26 (m, 1H), 0.76-0.65 (m, 1H), 0.40-0.32 (m, 2H), 0.05- -0.57 (m, 2H).
LC/MS、m/z=323.4[M+H]+(計算値:323.43)。
LC/MS、m/z=343.4[M+H]+(計算値:343.41)。
化合物1:1H NMR:δH(400 MHz, CD3OD): 7.00 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.81 (dd, J = 8.3, 2.4 Hz, 1H), 6.60-6.51 (m, 3H), 4.60 (d, J = 14.9 Hz, 1H), 4.08-4.03 (m, 0.8H), 4.01-3.91 (m, 1.2H), 3.72 (s, 3H), 3.62 (s, 3H), 3.35-3.22 (m, 3.2H), 3.19-3.10 (m, 1.4H), 3.09-2.90 (m, 2.6H), 2.83-2.70 (m, 1.2H), 2.69-2.55 (m, 1.8H), 2.50 (d, J = 17.3 Hz, 0.8H), 2.07 (td, J = Hz, 0.2H), 1.96 (dt, J = 4.8, 14.2 Hz, 0.8H), 1.78 (d, J = 13.1 Hz, 0.8H), 1.61 (d, J = 14.2 Hz, 0.2H), 1.06-0.93 (m, 1H), 0.72-0.63 (m, 2H), 0.40-0.30 (m, 2H).
LC/MS、m/z=446.3[M+H]+(計算値:446.58)。
化合物2:1H NMR:δH(400 MHz, CD3OD): 7.09-6.99 (m, 3H), 6.80-6.70 (m, 4H), 6.41 (d, J = 34.0 Hz, 1H), 4.72 (d, J = 14.2 Hz, 0.5H), 4.62-4.48 (m, 1.5H), 4.40-4.31 (m, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.37-3.23 (m, 3.5H), 3.19-3.09 (m, 0.8H), 3.08-2.94 (m, 2.3 H), 2.91-2.80 (m, 1H), 2.67 (t, J = 13.3 Hz, 0.5H), 2.14 (t, J = 12.9 Hz, 1H), 1.73 (dd, J = 67, 13.5 Hz, 1H), 1.05-0.89 (m, 1H), 0.70-0.60 (m, 2H), 0.40- 0.17 (m, 2H).
LC/MS、m/z=444.2[M+H]+(計算値:444.57)。
1H NMR:δH (400 MHz, CD3OD): 7.10 (d, J = 8.5 Hz, 1H), 6.83(d, J = 2.6 Hz, 1H), 6.78 (dd, J = 8.3, 2.4 Hz, 1H), 4.12 (s, 0.8H), 4.00 (s, 0.2H), 3.68 (s, 3H), 3.45-3.23 (m, 2.7H), 3.19-3.00 (m, 4.1H), 3.00-2.92 (m, 0.2H), 2.92-2.77 (m, 1.1H), 2.64 (dt, J = 3.2, 13.1 Hz, 1H), 2.59-2.47 (m, 1H), 2.39 (d, J = 17.5 Hz, 0.8H), 2.06 (dt, J = 3.0, 14.6 Hz, 0.2H), 1.96 (dt, J = 4.8, 14.2 Hz, 0.8H), 1.76 (d, J = 14.2 Hz, 0.8H), 1.58 (d, J = 14.0 Hz, 0.2H), 1.11-0.97 (m, 1H), 0.75-0.65 (m, 2H), 0.43-0.33 (m, 2H).
LC/MS、m/z=326.1[M+H]+(計算値:326.43)。
1H NMR:δH (400 MHz, CD3OD): 6.90 (d, J = 8.5 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.3, 2.1 Hz, 1H), 3.87 (d, J = 16.7 Hz, 1H), 3.55 (s, 3H), 3.37 (d, J = 16.6 Hz, 1H), 3.28 (広幅, 1H), 3.21 (dd, J = 12.2, 6.5 Hz, 1H), 3.00 (d, J = 17.3 Hz, 1H), 2.90-2.80 (m, 2H), 2.65-2.50 (m, 2H), 2.41-2.25 (m, 4H), 1.94 (t, J = 12.2 Hz, 1H), 1.67 (dt, J = 5.0, 12.5 Hz, 1H), 1.35 (d, J = 12.7 Hz, 1H), 0.76-0.64 (m, 1H), 0.37 (d, J = 7.8 Hz, 2H), 0.05- -0.08 (m, 2H).
LC/MS、m/z=383.2[M+H]+(計算値:383.48)。
1H NMR:δH (400 MHz, CD3OD): 7.01 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 8.3, 2.2 Hz, 1H), 4.13 (d, J = 16.6 Hz, 1H), 3.45-3.25 (m, 4H), 3.19-2.92 (m, 5.4H), 2.84-2.75 (m, 0.2H), 2.75-2.55 (m, 1.8H), 2.51 (d, J = 17.3 Hz, 0.8H), 2.06 (dt, J = 3.6, 14.0 Hz, 0.2H), 1.95 (td, J = 4.6, 14.0 Hz, 0.8H), 1.75 (d, J = 13.3 Hz, 0.8H), 1.56 (d, J = 14.2 Hz, 0.2H), 1.11-0.97 (m, 1H), 0.75-0.63 (m, 2H), 0.45-0.33 (m, 2H).
LC/MS、m/z=369.2[M+H]+(計算値:369.46)。
LC/MS、m/z=418.2[M+H]+(計算値:418.53)。
LC/MS、m/z=416.1[M+H]+(計算値:416.51)。
LC/MS、m/z=312.2[M+H]+(計算値:312.41)。
1H NMR:δH (400 MHz, CD3OD): 7.00 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 8.3, 2.4 Hz, 1H), 4.14-3.95 (m, 2H), 3.60 (d, J = 17.5 Hz, 1H), 3.44-3.24 (m, 2.8H), 3.18-2.93 (m, 5H), 2.82-2.52 (m, 2H), 2.47 (d, J = 17.5 Hz, 0.8H), 2.06 (t, J = 13.3 Hz, 0.2H), 1.93 (dt, J = 4.3, 13.2 Hz, 0.8H), 1.75 (d, J = 14.0 Hz, 0.8H), 1.55 (d, J = 13.5 Hz, 0.2H), 1.10-0.96 (m, 1H), 0.75-0.65 (m, 2H), 0.45-0.34 (m, 2H).
LC/MS、m/z=370.2[M+H]+(計算値:370.44)。
(4aS,5R,10bR)−13−(シクロプロピルメチル)−9−メトキシ−2,3,4,4a,5,6−ヘキサヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン(10)
2−((4aS,5R,10bR)−13−(シクロプロピルメチル)−9−ヒドロキシ−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−3(2H)−イル)アセトアミド(11)
(4aS,5R,10bR)−13−(シクロプロピルメチル)−3−(4−ヒドロキシベンジル)−2,3,4,4a,5,6−ヘキサヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−9−オール(12)
(4aS,5R,10bR)−13−(シクロプロピルメチル)−2,3,4,4a,5,6−ヘキサヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−9−オール(13)
(S)−2−アミノ−1−((4aS,5R,10bS)−13−(シクロプロピルメチル)−9−ヒドロキシ−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−3(2H)−イル)プロパン−1−オン(14)
2−((4aS,5R,10bR)−13−(シクロプロピルメチル)−9−ヒドロキシ−4,4a,5,6−テトラヒドロ−1H−5,10b−(エピミノエタノ)ベンゾ[f]イソキノリン−3(2H)−イル)酢酸(15)
1H NMR:δH (400 MHz, CD3OD): 7.27 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.7 Hz, 1H), 6.90-6.82 (m, 4H), 4.12-3.97 (m, 3H), 3.71 (s, 3H), 3.69 (s, 3H), 3.41-3.27 (m, 3H), 3.19-3.12 (m, 1.5H), 3.07-2.90 (m, 1.8H), 2.82-2.47 (m, 5H), 2.00-1.80 (m, 2H), 1.77-1.66 (m, 1H), 1.07-0.92 (m, 1H), 0.70-0.60 (m, 2H), 0.34 (d, J = 3.0 Hz, 2H).
LC/MS、m/z=432.2[M+H]+(計算値:432.60)。
1H NMR:δH (400 MHz, CD3OD): 7.15 (d, J = 8.7 Hz, 1H), 6.87-6.81 (m, 2H), 4.03 (s, 0.9H), 3.92 (s, 0.1H), 3.70 (s, 3H), 3.45-3.22 (m, 3.6H), 3.20-3.15 (m, 1.4H), 3.07-2.94 (m, 1.8H), 2.82-2.53 (m, 5H), 2.02-1.68 (m, 3H), 1.12-0.94 (m, 1H), 0.67 (d, J 7.0 = Hz, 2H), 0.35 (d, J = 3.5 Hz, 2H).
LC/MS、m/z=312.2[M+H]+(計算値:312.45)。
LC/MS、m/z=483.4[M+H]+(計算値:483.64)。
LC/MS、m/z=384.4[M+H]+(計算値:384.51)。
LC/MS、m/z=369.2[M+H]+(計算値:369.50)。
1H NMR:δH (400 MHz, CD3OD): 7.05 (d, J = 8.1 Hz, 1H), 6.74-6.65 (m, 2H), 4.04-3.90 (m, 1H), 3.85-3.70 (m, 2H), 3.60-3.26 (m, 3.5H), 3.05-2.85 (m, 3H), 2.81-2.53 (m, 4H), 1.95 (t, J = 13.1 Hz, 2H), 1.73 (d, J = 13.1 Hz, 1H), 1.10-0.93 (m, 1H), 0.72-0.60 (m, 2H), 0.42-0.30 (m, 2H).
LC/MS、m/z=355.2[M+H]+(計算値:355.47)。
LC/MS、m/z=404.1[M+H]+(計算値:404.54)。
LC/MS、m/z=298.3[M+H]+(計算値:298.42)。
LC/MS、m/z=369.2[M+H]+(計算値:369.50)。
1H NMR:δH (400 MHz, CD3OD): 7.04 (d, J = 8.3 Hz, 1H), 6.76-6.65 (m, 2H), 4.05-3.95 (m, 1H), 3.85-3.43 (m, 5H), 3.35 (d, J = 12.2 Hz, 1.5H), 3.16 (d, J = 20.4 Hz, 1.5H), 3.05-2.82 (m, 3H), 2.80-2.51 (m, 4H), 2.10-1.49 (m, 4H), 1.10-0.95 (m, 1H), 0.71-0.63 (m, 2H), 0.42-0.32 (m, 2H).
LC/MS、m/z=356.1[M+H]+(計算値:356.46)。
Claims (23)
- 式Iの化合物:
R1は、水素、OH、ハロ、シアノ、カルボキシ、もしくはアミノカルボニルであるか、またはアルキル、アルケニル、アルキニル、アルコキシ、アルケニルオキシ、もしくはアルキニルオキシ(これらのうちのいずれかは、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されている)であり、
R2は、
(a)水素もしくはカルボキサミドであるか、または
(b)アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、(シクロアルキル)アルキル、(シクロアルケニル)アルキル、(ヘテロシクロ)アルキル、アリールアルキル、ヘテロアリールアルキル、アルキルカルボニル、アルコキシカルボニル、(アリールアルコキシ)カルボニル、または(ヘテロアリールアルコキシ)カルボニルであり、これらのうちのいずれかは、ヒドロキシ、アルキル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されており、
R3は、水素、OH、もしくはハロであるか、またはアルコキシ、アルキルアミノ、もしくはジアルキルアミノ(これらのうちのいずれかは、ヒドロキシル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されている)であり、
R4は水素であるか、または
R3およびR4は一緒になって結合を形成し、
Zは、
a)水素、
b)(シクロアルキル)アルキル、
c)(シクロアルケニル)アルキル、
d)アリールアルキル、
e)ヘテロアリールアルキル、
f)(ヘテロシクロ)アルキル、
g)−アルキル−C(=O)NR5R6、
h)−アルキル−C(=O)OR7、
i)−C(=O)−アルキル−NR8R9、
j)−C(=O)−アルキル−OR10、および
k)シアノアルキル
からなる群から選択され、
前記シクロアルキル、アリール、ヘテロアリールおよびヘテロシクロ部分は、アルキル、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、
R5、R6、R7、R8、R9、およびR10は、水素、アルキル、およびアリールからなる群からそれぞれ独立して選択され、前記アルキルおよびアリール基は、アルキル、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1または2つの置換基で場合によって置換されており、
各R11は、ヒドロキシ、アルキル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、およびアルコキシカルボニルからなる群から独立して選択され、
YはC=OまたはCH2である)
または薬学的に許容されるその塩もしくは溶媒和物。 - 式II、III、IVまたはV:
- 式VI、VII、VIIIまたはIX:
- R1が水素、OH、ハロ、シアノ、カルボキシ、もしくはアミノカルボニルであるか、またはアルキル、アルケニル、アルキニル、アルコキシ、アルケニルオキシ、もしくはアルキニルオキシ(これらのうちのいずれかは、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されている)である、請求項1から3のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。
- R1がOHまたは非置換のC1〜6アルコキシである、請求項1から4のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。
- R2が、ヒドロキシ、C1〜4アルキル、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、およびC1〜4アルコキシカルボニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されているC3〜7(シクロアルキル)(C1〜4)アルキルまたはC3〜7(シクロアルケニル)(C1〜4)アルキルである、請求項1から5のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。
- R2が、ヒドロキシ、C1〜4アルキル、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、およびC1〜4アルコキシカルボニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されているシクロプロピル(C1〜4)アルキル、シクロブチル(C1〜4)アルキル、シクロペンチル(C1〜4)アルキル、またはシクロヘキシル(C1〜4)アルキルである、請求項1から6のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。
- R3が水素である、請求項1から7のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。
- Zが、
a)水素、
b)(C3〜7シクロアルキル)(C1〜6)アルキル、
c)(C3〜7シクロアルケニル)(C1〜6)アルキル、
d)C6〜12アリール(C1〜6)アルキル、
e)(5〜10員の)ヘテロアリール(C1〜6)アルキル、
f)(3〜10員の)(ヘテロシクロ)(C1〜6)アルキル、
g)−(C1〜6)アルキル−C(=O)NR5R6、
h)−(C1〜6)アルキル−C(=O)OR7、
i)−C(=O)−(C1〜6)アルキル−NR8R9、
j)−C(=O)−(C1〜6)アルキル−OR10、および
k)−(CH2)1〜6−CN
からなる群から選択され、
前記シクロアルキル、アリール、ヘテロアリールおよびヘテロシクロ部分が、C1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、C1〜4アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、
R5、R6、R7、R8、R9、およびR10が、水素、C1〜4アルキル、およびフェニルからなる群からそれぞれ独立して選択され、前記アルキルおよびフェニル基が非置換であるか、またはC1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、C1〜4アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1もしくは2つの置換基で置換されている、請求項1から8のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。 - Zが水素である、または、
ZがC6〜12アリール(C1〜4)アルキルであり、前記アリール部分が、C1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜2)アルキル、アミノ、C1〜2アルキルアミノ、ジ(C1〜2)アルキルアミノ、カルボキシ、C1〜2アルコキシ、C1〜2アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1または2つの置換基で場合によって置換されている、請求項1から9のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。 - Zが非置換のベンジルであるか、またはC1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜2)アルキル、アミノ、C1〜2アルキルアミノ、ジ(C1〜2)アルキルアミノ、カルボキシ、C1〜2アルコキシ、C1〜2アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1もしくは2つの置換基で置換されているベンジルである、請求項1から10のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。
- Zが、
g)−(C1〜4)アルキル−C(=O)NR5R6、
h)−(C1〜4)アルキル−C(=O)OR7、
i)−C(=O)−(C1〜4)アルキル−NR8R9、および
j)−C(=O)−(C1〜4)アルキル−OR10
からなる群から選択され、
R5、R6、R7、R8、R9、およびR10が、水素、C1〜4アルキル、およびフェニルからなる群からそれぞれ独立して選択され、前記アルキルおよびフェニル基が非置換であるか、またはC1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜4)アルキル、アミノ、C1〜4アルキルアミノ、ジ(C1〜4)アルキルアミノ、カルボキシ、C1〜4アルコキシ、C1〜4アルコキシカルボニル、およびアミノカルボニルからなる群からそれぞれ独立して選択される1もしくは2つの置換基で置換されている、請求項1から9のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。 - Zが、
g)−(C1〜2)アルキル−C(=O)NH2、
h)−(C1〜2)アルキル−C(=O)OR7、
i)−C(=O)−(C1〜2)アルキル−NR8R9、および
j)−C(=O)−(C1〜2)アルキル−OR10
であり、
R7、R8、R9、およびR10が、水素、メチル、またはエチルからなる群からそれぞれ独立して選択される、請求項12に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。 - 式X:
R3およびR4は両方とも水素であるか、またはR3およびR4は一緒になって結合を形成し、
YはC=OまたはCH2であり、
Zは、
R13はC1〜4アルキルであり、R14は、C1〜4アルキル、ヒドロキシ、ハロ、ハロ(C1〜2)アルキル、C1〜2アルコキシ、C1〜2アルコキシカルボニル、およびアミノカルボニルからなる群から選択される)
を有する請求項1に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。 - R2が非置換のシクロプロピル(C1〜4)アルキルである、請求項1から13のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物。
-
- 請求項1から16のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物の治療有効量と、1種または複数の薬学的に許容される担体とを含む、医薬組成物。
- 細胞におけるオピオイド受容体機能をインビトロで調節する方法であって、オピオイド受容体を発現することが可能な細胞を、請求項1から16のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物の有効量と接触させることを含み、μ−もしくはκ−オピオイド受容体が調節されるか、またはμ−およびκ−オピオイド受容体の両方が調節される、前記インビトロで調節する方法。
- 疼痛、便秘、下痢、掻痒症、嗜癖障害、アルコール中毒の禁断症状または薬物中毒の禁断症状を治療または予防するための医薬品の製造における、請求項1から16のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物の使用。
- 疼痛を治療または予防するためのものである、請求項19に記載の使用。
- 前記疼痛が急性疼痛、慢性疼痛または外科疼痛であり、前記慢性疼痛が神経障害性疼痛、術後疼痛、または炎症性疼痛である、請求項19または20に記載の使用。
- 請求項1から16のいずれか一項に記載の化合物または薬学的に許容されるその塩もしくは溶媒和物の有効量を含有する滅菌容器と、療法的使用のための使用説明書とを含むキット。
- 式XVIIIまたは式XIXの化合物:
R1は、水素、OH、ハロ、シアノ、カルボキシ、もしくはアミノカルボニルであるか、またはアルキル、アルケニル、アルキニル、アルコキシ、アルケニルオキシ、またはアルキニルオキシ(これらのうちのいずれかは、ヒドロキシ、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されている)であり、
R2は、
(a)水素もしくはカルボキサミドであるか、または
(b)アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、(シクロアルキル)アルキル、(シクロアルケニル)アルキル、(ヘテロシクロ)アルキル、アリールアルキル、ヘテロアリールアルキル、アルキルカルボニル、アルコキシカルボニル、(アリールアルコキシ)カルボニル、または(ヘテロアリールアルコキシ)カルボニルであり、これらのうちのいずれかは、ヒドロキシ、アルキル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、アルコキシカルボニル、アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルからなる群からそれぞれ独立して選択される1、2、または3つの置換基で場合によって置換されており、前記アリール、ヘテロアリール、ヘテロシクロ、シクロアルキル、およびシクロアルケニルは、1、2、または3つの、独立して選択されるR11基で場合によって置換されており、
各R11は、ヒドロキシ、アルキル、ハロ、ハロアルキル、アミノ、アルキルアミノ、ジアルキルアミノ、カルボキシ、アルコキシ、およびアルコキシカルボニルからなる群から独立して選択される)を調製するための方法であって、
式XVIIの化合物:
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