JP5982063B2 - 1,3−ジオキサノモルフィドおよび1,3−ジオキサノコジド - Google Patents
1,3−ジオキサノモルフィドおよび1,3−ジオキサノコジド Download PDFInfo
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- JP5982063B2 JP5982063B2 JP2015529137A JP2015529137A JP5982063B2 JP 5982063 B2 JP5982063 B2 JP 5982063B2 JP 2015529137 A JP2015529137 A JP 2015529137A JP 2015529137 A JP2015529137 A JP 2015529137A JP 5982063 B2 JP5982063 B2 JP 5982063B2
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- Prior art keywords
- alkyl
- compound
- group
- heterocyclo
- hydrogen
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 381
- 125000000217 alkyl group Chemical group 0.000 claims description 248
- -1 heterocyclo Chemical group 0.000 claims description 143
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 86
- 238000000034 method Methods 0.000 claims description 84
- 229910052739 hydrogen Inorganic materials 0.000 claims description 73
- 239000001257 hydrogen Substances 0.000 claims description 73
- 125000003282 alkyl amino group Chemical group 0.000 claims description 72
- 208000002193 Pain Diseases 0.000 claims description 66
- 239000012453 solvate Substances 0.000 claims description 66
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 64
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 63
- 239000003814 drug Substances 0.000 claims description 61
- 125000001424 substituent group Chemical group 0.000 claims description 60
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 56
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 55
- 239000000203 mixture Substances 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 45
- 230000036407 pain Effects 0.000 claims description 41
- 238000009739 binding Methods 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- 230000027455 binding Effects 0.000 claims description 36
- 125000001188 haloalkyl group Chemical group 0.000 claims description 36
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 35
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 125000000304 alkynyl group Chemical group 0.000 claims description 22
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- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 4
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- HTMQZWFSTJVJEQ-UHFFFAOYSA-N benzylsulfinylmethylbenzene Chemical compound C=1C=CC=CC=1CS(=O)CC1=CC=CC=C1 HTMQZWFSTJVJEQ-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 201000007930 alcohol dependence Diseases 0.000 claims description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims description 2
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D491/12—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 three hetero rings
- C07D491/18—Bridged systems
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
- C07D489/10—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
- C07D489/12—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14 the bridge containing only two carbon atoms
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
GはR1またはヒドロキシル保護基PGであり、
R1は、水素、アルキル、アルケニル、アルキニル、(シクロアルキル)アルキル、(ヘテロシクロ)アルキル、アリールアルキル、またはヘテロアリールアルキルであり、そのシクロアルキル、ヘテロシクロ、アリール、およびヘテロアリール部分は、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、および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おり、
R2は、
(a)水素、シアノ、カルボキシ、アルコキシカルボニル、また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、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、および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、もしくは3つの置換基で場合によって置換されており、
R3およびR4は、水素、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、およびヘテロアリールアルキルからなる群からそれぞれ独立して選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
R5は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
R3は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
R4は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
G、R1、R2、R5および
R3は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
R4は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、水素以外である場合、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、および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おり、
G、R1、R2、R5および
R1が、水素、C1〜6アルキル、またはベンジルであり、
R2が、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、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、C2〜6アルケニル、シクロプロピル(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)アルキルであり、
R5が水素、C1〜6アルキル、またはフェニルである、式X〜XIIのうちのいずれか1つの化合物である。
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調製することができる。例えば、式I〜XVIIIの化合物は、以下のスキーム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。
本発明の化合物を調製するための、出発物質のα−エピマーA−2およびβ−エピマーA’−2の合成
本発明の化合物(α−エピマー)を調製するための中間体化合物の合成のための一般的スキーム
本発明の化合物の一般的合成
G基の修飾の例
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)
1H NMR δ (300 MHz, CDCl3): 6.71 (d, 1H), 6.48 (d, 1H), 6.20 (bs, 1H), 5.14 (bs, 1H). 4.17 (s, 1H), 2.96-2.91 (m, 2H), 2.83 (dd, 1H), 2.54 (dd, 1H), 2.31-2.09 (m, 5H), 1.92-1.80 (m, 2H), 1.48-1.4 (m, 5H), 1.31-1.24 (m, 2H), 1.04 (s, 9H), 0.99-0.94 (m, 1H), 0.81-0.76 (m, 1H), 0.64-0.58 (m, 1H), 0.51-0.47 (m, 2H), 0.10-0.08 (m, 2H).
LC/MS(ESI)、m/z=454.16[M=H]+(計算値:453.6)。
1H NMR δ (300 MHz, CDCl3): 6.70 (d, 1H), 6.51 (d, 1H), 5.03 (d, 1H). 4.78 (d, 1H), 4.25 (d, 1H), 3.01-2.95 (m, 1H), 2.89-2.80 (m, 1H), 2.63-2.62 (m, 1H), 2.37-2.01 (m, 8H), 1.75-1.70 (m, 1H), 1.45-1.23 (m, 5H), 1.15-1.02 (m, 11H), 0.81-0.73 (m, 2H), 0.51-0.46 (m, 2H), 0.11-0.08 (m, 2H).
LC/MS(ESI)、m/z=466.2[M=H]+(計算値:465.6)。
1H NMR δ (300 MHz, CDCl3): 6.68 (d, 1H), 6.50 (d, 1H), 4.91 (bs, 1H), 4.79 (t, 1H), 4.20 (d, 1H), 3.01-2.95 (m, 2H), 2.89-2.83 (m, 1H), 2.65-2.61 (m, 1H), 2.34-1.99 (m, 7H), 1.73-1.57 (m, 3H), 1.43-1.24 (m, 5H), 1.14-1.01 (m, 10H), 0.96-0.88 (m, 3H), 0.80-0.75 (m, 2H), 0.51-0.46 (m, 2H), 0.10-0.07 (m, 2H).
LC/MS(ESI)、m/z=494.2[M=H]+(計算値:493.7)。
1H NMR δ (300 MHz, CDCl3): 6.68 (d, 1H), 6.49 (d, 1H), 4.50 (bs, 1H), 4.86 (t, 1H), 4.20 (d, 1H), 3.00-2.95 (m, 2H), 2.88-2.79 (m, 1H), 2.69-2.59 (m, 1H), 2.34-1.95 (m, 7H), 1.72-1.68 (m, 1H), 1.58-1.52 (m, 2H), 1.47-1.24 (m, 6H), 1.13-0.98 (m, 11H), 0.92-0.87 (m, 3H), 0.79-0.75 (m, 2H), 0.50-0.45 (m, 2H), 0.11-0.09 (m, 2H).
LC/MS(ESI)、m/z=508.3[M=H]+(計算値:507.7)。
1H NMR δ (300 MHz, CDCl3): 7.50 (d, 1H), 7.48 (d, 1H), 7.37-7-26 (m, 3H), 6.69 (d, 1H), 6.51 (d, 1H), 5.82 (s, 1H), 4.90 (bs , 1H), 4.28 (d, 1H), 3.72-3.66 (m, 1H), 3-61-3.57 (m, 1H), 3.02-2.85 (m, 3H), 2.69-2.62 (m, 1H), 2.34-2.21 (m, 5H), 2.08-1.98 (m, 1H), 1.92-1.83 (m, 1H), 1.75-1.69 (m, 1H), 1.55 (s, 3H), 1.54-1.43 (m, 1H), 1.07 (s, 9H), 0.82-0.79 (m, 2H), 0.51-0.47 (m, 2H), 0.12-0.10 (m, 2H).
LC/MS(ESI)、m/z=542.2[M=H]+(計算値:541.7)。
1H NMR δ (300 MHz, CDCl3): 7.45-7.42 (m, 2H), 7.35-7.26 (m, 3H), 6.71 (d, 1H), 6.48 (d, 1H), 5.25-5.13 (m, 2H), 5.02 (d, 1H), 4.78 (d, 1H), 4.23 (d, 1H), 2.97 (dd, 2H),2.88-2.80 (m, 1H), 2.62 (dd, 1H), 2.36-1.96 (m, 7H), 1.69 (dd, 1H), 1.44 (s, 3H), 1.40-1.35 (m, 1H), 1.14-0.99 (m, 11H), 0.81-0.74 (m, 2H), 0.51-0.46 (m, 2H), 0.12-0.08 (m, 2H).
LC/MS(ESI)、m/z=556.3[M=H]+(計算値:555.8)。
1H NMR δ (300 MHz, CDCl3): 6.70 (d, 1H), 6.55 (d, 1H), 5.00 (d, 1H), 4.76 (d, 1H), 4.22 (d, 1H), 3.79 (s, 3H), 3.01 (d, 1H), 2.97 (d, 1H), 2.83 (dd, 1H), 2.63 (dd, 1H), 2.33-2.00 (m, 7H), 1.70 (dd, 1H), 1.44 (s, 3H), 1.40-1.35 (m, 1H), 1.14-1.02 (m, 11H), 0.81-0.77 (m, 2H), 0.51-0.46 (m, 2H), 0.11-0.09 (m, 2H).
LC/MS(ESI)、m/z=480.2[M=H]+(計算値:479.7)。
1H NMR δ (300 MHz, CDCl3): 6.76 (bs, 1H), 6.60 (d, 1H), 6.43 (d, 1H), 5.74 (d, 1H), 5.28 (d, 1H), 4.46 (bs, 1H), 4.34 (s, 1H), 3.47 (d, 1H), 3.06 (d, 1H), 2.93 (dd, 1H), 2.62 (dd, 1H), 2.42-2.25 (m, 4H), 2.16-2.10 (m, 1H), 1.85-1.68 (m, 2H), 1.72-1.68 (m, 1H),1.13 (s, 3H), 1.01 (s, 9H), 0.99-0.94 (m, 1H), 0.83-0.81 (m, 1H), 0.54-0.48 (m, 2H), 0.15-0.13 (m, 2H).
LC/MS(ESI)、m/z=452.2[M=H]+(計算値:451.6)。
1H NMR δ (300 MHz, CDCl3): 6.60 (d, 1H), 6.44 (d, 1H), 5.94 (d, 1H), 5.42 (d, 1H), 5.05 (d, 1H), 4.91 (d, 1H), 4.66 (bs, 1H), 4.39 (d, 1H), 3.48 (d, 1H), 3.09 (d, 1H), 2.95 (dd, 1H), 2.71 (dd, 1H), 2.43-2.37 (m, 4H), 2.18-2.12 (m, 1H), 2.04-1.87 (m, 2H), 1.13 (s, 3H), 0.99 (s, 9H), 0.91-0.81 (m, 2H), 0.55-0.49 (m, 2H), 0.17-0.13 (m, 2H).
LC/MS(ESI)、m/z=464.2[M=H]+(計算値:463.6)。
1H NMR δ (300 MHz, CDCl3): 6.60 (d, 1H), 6.48 (d, 1H), 5.98 (d, 1H), 5.42 (d, 1H), 5.02 (d, 1H), 4.89 (d, 1H), 4.37 (d, 1H), 3.79 (s, 3H), 3.48 (d, 1H), 3.10 (d, 1H), 2.93 (dd, 1H), 2.70 (dd, 1H), 2.43-2.30 (m, 4H), 2.14 (dd, 1H), 2.00-1.84 (m, 2H), 1.12 (s, 3H), 0.98 (s, 9H), 0.88-0.82 (m, 2H), 0.55-0.49 (m, 2H), 0.17-0.13 (m, 2H).
LC/MS(ESI)、m/z=478.2[M=H]+(計算値:477.6)。
1H NMR δ (300 MHz, CDCl3): 7.42-7.40 (m, 2H), 7.34-7.25 (m, 3H), 6.61 (d, 1H), 6.42 (d, 1H), 5.95 (d, 1H), 5.41 (d, 1H), 5.19-5.03 (m, 3H), 4.90 (d, 1H), 4.38 (s, 1H), 3.47 (d, 1H), 3.08 (d, 1H), 2.94 (dd, 1H), 2.69 (dd, 1H), 2.43-2.290 (m, 4H), 2.17-2.11 (m, 1H), ,2.03-1.85 (m, 2H), 1.12 (s, 3H), 0.98 (s, 9H), 0.91-0.82 (m, 2H), 0.54-0.48 (m, 2H), 0.11-0.12 (m, 2H).
LC/MS(ESI)、m/z=554.3[M=H]+(計算値:553.7)。
1H NMR δ (300 MHz, CDCl3): 6.69 (d, 1H), 6.52 (d, 1H), 5.85 (s, 1H), 5.82-5.70 (m, 1H), 5.20 (dd, 1H), 5.10 (dd, 1H), 4.68 (bs, 1H), 4.46 (d, 1H), 3.53 (s, 3H), 3.07-2.99 (m, 3H), 2.86-2.80 (m, 1H), 2.77 (d, 1H), 2.53 (dd, 1H), 2.33 (dt, 1H), 2.26-2.11 (m, 1H), 2.04-1.92 (m 1H), 1.84-1.66 (m, 3H), 1.35 (s, 3H), 1.34-1.26 (m, 1H), 1.08-1.05 (m, 1H),1.03 (s, 9H), 0.74-0.62 (m, 1H)
LC/MS(ESI)、m/z=454.2[M=H]+(計算値:453.3)。
1H NMR δ (300 MHz, CDCl3): 6.75 (d, 1H), 6.48 (d, 1H), 5.82-5.68 (m, 1H), 5.16 (dd, 1H), 5.08 (dd, 1H), 4.13-4.09 (m, 1H), 3.02-2.92 (m, 3H), 2.77-2.70 (m, 2H), 2.39 (dd, 1H), 2.21-2.05 (m, 2H), 1.92-1.84 (m, 1H), 1.81-1.72 (m, 1H), 1.58-1.46 (m, 1H), 1.41 (s, 3H), 1.28-1.16 (m, 3H), 1.01 (s, 9H), 0.98-0.91 (m, 1H), 0.63-0.54 (m, 1H).
LC/MS(ESI)、m/z=440.1[M=H]+(計算値:439.2)。
1H NMR δ (300 MHz, CDCl3): 6.71 (d, 1H), 6.53 (d, 1H), 5.82-5.73 (m, 1H), 5.18 (dd, 1H), 5.10 (dd, 1H), 5.03 (d, 1H), 4.77 (d, 1H), 4.25 (d, 1H), 3.07-3.00 (m, 3H), 2.88-2.82 (m, 1H), 2.78-2.77 (m, 1H), 2.54 (dd, 1H), 2.39-2.34 (dd, 1H), 2.31-2.28 (m, 2H), 2.24-1.95 (m, 4H), 1.73 (dd, 1H), 1.43 (s, 3H), 1.39-1.35 (m, 1H), 1.15-1.04 (m, 1H), 1.02 (s, 9H), 0.81-0.70 (m, 1H).
LC/MS(ESI)、m/z=452.1[M=H]+(計算値:451.2)。
1H NMR δ (300 MHz, CDCl3): 6.70 (d, 1H), 6.56 (d, 1H), 5.83-5.71 (m, 1H), 5.18 (dd, 1H), 5.09 (dd, 1H), 5.00 (d, 1H), 4.75 (d, 1H), 4.22 (d, 1H), 3.85 (s, 3H), 3.07-3.01 (m, 3H), 2.86-2.81 (m, 1H), 2.77 (d, 1H), 2.54 (dd, 1H), 2.28-1.94 (m, 5H), 1.71 (dd, 1H), 1.43 (s, 3H), 1.41-1.32 (m, 1H), 1.14-1.05 (m, 2H), 1.02 (s, 9H), 0.82-0.71 (m, 1H).
LC/MS(ESI)、m/z=466.1[M=H]+(計算値:465.3)。
1H NMR δ (300 MHz, CDCl3): 7.45-7.42 (m, 2H), 7.35-7.28 (m, 3H), 6.72 (d, 1H), 6.49 (d, 1H), 5.78-5.72 (m, 1H), 5.25-5.07 (m, 4H), 5.01 (d, 1H), 4.77 (d, 1H), 4.22 (d, 1H), 3.06-2.99 (m, 3H), 2.93 (dd, 1H), 2.76 (d, 1H), 2.35-1.96 (m, 5H), 1.71 (dd, 1H), 1.56 (bs, 2H), 1.43 (s, 3H), 4.41-1.32 (m, 1H), 1.13-1.05 (m, 1H), 1.02 (s, 9H), 0.80-0.74 (m, 1H).
LC/MS(ESI)、m/z=542.2[M=H]+(計算値:541.3)。
1H NMR δ (300 MHz, CDCl3): 6.69 (d, 1H), 6.53 (d, 1H), 5.89 (s, 1H), 4.45 (d, 1H), 3.53 (s, 3H), 3.10 (d, 1H), 2.81-2.75 (m, 1H), 2.64 (d, 1H), 2.43 (dd, 1H), 2.33-2.15 (m, 6H), 2.05-1.94 (m, 1H), 1.85-1.22 (m 4H), 1.35 (s, 3H), 1.32-1.26 (m, 1H), 1.17-1.05 (m, 1H),1.02 (s, 9H), 0.77-0.68 (m, 1H).
LC/MS(ESI)、m/z=428.2[M=H]+(計算値:427.3)。
1H NMR δ (300 MHz, CDCl3): 6.72 (d, 1H), 6.46 (d, 1H), 5.48 (bs, 1H), 4.11 (s, 1H), 3.04 (d, 1H), 2.75-2.70 (m, 1H), 2.61-2.59 (m, 1H), 2.38-2.31 (m, 1H), 2.26 (s, 6H), 2.19-1.79 (m, 6H), 1.49-1.43 (m, 1H), 1.41 (s, 3H), 1.32-1.24 (m, 2H), 1.01 (s, 9H), 0.98-0.91 (m, 1H), 0.63-0.54 (m, 1H).
LC/MS(ESI)、m/z=414.2[M=H]+(計算値:413.3)。
1H NMR δ (300 MHz, CDCl3): 6.71 (d, 1H), 6.54 (d, 1H), 5.02 (d, 1H), 4.77 (d, 1H), 4.24 (d, 1H), 3.10 (d, 1H), 2.82-2.72 (m, 1H), 2.65 (d, 1H), 2.44 (dd, 1H), 2.35-2.30 (m, 1H), 2.29 (s, 3H), 2.27-1.86 (m, 4H), 1.72 (dd, 1H), 1.43 (s, 3H), 1.36-1.26 (m, 2H), 1.17-1.1.06 (m, 2H), 1.01 (s, 9H), 0.84-0.70 (m, 1H).
LC/MS(ESI)、m/z=425.9[M=H]+(計算値:425.3)。
1H NMR δ (300 MHz, CDCl3): 6.70 (d, 1H), 6.56 (d, 1H), 5.01 (d, 1H), 4.75 (d, 1H), 4.20 (d, 1H), 3.85 (s, 3H), 3.12 (d, 1H), 2.80-2.71 (m, 1H), 2.64 (d, 1H), 2.41 (dd, 1H), 2.35-1.95 (m, 8H), 1.70 (dd, 1H), 1.43 (s, 3H), 1.41-1.32 (m, 1H), 1.16-1.06 (m, 2H), 1.02 (s, 9H), 0.82-0.71 (m, 1H).
LC/MS(ESI)、m/z=440.0[M=H]+(計算値:439.3)。
1H NMR δ (300 MHz, CDCl3): 7.45-7.42 (m, 2H), 7.35-7.28 (m, 3H), 6.72 (d, 1H), 6.49 (d, 1H), 5.78-5.72 (m, 1H), 5.25-5.07 (m, 4H), 5.01 (d, 1H), 4.77 (d, 1H), 4.22 (d, 1H), 3.06-2.99 (m, 3H), 2.93 (dd, 1H), 2.76 (d, 1H), 2.35-1.96 (m, 5H), 1.71 (dd, 1H), 1.56 (bs, 2H), 1.43 (s, 3H), 4.41-1.32 (m, 1H), 1.13-1.05 (m, 1H), 1.02 (s, 9H), 0.80-0.74 (m, 1H).
LC/MS(ESI)、m/z=542.2[M=H]+(計算値:541.3)。
1H NMR δ (300 MHz, CDCl3): 7.42-7.24 (m, 10H), 6.64 (d, 1H), 6.48 (d, 1H), 5.66 (d, 1H), 5.32 (d, 1H), 5.15 (d, 1H), 5.07 (d, 1H), 4.30 (d, 1H), 4.11 (bs, 1H), 3.16 (bs, 1H), 3.25-3.17 (m, 2H), 2.98 (dd, 1H), 2.76-2.2.63 (m, 2H), 2.54-2.50 (m, 1H), 2.44-2.34 (m, 5H), 2.00-1.83 (m, 3H), 1.03 (s, 3H), 0.99-0.93 (m, 1H).
LC/MS(ESI)、m/z=536.3[M=H]+(計算値:535.3)。
1H NMR δ (300 MHz, CDCl3): 7.45-7.38 (m, 2H), 7.34-7.22 (m, 8H), 6.61 (d, 1H), 6.45 (d, 1H), 5.95 (d, 1H), 5.44 (d, 1H), 5.15 (d, 1H), 5.06 (d, 1H), 5.01 (d, 1H), 4.92 (d, 1H), 4.31 (d, 1H), 3.25-3.17 (m, 2H), 2.91 (dd, 1H), 2.79-2.2.68 (m, 2H), 2.55-2.51 (m, 1H), 2.44-2.34 (m, 5H), 2.00-1.83 (m, 3H), 1.03 (s, 3H), 1.01-0.94 (m, 1H).
LC/MS(ESI)、m/z=548.3[M=H]+(計算値:547.3)。
1H NMR δ (300 MHz, CDCl3): 7.30-7.26 (m, 5H), 6.71 (d, 1H), 6.55 (d, 1H), 4.99 (d, 1H), 4.79 (d, 1H), 4.17 (d, 1H), 3.13 (d, 1H), 2.88-2.71 (m, 4H), 2.48 (dd, 1H), 2.36-2.22 (m, 5H), 2.17-1.84 (m, 4H), 1.69 (dd, 1H), 1.42-1.32 (m, 4H), 1.25-1.07 (m, 3H), 0.90-0.78 (m, 1H).
LC/MS(ESI)、m/z=460.12[M=H]+(計算値:459.6)。
Claims (32)
- 式Iの化合物:
GはR1またはヒドロキシル保護基PGであり、該PGが、アルキル、アリールアルキル、ヘテロシクロ、(ヘテロシクロ)アルキル、アシル、シリル、およびカーボネートからなる群から選択され、これらのうちのいずれかが場合によって置換されており、
R1は、水素、アルキル、アルケニル、アルキニル、(シクロアルキル)アルキル、(ヘテロシクロ)アルキル、アリールアルキル、またはヘテロアリールアルキルであり、そのシクロアルキル、ヘテロシクロ、アリール、およびヘテロアリール部分は、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、および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おり、
R2は、
(a)水素、シアノ、カルボキシ、アルコキシカルボニル、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、(アリールアルコキシ)カルボニル、もしくは(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、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、および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おり、
R3およびR4は、水素、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、およびヘテロアリールアルキルからなる群からそれぞれ独立して選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
R5は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
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または式IIIを有する請求項1に記載の化合物:
R3は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
R4は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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おり、
G、R1、R2、R5および
または薬学的に許容されるその塩もしくは溶媒和物。 - 式IVを有する請求項1または2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Vまたは式VIを有する請求項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。 - 式VIIを有する請求項1または2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VIIIまたは式IXを有する請求項1または2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。 - a)GがR1である、または、
b)GがPGである、
ここで、PGが、アルキル、アリールアルキル、ヘテロシクロ、(ヘテロシクロ)アルキル、ベンゾイル、(ベンジルオキシ)カルボニル、アルコキシカルボニル、アルキルカルボニル、およびシリルからなる群から選択され、これらのうちのいずれかが場合によって置換されている、請求項1から6のいずれか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。 - PGが、メチル、tert−ブチル、場合によって置換されているベンジル、場合によって置換されているベンゾイル、アセチル、トリメチルシリル、tert−ブチルジメチルシリル、tert−ブチルジフェニルシリル、およびトリ−イソプロピルシリルからなる群から選択される、請求項7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。
- i)R2が、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、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、または、
ii)R2が非置換のC2〜6アルケニルまたは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。 - R 2 が、ヒドロキシ、ハロ、ハロ(C 1〜4 )アルキル、アミノ、C 1〜4 アルキルアミノ、ジ(C 1〜4 )アルキルアミノ、カルボキシ、およびC 1〜4 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(C 1〜4 )アルキル、シクロブチル(C 1〜4 )アルキル、シクロペンチル(C 1〜4 )アルキル、またはシクロヘキシル(C 1〜4 )アルキルである、請求項9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およびR4が、水素、C1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜7シクロアルキル、C3〜7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、C3〜7シクロアルキル(C1〜4)アルキル、C3〜7シクロアルケニル(C1〜4)アルキル、ヘテロシクロ(C1〜4)アルキル、アリール(C1〜4)アルキル、およびヘテロアリール(C1〜4)アルキルからなる群からそれぞれ独立して選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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、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。
- R 3 およびR 4 が、水素、C 1〜6 アルキル、およびC 2〜6 アルケニルからなる群からそれぞれ独立して選択され、前記C 1〜6 アルキルおよびC 2〜6 アルケニル基が、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、および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、請求項11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。
- R 3 およびR 4 が両方とも非置換のC 1〜6 アルキルである、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。
- R5が、水素、C1〜6アルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜7シクロアルキル、C3〜7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、C3〜7シクロアルキル(C1〜4)アルキル、C3〜7シクロアルケニル(C1〜4)アルキル、ヘテロシクロ(C1〜4)アルキル、アリール(C1〜4)アルキル、およびヘテロアリール(C1〜4)アルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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、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。
- R 5 が、水素、C 1〜6 アルキル、C 2〜6 アルケニル、C 2〜6 アルキニル、C 3〜7 シクロアルキル、C 3〜7 シクロアルケニル、ヘテロシクロ、アリール、およびヘテロアリールからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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、請求項14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。
- R 5 が、水素、C 1〜6 アルキル、C 2〜6 アルケニル、C 3〜7 シクロアルケニル、5もしくは6員のヘテロシクロ、フェニル、ナフチル、または5もしくは6員のヘテロアリールであり、これらのうちのいずれかは、これらが水素以外である場合、ヒドロキシ、ハロ、ハロ(C 1〜4 )アルキル、アミノ、C 1〜4 アルキルアミノ、ジ(C 1〜4 )アルキルアミノ、カルボキシ、およびC 1〜4 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、請求項15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。
- R 5 が水素、C 1〜6 アルキル、またはフェニルである、請求項16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。
- GがR1であり、R3がメチルであり、R4がtert−ブチルである、式X:
を有する、請求項1、3および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。 - a)式XIまたは式XII:
を有する、及び/又は、
b)R 1 が水素、C 1〜6 アルキル、またはベンジルであり、
R 2 が、ヒドロキシ、ハロ、ハロ(C 1〜4 )アルキル、アミノ、C 1〜4 アルキルアミノ、ジ(C 1〜4 )アルキルアミノ、カルボキシ、およびC 1〜4 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C 2〜6 アルケニル、シクロプロピル(C 1〜4 )アルキル、シクロペンチル(C 1〜4 )アルキル、またはシクロヘキシル(C 1〜4 )アルキルであり、
R 5 が水素、C 1〜6 アルキル、またはフェニルである、
請求項18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20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、組成物。
- 3H、11C、または14Cで放射標識した、請求項1から20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22に記載の放射標識した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を使用して、オピオイド受容体への結合能力について候補化合物をインビトロでスクリーニングする方法であって、a)固定濃度の放射標識した化合物を受容体に導入することによって錯体を形成するステップと、b)候補化合物を用いて錯体を滴定するステップと、c)候補化合物の前記受容体への結合を測定するステップとを含む、インビトロ方法。
- 医薬組成物を調製する方法であって、請求項1から20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を、薬学的に許容される担体と混和するステップを含む、方法。
- 疼痛、便秘、下痢、アルコール中毒の禁断症状または薬物中毒の禁断症状の治療のための医薬品の調製における、請求項1から20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。
- 前記疼痛が急性疼痛、慢性疼痛または外科疼痛である、請求項25に記載の使用。
- 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26に記載の使用。
- 請求項1から20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Iを有する、請求項1に記載の化合物を調製するための方法であって、
R5は、水素、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、およびヘテロアリールアルキルからなる群から選択され、これらのうちのいずれかは、これらが水素以外である場合、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、および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)と、
ハロゲン化トリアルキルシリルおよび非プロトン性溶媒の存在下で反応させることによって、式Iの化合物を得るステップを含む、方法。 - a)前記(R 5 CH 2 ) 2 SOが、ジメチルスルホキシド、ジ(n−プロピル)スルホキシド、ジ(n−ブチル)スルホキシド、およびジベンジルスルホキシドからなる群から選択され、
b)ハロゲン化トリアルキルシリルが、塩化トリメチルシリル、臭化トリメチルシリル、ヨウ化トリメチルシリル、またはこれらの組合せからなる群から選択され、
c)溶媒がテトラヒドロフランである、及び/又は、
d)周囲温度で行われる、請求項29に記載の方法。 - a)R2が、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、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、
b)R3およびR4が、水素、C1〜6アルキル、およびC2〜6アルケニルからなる群からそれぞれ独立して選択され、前記C1〜6アルキルおよびC2〜6アルケニル基が、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、および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、
c)GがR1である、及び/又は、
d)R5が、水素、C1〜6アルキル、C2〜6アルケニル、C3〜7シクロアルケニル、5もしくは6員のヘテロシクロ、フェニル、ナフチル、または5もしくは6員のヘテロアリールであり、これらのうちのいずれかは、これらが水素以外である場合、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、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、請求項29または30に記載の方法。 - 式XVの化合物:
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CA2674915C (en) | 2006-10-17 | 2015-06-30 | Penick Corporation | Process for preparing oxymorphone |
EP2099456A2 (en) * | 2006-11-22 | 2009-09-16 | Progenics Pharmaceuticals, Inc. | N-oxides of 4,5-epoxy-morphinanium analogs |
EP2342207B1 (en) | 2008-09-30 | 2015-11-11 | Mallinckrodt LLC | Processes for the alkylation of norbuprenorphine with reduced impurity formation |
KR101630912B1 (ko) * | 2010-09-21 | 2016-06-15 | 퍼듀 퍼머 엘피 | 부프레노르핀 유사체 |
US9315514B2 (en) | 2012-08-27 | 2016-04-19 | Rhodes Technologies | 1,3-dioxanomorphides and 1,3-dioxanocodides |
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AU2013308174A1 (en) | 2015-04-09 |
WO2014033530A1 (en) | 2014-03-06 |
US9315514B2 (en) | 2016-04-19 |
AU2013308174B2 (en) | 2016-10-20 |
EP2888267B1 (en) | 2017-01-18 |
ES2619636T3 (es) | 2017-06-26 |
JP2015526500A (ja) | 2015-09-10 |
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