JP6491213B2 - 疼痛および他の障害の治療のためのガンマ−アミノ酪酸(gaba)類似体 - Google Patents
疼痛および他の障害の治療のためのガンマ−アミノ酪酸(gaba)類似体 Download PDFInfo
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- JP6491213B2 JP6491213B2 JP2016540644A JP2016540644A JP6491213B2 JP 6491213 B2 JP6491213 B2 JP 6491213B2 JP 2016540644 A JP2016540644 A JP 2016540644A JP 2016540644 A JP2016540644 A JP 2016540644A JP 6491213 B2 JP6491213 B2 JP 6491213B2
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- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical group O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical group CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000008009 topical excipient Substances 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
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Description
電位依存性カルシウムチャネルは細孔形成α1サブユニットと補助タンパク質α2δ、β、およびγとが組み合わさって形成される(Caterall(2000)Annu.Rev.Cell Dev.Biol.16:521−555)。α2δタンパク質は、カルシウムチャネル密度およびこれらのチャネルの電位依存性の動態の両方を調節することが知られている(Felixら(1997)J.Neuroscience 17:6884−6891;Klugbauerら(1999)J.Neuroscience 19:684−691;Hobomら(2000)Eur.J.Neuroscience 12:1217−1226;およびQinら(2002)Mol.Pharmacol.62:485−496)。
R1、R2、R2’およびR4〜R8およびR8’がそれぞれ独立して、水素原子、ハロゲン原子、またはC1〜C6アルキル基であるか、R2およびR2’が、それらが結合している炭素原子とともにC3〜C7シクロアルキル基を形成し;かつ
R3が、水素原子、ハロゲン原子、C1〜C6アルキル基、C1〜C6ハロゲン化アルキル基、ヒドロキシ−Cl〜C6アルキル基、スルファニル−C1〜C6アルキル基、C1〜C6アルコキシ−C1〜C6アルキル基、C2〜C6アルケニル基、C2〜C6アルキニル基、C1〜C6アルコキシ基、C1〜C6アルキルスルファニル基、C1〜C6アルキルスルファニル−C1〜C6アルキル基、C2〜C7アシルチオ−C1〜C6アルキル基、C2〜C7アシルオキシ−C1〜C6アルキル基、またはC3〜C7シクロアルキル基である。
R1が、水素、ハロ、C1〜4アルキル基、C1〜4アルキルハライド基、(C1〜4アルコキシ)(C2〜4アルキル)基、C2〜4アルケニル基、C2〜4アルキニル基またはC3〜7シクロアルキル基を表し;
R2が、
R3が、水素、C1〜4アルキル基、(C1〜4アルコキシ)(C2〜4アルキル)基またはC3〜7シクロアルキル基を表す、
化合物またはその薬学的に許容される塩もしくは溶媒和物を提供する。
本発明は式1
R1が、水素、ハロ、C1〜4アルキル基、C1〜4アルキルハライド基、(C1〜4アルコキシ)(C2〜4アルキル)基、C2〜4アルケニル基、C2〜4アルキニル基またはC3〜7シクロアルキル基を表し;
R2が
R3が、水素、C1〜4アルキル基、(C1〜4アルコキシ)(C2〜4アルキル)基またはC3〜7シクロアルキル基を表す、
化合物またはその薬学的に許容される塩もしくは溶媒和物に関する。
R1が、水素、ハロ、C1〜4アルキル基、C1〜4アルキルハライド基、(C1〜4アルコキシ)(C2〜4アルキル)基、C2〜4アルケニル基、C2〜4アルキニル基またはC3〜7シクロアルキル基を表す、
化合物またはその薬学的に許容される塩もしくは溶媒和物である。
R1が、水素、ハロ、C1〜4アルキル基、C1〜4アルキルハライド基、(C1〜4アルコキシ)(C2〜4アルキル)基、C2〜4アルケニル基、C2〜4アルキニル基またはC3〜7シクロアルキル基を表す、
化合物またはその薬学的に許容される塩もしくは溶媒和物である。
3−(((1R,5S,6S)−6−(アミノメチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)−1,2,4−オキサジアゾール−5(4H)−オン、
3−(((1S,5R,6R)−6−(アミノメチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)−1,2,4−オキサジアゾール−5(4H)−オン、
ラセミ3−(((1R,5S,6S)−6−(アミノメチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)−1,2,4−オキサジアゾール−5(4H)−オン、
((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メタンアミン、
((1S,5R,6R)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メタンアミン、
ラセミ((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メタンアミン、
N−(((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)エタンアミン、
N−(((1S,5R,6R)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)エタンアミン、
ラセミN−(((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)エタンアミン
である。
R1は、水素、ハロ、C1〜4アルキル基、C1〜4アルキルハライド基、(C1〜4アルコキシ)(C2〜4アルキル)基、C2〜4アルケニル基、C2〜4アルキニル基またはC3〜7シクロアルキル基を表し;
R2aは、−R2、−CN、−CONH2、−COOH、−(C=NH)NHOHを表し;かつ
R2は
ラセミ3−(((1R,5S,6S)−6−(アミノメチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)−1,2,4−オキサジアゾール−5(4H)−オンの合成
ラセミ2−((1R,5S,6S)−3−エチル−6−ニトロメチル)ビシクロ[3.2.0]ヘプタ−3−エン−6−イル)酢酸
ラセミ2−((1R,5S,6S)−3−エチル−6−(ニトロメチル)ビシクロ[3.2.0]ヘプタ−3−エン−6−イル)アセトアミド
ラセミ2−((1R,5S,6S)−3−エチル−6−(ニトロメチル)ビシクロ[3.2.0]ヘプタ−3−エン−6−イル)アセトニトリル
ラセミ2−((1R,5S,6S)−3−エチル−6−(ニトロメチル)ビシクロ[3.2.0]ヘプタ−3−エン−6−イル)−N−ヒドロキシアセトイミドアミド
ラセミ3−(((1R,5S,6S)−3−エチル−6−(ニトロメチル)ビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)−1,2,4−オキサジアゾール−5(4H)−オン
ラセミ3−(((1R,5S,6S)−6−(アミノメチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)−1,2,4−オキサジアゾール−5(4H)−オン
ラセミ((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メタンアミンおよび鏡像異性体の合成
ラセミ5−(((1R,5S,6S−3−エチル−6−(ニトロメチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)−1H−テトラゾール
ラセミtert−ブチル(((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)カルバマート
LCMS(Agilent、X−Select、Waters X−Bridge C18、2.5μm、4.6×30mm、塩基性(0.1%炭酸水素アンモニウム)4分間法、5〜95%アセトニトリル/水):m/z 334(M+H)+(ES+);332(M−H)−(ES−)、1.51分、215nmにおける純度98%。
ラセミ((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メタンアミン
ラセミ((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メタンアミンの鏡像異性体のキラル分割
ラセミN−(((1R,5S,6S)−6−((1H−テトラゾール−5−イル)メチル)−3−エチルビシクロ[3.2.0]ヘプタ−3−エン−6−イル)メチル)エタンアミンの合成
段階1(式14の化合物)
ラセミ(2E/Z)−2−((1R,5S)−3−エチル−6−ビシクロ[3.2.0]ヘプタ−3−エニリデン)アセトニトリル
ラセミ2−((1R,5S,6S)−3−エチル−6−(ニトロメチル)ビシクロ[3.2.0]ヘプタ−3−エン−6−イル)アセトニトリル
ラセミ5−(((1R,5S,6S−3−エチル−6−(ニトロメチル−6−ビシクロ[3.2.0]ヘプタ−3−エニル)メチル)−1H−テトラゾール
ラセミ5−(((1R,5S,6S−3−エチル−6−(ニトロメチル−6−ビシクロ[3.2.0]ヘプタ−3−エニル)メチル−1H−テトラゾール
ラセミ2−((1R,5S,6S)−3−エチル−6−(ニトロメチル)ビシクロ[3.2.0]ヘプタ−3−エン−6−イル)アセトニトリル(170mg、0.772mmol)の1−メチル−2−ピロリジノン(2.7mL)溶液にピリジン塩酸塩(180mg、1.57mmol)およびアジ化ナトリウム(263mg、4.04mmol)を加えた。フラスコを窒素下で18時間、100℃に加熱した。次いで、さらに4時間、フラスコの温度を117〜120℃に上昇させた後、室温まで冷却させた。混合物を水(20mL)中に注加し、2M塩酸水溶液で慎重に酸性化した。水層を酢酸エチル(2×20mL)で抽出した後、有機層を2M水酸化ナトリウム水溶液(1×20mL、1×10mL)とともに振盪した。次いで、合わせた水層を濃塩酸でpH約1に酸性化し、酢酸エチル(3×20mL)で再抽出した。合わせた有機層を水(10mL)で洗浄し、硫酸マグネシウムで乾燥させた。ろ過し、蒸発させて、粗生成物を得、シリカでのクロマトグラフィー(7gシリカ、ジエチルエーテル:イソヘキサン:酢酸(200:300:8))により精製して、ラセミ5−(((1R,5S,6S)−3−エチル−6−(ニトロメチル)−6−ビシクロ[3.2.0]ヘプタ−3−エニル)メチル)−1H−テトラゾール(81mg、0.304mmol、収率40%)を得た。
α2δ−1結合親和性アッセイにより本発明の化合物の治療活性が示された。この試験は以下の方法で実施した。
この節では、α2δ−1を含む膜への[3H]ガバペンチン([3H]GBP)結合を測定するシンチレーション近接アッセイ(SPA)および化合物のプロファイリングへのその使用について記載する(Calvoら(2012)J.Biomol.Screen.17:1041−1049)。
化合物で得られた値から100μΜプレガバリンの添加によって得られたNSB値を減じて、特異的結合値を求めた。カウント毎分(cpm)で表した特異的結合を化合物濃度(M)に対してプロットし、4パラメータロジスティック方程式を用いてフィットさせた。化合物が特異的結合を50%阻害するときの化合物の濃度であるIC50値を算出した。被験化合物の結果を表1に示す。
α2δ−1サブユニットに対するGABA類似体の速度論的結合パラメータ(結合速度および解離速度)および親和性(KD)を決定する方法。
Claims (17)
- R1がエチルを表す、請求項1〜3のいずれか1項に記載の化合物。
- 請求項1〜7のいずれか1項で定められる化合物と薬学的に許容されるその担体とを含む、医薬組成物。
- 神経因性疼痛の治療における使用のための、請求項8に記載の医薬組成物。
- 中枢神経系および/または末梢神経系の疾患の治療における使用のための、請求項8に記載の医薬組成物。
- 中枢神経系の疾患の治療における使用のための、請求項10に記載の医薬組成物。
- 頭痛および片頭痛の治療における使用のための、請求項11に記載の医薬組成物。
- てんかん、虚血性脳血管疾患、脳卒中、脳腫瘍、アルツハイマー病、ピック病、ハンチントン病、認知症、パーキンソン病および他の錐体外路系障害、筋萎縮性側索硬化症および他の運動ニューロン障害、進行性神経筋萎縮症、網膜色素変性、遺伝性運動失調、多発性硬化症および他の脱髄性疾患、細菌性およびウイルス性髄膜炎、脳膿瘍、硬膜下蓄膿、硬膜外膿瘍、化膿性頭蓋内血栓性静脈炎、脊髄炎および神経根炎、ウイルス性中枢神経系疾患、クールー病、クロイツフェルト・ヤコブ病およびゲルストマン・シュトロイスラー・シャインカー症候群を含むプリオン病、致死性家族性不眠症、神経系の栄養疾患および代謝疾患、神経線維腫症、結節性硬化症、脳網膜血管芽細胞腫、脳三叉神経症候群、ダウン症候群を含む知的障害および他の中枢神経系の発達障害、脳性麻痺、神経骨格障害、自律神経障害、脳神経障害、脊髄疾患、筋ジストロフィーおよび他の神経筋障害、末梢神経障害、皮膚筋炎および多発性筋炎、先天性、代謝性、内分泌性および中毒性ミオパチー、重症筋無力症、周期性四肢麻痺、気分障害、不安障害および統合失調症を含む精神障害、季節性感情障害(SAD)、静座不能症、健忘症、緊張病、糖尿病性ニューロパチー、遅発性ジスキネジア、ジストニア、妄想性精神病、帯状疱疹後神経痛、トゥレット症、進行性核上性麻痺、大脳皮質基底核変性症、ならびに家族性前頭側頭型認知症から選択されるCNS障害に関連する疼痛の治療における使用のための、請求項8に記載の医薬組成物。
- 式1
R1が水素、ハロ、C1〜4アルキル基、C1〜4アルキルハライド基、(C1〜4アルコキシ)(C2〜4アルキル)基、C2〜4アルケニル基、C2〜4アルキニル基またはC3〜7シクロアルキル基を表し;
R2が
R3が水素、C1〜4アルキル基、(C1〜4アルコキシ)(C2〜4アルキル)基またはC3〜7シクロアルキル基を表す]
の鏡像異性体の混合物を分割することによって、式2a
R1が水素、ハロ、C1〜4アルキル基、C1〜4アルキルハライド基、(C1〜4アルコキシ)(C2〜4アルキル)基、C2〜4アルケニル基、C2〜4アルキニル基またはC3〜7シクロアルキル基を表す、
製造方法。
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