JP2018524306A - テトラヒドロ−n,n−ジメチル−2,2−ジフェニル−3−フランメタンアミン(anavex2−73)のエナンチオマーならびにシグマ1レセプターにより調節されるアルツハイマー型および他の傷害の処置におけるその使用 - Google Patents
テトラヒドロ−n,n−ジメチル−2,2−ジフェニル−3−フランメタンアミン(anavex2−73)のエナンチオマーならびにシグマ1レセプターにより調節されるアルツハイマー型および他の傷害の処置におけるその使用 Download PDFInfo
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- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
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- 230000010287 polarization Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 239000002464 receptor antagonist Substances 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 235000013343 vitamin Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- 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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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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- G01—MEASURING; TESTING
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
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Abstract
Description
2種のσレセプターサブタイプが、それらの薬理学的プロフィールに基づいて同定されてきた。シグマ−1(σ−1)レセプターは、クローニングされた(Hannerら, 1996)。シグマ−2レセプターは、別個の分子実体として報告された(Langaら, 2003)。σ−1レセプターは、ベゾモルファス(bezomorphas)(例えば、(+)−ペンタゾシンおよび(+)−SKF−10,047)の陽性アイソマーに対して高い親和性を有すると報告された。σ−2レセプターは、イボガインに対して高い親和性を有すると報告された(Vilner and Bowen, 2000)。特に、σ1レセプターアゴニストはまた、抗うつ効果を有すると報告された。この点において、σ1レセプターリガンドは、いくつかの動物モデルにおいて明らかな抗うつ効果を示す。例示すると、選択的σ1レセプターアゴニストである(+)−ペンタゾシン、(+)−SKF−10,047、イグメシン、OPC14523、DTGまたはSA4503は、強制水泳試験において無動時間を短縮するか、または尾懸垂試験において活発である(Ukaiら 1998、Matsunoら, 1996、Tottoriら 1997、Kinsoraら 1998)。米国特許第5,034,419号は、N−シクロアルキルアルキルアミン(これも、報告上σ1レセプターアゴニストである)を記載する。
Sigma Receptors: Chemistry, Cell Biology and Clinical Implications, Matsumotoら編, Springer; 2007年版(2014年11月16日)が参照される。この刊行物および本明細書で引用される全ての参考文献の教示は、それらの全体において本明細書に参考として援用される。さらに以下が参照される:
Nguyenら, 「Role of sigma−1 receptors in neurodegenerative diseases」, J Pharmacol Sci. 2015 Jan;127(1):17−29;
Guoら, 「Sigma−2 receptor ligands: neurobiological effects」, Curr Med Chem. 2015;22(8):989−1003;
USSN 62/065,833(標題「A19−144, A2−73 and Certain Anticholinesterase Inhibitor Compositions and Method for Anti−Seizure Therapy」、2014年10月20日出願);
Crawfordら, 「Sigma−2 Receptor Agonists Activate a Novel Apoptotic Pathway and Potentiate Antineoplastic Drugs in Breast Tumor Cell Lines」, Cancer Research, 62, 313−322, January 1, 2002;
Rossiら, 「A step forward in the sigma enigma: a role for chirality in the sigma1 receptor−ligand interaction?」 Medicinal Chemistry Communication (Impact Factor: 2.63). 09/2014; 6(1);
米国公報第20110206780(標題「Morphinan modulators of nmda receptors, sigma1 receptors, sigma2 receptors, and/or a3b4 nicotinic receptors」,(Gantら、優先日:2010年1月6日)
WO2013008044(Vamvakidesら、標題「SYNTHESIS OF (+) AND (−) 1−(5,5−DIPHENYLTETRAHYDROFURAN−3−YL)−N,N−DIMETHYLMETHANAMINE, (+) AND (−) 1−(2,2−DIPHENYLTETRAHYDROFURAN−3−YL)−N,N−DIMETHYLMETHANAMINE AND (+) AND (−) 1−(2,2−DFFHENYLTETRAHYDROFURAN−3−YL)−N−METIHYLMETHANAMINE」は、キラル分離方法論を示す。)
米国特許出願(標題「ANAVEX2−73 FOR THE TREATMENT OF ALZHEIMER’S DISEASE」およびこれまでに提出されたもの)
米国特許出願(標題「CRYSTAL FORMS OF tetrahydro−N,N−dimethyl−2,2−diphenyl−3−furanmethaneamine hydrochloride, PROCESSES OF MAKING SUCH FORMS, AND THEIR PHARMACEUTICAL COMPOSITIONS」およびこれまでに提出されたもの)。
本発明は、以下の定義に言及してよりよく理解される:
A. ANAVEX2−73、またはA2−73は、テトラヒドロ−N,N−ジメチル−2,2−ジフェニル−3−フランメタンアミンヒドロクロリドを意味するものとする。これは、試験データのうちのいくつかでは、AE 37として列挙される。A2−73は、低いマイクロモル範囲の親和性でムスカリン性アセチルコリンおよびσ−1レセプターに結合すると考えられている化合物である。
B. ANAVEX19−144またはA19−144は、1−(2,2−ジフェニルテトラヒドロフラン−3−イル)−N−メチルメタンアミンヒドロクロリドを意味するものとする。A19−144は、低いマイクロモル範囲の親和性でムスカリン性アセチルコリンおよびσ−1レセプターに結合すると考えられている化合物である。
C. ANAVEX1−41またはA1−41は、テトラヒドロ−N,N−ジメチル−5,5−ジフェニル−3−フランメタンアミンヒドロクロリドを意味するものとする。これは、試験データのうちのいくつかでは、AE 14として列挙される。A1−41は、Villardら, 「Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1−41 Against Amyloid b25−35−Induced Toxicity in Mice」, Neuropsychopharmacology, 1−15 (2008)において報告される。
D. 用語「エナンチオマー」または「エナンチオマーの」とは、ある分子をそのマイナーイメージの上に重ね合わせることができず、よって、光学的に活性であって、ここでエナンチオマーが偏光面を一方向に回転させ、そのマイナーイメージが偏光面を反対側に回転させる分子をいう。
E.
F. σ1またはσ2レセプター集団に関して細胞を「分類する」とは、所定の細胞集団において細胞表面上のσ1またはσ2いずれかのレセプターの存在および/または密度を決定することを意味するものとする。分類することは、生体マーカーとして使用されるσレセプターの差次的集団を利用する。バイオマーカーは、細胞集団の傾向(例えば、乳がんに関して増殖の見込み)を定義する手段として有用である。試験方法論は、以下でより十分に示される:
Hashimotoら, 「Sigma receotor ligands: possible application as therapeutic drugs and as radiopharmaceuticals」, Curr Pharm Des. 2006;12(30):3857−76;
Mach RHら, 「Sigma 2 receptors as potential biomarkers of proliferation in breast cancer」, Cancer Res 1997; 57: 156−61;
Al−Nabulsi, Iら, 「Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of σ−2 receptors in proliferating and quiescent tumour cells」, Br J Cancer 1999; 81: 925−33;および
Wheeler KTら, 「Sigma−2 receptors as a biomarker of proliferation in solid tumours」, Br J Cancer 2000; 82: 1223−32。
1.材料および方法
1.1. インビトロ薬理学:結合アッセイ
1.1.1. 一般的手順
レセプターへの特異的リガンド結合は、過剰の非標識リガンドの存在下で決定される全結合と非特異的結合との間の差異として定義される。
1.2.1. 一般的手順
ウサギ輸精管の前立腺セグメントを、酸素化し(95% O2および5% CO2)かつ予め温めておいた(30℃)、以下の組成(mM単位)の生理食塩水溶液:NaCl 118.0、KCl 4.7、MgSO4 0.6、CaCl2 2.5、KH2PO4 1.2、NaHCO3 25およびグルコース 11.0(pH7.4)、を含む20ml 器官バス中に吊り下げた。
アゴニスト活性の試験
組織を、最大でない濃度の参照アゴニストMcN−A−343(1μM)に曝して、応答を検証し、コントロール応答を得た。洗浄および最初の攣縮(twitch contraction)の回復の後に、その組織を試験化合物または同じアゴニストに曝し、これらを、安定な応答が得られるまで、または最大で15分間、組織と接触した状態にした。
組織を、最大でない濃度の参照アゴニストであるMcN−A−343(1μM)に曝して、コントロール応答を得た
測定したパラメーターは、化合物によって誘導される電気的に誘発された収縮振幅の最大変化であった。
1.3. 試験化合物
製造:EURO GENET Lab A.E.
* :単離器官バイオアッセイについて
1.4. インビトロ薬理学:結合アッセイ
試験化合物の効果に関する平均値を、表1−1にまとめる。試験化合物で得られた個々のデータを、表1−2中で報告する。
各実験において、それぞれの参照化合物を、アッセイ適性を評価するために、試験化合物と同時に試験した。それをいくつかの濃度で試験し、データを歴史的値(historical value)と比較した。相当する標準操作手順に従って適性基準を満たした場合、アッセイを有効にした。
ウサギ輸精管のムスカリン性M1レセプターでのアゴニストおよびアンタゴニスト活性に関して調査した(+)A1−41、(−)A1−41および(−)A2−73の効果を、表2−1に示す。この表では、参照化合物の効果もまた報告する。
βアミロイドに対する神経保護
早期のアルツハイマー型認知症と診断された67歳齢の男性を、3年間1週間に1回、
酸化的ストレスに対する神経保護
低酸素ストレスを予期する29歳齢の女性気球乗りに、気球で上昇する前に5日間毎日、
経口
神経毒性に対する神経保護
危険物取扱者で、神経毒ストレスを予期している37歳齢の男性に、破傷風毒素に曝される前に5日間毎日、
脳卒中患者における神経保護
57歳齢の男性は救急処置室に入り、中大脳動脈が関わる虚血事象と診断され、徴候の開始は、1時間未満である。直ぐに、患者に、制限された領域への血液供給を回復させる間に、
アミロイドに対する神経保護
80歳齢の女性患者は、ADと診断され、3年間毎日、
Claims (10)
-
- 約0.5〜約100mgの
- 約1〜約20mgの
- σ1レセプターの増強された刺激の必要性のある被験体の治療的処置のための方法であって、該方法は、
- 前記治療上有効な量は、約0.5〜約100mgの
- 前記治療上有効な量は、約1〜約20mgの
- アルツハイマー病を処置する必要性のある被験体においてアルツハイマーを処置するための方法であって、該方法は、
- 前記治療上有効な量は、約0.5〜約100mgの
- 前記治療上有効な量は、約1〜約20mgの
- σレセプタータイプに関して細胞を分類するための方法であって、該方法は、該細胞を、
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CN112105349A (zh) * | 2018-04-12 | 2020-12-18 | 阿纳韦克斯生命科学公司 | A2-73结晶多晶型物质组合物及其使用方法 |
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