JP7429942B2 - 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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- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 description 1
- VCZSWYIFCKGTJI-JLHYYAGUSA-N igmesine Chemical compound C1CC1CN(C)C(C=1C=CC=CC=1)(CC)C\C=C\C1=CC=CC=C1 VCZSWYIFCKGTJI-JLHYYAGUSA-N 0.000 description 1
- 229950004066 igmesine Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 229940125947 insurmountable antagonist Drugs 0.000 description 1
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- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003657 middle cerebral artery Anatomy 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical compound C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 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
- 229960004127 naloxone Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
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- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 229960005290 opipramol Drugs 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- KQOATKAFTRNONV-UHFFFAOYSA-N oxolan-2-amine Chemical class NC1CCCO1 KQOATKAFTRNONV-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 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
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940118376 tetanus toxin Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 238000005406 washing Methods 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- 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
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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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- General Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
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- Hospice & Palliative Care (AREA)
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- Tropical Medicine & Parasitology (AREA)
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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、
本発明は、例えば、以下の項目を提供する。
(項目1)
を実質的に含まない
の薬学的投与形態。
(項目2)
約0.5~約100mgの
を含む、項目1に記載の薬学的投与形態。
(項目3)
約1~約20mgの
を含む、項目2に記載の薬学的投与形態。
(項目4)
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、
を実質的に含まない
を含む治療上有効な用量の薬学的調製物を投与する工程を包含する方法。
(項目5)
前記治療上有効な量は、約0.5~約100mgの
を含む、項目4に記載の方法。
(項目6)
前記治療上有効な量は、約1~約20mgの
を含む、項目5に記載の方法。
(項目7)
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、
を実質的に含まない治療上有効な量の
を投与する方法による方法。
(項目8)
前記治療上有効な量は、約0.5~約100mgの
を含む、項目7に記載の方法。
(項目9)
前記治療上有効な量は、約1~約20mgの
を含む、項目8に記載の方法。
(項目10)
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、
を実質的に含まない検出可能な量の
に曝し、そしてσレセプター結合のレベルを決定する方法による方法。
Claims (4)
- (-)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含み、2%未満、1%未満、0.5%未満または0.1%(w/w)未満の(+)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含む、薬学的調製物であって、1~20mgの(-)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含む、薬学的調製物。
- 静脈投与または経口用剤の形態における、請求項1に記載の薬学的調製物。
- 疾患を処置する必要性のある被験体において疾患を処置するための方法における使用のための請求項1または2に記載の薬学的調製物であって、
前記疾患が、うつ、アルツハイマー型認知症、低酸素ストレス、神経毒ストレス、脳卒中、およびアルツハイマー病から選択され、
前記方法が、(-)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の治療上有効な量での前記薬学的調製物の投与を含み、前記薬学的調製物が、(+)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実質的に含まない、薬学的調製物。 - 前記治療上有効な量は、1日あたり、1~20mgの(-)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含む、請求項3に記載の使用のための薬学的調製物。
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