JP5877847B2 - mGluR2/3アンタゴニストとしての4−置換−3−フェニルスルファニルメチル−ビシクロ[3.1.0]ヘキサン化合物 - Google Patents
mGluR2/3アンタゴニストとしての4−置換−3−フェニルスルファニルメチル−ビシクロ[3.1.0]ヘキサン化合物 Download PDFInfo
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- JP5877847B2 JP5877847B2 JP2013539938A JP2013539938A JP5877847B2 JP 5877847 B2 JP5877847 B2 JP 5877847B2 JP 2013539938 A JP2013539938 A JP 2013539938A JP 2013539938 A JP2013539938 A JP 2013539938A JP 5877847 B2 JP5877847 B2 JP 5877847B2
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- hexane
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960001165 modafinil Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000008452 non REM sleep Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QQWYQAQQADNEIC-UHFFFAOYSA-N tert-butyl [[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)ON=C(C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- 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
- A61P25/24—Antidepressants
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
R3は、独立して各存在において、メチル、フルオロまたはクロロであり;
R4は、ヒドロキシル、アミノ、メチルカルボニルアミノまたは1,2,4−トリアゾリルチオであり;
nは、1または2である]
またはその薬学的に許容可能な塩を提供する。
1)R1およびR2の両方が、水素である;
2)R1もしくはR2またはその両方が、水素以外である;
3)R1およびR2の両方が、水素以外である;
4)R1およびR2が、同じであり、かつ水素以外である;
5)R1およびR2が各々、イソプロポキシカルボニルオキシメチルである;
6)nが、2である;
7)R3が、独立して各存在において、フルオロまたはクロロである;
8)nが、2であり、かつR3基が、フェニルの3および4位に存在する;
9)nが、2であり、かつR3基の各々が独立して、フルオロまたはクロロであり、かつフェニルの3および4位に存在する;
10)nが、2であり、両方のR3基が、フルオロであり、かつそのフルオロ基が、フェニルの3および4位に存在する;
11)nが、2であり、かつR3基が、それらが結合しているフェニル部分と一体となって3−クロロ−4−フルオロフェニルを形成する;
12)R4が、ヒドロキシルである、
化合物である。
13)nが2であり、両方のR3基がフルオロであり、かつそのフルオロ基がフェニルの3および4位に存在する(パラグラフ10)、パラグラフ1〜5のうちのいずれか1つの好ましい化合物(R1およびR2に対する好ましい選択);
14)nが2であり、かつR3基がそれらが結合しているフェニル部分と一体となって3−クロロ−4−フルオロフェニルを形成する(パラグラフ11)、パラグラフ1〜5のうちのいずれか1つの好ましい化合物(R1およびR2に対する好ましい選択);
15)R4がヒドロキシルである(パラグラフ12)、パラグラフ1〜5のうちのいずれか1つの好ましい化合物(R1およびR2に対する好ましい選択);
16)R4がヒドロキシルである(パラグラフ12)、パラグラフ13〜14のうちのいずれか1つの好ましい化合物。
(1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3,4−ジフルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸またはその薬学的に許容可能な塩;
(1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3−クロロ−4−フルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸またはその薬学的に許容可能な塩;
ビス({[(1−メチルエトキシ)カルボニル]オキシ}メチル)(1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3,4−ジフルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボキシレート;またはその薬学的に許容可能な塩;および
ビス({[(1−メチルエトキシ)カルボニル]オキシ}メチル)(1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3−クロロ−4−フルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボキシレートまたはその薬学的に許容可能な塩
(すなわち、実施例1、2、12、22および32の化合物ならびにそれらの代替の薬学的に許容可能な塩)である。
「BSA」は、ウシ血清アルブミンを意味する。
「DCG IV」は、(2S,2’R,3’R)−2−(2’,3’−ジカルボキシシクロプロピル)グリシンを意味する。
「DMEMは、ダルベッコ最小イーグル培地を意味する。
「DMSO」は、ジメチルスルホキシドを意味する。
「DPBS」は、ダルベッコリン酸緩衝食塩水を意味する。
「EDTA」は、エチレンジアミン四酢酸を意味する。
「GTP」は、グアノシン三リン酸を意味する。
「HBSS」は、ハンクス緩衝塩溶液を意味する。
「HEPES」は、4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸を意味する。
「HPLC」は、高圧液体クロマトグラフィを意味する。
「IBMX」は、3−イソブチル−1−メチルキサンチンを意味する。
「IC50」は、最大阻害の50%が達成される濃度を意味する。
「i.v.」は、静脈内のまたは静脈内に、を意味する。
「i.p.」は、腹腔内を意味する。
「L−AP−4」は、L−(+)−2−アミノ−4−ホスホノ酪酸を意味する。
「LC/MS」は、液体クロマトグラフィに続く質量分析を意味する。
「mFST」は、マウス強制水泳試験;抗うつ活性に対する動物モデルを意味する。
「MS」は、質量分析を意味する。
「MS(ES+)」は、エレクトロスプレーイオン化を用いた質量分析を意味する。
「NMR」は、核磁気共鳴を意味する。
「p.o.」は、口による経口的を意味する。
「tBu」は、第三級ブチル部分を意味する。
本発明の化合物は、当該分野において周知であり認められている方法による以下の合成スキームに従って調製され得る。これらのスキームの工程に適した反応条件は、当該分野で周知であり、溶媒および補助試薬(co−reagents)の適切な置換は、当該分野の技術範囲内である。同様に、合成中間体が、必要に応じまたは所望であれば、様々な周知の手法によって単離され得るおよび/または精製され得ること、ならびにしばしば、様々な中間体をほとんどまたは全く精製せずに直接その後の合成工程において使用することが可能であり得ることも当業者に認識されるだろう。さらに、当業者は、いくつかの状況では、部分が導入される順序が重大な意味を持たないことを認識するだろう。本発明の化合物を生成するために必要な特定の工程の順序は、合成される特定の化合物、出発化合物、および熟練の化学者が十分に認識しているような、置換部分の相対的な傾向に依存する。別段示されない限り、すべての置換基が、先に定義されたとおりであり、すべての試薬が、当該分野において周知でありかつ認識されているものである。
スキームI
アンタゴニスト活性は、ヒトmGlu2またはmGlu3受容体およびラットグルタミン酸トランスポーターEAAT1(興奮性アミノ酸トランスポーター1)を安定的に発現する組換えAV12細胞においてアッセイされる。その細胞株は、5%透析ウシ胎児血清(FBS)、1mMピルビン酸ナトリウム、1mM HEPESおよび1mM L−グルタミンが補充された、高グルコースおよび塩酸ピリドキシンを含むDMEM中で培養することによって維持される;ジェネテシンおよびハイグロマイシンBが、選択抗生物質として使用される。コンフルエントな培養物を、6.5%CO2を含む雰囲気中、37℃で生育し、2週間に1回継代する。0.25%トリプシンを用いて細胞を回収し、凍結培地(10%DMSOを含むFBS)に107細胞/mlで懸濁し、アリコートを液体窒素中で凍結する。アッセイの24時間前に、細胞を、組織培養処理済96ウェルハーフエリア黒色プレート(Costar3875)において、5%透析FBS、1mMピルビン酸ナトリウム、1mM HEPES、100μg/mlアンピシリンおよび250μM(mGlu2)または125μM(mGlu3)のL−グルタミンが補充された高グルコースおよび塩酸ピリドキシンを含む50μlのDMEM中、8,000〜10,000細胞/ウェルの密度でプレーティングする。
他のヒトmGlu受容体に対する本発明の化合物の相対的なアンタゴニスト効力は、cAMPアッセイまたは蛍光定量的なカルシウム反応アッセイを用いて評価され得る(例えば、Fellら、JPET(印刷中)を参照のこと)。簡潔には、ラットEAAT1グルタミン酸トランスポーターを含み、かつヒトmGlu1、2、3、4、5、6および8受容体を安定的に発現する個別のAV12細胞株が、本研究のために使用される。mGlu1および5受容体は、Gq共役型であるので、それらは、天然には、ホスホリパーゼCを介してシグナル伝達し、Fluorometric Imaging Plate Reader(FLIPR,Molecular Devices)を用いて受容体の活性化を測定するために使用され得るカルシウム流動反応を生じる。mGlu2、3、4および8受容体を発現する細胞株は、Gα15サブユニットを発現するように設計され、これらのGi共役型受容体は、mGlu1および5受容体を発現する細胞株と同様のカルシウム流動反応をもたらすことになる。mGlu6受容体は、上記のmGlu2およびmGlu3に対して開発された方法と類似の方法を用いて、cAMP形式で試験される。これらの細胞株は、L−グルタミンの量および選択薬剤(ジェネテシン、ハイグロマイシンB、ゼオシンおよびブラストサイジン)が細胞株に応じて変化し得ることを除いて、先に記載されたように維持される。コンフルエントな培養物が、2週間に1回継代される。
mFSTは、抗うつ活性に対して確立されたインビボアッセイである(Li et al.J Pharmacol Exp Ther.319(1):254−9,2006.)。公知の臨床的に有効な抗うつ薬(選択的セロトニン再取り込み阻害薬および/または三環系抗うつ薬)で処置されたマウスは、水槽に入れられた後に、不動で過ごす行動(絶望状態に関連する行動)の時間の短縮を示す。本質的には以前に公開された方法(例えば、Li et al.J Pharmacol Exp Ther.319(1):254−9,2006を参照のこと)に記載されているように、新規mGlu2/3アンタゴニストの潜在的な抗うつ様活性を評価するためにmFSTを使用した。簡潔には、体重が25〜30gの雄NIH−Swissマウス(Harlan Sprague−Dawley,Indianapolis,IN)を使用する。群で収容されている動物を、動物飼育施設から取り出して、それ専用のケージ内の試験エリアに移し、試験の前に少なくとも1時間、新しい環境に適応させる。R1およびR2の両方が水素である化合物を、溶解のために最小量のNaOHが加えられた水に溶解し、i.p.投与する。R1および/またはR2が水素以外である化合物は、使用当日に、2.0〜2.5%N−メチル−ピロリジノン中に調製され、次いで、1%HEC、0.25%Tween80および0.05%Dow消泡剤に懸濁し、経口的に投与される。マウスを、6cmの水(22〜25℃)で満たされた筒(直径:10cm;高さ:25cm)に6分間入れる。その試験時間の6分間のうちの最後の4分間における不動の時間をスコア付けした。マウスは、動かずに浮いているかまたは頭部を水より上で維持するのに必要な動きだけをするとき、不動と記録される。
(i)反跳性傾眠過剰は、有効な処置が施された後の8〜19時間における覚醒状態のレベルの低下として判定され得る。生物学的に有意な低下は、最初の7時間における50パーセントを超える累積的増加と定義される。したがって、覚醒状態が、最初の7時間において100分増加した場合、ビヒクルコントロールと比べて処置後の8〜19時間において累積覚醒状態が50分以上減少することが、生物学的に有意であると見なされる。表2に示される群平均値の変化は、反跳性傾眠過剰が無いことを示す。
(ii)運動活性の増大は、ビヒクルコントロールと比べたとき、有効性閾値用量においてEEGによって定義される覚醒状態の1分あたり5回のLMAを超え、かつその作用が用量関連性である、平均値の増加と定義される。表2における群平均値の増加はすべて、覚醒状態1分あたり5回を下回り、用量依存的でない。
Claims (10)
- R1およびR2が各々水素である、請求項1記載の化合物、またはその薬学的に許容可能な塩。
- R1およびR2が、同じでありかつ水素以外である、請求項1記載の化合物、またはその薬学的に許容可能な塩。
- nが2であり、R3基がフェニルの3および4位に存在する、請求項1から3のいずれか1項に記載の化合物。
- (1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3,4−ジフルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸である請求項1記載の化合物またはその薬学的に許容可能な塩。
- ビス({[(1−メチルエトキシ)カルボニル]オキシ}メチル)(1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3,4−ジフルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボキシレートである請求項1記載の化合物またはその薬学的に許容可能な塩。
- (1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3−クロロ−4−フルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸である請求項1記載の化合物またはその薬学的に許容可能な塩。
- ビス({[(1−メチルエトキシ)カルボニル]オキシ}メチル)(1S,2R,3S,4S,5R,6R)−2−アミノ−3−{[(3−クロロ−4−フルオロフェニル)スルファニル]メチル}−4−ヒドロキシビシクロ[3.1.0]ヘキサン−2,6−ジカルボキシレートである請求項1記載の化合物またはその薬学的に許容可能な塩。
- 少なくとも1つの薬学的に許容可能な担体、賦形剤または希釈剤とともに、請求項1から8のいずれか1項に記載の化合物またはその薬学的に許容可能な塩を含む、医薬組成物。
- 請求項1から8のいずれか1項に記載の化合物またはその薬学的に許容可能な塩を含む、うつ病性障害を処置するための医薬組成物。
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