JP2010507590A - Cb1受容体モジュレーターとしての1,5−ジフェニル−3−ベンジルアミノ−1,5−ジヒドロピロリジン−2−オン - Google Patents
Cb1受容体モジュレーターとしての1,5−ジフェニル−3−ベンジルアミノ−1,5−ジヒドロピロリジン−2−オン Download PDFInfo
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- JP2010507590A JP2010507590A JP2009533586A JP2009533586A JP2010507590A JP 2010507590 A JP2010507590 A JP 2010507590A JP 2009533586 A JP2009533586 A JP 2009533586A JP 2009533586 A JP2009533586 A JP 2009533586A JP 2010507590 A JP2010507590 A JP 2010507590A
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- phenyl
- compound
- cyclopropyl
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- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 title 1
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- 229940075993 receptor modulator Drugs 0.000 title 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
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- 125000004093 cyano group Chemical group *C#N 0.000 description 14
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 11
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- VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 description 1
- SCFVLCBATVDKDN-UHFFFAOYSA-N pyrrolidin-2-one;2,2,2-trifluoroacetic acid Chemical compound O=C1CCCN1.OC(=O)C(F)(F)F SCFVLCBATVDKDN-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/36—Oxygen or sulfur atoms
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Abstract
Description
R1は
a)−H、
b)ハロ、
c)−OCF3、
d)−OCH3、
e)メチル、
f)−SO2CH3、
g)−CF3、および
h)−CN
からなる群から選択され、
R2は独立に、
(a)−H、
(b)ハロ、
(c)−CF3、
(d)−(C1−C4)アルキル、
(e)シクロプロピル、
(f)−O−シクロプロピル、
(g)−SCF3、
(h)−OCF3、
(i)−OCH2CF3、
(j)−CN、および
(k)−O−(C1−C3)アルキル
からなる群から選択される少なくとも1つの置換基であり、
R3は、独立に
a)−H、
b)−CF3、
c)−(C1−C4)アルキル、
d)シクロプロピル、
e)−OCH3、
f)ハロ、および
g)フェニル
からなる群から選択される少なくとも1つの置換基であり、
R4およびR5の各々は独立に、水素、メチル、およびエチルからなる群から選択されるか、またはR4およびR5はともにその各々が結合する炭素と一緒になってシクロプロピル環を形成してもよい)
またはその薬理学的に許容できる塩を提供する。
R1は
a)−H、
b)ハロ、
c)−OCF3、
d)−OCHF2、
e)−OCH3、
f)メチル、
g)イソプロピル、
h)シクロプロピル、
i)−CF3、および
J)−CN
からなる群から選択され、
R2は独立に、
a)−O−シクロプロピル、
b)−SCF3、
c)−OCF3、
d)−OCHF2
e)−OCH2CF3、および
f)−OCF2CF2H
からなる群から選択される1つまたは2つの置換基であり、
R3は
a)−CF3、または
b)シクロプロピル
から選択される)
またはその薬理学的に許容できる塩を提供する。
R1は
a)−OCF3および
b)−OCHF2
からなる群から選択され、
R2は独立に、
a)−H、
b)ハロ、
c)−フッ素置換(C1−C3)アルキル、
d)−(C1−C4)アルキル、および
e)−CN
からなる群から選択される1つまたは2つの置換基であり、
R3は
a)−CF3、
b)−シクロプロピル、および
c)ハロ
からなる群から選択される)
またはその薬理学的に許容できる塩を提供する。
R1は
a)−H、
b)ハロ、
c)−OCF3、
d)−OCHF2、
e)−OCH3、
f)メチル、
g)イソプロピル、
h)シクロプロピル、
i)−CF3、および
j)−CN
からなる群から選択され、
R2は独立に、
a)−O−シクロプロピル、
b)−SCF3、
c)−OCF3、
d)−OCHF2、
e)−OCH2CF3、および
f)−OCF2CF2H
からなる群から選択される1つまたは2つの置換基であり、
R3は、
a)−H、
b)−CF3、
c)−(C1−C4)アルキル、
d)−シクロプロピル、
e)−OCH3、
f)ハロ、および
g)フェニル
からなる群から選択される)
またはその薬理学的に許容できる塩を提供する。
R1は
a)−H、
b)ハロ、
c)−OCF3、
d)−OCHF2、
e)−OCH3、
f)メチル、
g)イソプロピル、
h)シクロプロピル、
i)−CF3、および
j)−CN
からなる群から選択され、
R2は独立に
a)−O−シクロプロピル、
b)−SCF3、
c)−OCF3、
d)−OCHF2、
e)−OCH2CF3、および
f)−OCF2CF2H
からなる群から選択される1つまたは2つの置換基であり、
R3は
a)−H、
b)−CF3、
c)−(C1−C4)アルキル、
d)−シクロプロピル、
e)−OCH3、
f)ハロ、および
g)フェニル
からなる群から選択される)
またはその薬理学的に許容できる塩を提供する。
R1は
a)−OCF3および
b)−OCHF2
からなる群から選択され、
R2は独立に
a)−H、
b)ハロ、
c)−フッ素置換(C1−C3)アルキル、
d)−(C1−C4)アルキル、および
e)−CN
からなる群から選択される1つまたは2つの置換基であり、
R3は
a)−H、
b)−CF3、
c)−(C1−C4)アルキル、
d)−シクロプロピル、
e)−OCH3、
f)ハロ、および
g)フェニル
からなる群から選択される)
またはその薬理学的に許容できる塩を提供する。
R1は
a)−OCF3および
b)−OCHF2
からなる群から選択され、
R2は独立に
a)−H、
b)ハロ、
c)−フッ素置換(C1−C3)アルキル、
d)−(C1−C4)アルキル、および
e)−CN
からなる群から選択される1つまたは2つの置換基であり、
R3は
a)−H、
b)−CF3、
c)−(C1−C4)アルキル、
d)−シクロプロピル、
e)−OCH3、
f)ハロ、および
g)フェニル
からなる群から選択される)
またはその薬理学的に許容できる塩を提供する。
R1は
a)H、
b)ハロ、
c)−OCF3、
d)−OCH3、
e)メチル、
f)−SO2CH3、
g)−CF3、および
h)−CN
からなる群から選択され、
R2は独立に
a)H、
b)ハロ、
c)−CF3、
d)−(C1−C4)アルキル、
e)シクロプロピル、
f)−O−シクロプロピル、
g)−SCF3、
h)−OCF3、
i)−OCH2CF3、
j)−CN、および
k)−O−(C1−C3)アルキル
からなる群から選択される1つまたは2つの置換基である)
を提供する。
R1は
a)−H、
b)ハロ、
c)−OCF3、
d)−OCHF2、
e)−OCH3、
f)メチル、
g)イソプロピル、
h)シクロプロピル、
i)−CF3、および
j)−CN
からなる群から選択され、
R2は
a)−O−シクロプロピル、
b)−SCF3、
c)−OCF3、
d)−OCHF2、
e)−OCH2CF3、および
f)−OCF2CF2H
からなる群から選択される1つまたは2つの置換基であり、
Q2は
a)−H、
b)ハロ、および
c)−O(C1−C3)アルキル
からなる群から選択される)
を提供する。
R1は、
a)−OCF3および
b)−OCHF2
からなる群から選択され、
R2は独立に、
a)−H、
b)ハロ、
c)−フッ素置換(C1−C3)アルキル、
d)−(C1−C4)アルキル、および
e)−CN
からなる群から選択される1つまたは2つの置換基であり、
Q2は
a)−H、
b)ハロ、および
c)−O(C1−C3)アルキル
からなる群から選択される)
を提供する。
(a)鏡像体純度が80%の鏡像体過剰率を超える化合物;
(b)鏡像体純度が90%の鏡像体過剰率を超える化合物;
(c)鏡像体純度が95%の鏡像体過剰率を超える化合物;および
(d)鏡像体純度が99%の鏡像体過剰率を超える化合物。
HPLC方法についての条件は調製例および実施例全体を通して参照される。
LCカラム:Waters XTerra C18 2.1×50mm 3.5μM
勾配:5−100% アセトニトリル/メタノール(50/50)(0.2%ギ酸アンモニウムを含む)で7.0分間、次いで100%で1.0分間保持、カラム温度:50℃±10℃
オートサンプラ温度:周囲
流量1.0mL/分
信号を波長214nmで検出した。
LCカラム:Waters XTerra C18 2.1×50mm 3.5μM
勾配:5−100% アセトニトリル/メタノール(50/50)(0.2%ギ酸アンモニウムを含む)で3.5分間、次いで100%で0.5分間保持、カラム温度:50℃±10℃
オートサンプラ温度:周囲
流量:1.0mL/分
信号を波長214nmで検出した。
LCカラム:Phenomenex Gemini C18 2.0×50mm 3.0μM
勾配:5−100% ACN ACN(0.1%ギ酸を含む)で7.0分間、次いで100%で1.0分間保持、
カラム温度:50℃±10℃
オートサンプラ温度:周囲
流量:1.0mL/分
信号を波長300nmで検出した。
LCカラム:Zorbax RX−C18 4.6×250mm 5μm
勾配:50−90% アセトニトリル(0.03M リン酸緩衝液(2L Milli−Q H2O中のリン酸緩衝液=5.52g NaH2PO4および1.4mL H3PO4)で15分間。カラム温度:40℃
オートサンプラ温度:周囲
流量:1.5mL/分
信号を波長260nmで検出した。
方法A
カラム:0.46×15cm Chiralpak AD−H
定組成:0.2% ジメチルエチルアミンを含む無水エタノール
流量:0.6mL/分
UV250nm。
カラム:0.46×15cm Chiralpak AD−H
定組成:0.2% ジメチルエチルアミンを含む100% MeOH
流量:0.6mL/分
UV260nm。
(±)−5−(3−トリフルオロメトキシ−フェニル)−1−(4−フルオロ−フェニル)−3−(4−フルオロ−フェニルアミノ)−1,5−ジヒドロ−ピロール−2−オン
(±)−5−(3−メチル−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−3−(4−トリフルオロメトキシ−フェニルアミノ)−1,5−ジヒドロ−ピロール−2−オン
(±)5−フェニル−1−(4−トリフルオロメトキシフェニル)−3−(4−トリフルオロメトキシフェニルアミノ)−1,5−ジヒドロ−ピロール−2−オン
(±)−5−(3−トリフルオロメトキシ−フェニル)−1−(4−トリフルオロメチル−フェニル)−3−(4−トリフルオロメチル−フェニルアミノ)−1,5−ジヒドロ−ピロール−2−オン
(±)−1−(4−イソプロピル−フェニル)−5−(3−トリフルオロメトキシ−フェニル)−ピロリジン−2,3−ジオン
(±)−3−ヒドロキシ−5−(3−トリフルオロメトキシ−フェニル)−1−(4−イソプロピル−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(S)−1−(4−ブロモ−フェニル)−3−((R)−1−フェニル−エチルアミノ)−5−(3−トリフルオロメトキシ−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(R)−1−(4−ブロモ−フェニル)−3−((R)−1−フェニル−エチルアミノ)−5−(3−トリフルオロメトキシ−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(±)−3−ヒドロキシ−5−[3−(2,2,2−トリフルオロ−エトキシ)−フェニル]−1−(4−トリフルオロメチル−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(±)−5−[3−(2,2,2−トリフルオロ−エトキシ)−フェニル]−1−(4−トリフルオロメチル−フェニル)−ピロリジン−2,3−ジオン
(±)−5−(3−トリフルオロメトキシ−フェニル)−1−(4−トリフルオロメチル−フェニル)−1,5−ジヒドロ−ピロリジン−2,3−ジオン
(±)−3−ヒドロキシ−5−(3−トリフルオロメトキシ−フェニル)−1−(4−トリフルオロメチル−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(S)−1−(4−トリフルオロメチル−フェニル)−3−((R)−1−フェニル−エチルアミノ)−5−(3−トリフルオロメトキシ−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(調製例37)
(R)−1−(4−トリフルオロメチル−フェニル)−3−((R)−1−フェニル−エチルアミノ)−5−(3−トリフルオロメトキシ−フェニル)−1,5−ジヒドロ−ピロール−2−オン
1H NMR(400MHz,DMSO−d6)δ 7.74(d,2H,J=8.8Hz),7.62(d,2H,J=8.8Hz),7.39−7.34(m,3H),7.28(dd,2H,J=7.7,7.1Hz),7.21−7.14(m,4H),6.04(d,1H,J=7.5Hz),5.91(d,1H,J=2.6Hz),5.21(d,1H,J=2.6Hz),4.31−4.23(m,1H),1.42(d,3H,J=7.0Hz)。MS(m/z):507(M+1)。
1H NMR(400MHz,DMSO−d6)δ 7.76(d,2H,J=8.8Hz),7.62(d,2H,J=8.8Hz),7.34(d,2H,J=7.0Hz),7.28−7.20(m,3H),7.14−7.06(m,2H),7.02(d,1H,J=7.9Hz),6.96(s,1H),5.96−5.92(m,2H),5.19(d,1H,J=2.6Hz),4.36−4.27(m,1H),1.44(d,3H,J=7.0Hz)。MS(m/z):507(M+1)。
(5R)−1−(4−トリフルオロメトキシフェニル)−3−((1R)−1−フェニルエチルアミノ)−5−フェニル−1,5−ジヒドロ−ピロール−2−オン
(±)−5−m−トリル−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2,3−ジオン
(±)−3−ヒドロキシ−5−m−トリル−1−(4−トリフルオロメトキシ−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(調製例77)
(±)−3−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミノ]−5−(m−トリル)−1−(4−トリフルオロメトキシ−フェニル)−1,5−ジヒドロ−ピロール−2−オン
(5R)−3−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミノ]−5−フェニル−1−(4−トリフルオロメトキシ−フェニル)−1,5−ジヒドロ−ピロール−2−オン
1−(6−クロロピリジン−3−イル)−1−メチルエチルアミン
塩化セリウム(III)七水和物(22.4g、30.1mmol)を真空下、140℃で一晩乾燥した。周囲温度まで冷却し、THF(120mL)を加えた。混合物を30分間〜2時間撹拌した。この混合物を−78℃に冷却し、メチルリチウム(1.6M Et2O溶液;38mL、30mmol)を滴下した。反応混合物を−78℃で30分間〜1時間撹拌し、次いでTHF(20mL)中の2−クロロピリジン−5−カルボニトリル(2.77g、20.0mmol)の溶液を加えた。−78℃で30分間〜4時間撹拌し、反応混合物を1時間、20℃まで加温した。この反応混合物を−78℃に冷却し、アンモニア水(38mL)を加えた。反応混合物を1時間、20℃まで加温した。上澄みを静かに移し、固体残渣をジクロロメタンで洗浄した。合わせた有機層を真空中で濃縮した。得られた残渣をシリカゲル(330g)のカラムに移し、(0〜10%[メタノール中の1Mアンモニア]/ジクロロメタン)で溶出し、2.21g(64.8%)の標題の化合物を黄色油状物として得た。MS(m/z):171.0(M+1)。1H NMRは、純粋な所望の生成物であることを示した。1H NMR(CDCl3):δ=8.53(d,J=2.4Hz,1H),7.82(dd,J=8.4,2.4Hz,1H),7.26(dd,J=8.4,0.8Hz,1H),1.87(s,2H),1.50(s,6H)ppm。
3−トリフルオロメチルスルファニル−ベンズアルデヒド
6−シクロプロピルニコチノニトリル
6−トリフルオロメチル−ニコチン酸エチルエステル
2−(6−トリフルオロメチル−ピリジン−3−イル)−プロパン−2−オール
N−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチル]−アセトアミド
1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミン
1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミン;トルエン−4−スルホン酸との複合物
1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミン
3−エチル−ベンズアルデヒド
3−(1,1−ジフルオロ−エチル)−安息香酸エチルエステル
[3−(1,1−ジフルオロ−エチル)−フェニル]−メタノール
3−(1,1−ジフルオロ−エチル)−ベンズアルデヒド
3−シクロプロポキシベンゾニトリル
3−シクロプロポキシベンズアルデヒド
4−(3−フルオロ−フェニル)−N−(4−トリフルオロメトキシ−フェニル)−4−オキソ−ブチルアミド
(±)−4−(3−フルオロ−フェニル)−N−(4−トリフルオロメトキシ−フェニル)−4−ヒドロキシ−ブチルアミド
(R)−5−(3−フルオロ−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン
(調製例113)
(S)−5−(3−フルオロ−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン
6方向に通じるカラム・溶媒切り替え装置を備えたBerger Minigramシステムで超臨界流体クロマトグラフィ(SFC)分析を行った。Berger Multigram IIシステムでSFC精製を行った。両システムに、Mettler−Toledo AutoChem(Leicester、UK)から供給されたKnauer可変波長UV検出器を備え付けた。同様にMettler−Toledo AutoChemによって供給されたBerger GDS−3000システムによって、液体CO2を実験室に送達した。
(5R)−3−(4−クロロベンゾイル)−5−(3−フルオロ−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン
(5R)−3−ジアゾ−5−(3−フルオロ−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン
(3R,5R)−3−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミノ]−5−(m−トリル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン トシレート
(実施例2)
(3S,5S)−3−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミノ]−5−(m−トリル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン トシレート
(3R,5R)−3−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミノ]−5−[3−(2,2,2−トリフルオロ−エトキシ)−フェニル]−1−(4−トリフルオロメチル−フェニル)−ピロリジン−2−オン
(3R,5R)−3−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミノ]−5−フェニル−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン トシレート
(3R,5R)−3−[1−メチル−1−(6−トリフルオロメチルピリジン−3−イル)エチルアミノ]−5−(3−シクロプロポキシフェニル)−1−(4−トリフルオロメチルフェニル)ピロリジン−2−オン
(5R)−3−[1−メチル−1−(6−クロロ−ピリジン−3−イル)−エチルアミノ]−5−(3−フルオロ−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン L−酒石酸塩
6方向に通じるカラム・溶媒切り替え装置を備えたBerger Minigram システムで超臨界流体クロマトグラフィ(SFC)分析を行った。Berger Multigram IIシステムでSFC精製を行った。両システムに、Mettler−Toledo AutoChem(Leicester、UK)から供給されたKnauer可変波長UV検出器を備え付けた。同様にMettler−Toledo AutoChemによって供給されたBerger GDS−3000システムによって、液体CO2を実験室に送達した。25% メタノール/プロパン−2−アミンを含む超臨界二酸化炭素で溶出して、ADHカラムでの超臨界流体クロマトグラフィによってジアスレテオマー混合物を分離した。メタノール中で酒石酸(1当量)を用いて酒石酸塩を調製し、溶媒の蒸発によってその塩を単離し、実施例56および実施例57を得た。
(3R,5R)−3−[1−メチル−1−(6−クロロ−ピリジン−3−イル)−エチルアミノ]−5−(3−フルオロ−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン L−酒石酸塩
(3S,5R)−3−[1−メチル−1−(6−クロロ−ピリジン−3−イル)−エチルアミノ]−5−(3−フルオロ−フェニル)−1−(4−トリフルオロメトキシ−フェニル)−ピロリジン−2−オン L−酒石酸塩
(3R,5R)−3−[1−メチル−1−(6−トリフルオロメチル−ピリジン−3−イル)−エチルアミノ]−5−(3−トリフルオロメトキシ−フェニル)−1−(4−シクロプロピル−フェニル)−ピロリジン−2−オン
抗体捕捉SPA GTP−γ−35S結合
例示した化合物を試験した。GTP−γ35S結合を、以前に記載された(DeLappら、1999)修飾抗体捕捉技法を使用して96ウェル形式で測定した。それぞれCB1またはCB2を発現するCHO細胞膜またはSf9細胞膜(Applied Cell Sciences、メリーランド州、ゲイサーズバーグ;PerkinElmer Life Sciences、マサチューセッツ州、ボストン;以前に記載されたようにして(DeLappら、1999)調製した)、例示した化合物および500pM GTP−γ−35S(PerkinElmer Life Sciences、マサチューセッツ州、ボストン)を、GTP−結合試験緩衝液(20mM Hepes、100mM NaCl、5mM MgCl2、pH7.4)中で30分間、短時間インキュベーションした(すべて室温でインキュベーションした)。完全な作動薬(メタナンダミド(methanandamide))の飽和用量の存在下で拮抗薬用量反応を行った。0.27% Nonidet P40界面活性剤(Roche、インディアナ州、インディアナポリス)、抗Gi抗体(1:300の最終希釈;Covance、ニュージャージー州、プリンストン)、および1.25mg 抗ウサギ抗体シンチレーション近接アッセイビーズ(GE Healthcare、ピスカタウェイ、ニュージャージー州)を含有する混合物を加え、プレートを封鎖し、さらに3時間培養した。Beckman GS−6R遠心分離機を使用して、プレートを700×gで10分間遠心分離し、Wallac MicroBeta TriLuxシンチレーションカウンタ(PerkinElmer、マサチューセッツ州、ボストン)を使用して1ウェルあたり1分間カウントした。
DeLapp NW, McKinzie JH, Sawyer BD, Vandergriff A, Falcone J, McClure DおよびFelder CC (1999). Determination of [35S]guanosine−5’−O−(3−thio)triphosphate binding mediated by cholinergic muscarinic receptors in membranes from Chinese hamster ovary cells and rat striatum using an anti−G protein scintillation proximity assay(抗Gタンパク質シンチレーション近接アッセイを使用したチャイニーズハムスター卵巣細胞由来およびラット線条体由来の膜におけるコリン作動性ムスカリン受容体に媒介される[35S]グアノシン−5’−O−(3−チオ)三リン酸結合の測定). J Pharmacol Exp Ther 289:946−955。
Cheng YCおよびPrusoff WH. 1973. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction(阻害定数(Ki)と酵素反応の50%阻害(I50)を引き起こす阻害剤濃度との関係). Biochem Pharmacol 22:3099−3108。
NIH雄性Swissマウス(Harlan Sprague−Dawley、体重20〜25g)を試験の7〜10日前に入手した。1ケージあたり12匹のマウスを収容した。25〜30gの体重の動物を試験した。試験当日、投薬の少なくとも1時間前に動物を試験室に運び、投薬を開始し、各投薬の間に6〜8分間の間隔を空け、マウスが経口によりビヒクルまたは例示した化合物のいずれかを受け取るようにし、その後、マウスを無菌のケージに入れた(1ケージあたり4匹のマウス)。前処理時間に依存して、それに対応して試験を開始した。
NIH−Swissマウスを、6cmまで22〜25℃の水を入れた無菌のプラスチックの円筒(直径:10cm;高さ:25cm)に6分間入れた。6分間の試験のうちの最後の4分間、不動性時間を記録した。マウスは、身動きせず浮いているかまたはその頭を水の上に保つために必要な動作だけを行っているときに、動けないとみなした。
バイオアベイラビリティを評価するための方法は、当該分野で高く評価されている。かかる参考文献は、Medicinal Research Reviews 第21巻 第5号 382−396(2001)である。
Claims (30)
- 式
R1は
a)−H、
b)ハロ、
c)−OCF3、
d)−OCH3、
e)メチル、
f)−SO2CH3、
g)−CF3、および
h)−CN
からなる群から選択され、
R2は独立に、
(a)−H、
(b)ハロ、
(c)−CF3、
(d)−(C1−C4)アルキル、
(e)シクロプロピル、
(f)−O−シクロプロピル、
(g)−SCF3、
(h)−OCF3、
(i)−OCH2CF3、
(j)−CN、および
(k)−O−(C1−C3)アルキル
からなる群から選択される少なくとも1つの置換基であり、
R3は独立に、
a)−H、
b)−CF3、
c)−(C1−C4)アルキル、
d)シクロプロピル、
e)−OCH3、
f)ハロ、および
g)フェニル
からなる群から選択される少なくとも1つの置換基であり、
R4およびR5の各々は独立に、水素、メチル、およびエチルからなる群から選択されるか、またはR4およびR5はともにその各々が結合する炭素と一緒になってシクロプロピル環を形成してもよい)
の化合物またはその薬理学的に許容できる塩。 - 請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩と、薬理学的に許容できる担体、希釈剤、または賦形剤とを含む医薬組成物。
- 治療に使用するための請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩。
- 過剰な食物摂取に関連する摂食障害、肥満症、統合失調症、統合失調症に関連する認識機能障害、薬物乱用またはアルコール依存症、禁煙、および非定型抗精神病薬を用いた治療中に観察される治療によって発現した体重増加から選択される障害の治療において使用するための請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩。
- 体重増加、肥満症、統合失調症、統合失調症に関連する認識機能障害、薬物乱用またはアルコール依存症、禁煙、および非定型抗精神病薬を用いた治療中に観察される治療によって発現した体重増加から選択される障害の治療において、抗精神病薬と同時に組合せて、個別に組合せて、または連続的に組合せて使用するための、請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩。
- 過剰な食物摂取に関連する摂食障害、肥満症、統合失調症、統合失調症に関連する認識機能障害、薬物乱用またはアルコール依存症、禁煙、および非定型抗精神病薬を用いた治療中に観察される治療によって発現した体重増加から選択される障害の治療のための薬物の製造における、請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩の使用。
- 体重増加、肥満症、統合失調症、統合失調症に関連する認識機能障害、薬物乱用またはアルコール依存症、禁煙、および非定型抗精神病薬を用いた治療中に観察される治療によって発現した体重増加から選択される障害の治療のための併用療法において使用するための薬物であって、前記薬物が抗精神病薬と同時に組合せて、個別に組合せて、または連続的に組合せて投与される、薬物の製造のための、請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩の使用。
- 哺乳動物における、肥満症、統合失調症、統合失調症に関連する認識機能障害、薬物乱用またはアルコール依存症、禁煙、禁煙中に観察される治療によって発現した体重増加である病状の治療方法であって、前記哺乳動物に有効量の、請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩を抗精神病薬と同時に組合せて、個別に組合せて、または連続的に組合せて投与することを含む、方法。
- 前記病状が過剰な食物摂取に関連する摂食障害である、請求項15に記載の方法。
- 前記病状が肥満症である、請求項15に記載の方法。
- 前記病状が統合失調症である、請求項15に記載の方法。
- 前記病状が統合失調症に関連する認識機能障害である、請求項15に記載の方法。
- 前記病状が薬物乱用またはアルコール依存症である、請求項15に記載の方法。
- 前記病状が禁煙である、請求項15に記載の方法。
- 前記病状が禁煙中に観察される治療によって発現した体重増加である、請求項15に記載の方法。
- 哺乳動物における、統合失調症、体重増加、肥満症、統合失調症に関連する認識機能障害、薬物乱用またはアルコール依存症、禁煙、非定型抗精神病薬を用いた治療中に観察される治療によって発現した体重増加である病状の治療方法であって、前記哺乳動物に有効量の請求項1から請求項7のいずれか1項に記載の化合物、またはその薬理学的に許容できる塩を投与することを含む方法。
- 前記病状が統合失調症である、請求項23に記載の方法。
- 前記病状が体重増加である、請求項23に記載の方法。
- 前記病状が肥満症である、請求項23に記載の方法。
- 前記病状が統合失調症に関連する認識機能障害である、請求項23に記載の方法。
- 前記病状が薬物乱用またはアルコール依存症である、請求項23に記載の方法。
- 前記病状が禁煙である、請求項23に記載の方法。
- 前記病状が非定型抗精神病薬を用いた治療中に観察される治療によって発現した体重増加である、請求項23に記載の方法。
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JP2011518220A (ja) * | 2008-04-22 | 2011-06-23 | イーライ リリー アンド カンパニー | Cb−1リガンドとしての1,5−ジフェニル−ピロリジン−2−オン化合物 |
JP2011527988A (ja) * | 2008-04-22 | 2011-11-10 | イーライ リリー アンド カンパニー | Cb−1リガンドとしての1,5−ジフェニル−ピロリジン−2−オン化合物 |
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WO2010057000A2 (en) * | 2008-11-13 | 2010-05-20 | The Trustees Of Columbia University In The City Of New York | Neuraminidase inhibitors and uses thereof |
CA2805091A1 (en) | 2010-07-15 | 2012-01-19 | Oleg Iliich Epshtein | Pharmaceutical compositions comprising a homopathically potentized form of an antibody to human cannabinoid receptor |
WO2014078568A1 (en) | 2012-11-14 | 2014-05-22 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
WO2022132803A1 (en) * | 2020-12-14 | 2022-06-23 | The Board Of Trustees Of The Leland Stanford Junior University | Cb2 receptor agonists |
WO2023205180A1 (en) | 2022-04-19 | 2023-10-26 | Nurix Therapeutics, Inc. | Biomarkers for cbl, and compositions and methods for their use |
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