JP2012511011A - 置換されたテトラヒドロピランスピロピロリジノン及びピペリジノン、それらの製造及び治療上の使用 - Google Patents
置換されたテトラヒドロピランスピロピロリジノン及びピペリジノン、それらの製造及び治療上の使用 Download PDFInfo
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- JP2012511011A JP2012511011A JP2011539715A JP2011539715A JP2012511011A JP 2012511011 A JP2012511011 A JP 2012511011A JP 2011539715 A JP2011539715 A JP 2011539715A JP 2011539715 A JP2011539715 A JP 2011539715A JP 2012511011 A JP2012511011 A JP 2012511011A
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- methyl
- phenyl
- aza
- oxa
- spiro
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title description 5
- 230000001225 therapeutic effect Effects 0.000 title description 2
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- 102000004384 Histamine H3 receptors Human genes 0.000 claims abstract description 25
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- JSOMVCDXPUXKIC-UHFFFAOYSA-N tert-butyl 3-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C1 JSOMVCDXPUXKIC-UHFFFAOYSA-N 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
- 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
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- 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
- A61K31/395—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
- A61K31/407—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 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
Description
mは、1又は2であり、
nは、1又は2であり、
pは、1又は2であり、
R1は、水素、(C1−C4)アルキル、CF3、(C1−C4)アルコキシ−(C1−C4)アルキルであり、
R2は、水素、ハロゲン、(C1−C4)アルキル又はCF3である]の化合物が提供される。
本明細書に使用される用語は、以下の意味を有する:
本明細書に使用されるように、「(C1−C4)アルキル」の語句は、メチル及びエチル基、並びに直鎖又は分枝状プロピル及びブチル基を含む。具体的なアルキル基は、メチル、エチル、n−プロピル、イソプロピル及びtert−ブチルである。「(C1−C4)アルコキシ」、「(C1−C4)アルコキシ(C1−C4)アルキル」、又は「ヒドロキシ(C1−C4)アルキル」のような派生した語句は、それに応じて解釈すべきである。
Samuel H. Wilen and Lewis N. Mander, 編集者, Wiley-Interscience, John Wiley & Sons, Inc., New York, 1994に含まれる。
(i)疾患、障害及び/又は状態にかかりやすいかもしれないが、かかったとまだ診断されていない患者において疾患、障害又は状態が生じるのを予防すること;
(ii)疾患、障害又は状態を抑制すること、すなわち、その進行を抑えること;そして(iii)疾患、障害又は状態を軽減すること、すなわち、疾患、障害及び/又は状態の退縮させること。
mは、1又は2であり、
nは、1又は2であり、
pは、1又は2であり、
R1は、水素、(C1−C4)アルキル、CF3、(C1−C4)アルコキシ−(C1−C4)アルキルであり、
R2は、水素、ハロゲン、(C1−C4)アルキル又はCF3である]
の化合物が提供される。
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−メチル−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−(2−エチル−[1,3']ビピロリジニル−1'−イル)−2−フルオロ−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−(2−イソプロピル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−(2−プロピル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−フルオロ−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−(2−イソプロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−(2−プロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−(2−メトキシメチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−{4−[4−(2−イソプロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−(2−プロピル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−エチル−4−[4−(2−プロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−エチル−4−[4−(2−メトキシメチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−エチル−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン。
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−メチル−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−フルオロ−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン。
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−エチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン。
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−エチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)
−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン。
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン。
rehensive Organic Transformations,” VCH publishers, 1989参照。
ってそこなわれないように、遊離塩基と合わせたときに、薬学的に許容しうる塩、すなわちアニオンが塩の薬学的用量で患者に非毒性である塩を生じるものが含まれる。前記塩基性の化合物の薬学的に許容しうる塩は好ましいが、例えば、塩が精製及び同定のためにだけ形成されるとき、又はそれがイオン交換法によって薬学的に許容しうる塩を製造する際の中間体として用いられるときのように、特定の塩がそれ自体で中間生成物としてしか望まれない場合であっても、すべての酸付加塩は、遊離塩基の形態の供給源として有用である。
以下の実施例及び製造に使用したように、その中に使用される用語は、記載された意味を有する:「kg」は、キログラムのことであり、「g」は、グラムのことであり、「mg」は、ミリグラムのことであり、「μg」は、マイクログラムのことであり、「pg」は、ピコグラムのことであり、「lb」は、ポンドのことであり、「oz」は、オンスのことであり、「mol」は、モルのことであり、「mmol」は、ミリモルのことであり、「μmole」は、マイクロモルのことであり、「nmole」は、ナノモルのことであり、「L」は、リットルのことであり、「mL」又は「ml」は、ミリリットルのことであり、「μL」は、マイクロリットルのことであり、「gal」は、ガロンのことであり、「℃」は、摂氏の温度差のことであり、「Rf」は、保持因子のことであり、「mp」又は「m.p.」は、融点のことであり、「dec」は、分解のことであり、「bp」又は「b.p.」は、沸点のことであり、「mmHg」は、水銀のミリメートルにおける圧力のことであり、「cm」は、センチメートルのことであり、「nm」は、ナノメートルのことであり、「abs.」は、無水のことであり、「conc.」は、濃縮されたもののことであり、「c」は、g/mLにおける濃度のことであり、「DMSO」は、ジメチルスルホキシドのことであり、「DMF」は、N,N−ジメチルホルムアミドのことであり、「CDI」は、1,1'−カルボニルジイミダゾールのことであり、「DCM」又は「CH2Cl2」は、ジクロロメタンのことであり、「DCE」は、1,2−ジクロロエタンのことであり、「HCl」は、塩酸のことであり、「EtOAc」は、酢酸エチルのことであり、「PBS」は、リン酸緩衝食塩水のことであり、「IBMX」は、3−イソブチル−1−メチルキサンチンのことであり、「PEG」は、ポリエチレングリコールのことであり、「MeOH」は、メタノールのことであり、「MeNH2」は、メチルアミンのことであり、「N2」は、窒素ガスのことであり、「iPrOH」は、イソプロピルアルコールのことであり、「Et2O」は、エチルエーテルのことであり、「LAH」は、水素化アルミニウムリチウムのことであり、「ヘプタン」は、n−ヘプタンのことであり、「HMBA−AM」樹脂は、4−ヒドロキシメチルベ安息香酸ンアミノメチル樹脂のことであり、「PdCl2(dppf)2」は、1,1(−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドDCM錯体のことであり、「HBTU」は、2−(1H−ベンゾトリアゾール−1イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェートのことであり、「DIEA」は、ジイソプロピルエチルアミンのことであり、「CsF」は、フッ化セシウムのことであり、「MeI」は、ヨウ化メチルのことであり、「AcN」、「MeCN」又は「CH3CN」は、アセトニトリルのことであり、「TFA」は、トリフルオロ酢酸のことであり、「THF」は、テトラヒドロフランのことであり、「NMP」は、1−メチル−2−ピロリジノンのことであり、「H2O」は、水のことであり、「BOC」は、t−ブチルオキシカルボニルのことであり、「ブライン」は、飽和塩化ナトリウム水溶液のことであり、「M」は、モルのことであり、「mM」は、ミリモルのことであり、「 M」は、マイクロモルのことであり、「nM」は、ナノモルのことであり、「N」は、正常のことであり、「TLC」は、薄層クロマトグラフィのことであり、「HPLC」は、高性能液体クロマトグラフィのことであり、「HRMS」は、高分解能質量スペクトルのことであり、「L.O.D.」は、乾燥減量のことであり、「μCi」は、マイクロキュリーのことであり、「i.p.」は、腹腔内のことであり、「i.v.」は、静脈内のことであり、anhyd=無水;aq=水性;min=分;hr=時間;d=日;sat.=飽和;s=一重線、d=二重線;t=三重線;q=四重線;m=多重線;dd=二重線の二重線;br=ブロード;LC=液体クロマトグラフィ;MS=質量分析器;ESI/MS=エレクトロスプレーイオン化/質量分析器;RT=保持時間;M=分子イオン、約「〜」=約。
質量スペクトル(MS)は、Micromass質量分析器を用いて記録した。一般に、使用した方法は、陽電子スプレーイオン化であり、100から1000まで質量m/zを走査した。液体クロマトグラフィは、Hewlett Packard 1100 Series Binary Pump & Degasserにおいて実施した;使用した補助検出器は、以下の通りである:Hewlett Packard 1100 SeriesUV検出器、波長=220nm、そしてSedere SEDEX 75 Evaporative Light Scattering (ELS)検出器 温度=46℃N2圧力=4bar
LCT:勾配(AcN+0.05%TFA):(H2O+0.05%TFA)=5:95(0分)〜95:5(2.5分)〜95:5(3分)。カラム:YMC Jsphere 33×2 4μM,1ml/分
MUX:カラム:YMC Jsphere 33×2,1ml/分 勾配(AcN+0.05%TFA):(H2O+0.05%TFA)=5:95(0分)〜95:5(3.4分)〜95:5(4.4分)
LCT2:YMC Jsphere 33×2 4μM、(AcN+0.05%TFA):(H2O+0.05%TFA)=5:95(0分)〜95:5(3.4分)〜95:5(4.4分)
QU:YMC Jsphere 33×2 1ml/分,(AcN+0.08%ギ酸):(H2O+0.1%ギ酸)=5:95(0分)〜95:5(2.5分)〜95:5(3.0分)
中間体(i)
2−メチル−[1,3']ビピロリジニル−1'−カルボン酸tert−ブチルエステル
MS:255(M+H+);TLC:0.5(DCM中の10%MeOH)
2−メチル−[1,3']ビピロリジニル塩酸塩
LCMS:RT=0.35分,MS:155(M+H)
1H NMR (D2O, 300MHz):δ 4.30 (m), 3.85 (m), 3.76 (s), 3.5 (m), 3.46 (m), 3.32 (m), 2.66 (m), 2.28 (m), 2.10 (m), 1.46 (bs).
4−(2−プロピル−ピロリジン−1−イル)−ピペリジン
LC/MS:RT=3.42分;MS:197.19(M+H)
NMR: 1H NMR (300 MHz CDCl3) δ 4.72 (1H, br), 3.28 (1H, d, J = 12.65 Hz), 3.04 (2H, m), 2.86-2.53 (4H, m), 2.05-1.47 (10H, m), 1.47 (3H, m), 0.93 (3H, m)
4−(2−イソプロピル−ピロリジン−1−イル)−ピペリジン
LC/MS:RT=3.69分;MS:197.19(M+H)
NMR: 1H NMR (300 MHz CDCl3) δ : 5.77 (1H, br), 3.35 (1H, m), 2.98 (2H, m), 2.84-2.46 (4H, m), 2.05-1.46 (10H, m), 0.86 (6H, dt, J = 10.40, 6.05 Hz)
LC/MS:199(M+H)
2−プロピル−[1,3']ビピロリジニル
LC/MS:RT=3.64分;MS:183.18(M+H)
NMR: 1H NMR (300 MHz, CDCl3) δ : 3.39 (1H, m), 3.17 (1H, m), 2.94 (3H, m), 2.69-2.40 (4H, m), 2.13-1.10 (10H, m), 0.92 (3H, m)
2−イソプロピル−[1,3']ビピロリジニル
LC/MS:RT=0.45分;MS:183.19(M+H)
NMR: 1H NMR (300 MHz, CDCl3) δ : 3.39 (1H, m), 3.17 (1H, m), 3.05-2.74 (3H, m),
2.69-2.36 (3H, m), 2.10-1.69 (3H, m), 1.63 (4H, m), 0.84 (6H, m)
2−メトキシメチル−[1,3']ビピロリジニル
LC/MS:RT=0.42分;MS:185.16(M+H)
NMR: 1H NMR (300 MHz, CDCl3) δ : 3.38 (6H, m), 3.21 (2H, m), 3.06-2.40 (6H, m),
2.14-1.57 (5H, m)
4−(2−エチル−ピロリジン−1−イル)−ピペリジン
LC/MS:RT=3.57分;MS:183.18(M+H)
NMR: 1H NMR (300 MHz, CDCl3) δ : 3.19-2.76 (4H, m), 2.57 (4H, m), 2.15-1.20 (10H, m), 1.19 (1H, m), 0.86 (3H, t, J = 7.51 Hz)
2−エチル−[1,3']ビピロリジニル
LC/MS:RT=3.64分;MS:169.16(M+H)
1H NMR (300 MHz, CDCl3) δ :3.11-2.29 (8H, m), 2.19-1.11 (9H, m), 0.87 (3H, t, J
= 7.51 Hz)
MS:290(M+H+)
1H NMR (300 MHz, CDCl3), d (ppm): 8.10 (d, 9Hz, 1H), 6.36 (bd, 9 Hz, 1H), 6.28 (bs, 1H), 3.4-3.2 (m, 5H), 3.00-2.78 (m, 2H), 2.64 (s, 3H), 1.7-2.2 (m, 6H), 1.5 (m, 1H), 1.06 (m, 3H).
4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニルアミン
(R)−3−(トルエン−4−スルホニルオキシ)−ピロリジン−1−カルボン酸tert−ブチルエステル
MS:363(M+Na+);TLC(DCM)Rf=0.3
1H NMR (CDCl3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04
(bs, 1H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
(S)−3−(トルエン−4−スルホニルオキシ)−ピロリジン−1カルボン酸tert−ブチルエステル
TLC(DCM)Rf=0.3 LC:Rt=3.55分,全イオンに基づいて100%純粋,MS:363(M+Na);342,327,286(基準)
1H NMR (300MHz, CDCl3), δ (ppm): 7.81 (d, 8.7Hz, 2H), 7.37 (d, 8.7Hz, 2H), 5.04
(bs, 1H), 3.45 (m, 4H), 2.46 (s, 3H), 1.44 (s, 9H).
(2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−カルボン酸tert−ブチルエステル
LCMS:RT=1.27分,MS:255(M+H)
1H NMR (300 MHz, CDCl3), δ (ppm): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m, 1H), 2.71
(m, 1H), 2.47 (m, 1H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46 (s, 9H), 1.06 (d, 6.2Hz, 3H).
(2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−カルボン酸tert−ブチルエステル
LCMS:RT=1.05分,MS:255(M+H)
1H NMR (300 MHz, CDCl3), δ (ppm): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m, 1H), 2.75 (m, 1H), 2.51 (m, 1H), 2.07-1.69 (m, 6H), 1.46 (s, 9H), 1.10 (d, 6.0Hz, 3H).
(2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−カルボン酸tert−ブチルエステル
LCMS:RT=1.14分,MS:255(M+H)
1H NMR (300 MHz, CDCl3), δ (ppm): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m, 1H), 2.75 (m, 1H), 2.51 (m, 1H), 2.07-1.69 (m, 6H), 1.46 (s, 9H), 1.10 (d, 6.0Hz, 3H).
(2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−カルボン酸tert−ブチルエステル
LCMS:RT=1.09分,MS:255(M+H)
1H NMR (300 MHz, CDCl3), δ (ppm): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m, 1H), 2.71
(m, 1H), 2.47 (m, 1H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46 (s, 9H), 1.06 (d, 6.2Hz, 3H).
LC/MS:RT=1.95分 MS:269
4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル
LC/MS:RT=2.13分 MS:269
(2S,3'R)−2−メチル−[1,3']ビピロリジニル二塩酸塩
MS:155(M+H)
1H NMR: (D2O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 ( m, 1H) 3.5,
(m, 2H), 3.3-3.1 ( m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1H), 1.4(d, 6.0
Hz,3H).
(2S,3S')−2−メチル−[1,3']ビピロリジニル二塩酸塩
LCMS:RT=0.37分,MS:155(M+H)
1H NMR: (D2O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 ( m, 1H) 3.5,
(m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1H), 1.4(d, 6.0 Hz,3H)
(2R,3'S)−2−メチル−[1,3']ビピロリジニル二塩酸塩
MS:155(M+H)
1H NMR: (D2O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 ( m, 1H) 3.5,
(m, 2H), 3.3-3.1 ( m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1H), 1.4(d, 6.0
Hz,3H).
(2R,3'R)−2−メチル−[1,3']ビピロリジニル二塩酸塩
MS:155(M+H)
1H NMR: (D2O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 ( m, 1H) 3.5,
(m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1H), 1.4(d, 6.0 Hz,3H)
4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン
LC/MS:3.6分;MS:169.17(M+H)
1H NMR (300 MHz CDCl3) δ (ppm): 3.12 (2H, m), 2.88 (2H, m), 2.59 (4H, m), 2.02-1.59 (6H, m), 1.59-1.31 (3H, m), 1.05 (3H, d, J = 6.05 Hz)
(S)−2−メチル−[1,4']ビピペリジニル
LC/MS:RT=3.82分;MS:183(M+H)
1H NMR (300 MHz CDCl3) δ (ppm): 3.11 (2H, m), 2.86 (2H, m), 2.58 (4H, m), 2.17 (1H, m), 1.91 (1H, m) 1.66 (5H, m), 1.51-1.20 (4H, m), 1.07 (3H, d, J = 6.23 Hz)
(2S,3'R)−2−メチル−1'−(3−メチル−4−ニトロ−フェニル)−[1,3']ビピロリジニル
懸濁液に水2mL及びDCM5mLを加えた。二層を分離し、そして水層をDCM(10mL×2)で抽出した。合わせたDCM抽出物を炭酸水素ナトリウム(5mL)及びブライン(5mL×2)で洗浄し、乾燥(無水炭酸カリウム)させ、濾過し、そして真空で濃縮して粗生成物をシリカゲルカラム上で精製し、DCM中の5%MeOHで溶離して乾燥後、黄色固形物として表題化合物を得た。
LCMS:RT=1.38分,MS:290(M+H)
1H NMR (300 MHz, CDCl3), δ (ppm): 8.10 (d, 9.1Hz, 1H), 6.36 (dd, 9.2, 2.5 Hz, 1H), 6.28 (d, 2.4 Hz, 1H), 3.654(m, 2H), 3.37 (m, 3H), 2.99 (dt, 3.7Hz, 8.8Hz,1H), 2.84 (六重線, 6.6Hz, 1H), 2.65 (s, 3H), 2.56 (q , 8.1Hz, 1H), 2.31 (m, 2H), 2.11 (m ,2H) 1.87 (m,1H), 1.08 (d, 6.2Hz, 3H).
使用した分析キラルHPLC条件は、以下の通りである:0.5%IPAmine入り100%イソプロパノール均一 5ml/分 排出口圧力150bar,200nM 得られた結果は、以下の通りであった:RT=10.92分;鏡像体過剰率99%
2−(2S)−メチル−1'−(3−メチル−4−ニトロ−フェニル)−[1,3'(3'S)]ビピロリジニル
LCMS:RT=1.43分,MS:290(M+H)
1H NMR (300 MHz, CDCl3), δ (ppm): 8.10 (d, 9.2Hz, 1H), 6.36 (dd, 9.2, 2.8 Hz, 1H), 6.28 (d, 2.2 Hz, 1H), 3.6 (m, 2H), 3.3 (m, 3H), 3.00-2.78 (dt, 3.5Hz, 8.8Hz,2H), , 2.79 (m, 1H), 2.64 (s, 3H), 2.56 (m, 1H), 2.03 (m, 2H), 1.98 (m ,2H) 1.45 (m,1H), 1.08 (d, 6.2Hz, 3H).
使用した分析キラルHPLC条件は、以下の通りであった:0.5%IPAmine入り100%イソプロパノール均一 5ml/分 排出口圧力150bar,200nM 使用した結果は、以下の通りであった:RT=8.16分;鏡像体過剰率100%
2−(2R)−メチル−1'−(3−メチル−4−ニトロ−フェニル)−[1,3'(3'S)]ビピロリジニル
1H NMR (300 MHz, CDCl3), δ (ppm): 8.10 (d, 9.1Hz, 1H), 6.36 (dd, 9.2, 2.5 Hz, 1H), 6.28 (d, 2.4 Hz, 1H), 3.654(m, 2H), 3.37 (m, 3H), 2.99 (dt, 3.7Hz, 8.8Hz,1H), 2.84 (六重線, 6.6Hz, 1H), 2.65 (s, 3H), 2.56 (q , 8.1Hz, 1H), 2.31 (m, 2H), 2.11 (m ,2H) 1.87 (m,1H), 1.08 (d, 6.2Hz, 3H).
使用した分析キラルHPLC条件は、以下の通りであった:0.5%IPAmine入り100%イソプロパノール均一 5ml/分 排出口圧力150bar,200nM 使用した結果は、以下の通りであった:RT=11.93分;鏡像体過剰率100%
2−(2R)−メチル−1'−(3−メチル−4−ニトロ−フェニル)−[1,3'(3'R)]ビピロリジニル
1H NMR (300 MHz, CDCl3), δ (ppm): 8.10 (d, 9.2Hz, 1H), 6.36 (dd, 9.2, 2.8 Hz, 1H), 6.28 (d, 2.2 Hz, 1H), 3.6 (m, 2H), 3.3 (m, 3H), 3.00-2.78 (dt, 3.5Hz, 8.8Hz,2H), , 2.79 (m, 1H), 2.64 (s, 3H), 2.56 (m, 1H), 2.03 (m, 2H), 1.98 (m ,2H) 1.45 (m,1H), 1.08 (d, 6.2Hz, 3H).
使用した分析キラルHPLC条件は、以下の通りであった:0.5%IPAmine入り100%イソプロパノール均一 5ml/分 排出口圧力150bar,200nM 使用した結果は、以下の通りであった:RT=8.95分;鏡像体過剰率100%
2−メチル−4−(2−(2S)−メチル−[1,3'(3'R)]ビピロリジニル−1'−イル)−フェニルアミン
LC/MS:260,TLC(10%MeOH/DCM):0.3Rf
2−メチル−4−(2−(2S)−メチル−[1,3'(3'S)]ビピロリジニル−1'−イル)−フェニルアミン
LC/MS:260,TLC(10%MeOH/DCM):Rf0.3
LC/MS:260,TLC(10%MeOH/DCM):Rf=0.3
LC/MS:260,TLC(10%MeOH/DCM):Rf=0.3
4−アリル−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
これにTHF(10mL)中のテトラヒドロ−ピラン−4−カルボン酸メチルエステル(7.2g,50mmol)を加えた。色の変化はほとんどなかった(僅かに薄い)。これを−78℃で45分間撹拌した。そしてカニューレを介してHMPA5g及びヨウ化アリル10.92gの混合物を加えた。90%添加すると、白色沈殿が突然形成された。この混合物を−78℃で20分間撹拌し、次いで、乾燥氷浴をはずし、そして撹拌を続けて反応混合物を30分かけて室温に温まるのにまかせた。沈殿が溶解したら、反応混合物を氷水(100mL)及びエーテル(50mL)中に注いだ。二層を分離し、水層をエーテル(3x50mL)で抽出した。合わせた有機層をブラインで洗浄し、乾燥(K2CO3)させ、濾過し、そして真空で濃縮して黄色の液体として表題化合物8.75g(収率95%)を得た。
LCMS RT=2.70分;MS 185(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 5.55 (m, 1H), 5.02 (m, 2H), 3.85 (dt, 3.9Hz, 12.0Hz, 2H), 3.71 (s, 3H), 3.44 (dt, 2.4Hz, 11.4Hz, 2H), 2.30 (d, 7.5Hz, 2H), 2.09 (m 2H), 1.54 (m, 2H).
4−(2−オキソ−エチル)−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=1.26分;MS:187(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 9.68 (s, 1H), 3.85 (dt, 3.9Hz, 12.0Hz, 2H), 3.71 (s, 3H), 3.44 (dt, 2.4Hz, 11.4Hz, 2H), 2.30 (d, 7.5Hz, 2H), 2.09 (m 2H), 1.54
(m, 2H).
4−[2−(4−ブロモ−2−メチル−フェニルアミノ)−エチル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=3.29分;MS:356(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 7.20 (dd, 2.3Hz, 8.4Hz, 1H), 7.14 (m, 1H), 6.42 (d, 8.4Hz, 1H), 3.86 (dt, 3.6Hz, 11.7Hz, 2H), 3.69 (s, 3H), 3.51 (dt, 2.4Hz, 11.4Hz, 3H), 3.12 (m, 2H), 2.17 (m, 1H), 2.07 (s, 3H), 1.91 (t, 7.5Hz, 3H), 1.58 (m, 2H).
4−[2−(4−ブロモ−2−フルオロ−フェニルアミノ)−エチル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=1.05分;MS:360(M+H)
4−[2−(4−ブロモ−フェニルアミノ)−エチル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=1.0分;MS:342(M+H)
4−[2−(4−ブロモ−2−トリフルオロメチル−フェニルアミノ)−エチル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=1.12分;MS:410(M+H)
4−[2−(4−ブロモ−2−エチル−フェニルアミノ)−エチル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=1.10分;MS:370(M+H)
2−(4−ブロモ−2−メチル−フェニル)−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LCMS:RT=3.27分;MS:324(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 7.42 (d, 2.1Hz, 1H), 7.36 (dd, 2.1Hz, 8.4Hz, 1H), 7.00 (d, 8.4Hz, 1H), 4.06 (dt, 4.2Hz, 11.7Hz, 2H), 3.61 (m, 4H), 2.21 (t, 6.9Hz, 2H), 2.17 (s, 3H), 2.11 (m, 2H), 1.51 (m, 2H).
2−(4−ブロモ−2−フルオロ−フェニル)−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LCMS:RT=3.25分;MS:328(M+H)
1H NMR (300 MHz, CDCl3) δ: 7.34 (3H, m), 4.03 (2H, dt, J = 11.73, 4.22 Hz), 3.76 (2H, t, J = 6.96 Hz), 3.60 (2H, m), 2.19 (2H, t, J = 6.96 Hz), 2.08 (2H, m), 1.51 (2H, d, J = 13.56 Hz).
2−(4−ブロモ−フェニル)−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LCMS:RT=3.42分;MS:310(M+H)
1H NMR (300 MHz CDCl3) δ: 7.46 (2H, m), 7.57 (2H, m), 4.03 (2H, dt, J = 11.73, 4.22 Hz), 3.78 (2H, t, J = 6.78 Hz), 3.58 (2H, td, J = 10.81, 2.57 Hz), 2.17 (2H, t, J = 6.96 Hz), 2.08 (2H, m), 1.46 (2H, d, J = 13.56 Hz).
LCMS:RT=3.45分;MS:378(M+H)
1H NMR (300 MHz CDCl3) δ: 7.87 (1H, d, J = 2.20 Hz), 7.74 (1H, dd, J = 8.43, 1.83 Hz) 7.15 (1H, d, J = 8.43 Hz), 4.03 (2H, dt, J = 11.73, 4.40 Hz), 3.63 (4H, m), 2.22 (2H, t, J = 6.96 Hz), 2.08 (2H, m), 1.51 (2H, d, J = 13.75 Hz).
本質的に上記と同じやり方でエステル1.39gからこの中間体を合成して褐色の固形物として表題生成物560mg(収率55%)を得た。
MS:338.08(M+H)
1H NMR (300 MHz, CDCl3) δ: 7.45 (1H, d, J= 2.20 Hz), 7.35 (1H, dd, J = 8.43, 2.20 Hz), 6.97 (1H, d, J = 8.43 Hz), 4.04 (2H, dt, J = 11.73, 4.22 Hz), 3.62 (4H, m), 2.51 (2H, q, J = 7.51 Hz), 2.21 (2H, t, J = 6.96 Hz), 1.49 (2H, d, 13.38 Hz), 1.20 (3H, t, J = 7.51 Hz).
4−ブタ−3−エニル−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=3.07分;MS:199(M+H)
NMR (CDCl3, 300MHz) δ: 5.78 (ddt, 8.4Hz, 11.7Hz, 6.6 Hz, 1H), 4.97 (m, 2H), 3.90 (dt, 3.9Hz, 11.7Hz, 2H), 3.72 (s, 3H), 3.41 (dt, 2.6Hz, 11.7Hz, 2H), 2.10 (m, 2H), 1.98 (m, 2H), 1.58 (m, 4H).
4−(3−オキソ−プロピル)−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=2.10分;MS:201(M+H)
1H NMR (CDCl3, 300MHz) δ: 9.74 m, 1H), 3.86 (dt, 3.6Hz, 11.7Hz, 2H), 3.72 (s, 3H), 3.41 (dt, 2.3Hz, 11.7Hz, 2H), 2.42 (m, 2H), 2.09 (m, 2H), 1.88 (m, 2H), 1.52 (m, 2H).
4−[3−(4−ブロモ−2−メチル−フェニルアミノ)−プロピル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=3.872分;MS:372/370(M+H)
4−[3−(4−ブロモ−フェニルアミノ)−プロピル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=3.382分;MS:356/358(M+H)
4−[3−(4−ブロモ−2フルオロ−フェニルアミノ)−プロピル]−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LCMS:RT=4.253分;MS:374/376(M+H)
2−(4−ブロモ−2−メチル−フェニル)−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LCMS:RT=3.03分;MS:338/340(M+H)
1H NMR (CDCl3, 300MHz) δ (ppm): 7.35 (m, 2H), 6.96 (m, 1H), 3.96 (m, 2H), 3.75-3.52 (m, 2H), 3.37 (m, 2H), 2.22 (m, 2H), 2.12 (s, 3H), 1.98-2.10 (m, 4H), 1.53 (m, 2H).
2−(4−ブロモ−フェニル)−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LCMS:RT=2.91分;MS:324/326(M+H)
1H NMR (CDCl3, 300MHz) δ (ppm): 7.50 (d, 9.3Hz, 2H), 7.11 (d, 9.3Hz, 2H), 3.95 (m, 2H), 3.73-3.61 (m, 2H), 2.12 (m, 2H), 1.98 (bs, 4H), 1.52 (m, 2H).
2−(4−ブロモ−2−フルオロ−フェニル)−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LCMS:RT=3.01分;MS:342/344(M+H)
1H NMR (CDCl3, 300MHz) δ (ppm): 7.31 (m, 2H), 7.10 (m, 1H), 3.94 (bs, 2H), 3.70
(m, 2H), 3.56 (bs, 2H), 2.22 (bs, 2H), 1.99 (m, 4H), 1.56 (m, 3H).
4−{2−[2−メチル−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニルアミノ]−エチル}−テトラヒドロ−ピラン−4−カルボン酸メチルエステル
LC RT=2.72分;MS 430
1H NMR (300MHz, CDCl3), δ (ppm): 6.56 (d, 9.3Hz, 1H), 6.41 (m, 2H), 3.83 (m, 2H), 3.71 (s, 3H), 3.53-3.41 (m, 3H), 3.35-2.88 (m, 8H), 2.76 (六重線, 6.0Hz, 1H), 2.50 (q, 8.4Hz, 1H), 2.19-1.87 (m, 10H), 1.85-1.41 (m, 5H), 1.14 (d, 6.3Hz, 3H).
THF(70mL)中の4−{2−[2−メチル−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニルアミノ]−エチル}−テトラヒドロ−ピラン−4−カルボン酸メチルエステル(0.79g,1.84mmol)の透明な溶液に、室温でカリウムt−ブトキシド(THF中1M)1mLの溶液(2mL,2mmol,1.1当量)を加えた。透明な溶液は少し濁った。15分後、TLC(DCM中の5%7N NH3/MeOH)は、反応が完了したことを示し(スポットからスポットへ)、LC/MSは、微量の出発物質ピーク430/429と共に生成物ピーク398(t=2.491分)を検出した。撹拌をさらに45分続け、そしてLC/MSによって反応は完了した。DCM(20mL)及び水(10mL)及び炭酸水素ナトリウム(5mL)で希釈することによって反応混合物をクエンチした。二層を分離し、水層をDCM(2x10mL)で抽出した。合わせたDCM抽出物をブラインで洗浄し、乾燥(K2CO3)させ、濾過し、そして回転蒸発器において濃縮してほとんど純粋な粗生成物を得た。この物質をDCM(1mL)中に溶解し、25gシリカゲルカラム上に装填、DCM中のA:0〜40%(0〜4分);40〜50 4〜13分;50〜70 13〜25分(Aは、DCM中の7N NH3/MeOHの%である)を用いて溶離して純粋な化合物10の0.92g(85%)を得た。LC/MS 100%純粋,MS398
(2S,3S')−2−メチル−[1,3']ビピロリジニル二塩酸塩(2HCl.2H2O,MW263.18)(5.97g,22.71mmol,1.11当量)を超音波処理で補助してMeOH10mL中に溶解した。溶液にDCM100mLを加えた。溶液を氷水浴で冷却した。この溶液に、N2下で撹拌しながら粉末KOH(3.9g,59.02mmol,アミン塩に対して2.6当量)を加えた。撹拌を1時間続けた。粉末K2CO3 2gを撹拌しながら加えて微細な懸濁液を形成した。セライトパッドを通して懸濁液を濾過し、TLCによってアミンが溶出しなくなるまでDCMですすいだ(DCM中の20%MeOH,アニスアルデヒド可視化,起点のちょうど上の白色スポット)。溶液を乾燥するまで濃縮し;残留物を撹拌しながら高真空下で1時間さらに乾燥させ、無水トルエン50mL中に再溶解し、そして使用する準備ができた。
融点135.5℃
元素分析:C 72.51% H 8.87% N 10.57%
実測値:C 72.51%,H 9.07%,N10.65%
LCMS RT=1.96分;MS:398(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 6.94 (m, 1H), 6.39 (m, 2H), 4.05 (dt, 4.2Hz, 11.7Hz, 2H), 3.64-3.47 (m, 10H), 3.37 (dt, 2.6Hz, 9.0Hz, 1H), 2.76 (六重線, 6.3Hz, 1H), 2.52 (q, 8.4Hz, 1H), 2.14 (s, 3H), 2.12 (m, 4H), 1.98 (m, 2H), 1.77 (m, 2H), 1.48 (m, 3H), 1.14 (d, 6.3Hz, 3H).
旋光度:[α]D=+27.2°(c 0.5,MeOH)
キラル純度:99.9%(キラルHPLC)
方法A及び方法Bからの生成物は、NMR、LCMS、及び旋光度において相互に厳密に一致した。
2−[2−メチル−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LCMS:RT=1.98分;MS:412(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 6.93 (d, 9.3Hz, 1H), 6.39 (m, 2H), 3.98 (m, 2H), 3.75-3.14 (m, 9H), 3.01 (m, 1H), 2.76 (m, 1H), 2.53 (q, 8.4Hz, 1H), 2.31-2.10 (m, 4H), 2.10 (s, 3H), 1.96 (m, 5H), 1.76 (m, 2H), 1.50 (m, 3H), 1.13 (d, 6.3Hz, 3H).
2−[4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LCMS:RT=1.9分;MS:384(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 7.45 (d, 2H), 6.57 (d, 2H), 4.04-3.98 (m, 2H),
3.77-3.71 (m, 4H), 3.61-3.53 (m, 4H), 3.49-3.39 (m, 2H), 3.30-3.24 (m, 2H), 2.97-2.93 (m, 1H), 2.30-2.25 (m, 2H), 2.18-2.02 (m, 8H), 1.82-1.70 (m, 1H), 1.40 (d, 3H).
2−[3−フルオロ−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LCMS:RT=2.36分;MS:402(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 7.54 (dd, 1H), 7.15 (dd, 1H), 6.68 (t, 1H), 4.05-3.99 (m, 2H), 3.85-3.71 (m, 4H), 3.65-3.45 (m, 6H), 3.42-3.33 (m, 2H), 2.92 (q, 1H), 2.23-1.99 (m, 10H), 1.80-1.71 (m, 1H), 1.36 (d, 3H).
2−{2−メチル−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
工程1:2−[4−(4−ヒドロキシ−ピペリジン−1−イル)−2−メチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LCMS:RT=1.42分;MS:345(M+H)
1H NMR (300 MHz, CDCl3), δ (ppm): 6.99 (d, 8.4Hz, 1H), 6.78 (m, 2H), 4.05 (dt, 4.2Hz, 11.7Hz, 2H), 3.83 (m, 1H), 3.58 (m, 5H), 2.91 (m, 2H), 2.17 (m, 4H), 2.10
(s, 3H), 1.63 (m, 8H).
LCMS:RT=2.24分;MS:412(M+H)
1H NMR (300MHz, CDCl3), δ (ppm): 6.98 (d, 8.4Hz, 1H), 6.77 (m, 2H), 4.05 (dt, 4.2Hz, 11.7Hz, 2H), 3.76-3.53 (m, 5H), 2.97-2.51 (m, 4H), 2.15 (m, 2H), 2.14 (s, 3H), 1.96-1.42 9M, 15H), 1.08 (d, 6.3Hz, 3H).
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.95分;MS 398
1H NMR (300MHz, CDCl3), δ: 6.96 (m, 1H), 6.39 (m, 2H), 4.05 (dt, 4.2Hz, 11.4Hz,
2H), 3.64-3.47 (m, 10H), 3.37 (dt, 3.6Hz, 9.0Hz, 1H), 2.79 (六重線, 6.3Hz, 1H),
2.56 (q, 8.4Hz, 1H), 2.17 (m, 4H), 2.14 (s, 3H), 1.98 -1.69 (m, 4H), 1.48 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[4−(2−エチル−[1,3']ビピロリジニル−1'−イル)−2−フルオロ−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.11分;
MS 416
1H NMR (300 MHz CDCl3) δ 7.12 (1H, t, J = 9.35 Hz), 6.27 (2H, m), 4.03 (2H, dt,
J = 11.73, 4.22 Hz), 3.66 (2H, t, J = Hz), 3.59 (2H, m), 3.49-3.16 (5H, m), 3.01 (1H, m), 2.54 (2H, m), 2.20-2.03 (7H, m), 1.83-1.61 (3H, m), 1.49 (3H, d, J = 13.75 Hz), 1.27 (1H, m), 0.90 (3H, td, J = 7.33, 1.83 Hz).
2−[2−フルオロ−4−(2−イソプロピル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.15分;MS 430
1H NMR (300 MHz CDCl3) δ 7.13 (1H, m), 6.26 (2H, m), 4.04 (2H, dt, J = 11.55, 3.67 Hz), 3.64 (4H, m), 3.38 (2H, m), 3.22 (2H, m), 3.00 (1H, m), 2.48 (2H, m), 2.13 (7H, m), 1.65 (4H, m), 1.50 (3H, m), 0.87 (6H, m).
2−[2−フルオロ−4−(2−プロピル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.17分;MS 430
1H NMR (300 MHz CDCl3) δ 7.12 (1H, t, J = 9.16 Hz), 6.27 (2H. m), 4.03 (2H, dt,
J = 11.73, 4.22 Hz), 3.70-3.54 (4H, m), 3.50-3.18 (5H, m), 3.02 (1H, m), 2.65 (1H, m), 2.53 (1H, m), 2.11 (7H, m), 1.97-1.68 (2H, m), 1.52 (4H, m), 1.29 (3H, m), 0.94 (3H, m).
2−{2−フルオロ−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.87分;MS 416
1H NMR (300 MHz CDCl3) δ 7.18 (1H, t, J = 8.98 Hz), 6.66 (2H, m), 4.04 (2H, m),
3.77-3.55 (6H, m), 2.91 (2H, m), 2.73 (2H. m), 2.58 (2H, m), 1.11 (4H, m), 2.01-1.57 (7H, m), 1.50 (3H, m), 1.07 (3H, d, J = 6.23 Hz).
2−[2−フルオロ−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.97分;MS 402
1H NMR (300 MHz CDCl3) δ 7.11 (1H, t, 9.16 Hz), 6.27 (2H, m), 4.03 (2H, dt, J =
11.73, 4.22 Hz), 3.62 (4H, m), 3.48 (1H, t, J = 6.96 Hz), 3.42-3.17 (4H, m), 3.01 (1H, m), 2.79 (1H, m), 2.53 (1H, J = 8.25 Hz), 2.25-1.91 (7H, m), 1.78 (2H, m), 1.49 (3H, d, J = 13.75 Hz), 1.12 (3H, d, J = 6.23 Hz).
2−[2−フルオロ−4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.03分;MS 430
1H NMR (300 MHz CDCl3) δ 7.19 (1H, t, J = 9.16 Hz), 6.65 (2H, m), 4.03 (2H, dt,
J = 11.73, 4.22 Hz), 3.76 (1H, m), 3.69 (1H, t, J = 6.96 Hz), 3.59 (2H, m), 3.42-2.93 (2H, m), 2.77 (4H, m), 2.38 (2H, m), 2.22-2.01 (7H, m), 1.97-1.60 (6H, m), 1.49 (3H, d, J = 13.75), 1.26 (3H, m).
2−{4−[4−(2−イソプロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.08分;MS 426
1H NMR (300 MHz CDCl3) δ 7.50 (2H, d, J = 9.16 Hz), 6.93 (2H, d, J = 9.16 Hz), 4.02 (2H, dt, J = 11.55, 4.22 Hz), 3.76 (2H, t, J = 6.78 Hz), 3.69 (2H, m), 3.57
(2H, td, J = 11.00, 2.57 Hz), 2.92 (1H, m), 2.77-2.49 (5H, m), 2.17-2.01 (4H, m), 1.89-1.51 (9H, m), 1.44 (2H, d, J = 13.56), 0.86 (6H, dd, J = 16.13, 6.78 Hz).
2−{4−[4−(2−プロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.16分;MS 426
1H NMR (300 MHz CDCl3) δ : 7.50 (2H, d, J = 8.98 Hz), 6.93 (2H, d, J = 8.98 Hz), 4.02 (2H, dt, J = 11.73, 4.03 Hz), 3.75 (2H, t, J = 6.78 Hz), 3.70 (2H, d, J = 12.28), 3.58 (2H, td, J = 11.00, 2.57 Hz), 2.94 (1H, m), 2.69 (4H, q, J = 11.55 Hz), 2.54 (1H, q, J = 8.43 Hz), 2.17-2.02 (4H, m), 1.96-1.11 (14H, m), 0.93 (3H, t, J = 6.96 Hz).
2−[4−(2−メトキシメチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.95分;MS 414
1H NMR (300 MHz CDCl3) δ 7.44 (2H, d, J = 8.98 Hz), 6.53 (2H, d, J = 8.98 Hz), 4.03 (2H, dt, J = 11.73, 4.03 Hz), 3.74 (2H, t, J = 6.78 Hz), 3.58 (2H, m), 3.51-3.16 (10H, m), 3.05 (1H, m), 2.93 (1H, m), 2.54 (1H, m), 2.30-1.66 (10H, m), 1.45 (2H, d, J = 13.56 Hz).
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.86分;MS 398
1H NMR (300 MHz CDCl3) δ : 7.50 (2H, d, J = 8.98 Hz), 6.93 (2H, d, J = 8.98 Hz), 4.02 (2H, dt, J = 11.73, 4.03 Hz), 3.75 (2H, t, J = 6.78 Hz), 3.69 (2H, d, J = 12.10 Hz), 3.57 (2H, td, J = 8.80, 2.38 Hz), 2.91 (2H, m), 2.78-2.53 (4H, m), 2.13 (2H, t, J = 6.78 Hz), 2.06 (2H, m), 1.98-1.58 (7H, m), 1.44 (3H, d, J = 12.38), 1.07 (3H, d, J = 6.05 Hz).
2−[3−フルオロ−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=2.42分;MS 416
2−{4−[4−(2−エチル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.37分;MS 480
1H NMR (300 MHz CDCl3) δ: 7.18 (1H, s), 7.07 (2H, m), 4.03 (2H, dt, J = 11.73, 4.03 Hz), 3.77 (2H, d, J = 12.28 Hz), 3.61 (4H, m), 3.09-2.33 (5H, m), 2.18 (2H,
t, J = 6.78 Hz), 2.08 (2H, m), 1.96-1.40 (10H, m), 1.32-1.12 (3H, m), 0.88 (3H,
t, J = 7.33 Hz).
2−{4−[4−(2−イソプロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.38分;MS 494
1H NMR (300 MHz CDCl3) δ: 7.17 (1H, d, J = 2.38 Hz), 7.06 (2H, m), 4.03 (2H, m), 3.77 (2H, m), 3.61 (4H, m), 3.10-2.47 (5H, m), 2.78 (2H, t, J = 6.96 Hz), 2.08 (2H, m), 2.00-1.44 (12H, m), 0.88 (6H, dd J = 15.95, 6.96 Hz).
2−[4−(2−プロピル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.44分;MS 480
1H NMR (300 MHz CDCl3) δ: 7.05 (1H, d, J = 8.61 Hz), 6.77 (1H, d, J = 2.75 Hz),
6.65 (1H, dt, J = 8.61, 2.75 Hz), 4.03 (2H, dt, J = 11.55, 4.22 Hz), 3.59 (3H, m), 3.51-3.20 (4H, m), 2.99 (2H, m), 2.64 (1H, m), 2.52 (2H, m), 2.21-2.01 (4H, m), 1.97-1.67 (4H, m), 1.60-1.43 (4H, m), 1.41-1.18 (4H, m), 0.94 (3H, m).
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.19分;MS 466
1H NMR (300 MHz CDCl3) δ: 7.18 (1H, s), 7.07 (2H, s), 4.03 (2H, dt, J = 11.55, 4.22 Hz), 3.77 (2H, d, J = 12.46 Hz), 3.61 (4H, m), 2.99-2.53 (6H, m), 2.17 (2H,
t, J = 6.78 Hz), 2.08 (2H, m), 2.02-1.56 (7H, m), 1.50 (3H, m), 1.07 (3H, d, J = 6.23 Hz).
2−[4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.18分;MS 452
1H NMR (300 MHz CDCl3) δ: 7.05 (1H, d, J = 8.61 Hz), 6.77 (1H, s), 6.66 (1H, d,
J = 8.61 Hz), 4.02 (2H, m), 3.69-3.21 (9H, m), 3.00 (1H, m), 2.81 (1H, m), 2.55
(1H, q, J - 8.06 Hz), 2.23-1.90 (7H, m), 1.90-1.67 (2H, m), 1.49 (3H, d, J = 13.93 Hz), 1.13 (3H, d, J = 6.05 Hz).
2−[4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.37分;MS 480
1H NMR (300 MHz CDCl3) δ: 7.17 (1H, s), 7.06 (2H, m), 4.03 (2H, m), 3.77 (2H, m), 3.58 (4H, m), 3.04-2.74 (4H, m), 2.61 (2H, m), 2.36-1.88 (8H, m), 1.87-1.21 (8H, m), 1.11 (3H, t, J = 6.23 Hz).
2−{2−エチル−4−[4−(2−プロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=2.29分;MS 454
1H NMR (300 MHz CDCl3) δ: 6.95 (1H, d, J = 8.43 Hz), 6.79 (2H, m), 4.04 (2H, dt, J = 11.55, 4.03 Hz), 3.72 (2H, d, J = 10.81 Hz), 3.60 (4H, m), 3.13 (1H, d, J = 11.55 Hz), 2.94 (1H, m), 2.81-2.41 (8H, m), 2.22-2.05 (4H, m), 1.96-1.61 (8H, m), 1.49 (2H, m), 1.43-1.22 (2H, m), 1.18 (3H, t, J = 7.51 Hz), 0.93 (3H, m).
2−{2−エチル−4−[4−(2−メトキシメチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.97分;MS 456
1H NMR (300 MHz CDCl3) δ: 6.96 (1H, d, J = 8.43 Hz), 6.79 (2H, m), 4.04 (2H, dt, J = 11.55, 3.85 Hz), 3.71 (2H, d, J = 11.91 Hz), 3.60 (4H, m), 3.35 (3H, m), 3.18 (1H, m), 3.01 (3H, m), 2.81-2.41 (6H, m), 2.15 (4H, m), 2.00-1.43 (10H, m), 1.18 (3H, t, J = 7.70 Hz).
2−[2−エチル−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.98分;MS 426
1H NMR (300 MHz CDCl3) δ: 6.93 (1H, d, J = 8.25 Hz), 6.40 (2H, m), 4.03 (2H, dt, J = 11.73, 4.03 Hz), 3.59 (4H, m), 3.40 (1H, m), 3.27 (3H, m), 3.02 (1H, m), 2.79 (1H, m), 2.61-2.42 (3H, m), 2.14 (4H, m), 1.99 (1H, m), 1.89-1.65 (5H, m), 1.48 (3H, d, J = 12.83 Hz), 1.19 (3H, t, J = 7.51 Hz), 1.14 (3H, d, J = 6.23 Hz)
4−カルボン酸メチルエステル
4−{3−[2−フルオロ−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニルアミノ]−プロピル}−テトラヒドロ−ピラン−4−カルボン酸メチルエステル(40mg,0.1mmol,1当量)をTHF2mL中に溶解し、そして0℃に冷却した。ここでヘプタン中のn−BuLiの2.5M溶液(0.11mL,0.17mmol,3当量)を滴加し、そして氷浴をはずした。30分後、反応混合物を水でクエンチし、分液ロートに移し、そしてジエチルエーテル(2×50mL)で抽出した。合わせた有機物をNa2SO4で乾燥させ、そしてシリカゲル上のカラムクロマトグラフィによって精製した(40gカラム,CH2Cl2中の10%MeOH;35mL/分)。これによりオフホワイトのゴムとして表題化合物38mg(98%)を得た。
LC/MS:RT=1.89分,MS:416
1H NMR (300 MHz CDCl3) δ: 6.99 (m, 1H), 6.29 (m, 2H), 3.98 (m, 2H), 3.69 (m, 2H), 3.54 (m, 2H), 3.47 (m, 1H), 3.35 (m, 1H), 3.31-3.15 (m, 3H), 3.00 (m, 1H), 2.77 (m, 1H), 2.52 (q, 8.4Hz, 1H), 2.21 (m, 3H), 2.10-1.68 (m, 8H), 1.50 (m, 3H), 1.13 (d, 6.3Hz, 3H).
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC/MS:RT=1.96分,MS:412
1H NMR (300 MHz CDCl3) δ: 6.93 (1H, d, J = 8.25 Hz), 6.40 (2H, m), 4.03 (2H, dt, J = 11.73, 4.03 Hz), 3.59 (4H, m), 3.40 (1H, m), 3.27 (3H, m), 3.02 (1H, m), 2.79 (1H, m), 2.61-2.42 (3H, m), 2.14 (4H, m), 1.99 (1H, m), 1.89-1.65 (5H, m), 1.48 (3H, d, J = 12.83 Hz), 1.19 (3H, t, J = 7.51 Hz), 1.14 (3H, d, J = 6.23 Hz).
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.95分;MS 398
1H NMR (300 MHz CDCl3) δ 6.94 (m, 1H), 6.39 (m, 2H), 4.05 (dt, 4.2Hz, 11.7Hz, 2H), 3.64-3.47 (m, 10H), 3.37 (dt, 2.6Hz, 9.0Hz, 1H), 2.76 (六重線, 6.3Hz, 1H), 2.52 (q, 8.4Hz, 1H), 2.14 (s, 3H), 2.12 (m, 4H), 1.98 (m, 2H), 1.77 (m, 2H), 1.48 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.95分;MS 398
1H NMR (300 MHz CDCl3) δ 6.96 (m, 1H), 6.39 (m, 2H), 4.05 (dt, 4.2Hz, 11.4Hz, 2H), 3.64-3.47 (m, 10H), 3.37 (dt, 3.6Hz, 9.0Hz, 1H), 2.79 (六重線, 6.3Hz, 1H), 2.56 (q, 8.4Hz, 1H), 2.17 (m, 4H), 2.14 (s, 3H), 1.98 -1.69 (m, 4H), 1.48 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[2−メチル−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン
LC RT=1.96分;MS 398
1H NMR (300 MHz, CDCl3) 二組のスペクトルを示した。
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.85分;MS 412
1H NMR (300 MHz CDCl3) δ 6.94 (m, 1H), 6.39 (m, 2H), 3.98 (m, 2H), 3.77-3.16 (m, 9H), 3.00 (m, 1H), 2.797(六重線, 6.9Hz, 1H), 2.52 (q, 8.4Hz, 1H), 2.24 (m, 3H), 2.10 (s, 3H), 2.04-1.68 (m, 8H), 1.60-1.41 (m, 3H), 1.13 (d, 6.3Hz, 3H).
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.91分;MS 412
1H NMR (300 MHz CDCl3) δ 6.93 (m, 1H), 6.40 (m, 2H), 3.98 (m, 2H), 3.73-3.51 (m, 3H), 3.44-3.19 (m, 6H), 2.98 (m, 1H), 2.79 (六重線, 6.9Hz, 1H), 2.53 (q, 8.4Hz, 1H), 2.33-2.16 (m, 3H), 2.10 (s, 3H), 2.05-1.65 (m, 8H), 1.60-1.41 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.75分;MS 398
1H NMR (300 MHz CDCl3) δ 7.04 (d, 8.7Hz, 2H), 6.54 (d, 8.7Hz, 2H), 3.98 (m, 2H), 3.73-3.56 (m 4H), 3.44-3.20 (m, 5H), 2.98 (m, 1H), 2.79 (m, 1H), 2.53 (q, 8.4Hz, 1H), 2.23 (m, 3H), 2.08-1.69 (m, 8H), 1.49 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.83分;MS 398
1H NMR (300 MHz CDCl3) δ 7.04 (d, 8.7Hz, 2H), 6.54 (d, 8.7Hz, 2H), 3.98 (m, 2H)
, 3.68 (m, 2H), 3.59 (m, 2H), 3.44-3.20 (m, 5H), 3.01 (m, 1H), 2.77 (m, 1H), 2.53 (q, 8.4Hz, 1H), 2.23 (m, 3H), 2.18-1.67 (m, 8H), 1.50 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.85分;MS 398
1H NMR (300 MHz CDCl3) δ 7.04 (d, 8.7Hz, 2H), 6.54 (d, 8.7Hz, 2H), 3.98 (m, 2H), 3.73-3.56 (m 4H), 3.44-3.20 (m, 5H), 2.98 (m, 1H), 2.79 (m, 1H), 2.53 (q, 8.4Hz, 1H), 2.23 (m, 3H), 2.08-1.69 (m, 8H), 1.49 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.83分;MS 398
1H NMR (300 MHz CDCl3) δ 7.04 (d, 8.7Hz, 2H), 6.54 (d, 8.7Hz, 2H), 3.98 (m, 2H), 3.68 (m, 2H), 3.59 (m, 2H), 3.44-3.20 (m, 5H), 3.01 (m, 1H), 2.77 (m, 1H), 2.53 (q, 8.4Hz, 1H), 2.23 (m, 3H), 2.18-1.67 (m, 8H), 1.50 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[2−フルオロ−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.89分;MS 416
1H NMR (300 MHz CDCl3) d 6.99 (m, 1H), 6.29 (m, 2H), 3.98 (m, 2H), 3.69 (m, 2H),
3.54 (m, 2H), 3.43-3.16 (m, 5H), 2.97 (dt, 3.6Hz, 7.8Hz, 1H), 2.79 (六重線, 6.0Hz, 1H), 2.52 (q, 8.4Hz, 1H), 2.21 (m, 3H), 2.10-1.68 (m, 8H), 1.50 (m, 3H), 1.14 (d, 6.3Hz, 3H).
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.93分;MS 416
1H NMR (300 MHz CDCl3) δ 6.99 (m, 1H), 6.29 (m, 2H), 3.98 (m, 2H), 3.69 (m, 2H), 3.54 (m, 2H), 3.47 (m, 1H), 3.35 (m, 1H), 3.31-3.15 (m, 3H), 3.00 (m, 1H), 2.77 (m, 1H), 2.52 (q, 8.4Hz, 1H), 2.21 (m, 3H), 2.10-1.68 (m, 8H), 1.50 (m, 3H), 1.13 (d, 6.3Hz, 3H).
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン
LC RT=1.95分;MS 416
1H NMR (300 MHz CDCl3) δ 6.99 (m, 1H), 6.29 (m, 2H), 3.98 (m, 2H), 3.69 (m, 2H), 3.54 (m, 2H), 3.43-3.16 (m, 5H), 2.97 (dt, 3.6Hz, 7.8Hz, 1H), 2.79 (六重線, 6.0Hz, 1H), 2.52 (q, 8.4Hz, 1H), 2.21 (m, 3H), 2.10-1.68 (m, 8H), 1.50 (m, 3H), 1.14 (d, 6.3Hz, 3H).
実施例41
本実施例41は、H3受容体リガンドとして本発明の化合物の有効性を示す。本発明の化合物は、アカゲザル(Macacca Mulatta)H3受容体を発現する哺乳動物細胞膜に結合する[3H]―メチルヒスタミン放射性リガンドと置き換わることが示された。これらの化合物は、1μM〜<1nMの範囲のアカゲザルH3親和定数(Ki)を示す。さらに、本発明の化合物は、GTPγS放射性リガンド結合アッセイによって細胞膜中のアカゲザルH3構成的機能活性を阻害することがわかった。基礎アカゲザルH3介在GTPgS放射性リガンド結合のこの阻害は、本発明の化合物がインバースアゴニストとして有用性を見出されることを示している。これらの化合物は、アカゲザルH3 GTPγS放射性リガンド結合を基礎レベルよりも0〜40%ほど低下させる。
本実施例は、動物モデルの覚醒状態の増強における本発明の化合物の有効性の研究を説明する。
雄Sprague Dawleyラット(Charles River, France)体重250±10gをZOLETILR 50(60mg/kg ip)で麻酔し、そして定位固定装置に取り付けた。皮質電極(直径0.9mmの小さなステンレス鋼ネジ式電極)を感覚運動皮質(縫合線の中央に対して側方1.5mm、そして冠状縫合線の後方1.5mm)、視覚による皮質(縫合線の中央に対して側方1.5mm、そして頭頂後頭縫合線の前方1.5mm)上、そして小脳(参照電極)上で骨にねじ込んだ。皮質電極をコネクター(Winchester,7リード線)に取り付け、そして歯科用のセメントで頭蓋に固定した。
・低電位の速い皮質電気(ECoG)活性を特徴とする覚醒状態(W);
・皮質電気活性における増加;睡眠紡錘波のいくつかのバーストで高振幅徐波の出現を特徴とするNREM睡眠(非急速眼球運動又は徐波睡眠:SWS);
・視覚野におけるシータ律動の過同期化(hypersynchronization)を特徴とするREM睡眠(急速眼球運動又は逆説睡眠:PS)。
動的に実施した。
成体ラットにおけるストレス誘発性の超音波啼鳴試験(Stress-induced ultrasonic vocalizations test)
本実施例は、動物モデルにおける抗うつ剤として本発明の化合物の有効性の研究を説明する。
使用した方法は、Van Der Poel A.M, Noach E.J.K, Miczek K.A (1989) Temporal patterning of ultrasonic distress calls in the adult rat: effects of morphine and benzodiazepines. Psychopharmacology 97:147-8によって記載された技術を応用した。訓練セッションのため、ステンレス鋼の格子床を有するケージ(MED Associates, Inc., St. Albans, VT)中にラットを入れた。4回の電気ショック(0.8mA、3秒)を7秒毎に送り、続いて、超音波啼鳴(UV,22kHz)をUltravoxシステム(Noldus, Wageningen, The Netherlands)により2分間記録した。マイクロホンに接続した改良された超音波検出器(Mini-3 batモデル)を用いて超音波を可聴音に変換した。次いで、シグナルをフィルタリングしてコンピュータに送り、そこでUltravoxソフトウェアにより10ミリ秒を超えて持続したUVの各発作(bout)を記録した。UV持続時間(>40秒)に基づいてラットを選択し、そして訓練の4時間後に、試験にかけた。試験では、訓練に用いたものと同じケージ中にラットを入れた。1回の電気ショック(0.8mA、3秒)を送り、続いてUltravoxシステムによりUV(持続時間及び周波数)を2分間記録した。試験60分前に、本発明の化合物を経口投与した。
ラットにおける強制水泳試験
この実施例は、動物モデルにおける抗うつ剤として本発明の化合物の有効性の研究をさらに説明する。
方法は、Porsolt et al. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730-2によって記載されたのを改良したものである。高さ30cmまで水(21℃)が入った個別のガラス円筒(高さ40cm、直径17cm)にラットを入れた。2回の水泳セッションを行った(訓練セッション15分、続いて24時間後、試験6分)。各水泳セッション後、ラットを加熱灯の下に置いて低体温を回避した。6分の試験中に無動持続時間(duration of immobility)を測定した。本発明の化合物を2回経口投与した(訓練セッションの15分後及び試験の60分前)。
Claims (15)
- m、n及びpは、1であり;
R1は、メチル、エチル、イソプロピル、n−プロピル又はメトキシメチルであり;
R2は、水素、フッ素、塩素、メチル、エチル又はCF3である、
請求項1に記載の化合物。 - nは2であり、そしてmは1であり;又は
nは1であり、そしてmは2であり;
pは、1又は2であり;
R1は、メチル、エチル、イソプロピル、n−プロピル又はメトキシメチルであり;
R2は、水素、フッ素、塩素、メチル、エチル又はCF3である;
請求項1に記載の化合物。 - 2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−メチル−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−(2−エチル−[1,3']ビピロリジニル−1'−イル)−2−フルオロ−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−(2−イソプロピル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−(2−プロピル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−フルオロ−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−(2−イソプロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−(2−プロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−(2−メトキシメチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−{4−[4−(2−エチル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−(2−イソプロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−(2−プロピル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−エチル−4−[4−(2−プロピル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−エチル−4−[4−(2−メトキシメチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−エチル−4−((2S,3S')−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
からなる群より選ばれる請求項1に記載の化合物、又はその塩、又はそのエナンチオマー若しくはジアステレオマー。 - 2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−メチル−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{2−フルオロ−4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−{4−[4−((S)−2−メチル−ピロリジン−1−イル)−ピペリジン−1−イル]−2−トリフルオロメチル−フェニル}−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[4−((S)−2−メチル−[1,4']ビピペリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−エチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
からなる群より選ばれる請求項1に記載の化合物、又はその塩、又はそのエナンチオマー若しくはジアステレオマー。 - 2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[3−フルオロ−4−(2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−2−トリフルオロメチル−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−エチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−メチル−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
からなる群より選ばれる請求項1に記載の化合物、又はその塩、又はそのエナンチオマー若しくはジアステレオマー。 - 2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−エチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[2−フルオロ−4−((2R,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[2−フルオロ−4−((2S,3'R)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
からなる群より選ばれる請求項1に記載の化合物、又はその塩、又はそのエナンチオマー若しくはジアステレオマー。 - 2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−メチル−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−
1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−8−オキサ−2−アザ−スピロ[4.5]デカン−1−オン;
2−[2−フルオロ−4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;及び
2−[4−((2S,3'S)−2−メチル−[1,3']ビピロリジニル−1'−イル)−フェニル]−9−オキサ−2−アザ−スピロ[5.5]ウンデカン−1−オン;
からなる群より選ばれる請求項1に記載の化合物、又はその塩、又はそのエナンチオマー若しくはジアステレオマー。 - 請求項1〜9のいずれかの1項に記載の化合物、又はその薬学的に許容しうる塩、エナンチオマー若しくはジアステレオマーを、1つ又はそれ以上の薬学的に許容しうる担体、希釈剤又は賦形剤と組み合わせて含む、薬学的組成物。
- 統合失調症に関連する認知障害(CIAS)、全般性不安、パニック障害及び心的外傷後ストレス障害のような不安障害、大うつ病性障害、アルツハイマー型認知症(DAT)、アルツハイマー、パーキンソン又はハンチントンから選ばれる神経系疾患に関連する認知障害、加齢による認知障害、軽度認知障害、血管性認知症、レビー小体型認知症、認知関連の認知障害、睡眠関連障害、注意欠陥多動性障害及びうつ病、及び肥満を治療するため、化合物がH3受容体機能を調節することができる薬学的組成物を製造するための請求項1〜9のいずれか1項に記載の化合物、又はその薬学的に許容しうる塩、エナンチオマー、若しくはジアステレオマーの使用。
- 睡眠障害は、ナルコレプシー、概日リズム睡眠障害、閉塞型睡眠時無呼吸、周期性四肢運動及びレストレスレッグ症候群、薬物副作用に起因する過度の眠気及び嗜眠状態からなる群より選ばれる請求項11に記載の使用。
- 睡眠障害はナルコレプシーである、請求項11に記載の使用。
- 疾患は統合失調症に関連する認知障害(CIAS)である、請求項11に記載の使用。
- 疾患はアルツハイマー型認知症(DAT)である、請求項11に記載の使用。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12008708P | 2008-12-05 | 2008-12-05 | |
US61/120,087 | 2008-12-05 | ||
FR0955909 | 2009-08-28 | ||
FR0955909 | 2009-08-28 | ||
PCT/US2009/066666 WO2010065798A1 (en) | 2008-12-05 | 2009-12-04 | Substituted tetrahydropyran spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof |
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EP (1) | EP2373659B1 (ja) |
JP (1) | JP5410544B2 (ja) |
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CA (1) | CA2745715C (ja) |
CO (1) | CO6390059A2 (ja) |
CR (1) | CR20110289A (ja) |
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PE (1) | PE20110773A1 (ja) |
RU (1) | RU2519778C2 (ja) |
TN (1) | TN2011000223A1 (ja) |
TW (1) | TWI441826B (ja) |
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Cited By (1)
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JP2013526527A (ja) * | 2010-05-11 | 2013-06-24 | サノフイ | 置換フェニルシクロアルキルピロリジン(ピペリジン)スピロラクタム類及びアミド類、それらの製造及び治療的使用 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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AR074466A1 (es) | 2008-12-05 | 2011-01-19 | Sanofi Aventis | Piperidina espiro pirrolidinona y piperidinona sustituidas y su uso terapeutico en enfermedades mediadas por la modulacion de los receptores h3. |
TW201206910A (en) | 2010-05-11 | 2012-02-16 | Sanofi Aventis | Substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives, preparation and therapeutic use thereof |
EP2569304A1 (en) | 2010-05-11 | 2013-03-20 | Sanofi | Substituted n-heteroaryl spirolactam bipyrrolidines, preparation and therapeutic use thereof |
AR081498A1 (es) | 2010-05-11 | 2012-09-19 | Sanofi Aventis | Derivados de n-alquil -y n-acil-tetrahidroisoquinolina sustituidos, preparacion y su uso terapeutico de los mismos |
WO2011143162A1 (en) | 2010-05-11 | 2011-11-17 | Sanofi | Substituted n-heteroaryl bipyrrolidine carboxamides, preparation and therapeutic use thereof |
WO2011143163A1 (en) * | 2010-05-11 | 2011-11-17 | Sanofi | Substituted n-phenyl spirolactam bipyrrolidines, preparation and therapeutic use thereof |
WO2011143155A1 (en) | 2010-05-11 | 2011-11-17 | Sanofi | Substituted n-heteroaryl tetrahydro-isoquinoline derivatives, preparation and therapeutic use thereof |
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