JP4738421B2 - Glyt−1阻害剤としてのベンゾイル−テトラヒドロピリジン - Google Patents
Glyt−1阻害剤としてのベンゾイル−テトラヒドロピリジン Download PDFInfo
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- JP4738421B2 JP4738421B2 JP2007549822A JP2007549822A JP4738421B2 JP 4738421 B2 JP4738421 B2 JP 4738421B2 JP 2007549822 A JP2007549822 A JP 2007549822A JP 2007549822 A JP2007549822 A JP 2007549822A JP 4738421 B2 JP4738421 B2 JP 4738421B2
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- Prior art keywords
- phenyl
- compound
- formula
- methanesulfonyl
- dihydro
- Prior art date
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- XLQSXGGDTHANLN-UHFFFAOYSA-N 1-bromo-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(Br)C=C1 XLQSXGGDTHANLN-UHFFFAOYSA-N 0.000 description 1
- HXVUCIYXBTYQLK-UHFFFAOYSA-N 2-chloro-5-fluorosulfonylbenzoic acid Chemical compound OC(=O)C1=CC(S(F)(=O)=O)=CC=C1Cl HXVUCIYXBTYQLK-UHFFFAOYSA-N 0.000 description 1
- ICXSHFWYCHJILC-UHFFFAOYSA-N 2-fluoro-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1F ICXSHFWYCHJILC-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- SXOMHACGFSJBIO-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine Chemical compound C1=CC(Cl)=CC=C1C1=CCNCC1 SXOMHACGFSJBIO-UHFFFAOYSA-N 0.000 description 1
- GJTLANBQTZXEKL-UHFFFAOYSA-N 4-[4-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=CCNCC1 GJTLANBQTZXEKL-UHFFFAOYSA-N 0.000 description 1
- OMPXTQYWYRWWPH-UHFFFAOYSA-N 4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1NCCC(C=2C=CC=CC=2)=C1 OMPXTQYWYRWWPH-UHFFFAOYSA-N 0.000 description 1
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- RHPZICAQEROVQV-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(=CC1)C1=CC=C(C=C1)C(F)(F)F.CN(C=O)C Chemical compound C(C)(C)(C)OC(=O)N1CCC(=CC1)C1=CC=C(C=C1)C(F)(F)F.CN(C=O)C RHPZICAQEROVQV-UHFFFAOYSA-N 0.000 description 1
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- 206010012239 Delusion Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- 102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
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- WXDQNOQPVRGUGJ-UHFFFAOYSA-N [4-(4-chlorophenyl)-3,6-dihydro-2h-pyridin-1-yl]-(2-morpholin-4-yl-5-nitrophenyl)methanone Chemical compound C1CC(C=2C=CC(Cl)=CC=2)=CCN1C(=O)C1=CC([N+](=O)[O-])=CC=C1N1CCOCC1 WXDQNOQPVRGUGJ-UHFFFAOYSA-N 0.000 description 1
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- 230000000295 complement effect Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
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- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 208000024714 major depressive disease Diseases 0.000 description 1
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- 239000011976 maleic acid Substances 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
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- 238000003801 milling Methods 0.000 description 1
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- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- 230000002085 persistent effect Effects 0.000 description 1
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- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61P25/28—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
[式中、
R1は、非芳香族複素環、又はOR’であり;
R’は、低級アルキル、ハロゲンで置換されている低級アルキル、又は−(CH2)n−シクロアルキルであり;
R2は、NO2、CN、又はSO2R’’であり;
R’’は、低級アルキルであり;
Arは、フェニル(場合により、ハロゲン、シアノ、ハロゲンで置換されている低級アルキル、又はSO2R’’で置換されている)であり;
nは、0、1、又は2である]
の化合物、及び薬学的に活性な酸付加塩に関する。
4−[1−(2−モルホリン−4−イル−5−ニトロ−ベンゾイル)−1,2,3,6−テトラヒドロ−ピリジン−4−イル]ベンゾニトリル、
(5−メタンスルホニル−2−モルホリン−4−イル−フェニル)−[4−(4−トリフルオロメチル−フェニル)−3,6ジヒドロ−2H−ピリジン−1−イル]−メタノン、又は
[4−(4−メタンスルホニル−フェニル)−3,6ジヒドロ−2H−ピリジン−1−イル]−(2−モルホリン−4−イル−5−ニトロ−フェニル)−メタノン。
[5−メタンスルホニル−2−(2,2,2−トリフルオロ−エトキシ)−フェニル]−[4−(4−トリフルオロメチル−フェニル)3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン
である。
3−[4−(4−クロロ−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−カルボニル]−4−イソプロポキシ−ベンゾニトリル
である。
(2−シクロペンチルオキシ−5−メタンスルホニル−フェニル)−[4−(4−メタンスルホニル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン、又は
[4−(4−クロロ−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−(2−シクロプロピルメトキシ−5−メタンスルホニル−フェニル)−メタノン。
a)式
の化合物を、式
の化合物と、式III−1の化合物についてはTBTU(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テトラフルオロボラート)のような活性化剤の存在下で、反応させて、
式
[式中、halは、塩素などのハロゲン原子であり、Ar、R1及びR2は、上記と同義である]の化合物にすること、及び
所望であれば、得られた化合物を薬学的に許容されうる酸付加塩に変換することを含む。
DMEM完全培地:Nutrient mixture F-12(Gibco life technologies)、ウシ胎児血清(FBS)5%(Gibco life technologies)、ペニシリン/ストレプトマイシン1%(Gibco life technologies)、ハイグロマイシン0.6mg/ml(Gibco life technologies)、グルタミン1mM(Gibco life technologies)
Flp−in(商標)−CHO(Invitrogen Cat n°R758-07)細胞に、mGlyT1b cDNAを安定にトランスフェクトさせた。
1日目に、哺乳動物の細胞(Flp−in(商標)−CHO、mGlyT−1b cDNAをトランスフェクトしたもの)を、96−ウエル培養プレートに、ハイグロマイシンなしで、完全F−12培地中40,000細胞/ウエルの密度で接種した。2日目に、培地を吸引し、細胞を取込緩衝液(UB)で2回洗浄した。次に細胞を(i)潜在的競合物無し、(ii)10mM 非放射性グリシン、(iii)ある濃度の潜在的阻害剤のいずれかと22℃で20分間インキュベートした。潜在的阻害剤の濃度範囲を、50%の効果(例えばIC50、50%のグリシン取込みを阻害する競合物濃度)を生じる阻害剤の濃度を計算するためのデータを生成するのに使用した。次に[3H]−グリシン60nM(11〜16Ci/mmol)及び25μM非放射性グリシンを含む溶液に直ちに加えた。プレートを、穏やかに振とうしながらインキュベートし、混合物を吸引して反応を止め、氷冷UBで洗浄した(3回)。細胞をシンチレーション液で溶解し、3時間振とうし、細胞中の放射能をシンチレーションカウンターを用いてカウントした。
項目 成分 mg/錠剤
5mg 25mg 100mg 500mg
1.式IA又はIBの化合物 5 25 100 500
2.無水乳糖DTG 125 105 30 150
3.Sta-Rx 1500 6 6 6 30
4.微晶質セルロース 30 30 30 150
5.ステアリン酸マグネシウム 1 1 1 1
合計 167 167 167 831
1.項目1、2、3及び4を混合し、精製水で造粒する。
2.顆粒を50℃で乾燥させる。
3.顆粒を適切な微粉砕装置に通す。
4.項目5を加え、3分間混合し、適切な成形機で圧縮する。
項目 成分 mg/カプセル
5mg 25mg 100mg 500mg
1.式IA又はIBの化合物 5 25 100 500
2.含水乳糖 159 123 148 ---
3.トウモロコシデンプン 25 35 40 70
4.タルク 10 15 10 25
5.ステアリン酸マグネシウム 1 2 2 5
合計 200 200 300 600
1.項目1、2及び3を適切なミキサーで30分間混合する。
2.項目4及び5を加え、3分間混合する。
3.適切なカプセルに充填する。
(2−モルホリン−4−イル−5−ニトロ−フェニル)−(4−フェニル−3,6−ジヒドロ−2H−ピリジン−1−イル)−メタノン
ジオキサン(50ml)中の2−フルオロ−5−ニトロ安息香酸(4.86g、26.2mmol)の溶液に、モルホリン(11.5ml)を加えた。混合物を室温で2時間撹拌した。溶媒を減圧下で除去した。残渣を水に溶解し、混合物を2N HClで酸性化した。固体を濾過し、水で洗浄し、乾燥して、標記化合物(6.2g、93%)を黄色の固体として得た。MS(m/e):251.2(M−H、100%)
トルエン中の2−モルホリン−4−イル−5−ニトロ−安息香酸(4.0g、16mmol)の懸濁液に、DMF2滴及びチオニルクロリド(5.7ml、79.3mmol)を加えた。混合物を80℃まで50分間加熱した。溶媒を減圧下で除去し、得られた固体をエーテル中で撹拌し、濾過し、乾燥して、標記化合物(4.0g、93%)を黄色の固体として得た。
DCM 1ml中の2−モルホリン−4−イル−5−ニトロ−ベンゾイルクロリド40.6mg(0.15mmol)、4−フェニル−1,2,3,6−テトラヒドロ−ピリジン(市販)29mg(0.18mmol)及びNEt3 62.5ul(0.45mmol)の混合物を、室温で16時間撹拌した。揮発物を蒸発した後、残渣をCH3CN/DMF/HCOOH 3/5/2 1mlに取り、アセトニトリル/水勾配で溶離する逆相の分取HPLC精製に付して、蒸発した後、標記化合物を得た。MS(m/e):394.1(MH+、100%)
[4−(4−クロロ−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−(2−モルホリン−4−イル−5−ニトロフェニル)メタノン
4−[1−(2−モルホリン−4−イル−5−ニトロ−ベンゾイル)−1,2,3,6−テトラヒドロ−ピリジン−4−イル]ベンゾニトリル
[5−メタンスルホニル−2−(2,2,2−トリフルオロ−エトキシ)−フェニル]−[4−(4−トリフルオロメチル−フェニル)3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン
水100ml中の亜硫酸ナトリウム33.59g(267mmol)の溶液を、2−クロロ−5−フルオロスルホニル−安息香酸21.2g(89mmol)及び10M NaOH水溶液26.6ml(267mmol)で0℃で処理した。混合物を室温で3時間撹拌し、濃HCl(pH=4)で酸性化し、水を減圧下で除去した。メタノールを加え、沈殿物を濾取し、濾液を濃縮した。メタノール及びジエチルエーテルを加え、沈殿物を濾取し、エーテルで洗浄し、乾燥して、標記化合物15g(76.5%)を白色のガム状物として得た。MS(m/e):219.1(M−H、100%)
メタノール20ml及び水20ml中の2−クロロ−5−スルフィノ−安息香酸1g(4mmol)の混合物を、10N NaOHでpH=9に処理し、その後ヨウ化メチル1.7g(12mmol)を加えた。混合物を、NaOHを時々加えてpH=9を維持しながら80℃まで48時間加熱した。全ての揮発物を除去した後、濃HClを加え、混合物を酢酸エチルで抽出した。合わせた有機層をMgSO4で乾燥し、蒸発乾固した。残渣をメタノールに取り、アセトニトリル/水勾配で溶離する逆相HPLC精製に付して、生成物画分を蒸発した後、標記化合物323mg(34%)を得た。MS(m/e):233.0(M−H、100%)
2−クロロ−5−メタンスルホニル−安息香酸2.13mmol、NEt3 5ml中のCu(I)Br 0.64mmol及び2,2,2−トリフルオロ−エタノール25mlの混合物を、密閉管中で120℃まで16時間加熱した。揮発物を減圧下で除去し、残渣を1N HCl 70mlに取った。酢酸エチルで抽出し、合わせた有機画分を乾燥し、蒸発して、残渣を得て、それをアセトニトリル/水勾配で溶離する逆相分取HPLCにより精製した。生成物画分を蒸発して、標記化合物を得た。MS(m/e):297.0(M−H、100%)
ジメチルホルムアミド6ml中の4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸tert−ブチルエステル(CAS:286961-14-6)0.97mmolの溶液に、炭酸カリウム2.91mmol、p−ブロモベンゾトリフルオリド1.02mmol、及びジクロロ(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)ジクロロメタン錯体0.06mmolを順次加えた。次に反応物を80℃で6時間撹拌し、減圧下で濃縮し、カラムクロマトグラフィー(SiO2、20g、ヘプタン)により精製して、標記化合物を得た。MS(m/e):271.1(M−イソブチレン)
ジクロロメタン2ml中の4−(4−トリフルオロメチル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸tert−ブチルエステル0.52mmolの混合物を、トリフルオロ酢酸0.2mlで処理した。混合物を40℃で3時間撹拌し、次に濃縮し、水/NaOHで処理し、ジクロロメタンで抽出した。合わせた有機相を飽和NaClで洗浄し、MgSO4で乾燥し、蒸発して、標記化合物を得た。MS(m/e):228.3(MH+、100%)
ジメチルホルムアミド0.75ml中の5−メタンスルホニル−2−(2,2,2−トリフルオロ−エトキシ)−安息香酸0.17mmolの溶液に、TBTU 0.19mmol、N−エチルジイソプロピルアミン0.855mmol及び4−(4−トリフルオロメチル−フェニル)−1,2,3,6−テトラヒドロ−ピリジン0.205mmolを順次加えた。次に反応物を室温で45分間撹拌し、減圧下で濃縮し、カラムクロマトグラフィー(SiO2、10g、ヘプタン、酢酸エチル 0〜100%)により精製して、標記化合物を得た。MS(m/e):508.6(MH+、100%)
(5−メタンスルホニル−2−モルホリン−4−イル−フェニル)−[4−(4−トリフルオロメチル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン
モルホリン2ml中の2−クロロ−5−メタンスルホニル−安息香酸(実施例4、工程b)163.8mg(0.7mmol)の混合物を、100℃まで16時間加熱した。全ての揮発物を蒸発した後、残渣をメタノール/ギ酸 3/1 2mlに取り、アセトニトリル/水勾配で溶離する逆相HPLC精製に付して、生成物画分蒸発した後、標記化合物を得た。MS(m/e):284.1(M−H、100%)
実施例4、工程fの合成について記載の手順に従って、標記化合物を5−メタンスルホニル−2−モルホリン−4−イル−安息香酸及び4−(4−トリフルオロメチル−フェニル)−1,2,3,6−テトラヒドロ−ピリジンから合成した。MS(m/e):495.4(MH+、100%)
[4−(4−メタンスルホニル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−(2−モルホリン−4−イル−5−ニトロ−フェニル)−メタノン
標記化合物を、実施例4、工程d及びeに記載の手順に従って、4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸tert−ブチルエステル及び4−ブロモメチルスルホンから合成した。MS(m/e):336.0(M−H、100%)
実施例4、工程fの合成について記載の手順に従って、標記化合物を2−モルホリン−4−イル−5−ニトロ−安息香酸及び4−(4−メタンスルホニル−フェニル)−1,2,3,6−テトラヒドロ−ピリジンから合成した。MS(m/e):470.1(M−H、100%)
(2−イソプロポキシ−5−メタンスルホニル−フェニル)−[4−(4−メタンスルホニル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン
実施例4、工程cの合成について記載の手順に従って、標記化合物を2−クロロ−5−メタンスルホニル−安息香酸及びイソプロパノールから合成した。MS(m/e):257.0(M−H、100%)
実施例4、工程fの合成について記載の手順に従って、標記化合物を2−イソプロポキシ−5−メタンスルホニル−安息香酸及び4−(4−メタンスルホニル−フェニル)−1,2,3,6−テトラヒドロ−ピリジンから合成した。MS(m/e):495.4(M+NH4 +、100%)
(2−シクロペンチルオキシ−5−メタンスルホニル−フェニル)−[4−(4−メタンスルホニル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン
実施例4、工程cの合成について記載の手順に従って、標記化合物を2−クロロ−5−メタンスルホニル−安息香酸及びシクロペンタノールから合成した。MS(m/e):282.9(M−H、100%)
実施例4、工程fの合成について記載の手順に従って、標記化合物を2−シクロペンチルオキシ−5−メタンスルホニル−安息香酸及び4−(4−メタンスルホニル−フェニル)−1,2,3,6−テトラヒドロ−ピリジンから合成した。MS(m/e):503.9(M+、100%)
3−[4−(4−クロロ−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−カルボニル]−4−イソプロポキシ−ベンゾニトリル
[4−(4−クロロ−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−(2−シクロプロピルメトキシ−5−メタンスルホニル−フェニル)−メタノン
Claims (14)
- R1が、モルホリンである、請求項1記載の式Iの化合物。
- 化合物が、4−[1−(2−モルホリン−4−イル−5−ニトロ−ベンゾイル)−1,2,3,6−テトラヒドロ−ピリジン−4−イル]ベンゾニトリル、(5−メタンスルホニル−2−モルホリン−4−イル−フェニル)−[4−(4−トリフルオロメチル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン、又は
[4−(4−メタンスルホニル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−(2−モルホリン−4−イル−5−ニトロ−フェニル)−メタノンである、請求項2記載の式Iの化合物。 - R1が、−O−C 1−7 アルキル(ハロゲンで置換されている)である、請求項1記載の式Iの化合物。
- 化合物が、[5−メタンスルホニル−2−(2,2,2−トリフルオロ−エトキシ)−フェニル]−[4−(4−トリフルオロメチル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノンである、請求項4記載の式Iの化合物。
- R1が、−O−C 1−7 アルキルである、請求項1記載の式Iの化合物。
- 化合物が、3−[4−(4−クロロ−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−カルボニル]−4−イソプロポキシ−ベンゾニトリルである、請求項6記載の式Iの化合物。
- R1が、−O−(CH2)n−シクロアルキルである、請求項1記載の式Iの化合物。
- 化合物が、(2−シクロペンチルオキシ−5−メタンスルホニル−フェニル)−[4−(4−メタンスルホニル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−メタノン、又は
[4−(4−クロロ−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−イル]−(2−シクロプロピルメトキシ−5−メタンスルホニル−フェニル)−メタノンである、請求項8記載の式Iの化合物。 - 請求項10に記載した方法により製造される、請求項1〜9のいずれか1項記載の化合物。
- 請求項1〜9のいずれか1項記載の1個以上の化合物と、薬学的に許容されうる賦形剤とを含む医薬。
- アルツハイマー病を処置するための、請求項12記載の医薬。
- アルツハイマー病を処置するための医薬を製造するための、請求項1〜9のいずれか1項記載の化合物の使用。
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- 2005-12-27 KR KR1020077017900A patent/KR100957280B1/ko not_active IP Right Cessation
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- 2005-12-27 BR BRPI0519746-5A patent/BRPI0519746A2/pt not_active IP Right Cessation
- 2005-12-27 DE DE602005012997T patent/DE602005012997D1/de active Active
- 2005-12-27 ES ES05820269T patent/ES2319220T3/es active Active
- 2005-12-27 CA CA002594260A patent/CA2594260A1/en not_active Abandoned
- 2005-12-27 AU AU2005324109A patent/AU2005324109B2/en not_active Ceased
- 2005-12-27 RU RU2007124546/04A patent/RU2007124546A/ru not_active Application Discontinuation
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IL184206A0 (en) | 2007-10-31 |
AR052553A1 (es) | 2007-03-21 |
CA2594260A1 (en) | 2006-07-13 |
NO20073275L (no) | 2007-07-31 |
CN101111477B (zh) | 2010-05-26 |
BRPI0519746A2 (pt) | 2009-03-10 |
KR20070094953A (ko) | 2007-09-27 |
EP1836168B1 (en) | 2009-02-25 |
US7485637B2 (en) | 2009-02-03 |
ATE423770T1 (de) | 2009-03-15 |
WO2006072432A1 (en) | 2006-07-13 |
AU2005324109B2 (en) | 2011-01-20 |
IL184206A (en) | 2011-09-27 |
DE602005012997D1 (de) | 2009-04-09 |
ZA200705383B (en) | 2008-09-25 |
CN101111477A (zh) | 2008-01-23 |
EP1836168A1 (en) | 2007-09-26 |
US20060148797A1 (en) | 2006-07-06 |
RU2007124546A (ru) | 2009-02-20 |
KR100957280B1 (ko) | 2010-05-12 |
ES2319220T3 (es) | 2009-05-05 |
TW200635898A (en) | 2006-10-16 |
JP2008526794A (ja) | 2008-07-24 |
MX2007008043A (es) | 2007-07-16 |
AU2005324109A1 (en) | 2006-07-13 |
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