JP4317955B2 - アミロイド斑凝集阻害剤および診断用造影剤 - Google Patents
アミロイド斑凝集阻害剤および診断用造影剤 Download PDFInfo
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- JP4317955B2 JP4317955B2 JP2002583430A JP2002583430A JP4317955B2 JP 4317955 B2 JP4317955 B2 JP 4317955B2 JP 2002583430 A JP2002583430 A JP 2002583430A JP 2002583430 A JP2002583430 A JP 2002583430A JP 4317955 B2 JP4317955 B2 JP 4317955B2
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- 208000037259 Amyloid Plaque Diseases 0.000 title claims abstract description 40
- 230000002776 aggregation Effects 0.000 title claims abstract description 9
- 238000004220 aggregation Methods 0.000 title claims abstract description 9
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- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 238000003384 imaging method Methods 0.000 claims abstract description 11
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 229910052740 iodine Inorganic materials 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 125000002034 haloarylalkyl group Chemical group 0.000 claims description 5
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- 235000019439 ethyl acetate Nutrition 0.000 description 6
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- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
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- KDHWCFCNNGUJCP-UHFFFAOYSA-N 2-phenylimidazo[1,2-a]pyridine Chemical compound N1=C2C=CC=CN2C=C1C1=CC=CC=C1 KDHWCFCNNGUJCP-UHFFFAOYSA-N 0.000 description 5
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 125000003386 piperidinyl group Chemical group 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
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- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 208000008864 scrapie Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical group [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
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- A61K51/04—Organic compounds
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- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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- 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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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Description
本発明の開発中に行われた一部の仕事は米国政府資金を利用した。米国政府は、老化研究所(Institute for the Study of Aging)により授与された助成番号NS−18509およびPO1 AG−11542のもと本発明にある種の権利を有する。
発明の分野
本発明は、新規な生物活性化合物、放射性標識化合物を用いた診断造影方法、ならびに放射性標識化合物の製造方法に関する。
アルツハイマー病(AD)は、認識低下、不可逆的な記憶喪失、失見当識および言語の障害により特徴付けられる進行性の神経変性傷害である。AD脳切片の検死検査は、アミロイド−β(Aβ)ペプチドならびに高度にリン酸化されたタウ蛋白質のフィラメントにより形成された多数の神経原線維変化(NFT)よりなる豊富な老人斑(SP)を明らかとする(最近の総説およびさらなる引用例について、Ginsberg、S. D.ら,「Molecular Pathology of Alzheimer's Disease and Related Disorders,」in Cerebral Cortex:Neurodegenerative and Age−related Changes in Structure and Function of Cerebral Cortex、Kluwer Academic/Plenum、NY(1999)、pp. 603−654;Vogelsberg−Ragaglia、V.ら,「Cell Biology of Tau and Cytoskeletal Pathology in Alzheimer's Disease,」Alzheimer's Disease、Lippincot, Williams & Wilkins、Philadelphia、PA(1999)、pp. 359−372参照)。家族性AD(FAD)は、A前駆体蛋白質(APP)、プレセニリン1(PS1)およびプレセニリン2(PS2)遺伝子中の複数の突然変異により惹起される(Ginsberg、S. D.ら,「Molecular Pathology of Alzheimer's Disease and Related Disorders,」in Cerebral Cortex: Neurodegenerative and Age−related Changes in Structure and Function of Cerebral Cortex、Kluwer Academic/Plenum、NY(1999)、pp. 603−654;Vogelsberg−Ragaglia、V.ら,「Cell Biology of Tau and Cytoskeletal Pathology in Alzheimer's Disease,」Alzheimer's Disease, Lippincot, Williams & Wilkins, Philadelphia、PA(1999)、pp. 359−372)。
本発明は、アミロイド凝集物に優先的に結合する式I、II、IIIまたはIII’で表される新規化合物を提供する。
本発明の第1の態様は、以下の式I:
mおよびnは共に0(ゼロ)であるか、あるいはmおよびnは共に1であり;
R3はCH3、Br、I、F、125I、131I、123I、18F、76Br、77BrまたはSn(アルキル)3;
R1およびR2は独立して、水素、C1−4アルキル、C2−4アミノアルキル、C1−4ハロアルキル、ハロアリールアルキル、−L−Chであるか、あるいはR1およびR2はそれらが結合する窒素と一緒になって、所望により環内にO、SまたはNR6を有してもよい5ないし7員の複素環を形成し、ここに、
R6は水素またはC1−4アルキルであって;
R4はC1−4アルキルであって;
Lは、−(CH2)n−もしくは−(CH2)n−C(O)−のごとき共有結合または連結基、ここに、nは0〜5であり;および
Chは、
ここに、R9は、水素であるか、あるいはメトキシメチル、メトキシエトキシメチル、p−メトキシベンジルまたはベンジルのごときイオウ保護基であり、他の変数基は本明細書に記載された好ましい値を有する]
で表される化合物またはその医薬上許容される塩に指向される。
R3は、Br、I、F、125I、131I、123I、18F、76Br、77BrまたはSn(アルキル)3;
R1およびR2は独立して、水素、C1−4アルキル、C2−4アミノアルキル、C1−4ハロアルキル、ハロアリールアルキルであるか、あるいはR1およびR2は、それらが結合する窒素と一緒になって、所望により環内にO、SまたはNR5を有してもよい5ないし7員の複素環を形成し、ここに、
R5は水素またはC1−4アルキルである]
で表される化合物またはその医薬上許容される塩に指向される。
R1およびR2が独立して、水素、C1−4アルキル、C2−4アミノアルキル、C1−4ハロアルキル、ハロアリールアルキル、−L−Chであるか、あるいはR1およびR2は、それらが結合する窒素と一緒になって、所望により環内にO、SまたはNR5を有してもよい5ないし7員の複素環を形成し、ここに、
R5は水素またはC1−4アルキルである]
で表される化合物またはその医薬上許容される塩に指向される。
但し、A、BおよびDのうち2以下はNであり;
R3はBr、I、F、125I、131I、123I、18F、76Br、77Br、ハロアルキルまたはSn(アルキル)3;
R1およびR2は独立して、水素、C1−4アルキル、C2−4アミノアルキル、C1−4ハロアルキル、ハロアリールアルキル、−L−Chであるか、あるいはR1およびR2はそれらが結合する窒素と一緒になって、所望により環内にO、SまたはNR5を有してもよい5ないし7員の複素環を形成し、ここに、
R5は水素またはC1−4アルキルである]
で表される化合物またはその医薬上許容される塩に指向される。
(1) 本発明の非放射性標識化合物、ここに、該化合物は、所望により、乾燥条件下にあり;また、所望により、不活性の、医薬上許容される担体および/またはそれに添加された補助物質を有してもよく;および
(2) 還元剤および所望によりキレート剤;
ここに、成分(1)および(2)は、所望により、組み合わせてもよく;および
さらに、成分(1)および(2)と過テクネチウム酸塩の形態でのテクネチウム−99mとを反応させることにより前記方法を行うための指示を含む使用説明書を所望により含むことができる。
2−(4'−ジメチルアミノフェニル)−6−ヨードベンゾチアゾール,(3)
2−(4'−ジメチルアミノフェニル)−6−ブロモベンゾチアゾール(1):(Stevens, M. F. G.ら、J. Med. Chem. 37:1689−1695(1994);Stevens、M. F. G.ら、PCT国際出願WO19940830:47(1995))
2−[4'−(4''−メチルピペラジン−1−イル)−フェニル]−6−ヨードベンゾチアゾール,(6)
1を調製するための前記の手順を使用して、4−(4−メチルピペラジン−1−イル) ベンズアルデヒド(Tanaka、A.ら、J. Med. Chem. 41:2390(1998))(204mg、1ミリモル)および5−ブロモ−2−アミノ− ベンゼンチオール(204mg、1ミリモル)から57.2%の生成物4を得た。
6−トリブチルスタンニル−2−(4'−ジメチルアミノ−)フェニル−イミダゾ[1,2a]ピリジン(18)の調製
6−ブロモ−2−(4'−ジメチルアミノ−)フェニル−イミダゾ[1,2−a]ピリジン(17)
8.21(d、d、J=1.7、0.8Hz、1H). 元素分析3a,(C15H14BrN3)
8.32(d、J=0.7Hz、1H). 元素分析 3b、(C15H14IN3).
放射ヨウ素化リガンド:[125I]IMPY、[125I]19
分配係数測定
溶液中で凝集したAβ(1−40)またはAβ(1−42)ペプチドを用いる結合アッセイ
ペプチドAβ(1−40)およびAβ(1−42)の固体形態をBachem(King of Prussia、PA)から購入した。ペプチドの凝集は、10mMリン酸ナトリウムおよび1mM EDTAを含有する緩衝液(pH7.4)中のそのペプチド[Aβ(1−40)では、0.5mg/mLおよびAβ(1−42)では0.25mg/mLを穏やかに溶解することにより行った。溶液を緩やかにかつ一定に振盪させつつ、37℃にて36〜42時間インキュベートした。結合試験は、いくらかの修飾を含み記載された手法(Klunk, W. E.ら, Biol. Psychiatry 35:627(1994))に従い12×75mmのホウケイ酸ガラス試験管中で行った。凝集した線維(最終アッセイ混合物中10〜50nM)を飽和試験用の1mlの最終容積中の40% EtOHおよび10% EtOH中の50mlの放射リガンド(0.01〜0.5nM)を含む混合物に添加した。非特異的な結合は、チオフラビンにつき2mMチオフラビンTの存在下で規定した。阻害試験では、1mlの反応混合物は、40% EtOH中の40mlの阻害剤(10% EtOH中の10−5−10−10M)および0.05nM放射性追跡子を含有した。その混合物を室温にて3時間インキュベートし、結合および遊離の放射能をBrandel M−24Rセル・ハーベスターを用いてWhatman GF/Bフィルターを通し真空濾過に続けて、室温にて10%エタノールの2×3mLの洗浄により分離した。結合したI−125リガンドを含むフィルターを70%のカウント効率でガンマカウンター(Packard 5000)中でカウントした。飽和および阻害実験の結果をソフトウェアEBDA52を用いる非線形回帰分析に付し、それにより、KdおよびKi値を計算した。本発明の化合物に対するさらなるKi値を図1Aおよび図1Bに供する。
正常なマウスにおける新しいプローブのin vivo生物学的分布
Claims (13)
- 式III:
R1およびR2は独立して、水素、C1−4アルキル、C2−4アミノアルキル、C1−4ハロアルキル、ハロアリールアルキルであるか、あるいはR1およびR2はそれらが結合する窒素と一緒になって、5ないし7員の複素環を形成する]
で表される化合物またはその医薬上許容される塩。 - 前記複素環が、該複素環内にO、S、またはNR 5 のうちの少なくとも一つを含み、ここに、R 5 は水素またはC 1−4 アルキルである請求項1記載の化合物。
- R3が125I、131I、123I、18F、76Brまたは77Brである請求項1または2記載の化合物。
- R1およびR2が独立して、水素、C1−4アルキル、C1−4ハロアルキルまたは4−フルオロベンジルから選択された請求項3記載の化合物。
- R3が123Iまたは125Iであって;
R1およびR2が共にメチルである請求項1または2記載の化合物。 - R3がSn(アルキル)3であって;
R1およびR2が独立して、水素、C1−4アルキル、C1−4ハロアルキルまたは4−フルオロベンジルから選択された請求項1記載の化合物。 - R1およびR2がC1−4アルキルである請求項6記載の化合物。
- R1およびR2がメチルである請求項7記載の化合物。
- 式III’:
- 請求項9記載の化合物;および
医薬上許容される賦形剤または希釈剤を含む医薬組成物。 - 請求項9記載の放射性標識化合物;および
医薬上許容される賦形剤または希釈剤を含むアミロイド沈着物を画像化するための診断用組成物。 - アミロイド斑凝集を阻害するのに有効な量の請求項10記載の組成物を含む、哺乳動物におけるアミロイド斑凝集を阻害するための組成物。
- a.検出可能量の請求項11記載の診断用組成物を含むアミロイド沈着物を画像化するための組成物であって、該組成物は、1以上のアミロイド沈着物と会合することを特徴とする、組成物。
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PCT/US2002/012626 WO2002085903A2 (en) | 2001-04-23 | 2002-04-23 | Amyloid plaque aggregation inhibitors and diagnostic imaging agents |
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Also Published As
Publication number | Publication date |
---|---|
US20030059369A1 (en) | 2003-03-27 |
KR20040058111A (ko) | 2004-07-03 |
WO2002085903A3 (en) | 2003-02-27 |
DE60217090T2 (de) | 2007-07-12 |
WO2002085903A2 (en) | 2002-10-31 |
USRE44338E1 (en) | 2013-07-02 |
CN100422180C (zh) | 2008-10-01 |
USRE44354E1 (en) | 2013-07-09 |
US20060051293A1 (en) | 2006-03-09 |
US7425318B2 (en) | 2008-09-16 |
EP1381604B1 (en) | 2006-12-27 |
ATE349446T1 (de) | 2007-01-15 |
TWI245764B (en) | 2005-12-21 |
CN1620454A (zh) | 2005-05-25 |
JP2005512945A (ja) | 2005-05-12 |
US20040131545A1 (en) | 2004-07-08 |
ES2274973T3 (es) | 2007-06-01 |
US6946116B2 (en) | 2005-09-20 |
AU2002258915B2 (en) | 2007-11-15 |
CA2444214A1 (en) | 2002-10-31 |
EP1381604A2 (en) | 2004-01-21 |
US6696039B2 (en) | 2004-02-24 |
DE60217090D1 (de) | 2007-02-08 |
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