JP5113823B2 - 代謝調節剤として有用なマロニル−CoA脱炭酸酵素阻害剤 - Google Patents
代謝調節剤として有用なマロニル−CoA脱炭酸酵素阻害剤 Download PDFInfo
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- JP5113823B2 JP5113823B2 JP2009261692A JP2009261692A JP5113823B2 JP 5113823 B2 JP5113823 B2 JP 5113823B2 JP 2009261692 A JP2009261692 A JP 2009261692A JP 2009261692 A JP2009261692 A JP 2009261692A JP 5113823 B2 JP5113823 B2 JP 5113823B2
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- Prior art keywords
- ethyl
- trifluoro
- trifluoromethyl
- hydroxy
- methyl
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- 230000002503 metabolic effect Effects 0.000 title description 14
- 229940122874 Malonyl-CoA decarboxylase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 102100029461 Malonyl-CoA decarboxylase, mitochondrial Human genes 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 108010081805 Malonyl-CoA decarboxylase Proteins 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- -1 3- 4 Chemical group 0.000 claims description 77
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- OOQFSXGQDWAVIH-UHFFFAOYSA-N 1-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)furan-2-yl]pentan-1-one Chemical compound CCCCC(=O)C1=CC=C(C(O)(C(F)(F)F)C(F)(F)F)O1 OOQFSXGQDWAVIH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- HRYKHSXEYCFLLD-UHFFFAOYSA-N (4-chlorophenyl)-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,2-oxazol-3-yl]methanone Chemical compound O1C(C(O)(C(F)(F)F)C(F)(F)F)=CC(C(=O)C=2C=CC(Cl)=CC=2)=N1 HRYKHSXEYCFLLD-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- BONCZXUMYYKTDH-UHFFFAOYSA-N n-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-n-(pyridin-4-ylmethyl)formamide Chemical compound S1C(C(O)(C(F)(F)F)C(F)(F)F)=CN=C1N(C=O)CC1=CC=NC=C1 BONCZXUMYYKTDH-UHFFFAOYSA-N 0.000 claims description 2
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- XMNWXXVTSDCTJE-UHFFFAOYSA-N n-methyl-3-phenyl-n-[5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)pent-2-ynyl]propanamide Chemical compound FC(F)(F)C(O)(C(F)(F)F)C#CCN(C)C(=O)CCC1=CC=CC=C1 XMNWXXVTSDCTJE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 8
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims 4
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 3
- 229940095102 methyl benzoate Drugs 0.000 claims 2
- GJZCWVFMDJMTRC-UHFFFAOYSA-N 1-[(4-cyanophenyl)methyl]-1-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-3-propan-2-ylurea Chemical compound N=1C=C(C(O)(C(F)(F)F)C(F)(F)F)SC=1N(C(=O)NC(C)C)CC1=CC=C(C#N)C=C1 GJZCWVFMDJMTRC-UHFFFAOYSA-N 0.000 claims 1
- KQVGDYUTXJZOGV-UHFFFAOYSA-N 1-[(4-cyanophenyl)methyl]-1-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-3-propylurea Chemical compound N=1C=C(C(O)(C(F)(F)F)C(F)(F)F)SC=1N(C(=O)NCCC)CC1=CC=C(C#N)C=C1 KQVGDYUTXJZOGV-UHFFFAOYSA-N 0.000 claims 1
- ACURLKULSMZUPR-UHFFFAOYSA-N 1-[(4-cyanophenyl)methyl]-3-cyclohexyl-1-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]urea Chemical compound S1C(C(O)(C(F)(F)F)C(F)(F)F)=CN=C1N(C(=O)NC1CCCCC1)CC1=CC=C(C#N)C=C1 ACURLKULSMZUPR-UHFFFAOYSA-N 0.000 claims 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- SKYYSKPMJJPNTM-UHFFFAOYSA-N 3-ethyl-1-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-1-(pyridin-4-ylmethyl)urea Chemical compound N=1C=C(C(O)(C(F)(F)F)C(F)(F)F)SC=1N(C(=O)NCC)CC1=CC=NC=C1 SKYYSKPMJJPNTM-UHFFFAOYSA-N 0.000 claims 1
- QMBDGUNNDQBPDW-UHFFFAOYSA-N 4-[(4-cyanophenyl)methyl-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]amino]-4-oxobutanoic acid Chemical compound N=1C=C(C(O)(C(F)(F)F)C(F)(F)F)SC=1N(C(=O)CCC(=O)O)CC1=CC=C(C#N)C=C1 QMBDGUNNDQBPDW-UHFFFAOYSA-N 0.000 claims 1
- CKKLCLNZYOCSHR-UHFFFAOYSA-N 4-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]benzonitrile Chemical compound O1C(C(O)(C(F)(F)F)C(F)(F)F)CC(C=2C=CC(=CC=2)C#N)=N1 CKKLCLNZYOCSHR-UHFFFAOYSA-N 0.000 claims 1
- QAWWDKODHQYNBE-UHFFFAOYSA-N 4-[[(3,5-dichlorobenzoyl)-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]amino]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN(C=1SC(=CN=1)C(O)(C(F)(F)F)C(F)(F)F)C(=O)C1=CC(Cl)=CC(Cl)=C1 QAWWDKODHQYNBE-UHFFFAOYSA-N 0.000 claims 1
- BPJQKWXHVVFKRN-UHFFFAOYSA-N 4-[[(4-bromobenzoyl)-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]amino]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN(C=1SC(=CN=1)C(O)(C(F)(F)F)C(F)(F)F)C(=O)C1=CC=C(Br)C=C1 BPJQKWXHVVFKRN-UHFFFAOYSA-N 0.000 claims 1
- JDQQRDLYRGGWQT-UHFFFAOYSA-N 4-[[[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-(2-methylpropanoyl)amino]methyl]benzoic acid Chemical compound N=1C=C(C(O)(C(F)(F)F)C(F)(F)F)SC=1N(C(=O)C(C)C)CC1=CC=C(C(O)=O)C=C1 JDQQRDLYRGGWQT-UHFFFAOYSA-N 0.000 claims 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- UNOCSFJUHMZNAU-UHFFFAOYSA-N 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-n,n-bis(2-methylpropyl)-4,5-dihydro-1,2-oxazole-3-carboxamide Chemical compound CC(C)CN(CC(C)C)C(=O)C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1 UNOCSFJUHMZNAU-UHFFFAOYSA-N 0.000 claims 1
- MRERBCAKAZSFTL-UHFFFAOYSA-N 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-n-(pyridin-3-ylmethyl)-4,5-dihydro-1,2-oxazole-3-carboxamide Chemical compound O1C(C(O)(C(F)(F)F)C(F)(F)F)CC(C(=O)NCC=2C=NC=CC=2)=N1 MRERBCAKAZSFTL-UHFFFAOYSA-N 0.000 claims 1
- WMYDNRXKYVZEAA-UHFFFAOYSA-N 5-[(4-cyanophenyl)methyl-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]amino]-2,2-dimethyl-5-oxopentanoic acid Chemical compound N=1C=C(C(O)(C(F)(F)F)C(F)(F)F)SC=1N(C(=O)CCC(C)(C)C(O)=O)CC1=CC=C(C#N)C=C1 WMYDNRXKYVZEAA-UHFFFAOYSA-N 0.000 claims 1
- CRCKRSGNYZJYGI-UHFFFAOYSA-N 5-[(4-cyanophenyl)methyl-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]amino]-5-oxo-2-phenylpentanoic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)CCC(=O)N(C=1SC(=CN=1)C(O)(C(F)(F)F)C(F)(F)F)CC1=CC=C(C#N)C=C1 CRCKRSGNYZJYGI-UHFFFAOYSA-N 0.000 claims 1
- 125000006286 dichlorobenzyl group Chemical group 0.000 claims 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims 1
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- VSRBKQFNFZQRBM-UHFFFAOYSA-N tuaminoheptane Chemical compound CCCCCC(C)N VSRBKQFNFZQRBM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
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- C07C215/24—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and acyclic
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Description
本発明は、特定の代謝疾患および酵素マロニル-コエンザイムA脱炭酸酵素(マロニル-CoA脱炭酸酵素、MCD)の阻害によって調節される疾患を治療する際に有用な、新規化合物、それらのプロドラッグ、および薬学的に許容される塩、ならびにそのような化合物を含む薬学的組成物に関する。特に、本発明は、マロニル-CoA脱炭酸酵素の阻害を通じて、心血管疾患、糖尿病、アシドーシス、癌、および肥満を予防、管理および治療するための化合物および組成物ならびに方法に関する。
マロニル-CoAは、体内で酵素アセチルCoAカルボキシラーゼ(ACC)によって産生される重要な代謝中間体である。肝、脂肪細胞、および他の組織において、マロニル-CoAは脂肪酸合成酵素(FAS)の基質である。ACCおよびマロニル-CoAは、脂肪酸合成酵素レベルが低い骨格筋および心筋組織で見いだされる。マロニル-CoA脱炭酸酵素(MCD、EC4.1.1.9)は、マロニル-CoAのアセチル-CoAへの変換を触媒し、それによりマロニル-CoAレベルを調節する。MCD活性は、原核生物、鳥類、および哺乳類を含む広範な生物において記載されている。この酵素は細菌リゾビウム・トリフォリ(Rhizobium trifolii)(Anら、J. Biochem. Mol. Biol. 32: 414-418 (1999))、水鳥の尾腺(Bucknerら、Arch. Biochem. Biophys 177: 539 (1976);KimおよびKolattukudy、Arch. Biochem. Biophys 190: 585 (1978))、ラット肝ミトコンドリア(KimおよびKolattukudy、Arch. Biochem. Biophys. 190: 234 (1978))、ラット乳腺(KimおよびKolattukudy、Biochim. Biophys, Acta 531: 187 (1978))、ラット膵β-細胞(Voilleyら、Biochem. J. 340: 213 (1999))およびガチョウ(ハイイロガン)(Jangら、J. Biol. Chem. 264: 3500 (1989))から精製されている。MCD欠損症患者の同定は、ガチョウおよびラットMCD遺伝子に相同のヒト遺伝子のクローニングにつながる(Gaoら、J. Lipid. Res. 40: 178 (1999);Sackstederら、J. Biol. Chem. 274: 24461 (1999);FitzPatrickら、Am. J. Hum. Genet. 65: 318 (1999))。ノーザンブロット分析で単一のヒトMCD mRNAが観察される。筋および心臓組織で最も高いmRNA発現レベルが観察され、肝、腎および膵ではその次に高く、検査したその他の組織すべてにおいて検出可能な量が認められる。
健康なヒトの心臓は利用可能な代謝基質を利用している。血糖値が高い場合、グルコースの取り込みおよび代謝によって心臓の主な燃料源が得られる。絶食状態では、脂肪組織によって脂質が提供され、心臓での脂肪酸取り込みおよび代謝によってグルコース代謝が下方制御される。脂肪酸およびグルコースの血清レベルによる中間代謝の調節は、グルコース-脂肪酸回路を含む(Randleら、Lancet, 1: 785-789 (1963))。虚血状態では、酸素供給が限られるため、脂肪酸およびグルコース両方の酸化が低下し、心臓組織における酸化的リン酸化によって産生されるATPの量が減少する。十分な酸素がない状態では、ATPレベルを維持しようとして解糖が増大し、その結果、乳酸の増加および細胞内pHの低下が起こる。エネルギーを費やしてイオンの恒常性を維持し、異常に低いATPレベルおよび細胞の浸透性崩壊の結果、筋細胞死が起こる。加えて、AMPKが虚血中に活性化されてリン酸化し、したがってACCを不活化する。全体の心臓マロニル-CoAレベルが低下し、したがってCPT-I活性が上昇し、脂肪酸の酸化がグルコースの酸化よりも有利となる。心臓組織における代謝調節剤の有益な効果は、酸素1モルあたりのATPの有効性が脂肪酸に比べてグルコースで高まることで、より重要なことには、解糖とグルコース酸化の結合が増大することにより、虚血組織におけるプロトン負荷の正味の低下が起こる。
糖尿病に最もよく付随する二つの代謝性合併症は、肝のケトン体過剰産生(NIDDMにおいて)および持続性のグルコースレベル上昇に伴う臓器毒性である。脂肪酸酸化の阻害は、血糖値を調節し、II型糖尿病のいくつかの症状を寛解することができる。CPT-Iのマロニル-CoA阻害は、低インスリン-高グルカゴン血症状態発症中の脂肪酸酸化速度を制御する最も重要な調節機構である。いくつかの不可逆的および可逆的CPT-I阻害剤が、その血糖値を制御する能力について評価されており、これらはすべて決まって血糖降下性である(Anderson、Current Pharmaceutical Design 4: 1 (1998))。肝特異的かつ可逆的なCPT阻害剤であるSDZ-CPI-975は、18時間絶食させた健常な非ヒト霊長類およびラットで、心肥大を引き起こすことなくグルコースレベルを著しく低下させる(Deemsら、Am. J. Physiology 274: R524 (1998))。マロニル-CoAは膵β-細胞におけるグルコースおよび脂肪酸の相対的利用可能性のセンサーとしての重大な役割を果たしており、したがってグルコース代謝を細胞のエネルギー状態およびインスリン分泌に連結している。インスリン分泌促進物質がβ-細胞におけるマロニル-CoA濃度を高めることが明らかにされている(Prentkiら、Diabetes 45: 273 (1996))。しかし、糖尿病をCPT-I阻害剤で直接治療することは、機構に基づく肝および心筋毒性の原因となっている。したがって、CPT-Iをその内因性阻害物質、マロニル-CoAの増加を通じて阻害するMCD阻害剤は、糖尿病性疾患の治療のために、CPT-I阻害剤と比べて安全かつ優れている。
マロニル-CoAは、ヒト乳癌細胞および異種移植片において脂肪酸合成酵素阻害により誘導される細胞毒性の媒介物質である可能性が示唆されている(Pizerら、Cancer Res. 60: 213 (2000))。抗腫瘍抗生物質セルレニンまたは合成類縁体C75を用いての脂肪酸合成酵素の阻害は、乳癌細胞のマロニル-CoAレベルを著しく上昇させることが判明している。一方、アセチル-CoAカルボキシラーゼ(ACC)のレベルでのみ阻害する、脂肪酸合成阻害剤TOFA(5-(テトラデシロキシ)-2-フロン酸)は、抗腫瘍活性は全く示さないが、同時にマロニル-CoAレベルは対照の60%に低下する。マロニル-CoAレベルの上昇はこれらの脂肪酸合成酵素阻害剤の抗腫瘍活性を担っていると考えられる。MCD阻害剤を用いてマロニル-CoAレベルを調節することは、したがって、癌性疾患治療のための価値ある治療戦略となる。
マロニル-CoAはニューロペプチドY経路の阻害により、脳の食欲シグナリングにおいて主要な役割を果たすことが示唆されている(Loftusら、Science 288: 2379 (2000))。脂肪酸合成酵素(FAS)阻害剤セルレニンまたはC75によるマウスの全身または脳室内治療は、摂食阻害および劇的な体重減少を引き起こした。C75は海馬において摂食亢進性(prophagic)シグナルニューロペプチドYの発現を阻害し、マロニル-CoAによって仲介されると考えられるレプチン非依存性の様式で作用することが判明した。したがって、MCDの阻害を通じてのマロニル-CoAレベルの制御は、肥満の予防および治療への新規アプローチを提供する。
ならびにそのプロドラッグ、および薬学的に許容される塩である。本発明の他の局面は本発明の説明を続けるうちに明らかになると思われる。したがって、前記は単に本発明の特定の局面の概要を示しているにすぎず、いかなる様式でも本発明を限定することを意図するものではなく、本発明を限定すると解釈されるべきでもない。
下記の本発明の詳細な説明は、網羅的であること、または開示する正確な詳細に本発明を限定することを意図してはいない。これは、他の当業者に本発明の詳細を十分に説明するために選択され、記載されたものである。
下記の式(Ia)および(Ib)
下記の式(Ic)および(Id)
下記の式(Ie)
下記の式(IIa)および(IIb)
下記の式(IIc)および(IId)はピラゾール環を含まないという条件下で、式(IIc)、(IId)、(IIe)および(IIf)
から独立に選択され;
R1はハロ、ハロアルキル、ヒドロキシ、チオール、置換チオール、スルホニル、スルフィニル、ニトロ、シアノ、アミノ、置換アミノ、C1〜C6アルキルおよびC1〜C6アルコキシから独立に選択され、R1がヒドロキシ、C1〜C6アルコキシ、チオール、置換チオール、アミノ、置換アミノ、またはC1〜C6アルキルである場合、そのような基は、R1がR2またはR14の隣に位置する場合にはR2またはR14と共に5〜7員環を形成してもよく;
R2は-N(R3)C(O)R4、-C(O)NR4R5、-N(R3)C(O)NR4R5、N(R3)SO2R7、-N(R3)SO2NR4R3、-N(R3)C(O)OR4、-C(O)OR4、-C(S)OR4、-SR3、フェニル、-N(R3)C(S)NR4R5、-NR3R4、-N(R3)C(=NR3)NR4R5、-N(R3)C(=NCN)NR4R5、-N(R3)C(=CHNO2)NR4R5、-NR3P(O)R4R5、-NR3P(O)(OR4)(OR5)、-NR3P(O)(OR4)(NR5)、-N(R3)P(O)(NR4)(NR5)、-N(R3)C(=NR3)R6、-COR6、-C(R6)(OH)R7、-C(R8)=NOR4、-C(R8)=NR3、-C(R8)=NNR4R5、-SOR7、-SO2R7、-P(O)(OR4)(OR5)、-P(O)(R4)(R5)、-P(O)(OR4)(OR5)、-P(O)(NR3)(OR4)、-P(O)(NR4)(NR5)、O、N、またはSから選択される0個から3個のヘテロ原子を含む3〜7員環から選択され、これらはR9、R10、R11、R12もしくはR13で置換されていてもよく、またはR1がR2の隣に位置する場合にはR1と共に5〜7員環を形成してもよく;
R3は水素、アルキル、アリール、アリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アシルであるか、またはR4もしくはR5と共に5〜7員環を形成してもよく;
R4は水素、アルキル、アリール、ヘテロシクリル、アシルであるか、またはR5もしくはR3と共に5〜7員環を形成してもよく;
R5は水素、アルキル、アリール、またはヘテロシクリル、アシルであるか、またはR3もしくはR4と共に5〜7員環を形成してもよく;
R6およびR7は同じでも異なっていてもよく、水素、アルキル、アリール、またはヘテロシクリルから選択され;
R8は水素、アルキル、アリール、ヘテロシクリル、アミノまたは置換アミノであり;
R9、R10、R11およびR12は同じでも異なっていてもよく、水素、アルキル、アリール、ヘテロシクリル、ニトロ、シアノ、カルボン酸、エステル、アミド、ハロ、ヒドロキシル、アミノ、置換アミノ、アルコキシ、アシル、ウレイド、スルホンアミド、スルファミド、スルホニル、スルフィニル、またはグアナジニルから選択され;
R13は水素、アルキル、アリール、エステル、ヘテロシクリル、アシル、スルホニル、ウレイド、またはグアナジニルであり;
R14は-NR3C(S)NR4R5、-NR3C(=NR3)NR4R5、-NR3C(=NCN)NR4R5、-NR3C(=CHNO2)NR4R5、-NR3P(O)R4R5、-NR3P(O)(OR4)(OR5)、-NR3P(O)(OR4)(NR5)、-NR3P(O)(NR4)(NR5)、-NR3C(=NR3)R6、-COR6、-C(R6)(OH)R7、-C(R8)=NOR4、-C(R8)=NR3、-C(R8)=NNR4R5、-SOR7、-SO2R7、-P(O)(OR4)(OR5)、-P(O)(R4)(R5)、-P(O)(OR4)(OR5)、-P(O)(NR3)(OR4)、-P(O)(NR4)(NR5)、O、N、またはSから選択される0個から3個のヘテロ原子を含む3〜7員環から選択され、これらはR9、R10、R11、R12もしくはR13で置換されていてもよく、またはR1がR14の隣に位置する場合にはR1と共に5〜7員環を形成してもよく;
AはO、S、またはNR3であり;
mは0から3であり;
XはH、CF2Z、もしくはCF3であるか、またはAがOである場合にはYと共に二重結合を形成し;
Yは水素であるか、またはAがOである場合にはXと共に二重結合を形成し;
ZはF、Br、Cl、IまたはCF3である]。
本明細書において用いられる「アルキル」とは、メチル、ペンチル、およびアダマンチルなどの、炭素および水素のみを含む環状、分枝状、または直鎖化学基を意味する。アルキル基は無置換でもよく、または、本発明の目的のために必要であれば、保護基で適当にブロックされていてもよい、一つもしくは複数の置換基、例えばハロゲン、アルコキシ、アシルオキシ、アミノ、アミド、シアノ、ニトロ、ヒドロキシ、メルカプト、カルボキシ、カルボニル、ベンジルオキシ、アリール、ヘテロアリール、もしくは他の官能基で置換されていてもよい。アルキル基は飽和でもよく、または一つまたは複数の位置で不飽和(例えば、-C=C-または-C≡C-サブユニットを含んでいる)でもよい。典型的には、アルキル基は1個から12個の炭素原子、好ましくは1個から10個、より好ましくは1個から8個の炭素原子または3個から8個の炭素を含む環状基を含むことになる。
本発明の組成物は下記を含む:
(a)MCD阻害化合物(I)、そのプロドラッグまたは薬学的塩の安全かつ有効な量;および
(b)薬学的に許容される担体。
本発明の化合物および組成物は、局所または全身投与することができる。全身適用には、化合物を体の組織内に導入する任意の方法、例えば関節内、くも膜下腔内、硬膜外、筋肉内、経皮、静脈内、腹腔内、皮下、舌下投与、吸入、直腸内、または経口投与が含まれる。本発明の化合物は、経口投与することが好ましい。
本発明の化合物を調製する際に用いる出発原料は公知であるか、公知の方法によって調製するか、または市販されている。当業者には、本明細書において特許請求されている化合物に関連する前駆体および官能基を調製する方法は、文献中に一般に記載されていることが明らかであると思われる。当業者は、文献および本開示を読めば、特許請求されているいかなる化合物も調製する能力が十分にあると考えられる。
インビトロMCD阻害アッセイ:
文献に記載されているマロニル-CoA脱炭酸酵素活性アッセイのための分光光度的方法を、高処理量様式でMCD阻害活性アッセイに合わせて改変する(Kolattukudyら、Methods in Enzymology 71: 150 (1981))。下記の試薬を96穴滴定プレートに加える:トリス-HCl緩衝液、20μL;DTE、10μL;l-リンゴ酸塩、20μL;NAD、10μL;NADH、25μL;水、80μL;リンゴ酸脱水素酵素、5μL。これらの内容物を混合し、2分間インキュベートした後、クエン酸シンターゼ5μLを加える。化合物と、続いてラット心臓から調節したマロニル-CoA脱炭酸酵素5μLおよびマロニル-CoA 20μLを加える。内容物をインキュベートし、460nMでの吸光度を測定する。
雄Sprague-Dawleyラット由来の動いている摘出心臓を、5mmol/Lのグルコース;100μU/mLのインスリン;3%BAS;および1.2mmol/Lのパルミチン酸塩を含む、改変クレブス-ヘンゼライト液と共に60分間の有酸素灌流期間に供する。これらの試験では、インビボで認められる心臓の代謝的需要を概算するために、動いている心臓を用いる(Kantorら、Circulation Research 86: 580-588 (2000))。被験化合物を灌流期間開始の5分後に加える。
本発明をさらに詳しく例示するために、下記の実施例が含まれる。実施例は、当然のことながら、本発明を特に制限すると解釈されるべきではない。特許請求の範囲内でのこれらの実施例の変更は、当業者の範囲内であり、本明細書において記載され、主張されている本発明の範囲内に入ると考えられる。読者は、本開示を読み、当技術分野の技能を備えた当業者であれば、網羅的な実施例なしで、本発明を調製し、用いることができることを理解すると思われる。
Bn=ベンジル
DMAP=4-(ジメチルアミノ)-ピリジン
DMF=N,N-ジメチルホルムアミド
DMSO=ジメチルスルホキシド
ESIMS=電子スプレー質量分析
Et3N=トリエチルアミン
EtOAc=酢酸エチル
ロウェッソン試薬=2,4-ビス(4-メトキシフェニル)-1,3,2,4-ジチアジホスフェタン-2,4-ジスルフィド
MgSO4=硫酸マグネシウム
NaHCO3=炭酸水素ナトリウム
NBS=N-ブロモスクシンイミド
NCS=N-クロロスクシンイミド
NH4Cl=塩化アンモニウム
Ph=フェニル
Py=ピリジル
r.t.=室温
THF=テトラヒドロフラン
TLC=薄層クロマトグラフィ
アルキル基の略語
Me=メチル
Et=エチル
n-Pr=ノルマルプロピル
i-Pr=イソプロピル
c-Pr=シクロプロピル
n-Bu=ノルマルブチル
i-Bu=イソブチル
t-Bu=三級ブチル
s-Bu=二級ブチル
c-Hex=シクロヘキシル
2-メチル-N-{5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオメチル)エチル]-1,3-チアゾル-2-イル}プロパンアミドの調製
2-(2-アミノ-1,3-チアゾル-5-イル)-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オールの調製
2-アミノチアゾール200mg(2mmol)およびヘキサフルオロアセトン三水和物(880mg、4mmol)の混合物に触媒量のモレキュラーシーブス粉末(4A)を加えた。混合物を100℃で8時間加熱した。酢酸エチルを加え、混合物をろ過した。有機溶媒を減圧下で蒸発させた。残渣をTHFおよびヘキサン中で再結晶して、表題生成物(389mg)を白色固体で得た。
上で得た2-(2-アミノ-1,3-チアゾル-5-イル)-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オール(267mg、1mmol)のトリエチルアミン(150mg、1.49mmol)およびTHF(10ml)の溶液に、塩化イソブチリル(110mg、1.03mmol)を室温で加えた。反応混合物を30分間撹拌した。溶媒を減圧下で除去し、残渣をEtOAcに溶解した。有機層を水および食塩水で洗浄し、乾燥(MgSO4)し、濃縮した。残渣をTHFおよびヘキサン中で再結晶して、表題化合物(282mg)を白色固体で得た。
N-(ピリジン-4-イルメチル)-N-{5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-1,3-チアゾル-2-イル}ピリジン-4-カルボキサミドの調製
1,1,1,3,3,3-ヘキサフルオロ-2-{2-[(ピリジン-4-イルメチル)アミノ]-1,3-チアゾル-5-イル}-プロパン-2-オールの調製
トルエン(50ml)中、2-アミノチアゾール(3g、30mmol)および4-ピリジンカルボキシアルデヒド(3.21g、30mmol)の混合物を、ディーン-スターク水分離器を用いて3時間還流した。溶媒を減圧下で除去し、得られた黄色固体をCH3OH(80ml)に溶解した。溶液を水素化ホウ素ナトリウム(1.8g)で注意深く処理し、20分間撹拌した。反応混合物を1N NaOHで反応停止し、蒸発乾固させた。残渣をEtOAcに溶解し、食塩水で洗浄し、乾燥(MgSO4)した。溶媒を蒸発させて、粗中間体N-(ピリジン-4イルメチル)-1,3-チアゾール-2-アミンを褐色固体で得た(4.2g)。
段階1から得た1,1,3,3,3-ヘキサフルオロ-2-{2-[(ピリジン-4-1イルメチル)アミノ]-1,3-チアゾル-5-イル}プロパン-2-オール(714.5mg、2mmol)のジオキサン(8ml)溶液に、イソニコチン酸無水物(912mg、4mmol)を加えた。反応混合物を100℃で2時間還流し、次いで減圧下で濃縮した。残渣をEtOAc(3×100ml)で抽出した。有機層をH2O(3×40ml)で洗浄し、MgSO4で乾燥した。溶媒を蒸発させて残渣を得、これを酢酸エチルおよびヘキサンからの再結晶により精製して、表題化合物を淡黄色固体で得た(528mg)。
N-ブチル-N'-エチル-N-{5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-1,3-チアゾル-2-イル}尿素の調製
2-[2-(ブチルアミノ)-1,3-チアゾル-5-イル]-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オールの調製
2-アミノチアゾール(1g、10mmol)およびブチルアルデヒド(1.44g、20mmol)をジクロロエタン(45ml)中で混合し、次いでトリアセトキシボロ水素化ナトリウム(6g、28mmol)および酢酸(3.6g、60mmol)で処理した。反応混合物を窒素雰囲気下、室温で終夜撹拌した。次いで、反応混合物を1N NaOHで反応停止し、EtOAcで抽出した。有機層を飽和NaHCO3、食塩水で洗浄し、MgSO4で乾燥した。溶媒を蒸発させて、2-ブチルアミノチアゾールを褐色残渣で得た(1.02g)。
ベンゼン(2ml)中、段階1から得た2-[2-(ブチルアミノ)-1,3-チアゾル-5-イル]-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オール(65mg、0.202mmol)の混合物に、窒素雰囲気下、イソシアン酸エチル(24μL、0.3mmol)を加えた。反応混合物を4時間還流した。溶媒を減圧下で除去して油状物を得、これをEtOAcに溶解した。得られた溶液をH2O、飽和NaHCO3および食塩水で洗浄し、MgSO4で乾燥した。溶媒を蒸発させて粗生成物を得、これを調製用TLC(EtOAc:ヘキサン=1:3)で精製して、対応する生成物を白色固体で得た(31mg)。
ピリジン-4-イルメチル{5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-1,3-チアゾル-2-イル}ホルムアミドの調製
5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-1,3-チアゾル-2-イル-アミドリン酸ジエチルの調製
4-クロロ-N-{5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-1,3-チアゾル-2-イル}ベンゼンスルホンアミドの調製
N-エチル-2-メチル-N-{5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-1,2,4-チアジアゾル-3-イル}プロパンアミドの調製
2-(エチルアミノ)-1,3,4-チオアジアゾール(1.29g、10mmol)のピリジン(5ml)溶液に、塩化イソブチリル(1.06g、10mmol)を0℃で加えた。反応混合物を室温で終夜撹拌した。溶媒を減圧下で除去し、酢酸エチルを加えた。有機層をH2Oおよび食塩水で洗浄し、MgSO4で乾燥した。溶媒を蒸発させ、残渣をCHCl3およびヘキサン中で再結晶して、中間体を橙色固体で得た(1.05g)。
上で調製した中間体(400mg、2.0mmol)のTHF(12ml)溶液に、n-ブチルリチウムのヘキサン溶液(2.5M、1.2ml、3.0mmol)を窒素雰囲気下、-78℃で加え、得られた溶液を-78℃で30分間撹拌した。ヘキサフルオロアセトン(890mg、5.36mmol)をこの溶液にバブリングさせ、得られた混合物を-78℃でさらに30分間撹拌した。反応混合物をH2Oで反応停止し、温度を戻した。溶媒を除去し、酢酸エチルを加えた。有機層をNH4Cl水溶液、H2Oおよび食塩水で洗浄し、次いで乾燥(MgSO4)し、蒸発させた。調製用TLC(ヘキサン:酢酸エチル=50:50)により精製して、表題化合物を白色固体で得た(186mg)。
1-{5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]フラン-2-イル}ペンタン-1-オンの調製
5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]ピリミジン-2-イル-カルバミン酸1,1-ジメチルエチルの調製
THF(60ml)中、2-アミノ-5-ブロモピリジン(3.48g、20mmol)、トリエチルアミン(6.1ml、43.7mmol)、および4-(ジメチルアミノ)-ピリジン(244mg、2mmol)の混合物に、ジ-t-ブチルジカーボネート(9.82g、45mmol)を加えた。反応混合物を室温で3日間撹拌した。溶媒を減圧下で除去し、残渣をTHFおよびヘキサン中で再結晶した。フラッシュクロマトグラフィ(シリカゲル、酢酸エチル:ヘキサン=1:4)でさらに精製して、ジ(t-ブチル)5-ブロモピリミドジカーボネート(6.1g)を白色固体で得た。
前述の中間体(190mg、0.51mmol)のTHF(8ml)溶液に、n-ブチルリチウムのヘキサン溶液(2.5M、0.8ml、2mmol)を窒素雰囲気下、-100℃で加え、得られた反応混合物を-100℃で30分間撹拌した。ヘキサフルオロアセトン(540mg、3.35mmol)をこの混合物にバブリングさせ、得られた溶液を-100℃でさらに30分間撹拌した。反応混合物をH2Oで反応停止し、室温まで戻した。溶媒を除去し、酢酸エチルを加えた。有機層をH2Oおよび食塩水で洗浄し、乾燥(MgSO4)し、蒸発させた。調製用TLC(ヘキサン:酢酸エチル=3:1)により精製して、対応する化合物を白色固体で得た(18.6mg)。
N-メチル-3-フェニル-N-[5,5,5-トリフルオロ-4-ヒドロキシ-4-(トリフルオロメチル)ペント-2-イニル]プロパンアミドの調製
N-メチルプロパルグリアミン(691mg、10mmol)およびトリエチルアミン(1.21g、12mmol)のCH2Cl2(40ml)溶液に、塩化ヒドロシンナモイル(1.68g、10mmol)のCH2Cl2(10ml)溶液を室温で滴加した。反応混合物を室温で2時間撹拌した。溶媒を減圧下で除去し、残渣をEtOAcに溶解した。有機層を水、食塩水で洗浄し、MgSO4で乾燥した。濃縮により中間体(1.72g)を褐色油状物で得、これを数日間さらに減圧乾燥した。
上で調製した中間体(402mg、2mmol)のエーテル(8ml)溶液に、n-ブチルリチウムのヘキサン溶液(2.5M、1.2ml、3mmol)を窒素雰囲気下、-78℃で加えた。得られた混合物を-78℃で90分間撹拌した。ヘキサフルオロアセトン(780mg、4.7mmol)を反応混合物にバブリングさせ、得られた溶液を-78℃でさらに30分間撹拌した。反応混合物を室温まで戻し、H2Oで反応停止した。混合物をエーテルと水との間で分配した。有機層をH2Oおよび食塩水で洗浄し、乾燥(MgSO4)し、蒸発させた。残渣をエーテルおよびヘキサンから再結晶して、表題化合物(123mg)を白色固体で得た。
1,1,1-トリフルオロ-2-トリフルオロメチル-ブタ-3-エン-2-オールの調製
THF中1.6Mの塩化ビニルマグネシウム(200mL、0.32mL)を-78℃で撹拌しながら、これにヘキサフルオロアセトン(50g、0.31mol)をカニューレで3時間かけて加えた。反応混合物を室温まで戻し、さらに2時間撹拌し、次いで40℃でさらに1時間加熱した。反応混合物をNH4Cl水溶液で反応停止した。混合物をペンタンで希釈し、ろ過し、有機相をMgSO4で乾燥した。100℃〜103℃での分別蒸留(12インチヴィグロウカラム)により、生成物1,1,1-トリフルオロ-2-トリフルオロメチル-ブタ-3-エン-2-オール(約66mol%のTHFを含む混合物)を澄明な液体で得た(50g)。
5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-4,5-ジヒドロイソキサゾール-3-カルボン酸エチルの調製
段階1からの1,1,1-トリフルオロ-2-トリフルオロメチル-ブタ-3-エン-2-オール(約90mmol)中、市販のクロロオキシイミド酢酸エチル(3.03g、20mmol)の溶液を室温で撹拌しながら、これにトリエチルアミン(2.23g、22mmol)のTHF(10mL)溶液をシリンジポンプで68時間かけて加えた。反応混合物をろ過し、ろ過ケークをエーテルおよびペンタンで洗浄した。ろ液を希酸および水で洗浄した。溶媒を大気圧で除去し、残渣をカラムクロマトグラフィ(EtOAc:ヘキサン=2:1)で精製して、エチルエステル(3.06g、50%)を白色固体で得た。
5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-4,5-ジヒドロイソキサゾール-3-カルボン酸の調製
N-(1-メチルヘキシル)-5-[2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル]-4,5-ジヒドロイソキサゾール-3-カルボキサミドの調製
2-(3-ブロモ-4,5-ジヒドロイソキサゾル-5イル)-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オールの調製
1,1,1,3,3,3-ヘキサフルオロ-2-(3-ピロリジン-1-4,5-ジヒドロイソキサゾル-5-イル)プロパン-2-オールの調製
3-イソプロピル-1-ペンチル)-1-[5-(2,2,2-トリフルオロ-1ヒドロキシ-1-トリフルオロメチル-エチル)-4,5-ジヒドロイソキサゾル-3-イル]-尿素の調製
トリエチルアミン0.5ml中、実施例9-1からの2-(3-ブロモ-4,5-ジヒドロイソキサゾル-5イル)-1,1,1,3,3,3-ヘキサフルオロプロパン-2-オール(31.6mg、0.1mmol)およびアミルアミン(26.1mg、0.3mmol)の混合物を圧力管内、110℃で終夜加熱した。反応混合物を減圧下で5時間濃縮し、乾固した。残渣を次の段階の出発原料として直接用いた。
トルエン0.5ml中、段階1からの残渣の混合物に、イソシアン酸イソプロピル(30μL、0.3mmol)を加えた。反応混合物を圧力管内、110℃で終夜加熱した。有機溶媒を減圧下で除去し、残渣をEtOAcと水との間で分配した。有機層を水および食塩水で洗浄し、乾燥(MgSO4)し、濃縮乾固した。粗生成物を調製用TLC(シリカゲル、CHCl3:CH3OH=10:1)で精製して、表題化合物(22.2mg)を油状物で得た。
1,1,1,3,3,3-ヘキサフルオロ-2-[3-(4-メチルフェニル)-4,5-ジヒドロイソキサゾル-5-イル]プロパン-2-オールの調製
エタノール30ml中、p-トルアルデヒド(1.2g、10mmol)および塩酸ヒドロキシルアミン(700mg、10mmol)の混合物に、ナトリウムメトキシド(540mg、10mmol)を加えた。反応混合物を室温で8時間撹拌した。混合物をろ過し、蒸発乾固した。得られた白色固体をCH2Cl2(30ml)で希釈し、これにNCS(1.33g、10mmol)を加えた。反応混合物を室温で終夜撹拌した。混合物をろ過した。溶媒を除去し、残渣をシリカゲルのフラッシュクロマトグラフィ(ヘキサン:酢酸エチル=3:1)で精製して、固体を44%の収率で得た。
1,1,1-トリフルオロ-2-トリフルオロメチル-ブタ-3-エン-2-オール(2mmol)中の前記化合物(170mg、1mmol)の溶液を撹拌しながら、これにトリエチルアミン(121mg、1.2mmol)のTHF(10ml)溶液を室温で30時間かけてシリンジポンプにより滴加した。混合物を減圧下で濃縮し、EtOAcで希釈した。有機層を1N HCl、H2Oで洗浄し、MgSO4で乾燥した。溶媒を減圧下で蒸発させ、残渣を調製用TLC(ヘキサン:EtOAc=5:1)で精製して、表題化合物を白色固体で得た(89.2mg)。
(4-クロロ-フェニル)-[5-(2,2,2-トリフルオロ-1-ヒドロキシ-1-トリフルオロメチル-エチル)-4,5-ジヒドロイソキサゾル-3-イル]メタノンの調製
(4-クロロ-フェニル)-[5-(2,2,2-トリフルオロ-1-ヒドロキシ-1-トリフルオロメチル-エチル)-イソキサゾル-3-イル]メタノンの調製
1,1,1-トリフルオロ-2-トリフルオロメチル-ブタ-3-イン-2-オールの調製
アセトン-エタノールドライアイス浴中、臭化エチニルマグネシウムの溶液(THF中0.5M)100mlに、ヘキサフルオロアセトンガス(6.1g、36.7mmol)を2時間かけてバブリングした。反応混合物を室温に戻し、次いで0.5時間還流した。反応混合物をNH4Cl水溶液で反応停止し、エーテルで抽出した。合わせた有機相を食塩水で洗浄し、MgSO4で乾燥した。蒸留(12インチヴィグロウカラム)により沸点100℃〜103℃で1,1,1-トリフルオロ-2-トリフルオロメチル-ブタ-3-イン-2-オールとTHFとの液体混合物を得た(4.7g、約68mol%のTHFを含む)。
Claims (8)
- 下記の式の化合物またはその薬学的に許容される塩:
(式中、R3は、水素、エチル、n−ブチル、MeOCH2CH2、フェニル、ベンジル、4−シアノベンジル、4−MeOCO−ベンジル、4−HOCO−ベンジル、4−クロロ−ベンジル、3−4,ジクロロ−ベンジル、4−メタンスルホニル−ベンジル、4−(2−カルボキシ−ビニル)−ベンジル、4−メトキシ−ベンジル、4−メチル−ベンジル、4−(5H−テトラゾール−5−イル)−ベンジル、4−ピリジルメチレン、3−ピリジルメチレン、2−ピリジルメチレン、2−フラニルメチレン、2−(1−メチル−1H−イミダゾリル)−CH2、および2−チアゾリル−CH2から選択され;かつ
R4は、水素、メチル、n−プロピル、イソ−プロピル、フェニル、フェニルエチル、3,5−ジクロロ−フェニル、4−ブロモ−フェニル、ピリジル、4−ピリジル、−CH2CH2COOH、−(CH2)3COOH、−CH2CH2C(CH3)2COOH、−CH2C(CH3)2CH2COOH、−CH(Ph)CH2COOH、−CH(Ph)CH2CH2COOH、−CH2CH2CH(Ph)COOH、および−CH2CH(Ph)COOHから選択される)である。 - 下記の式の化合物またはその薬学的に許容される塩:
(式中、R2’は、R9C(=O)−、ブロモ、N−ピロリジニル、3−イソプロピル−2−ペンチル−3−ウレア、p−トリル,p−CN−Ph、5−メチルフリル、p−ブロモ−Ph、および5−(1−Me−2−Cl−ピロリル)から選択され、
ここで、R9は、1−メチル−ヘキシル−NH−、ピリジン−4イル−メチル−N(Et)−、(i−Pr)2N−、(i−Bu)2N−、PhCH2CH2N(Me)−、t−BuOC(O)CH2CH2NH−、BnNH、(2−ピリジン−2−イル−エチル)−N(Me)−、HOCH2CH2N(Et)、Et(Ph)N(Me)、EtOC(O)CH2N(Bn)、HO(O)CCH2CH2NH、EtOC(O)CH2CH2NH、1−(2−Et−ピペリジニル)、1−(2−Me−ピロリジニル)、ビス−(2−エチル−ヘキシル)N、t−BuOC(O)CH(i−Pr)NH、MeOC(O)CH2CH2COCH2NH、t−BuOCOCH(Bn)NH、1−アゼパニル,1−ピペリジニル、1−(2−メチル−アジリジニル)、(5−t−ブトキシカルボニル−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル)、(イソアミル)2N、t−BuOC(O)CH2CH2N(i−Bu)、EtOC(O)CH2NH、EtOC(O)(CH2)3NH、1−アゼチジニル、1−ピロリジニル、1−(2,5−ジメチル−ピロリジニル)、(2−オキサ−5−アザ−ビシクロ[2.2.1]ヘプタ−5−イル)、i−BuNH、c−PrCH2N(n−Pr)、2−エチル−ヘキシル−N(ピリジン−2−イルメチル)N、t−BuCH2CH2NH、EtOC(O)CH2CH(CO2Et)NH、EtOC(O)CH(i−Bu)NH、t−BuOCO(CH2)2CH(CO2Me)NH、1−(2−CO2Me)−ピペリジニル、ピリジン−2−イルメチル−NH、ピリジン−3−イルメチル−NH、ピリジン−4−イルメチル−NH、ピリジン−2−イル−NH、ピリジン−3−イル−メチル−N(Me)、(EtO)C(O)CH(Me)NH、i−BuN(Me)、t−BuOC(O)CH(s−Bu)NH−、エトキシ、ヒドロキシル、および4−クロロ−フェニル−から選択される)。 - 以下から選択される化合物またはその薬学的に許容される塩:
N−エチル−2−メチル−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,2,4−チアジアゾル−3−イル}プロパンアミド;
1−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]フラン−2−イル}ペンタン−1−オン;
5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]ピリミジン−2−イル−カルバミン酸1,1−ジメチルエチル;
(4−クロロ−フェニル)−[5−(2,2,2−トリフルオロ−1−ヒドロキシ−1−トリフルオロメチル−エチル)−イソキサゾル−3−イル]メタノン;
5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル−アミドリン酸ジエチル;および
4−クロロ−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}ベンゼンスルホンアミド。 - 以下からなる群より選択される、請求項1、4、5および6のいずれか一項に記載の化合物:
1,1,1−トリフルオロ−5−[メチル(フェニルメチル)アミノ]−2−(トリフルオロメチル)ペント−3−イン−2−オール;
N−エチル−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3,4−チアジアゾル−2−イル}ベンズアミド;
N−メチル−3−フェニル−N−[5,5,5−トリフルオロ−4−ヒドロキシ−4−(トリフルオロメチル)ペント−2−イニル]プロパンアミド;
2−メチル−N−(ピリジン−3−イルメチル)−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}プロパンアミド;
2−メチル−N−(ピリジン−4−イルメチル)−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}プロパンアミド;
N−[(4−シアノフェニル)メチル]−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アセトアミド;
N−(ピリジン−4−イルメチル)−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}ピリジン−4−カルボキサミド;
N−[(4−シアノフェニル)メチル]−2−メチル−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}プロパンアミド;
2−メチル−N−(1,3−チアゾル−2−イルメチル)−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}プロパンアミド;
4−[((2−メチルプロパノイル){5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)メチル]安息香酸メチル;
N−[(4−シアノフェニル)メチル]−N'−(1−メチルエチル)−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}尿素;
4−[((2−メチルプロパノイル){5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)メチル]安息香酸;
2−メチル−N−{[4−(メチルスルホニル)フェニル]メチル}−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}プロパンアミド;
N−[(4−シアノフェニル)メチル]−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}ピリジン−4−カルボキサミド;
5−([(4−シアノフェニル)メチル]{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)−2,2−ジメチル−5−オキソペンタン酸;
4−([(4−シアノフェニル)メチル]{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)−4−オキソブタン酸;
4−[((ピリジン−4−イルカルボニル){5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)メチル]安息香酸メチル;
4−[((3,5−ジクロロベンゾイル){5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)メチル]安息香酸;
4−[((4−ブロモベンゾイル){5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)メチル]安息香酸;
5−((4−シアノベンジル){5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)−5−オキソ−2−フェニルペンタン酸;
N'−エチル−N−(ピリジン−4−イルメチル)−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}尿素;
N−[(4−シアノフェニル)メチル]−N'−シクロヘキシル−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}尿素;
N−[(4−シアノフェニル)メチル]−N'−プロピル−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}尿素;
N−[([(4−シアノフェニル)メチル]{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}アミノ)カルボニル]グリシン酸エチル;
N−ブチル−N'−エチル−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}尿素;
4−クロロ−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}ベンゼンスルホンアミド;
4−フルオロ−N−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}ベンゼンスルホンアミド;
ピリジン−4−イルメチル{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−1,3−チアゾル−2−イル}ホルムアミド;
N,N−ビス(2−メチルプロピル)−5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾール−3−カルボキサミド;
3−[({5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾル−3−イル}カルボニル)アミノ]プロパン酸1,1−ジメチルエチル;
3−メチル−2−[({5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾル−3−イル}カルボニル)アミノ]ブタン酸1,1−ジメチルエチル;
N−(2−エチルヘキシル)−N−(ピリジン−2−イルメチル)−5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾール−3−カルボキサミド;
N−(1−メチルヘキシル)−5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾール−3−カルボキサミド;
N−(ピリジン−3−イルメチル)−5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾール−3−カルボキサミド;
N−[(6,6−ジメチルビシクロ[3.1.1]ヘプタ−2−イル)メチル]−5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾール−3−カルボキサミド;
3−メチル)−2−{[5−(2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル)−4,5−ジヒドロイソキサゾール−3−カルボニル]−アミノ}−ペンタン酸tert−ブチルエステル;
4−{5−[2,2,2−トリフルオロ−1−ヒドロキシ−1−(トリフルオロメチル)エチル]−4,5−ジヒドロイソキサゾル−3−イル}ベンゾニトリル;
4−クロロフェニル)−[5−(2,2,2−トリフルオロ−1−ヒドロキシ−1−トリフルオロメチル−エチル)−イソキサゾル−3−イル]メタノン;
1,1,1,3,3,3−ヘキサフルオロ−2−(3−ピロリジン−1−4,5−ジヒドロイソキサゾル−5−イル)プロパン−2−オール;および
3−イソプロピル−1−ペンチル)−1−[5(2,2,2−トリフルオロ−1ヒドロキシ−1−トリフルオロメチル−エチル)−4,5−ジヒドロイソキサゾル−3−イル]−尿素。 - 請求項1、4、5および6のいずれか一項に記載の化合物またはその薬学的に許容される塩を薬学的に許容される担体と共に含む、マロニル−CoA脱炭酸酵素の阻害用薬学的組成物。
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DE60219595T2 (de) * | 2001-01-26 | 2008-01-10 | Chugai Seiyaku K.K. | Verfahren zur behandlung von erkrankungen mit malonyl coa-decarboxylase-inhibitoren |
US7709510B2 (en) | 2001-02-20 | 2010-05-04 | Chugai Seiyaku Kabushiki Kaisha | Azoles as malonyl-CoA decarboxylase inhibitors useful as metabolic modulators |
PT1370260E (pt) | 2001-02-20 | 2011-02-01 | Chugai Pharmaceutical Co Ltd | Azóis como inibidores da malonil-coa-descarboxilase úteis como moduladores metabólicos |
WO2003090869A1 (en) * | 2002-04-23 | 2003-11-06 | Chugai Seiyaku Kabushiki Kaisha | Lxr modulators |
GB0302094D0 (en) | 2003-01-29 | 2003-02-26 | Pharmagene Lab Ltd | EP4 receptor antagonists |
CN1964630A (zh) * | 2003-02-13 | 2007-05-16 | 耶希瓦大学艾伯塔·爱恩斯坦医学院 | 通过控制下丘脑的长链脂肪酰基-辅酶A(LC-CoA)的水平来调控食物摄取和葡萄糖产生 |
EP1658071B1 (en) | 2003-08-01 | 2008-09-10 | Chugai Seiyaku Kabushiki Kaisha | Cyanoguanidine-based azole compounds useful as malonyl-coa decarboxylase inhibitors |
EP1653957B1 (en) | 2003-08-01 | 2008-07-09 | Chugai Seiyaku Kabushiki Kaisha | Piperidine compounds useful as malonyl-coa decarboxylase inhibitors |
ES2353306T3 (es) | 2003-08-01 | 2011-03-01 | Chugai Seiyaku Kabushiki Kaisha | Compuestos heterocíclicos útiles como inhibidores de la malonil-coa-descarboxilasa. |
JP4727579B2 (ja) * | 2003-08-01 | 2011-07-20 | 中外製薬株式会社 | マロニル−CoAデカルボキシラーゼ阻害剤として有用なシアノアミド化合物 |
GB0324269D0 (en) | 2003-10-16 | 2003-11-19 | Pharmagene Lab Ltd | EP4 receptor antagonists |
RU2361868C2 (ru) * | 2003-12-08 | 2009-07-20 | Ф.Хоффманн-Ля Рош Аг | Новые производные тиазола |
WO2005117827A1 (fr) | 2004-05-28 | 2005-12-15 | Laboratoires Expanscience | Utilisation d’alkyle furannes pour le traitement cosmetique de la cellulite |
ATE462431T1 (de) | 2004-05-28 | 2010-04-15 | Expanscience Lab | Verwendung von furanalkylen zur herstellung eines arzneimittels für die behandlung von adipositas sowie kosmetische behandlung von übergewicht |
FR2870742B1 (fr) | 2004-05-28 | 2008-03-14 | Expanscience Laboratoires Sa | Utilisation d'alkyle furannes pour la preparation d'un medicament destine au traitement du diabete, de l'obesite et pour le traitement cosmetique de la cellulite et de la surcharge ponderale |
FR2870743B1 (fr) * | 2005-03-21 | 2012-03-09 | Expanscience Lab | Utilisation d'alkyle furannes pour la preparation d'un medicament destine au traitement de l'obesite et pour le traitement cosmetique de la surcharge ponderale |
SG156650A1 (en) | 2004-07-16 | 2009-11-26 | Sunesis Pharmaceuticals Inc | Thienopyrimidines useful as aurora kinase inhibitors |
WO2006041922A2 (en) * | 2004-10-08 | 2006-04-20 | Dara Biosciences, Inc. | Agents and methods for administration to the central nervous system |
US20070026079A1 (en) * | 2005-02-14 | 2007-02-01 | Louis Herlands | Intranasal administration of modulators of hypothalamic ATP-sensitive potassium channels |
US9808544B2 (en) | 2005-08-31 | 2017-11-07 | Ultraviolet Sciences, Inc. | Ultraviolet light treatment chamber |
KR102401408B1 (ko) * | 2014-07-28 | 2022-05-23 | 스미또모 가가꾸 가부시끼가이샤 | 아미드 화합물 및 그 유해 절족 동물 방제 용도 |
TWI664905B (zh) * | 2014-07-29 | 2019-07-11 | 日商住友化學股份有限公司 | 含有醯胺化合物之有害節肢動物控制劑 |
CA2965467A1 (en) * | 2014-10-24 | 2016-04-28 | Ono Pharmaceutical Co., Ltd. | Kcnq2-5 channel activator |
TWI773657B (zh) | 2015-12-18 | 2022-08-11 | 美商亞德利克斯公司 | 作爲非全身tgr5促效劑之經取代之4-苯基吡啶化合物 |
AU2018289303B2 (en) | 2017-06-20 | 2023-12-21 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
WO2020081361A1 (en) | 2018-10-17 | 2020-04-23 | Imbria Pharmaceuticals, Inc. | Methods of treating rheumatic diseases using trimetazidine-based compounds |
US11780811B2 (en) | 2020-06-30 | 2023-10-10 | Imbria Pharmaceuticals, Inc. | Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
US11530184B2 (en) | 2020-06-30 | 2022-12-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
US11883396B2 (en) | 2021-05-03 | 2024-01-30 | Imbria Pharmaceuticals, Inc. | Methods of treating kidney conditions using modified forms of trimetazidine |
JPWO2022244317A1 (ja) * | 2021-05-17 | 2022-11-24 |
Family Cites Families (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3666769A (en) * | 1969-10-09 | 1972-05-30 | Du Pont | Thermally stable 2-perfluoro-substituted benzothiazoles |
JPS57134480A (en) | 1980-12-29 | 1982-08-19 | Du Pont | Antiinflammatory 4,5-diaryl-alpha- (polyhalomethyl)-2-thiophene methanols |
US4381311A (en) * | 1980-12-29 | 1983-04-26 | E. I. Du Pont De Nemours And Company | Antiinflammatory 4,5-diaryl-α-(polyhalomethyl)-2-thiophenemethanols |
US4632930A (en) * | 1984-11-30 | 1986-12-30 | E. I. Du Pont De Nemours And Company | Antihypertensive alkyl-arylimidazole, thiazole and oxazole derivatives |
US4783443A (en) | 1986-03-03 | 1988-11-08 | The University Of Chicago | Amino acyl cephalosporin derivatives |
GB8714537D0 (en) | 1987-06-22 | 1987-07-29 | Ici Plc | Pyrazine derivatives |
EP0733366B1 (en) | 1988-01-07 | 1998-04-01 | E.I. Du Pont De Nemours And Company | Pharmaceutical compositions comprising angiotensin II receptor blocking imidazoles and diuretics |
US4832930A (en) * | 1988-05-02 | 1989-05-23 | Tekatch William M | Decomposition of ammonium thiocyanate |
AU644802B2 (en) | 1989-06-30 | 1993-12-23 | E.I. Du Pont De Nemours And Company | Substituted imidazoles |
AU645022B2 (en) | 1989-06-30 | 1994-01-06 | E.I. Du Pont De Nemours And Company | Fused-ring aryl substituted imidazoles |
US5117097A (en) * | 1990-02-27 | 1992-05-26 | Kabushiki Kaisha Tokai Rika Denki Seisakusho | Key system for a vehicle |
RU1743153C (ru) | 1990-06-04 | 1995-02-27 | ВНИИ химических средств защиты растений | N-[4-2'-гидроксигексафторизопропил)фенил] -n-этил-n'-фенилмочевина, обладающая рострегулирующим и антидотным действием |
JPH05509086A (ja) | 1990-06-22 | 1993-12-16 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | イミダゾールアンジオテンシン―2受容体拮抗薬による慢性腎不全の治療 |
EP0480716A1 (en) * | 1990-10-12 | 1992-04-15 | Merck Frosst Canada Inc. | Saturated hydroxyalkylquinoline acids as leukotriene antagonists |
US5470975A (en) * | 1990-10-16 | 1995-11-28 | E.R. Squibb & Sons, Inc. | Dihydropyrimidine derivatives |
CA2053148A1 (en) | 1990-10-16 | 1992-04-17 | Karnail Atwal | Dihydropyrimidine derivatives |
US5374615A (en) * | 1990-10-31 | 1994-12-20 | E. R. Squibb & Sons, Inc. | Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives |
SU1825496A3 (ru) | 1991-04-04 | 1994-12-30 | Всесоюзный научно-исследовательский институт химических средств защиты растений | Производные n-[4-(1-гидрокси-1-трифторметил-2,2,2-трифторэтил)фенил]мочевины, обладающие антидотной активностью к 2-хлор-n-[(4-метокси-6-метил-1,3,5-триазин-2-ил)аминокарбонил] бензолсульфамиду в посевах льна |
US5190942A (en) * | 1991-04-22 | 1993-03-02 | E. R. Squibb & Sons, Inc. | Benzoxazole and related heterocyclic substituted imidazole and benzimidazole derivatives |
US5177097A (en) * | 1991-07-24 | 1993-01-05 | E. R. Squibb & Sons, Inc. | Acyl amidine and acyl, guanidine substituted biphenyl derivatives |
US5256695A (en) * | 1991-07-24 | 1993-10-26 | E. R. Squibb & Sons, Inc. | Acyl amidine and acyl guanidine substituted biphenyl derivatives |
CA2115990A1 (en) * | 1991-08-19 | 1993-03-04 | George Albert Boswell | Angiotensin ii receptor blocking imidazolinone derivatives |
US5350752A (en) | 1991-12-16 | 1994-09-27 | E. R. Squibb & Sons, Inc. | Dihydropyrimidine derivatives |
US5212177A (en) * | 1991-12-16 | 1993-05-18 | E. R. Squibb & Sons, Inc. | Indole and benzimidazole-substituted dihydropyrimidine derivatives |
US5225408A (en) * | 1991-12-20 | 1993-07-06 | E. R. Squibb & Sons, Inc. | Biphenyl oxadiazinone angiotensin II inhibitors |
TW297025B (ja) | 1992-02-14 | 1997-02-01 | Squibb & Sons Inc | |
US5208235A (en) * | 1992-03-10 | 1993-05-04 | E. R. Squibb & Sons, Inc. | Indole- and benzimidazole-substituted imidazole derivatives |
US5208234A (en) * | 1992-03-10 | 1993-05-04 | E. R. Squibb & Sons, Inc. | Substituted imidazole phosphonic and phosphinic acid derivatives |
CA2132724A1 (en) | 1992-04-10 | 1993-10-28 | Robert Zamboni | Thiazole-substituted benzyl alcohols as leukotriene antagonists |
US5506227A (en) | 1992-04-13 | 1996-04-09 | Merck Frosst Canada, Inc. | Pyridine-substituted benzyl alcohols as leukotriene antagonists |
US5378704A (en) * | 1992-04-15 | 1995-01-03 | E. R. Squibb & Sons, Inc. | Non-peptidic angiotensin-II-receptor-antagonists |
US5534347A (en) * | 1992-09-04 | 1996-07-09 | Eastman Kodak Company | Fusing roll having a fluorocarbon-silicone barrier layer |
EP0672293A4 (en) | 1992-10-30 | 1996-04-17 | Lord Corp | LOW VISCOSITY MAGNETORHEOLOGICAL MATERIALS. |
GB9226860D0 (en) | 1992-12-23 | 1993-02-17 | Leo Pharm Prod Ltd | Novel treatment |
WO1994015932A1 (en) | 1993-01-15 | 1994-07-21 | G.D. Searle & Co. | Novel 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
DE4302681A1 (de) | 1993-02-01 | 1994-08-04 | Hoechst Ag | Sulfonsäureester, damit hergestellte strahlungsempfindliche Gemische und deren Verwendung |
DE4306152A1 (de) * | 1993-02-27 | 1994-09-01 | Hoechst Ag | Positiv arbeitendes strahlungsempfindliches Gemisch und damit hergestelltes Aufzeichnungsmaterial |
GB9408577D0 (en) | 1994-04-29 | 1994-06-22 | Fujisawa Pharmaceutical Co | New compound |
WO1995035311A1 (en) | 1994-06-17 | 1995-12-28 | Corvas International, Inc. | 3-amino-2-oxo-1-piperidineacetic derivatives as enzyme inhibitors |
US5932733A (en) | 1994-06-17 | 1999-08-03 | Corvas International, Inc. | 3-amino-2-oxo-1-piperidineacetic derivatives containing an arginine mimic as enzyme inhibitors |
US5637599A (en) | 1994-06-17 | 1997-06-10 | Corvas International, Inc. | Arginine mimic derivatives as enzyme inhibitors |
US5519143A (en) * | 1994-09-19 | 1996-05-21 | The Du Pont Merck Pharmaceutical Company | Process for the isolation and purification of an imidazole stereoisomer from a mixture of stereoisomers by selective precipitation |
US5527827A (en) | 1994-10-27 | 1996-06-18 | Merck Frosst Canada, Inc. | Bisarylcarbinol cinnamic acids as inhibitors of leukotriene biosynthesis |
US5552437A (en) | 1994-10-27 | 1996-09-03 | Merck Frosst Canada, Inc. | Bisarylcarbinol derivatives as inhibitors of leukotriene biosynthesis |
JPH08311036A (ja) | 1995-03-14 | 1996-11-26 | Takeda Chem Ind Ltd | ピラゾール誘導体、その用途 |
IL117534A0 (en) | 1995-03-24 | 1996-07-23 | Rhone Poulenc Agrochimie | Reagent and process which are useful for grafting a substituted difluoromethyl group onto a compound containing at least one electrophilic function |
JPH0912585A (ja) | 1995-06-30 | 1997-01-14 | Ube Ind Ltd | 高配位典型元素錯体 |
JPH0912795A (ja) | 1995-06-30 | 1997-01-14 | Sumitomo Chem Co Ltd | 押出成形用エチレン系樹脂組成物及び押出成形体 |
GB2321244B (en) | 1997-01-20 | 2000-11-22 | Pharmacia & Upjohn Spa | Vitamin D3 analogues,process for preparing them,and their use as antiproliferative and antitumour agents |
DE19716231A1 (de) | 1997-04-18 | 1998-10-22 | Studiengesellschaft Kohle Mbh | Olefinmetathese in komprimiertem Kohlendioxid |
DE19722952A1 (de) | 1997-05-31 | 1998-12-03 | Huels Chemische Werke Ag | Verwendung von Polymeren zur Inhibierung der Denaturierung von adsorbierten Eiweißstoffen |
US5895771A (en) * | 1997-06-05 | 1999-04-20 | Akzo Nobel Nv | Fluorinated alkoxy and/or aryloxy aluminates as cocatalysts for metallocene-catalyzed olefin polymerizations |
US5977413A (en) * | 1997-08-04 | 1999-11-02 | Nippon Kayaku Kabushiki Kaisha | Method for producing bis(3-amino-4-hydroxyphenyl) compounds |
DE69814109T2 (de) * | 1997-09-08 | 2004-02-26 | F. Hoffmann-La Roche Ag | 1,3-dihydroxy-20,20-dialkyl-vitamin d3 analoga |
ATE285413T1 (de) | 1997-09-11 | 2005-01-15 | Univ Colorado State Res Found | Schwach koordinierende, polyfluoralkoxid-liganden enthaltende anionen |
EP1071648A2 (en) | 1998-03-13 | 2001-01-31 | Merck Frosst Canada & Co. | Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment |
GB2337701A (en) | 1998-05-26 | 1999-12-01 | United Medical And Dental Schools Of Guys St Thomas Hospitals | Treatment of ischemia with an angiotensin II antagonist |
AU768751B2 (en) | 1998-06-18 | 2004-01-08 | Bristol-Myers Squibb Company | Carbon substituted aminothiazole inhibitors of cyclin dependent kinases |
FR2784114B1 (fr) | 1998-09-18 | 2001-02-02 | Thomson Csf | Materiaux polymeres absorbant les composes organophosphores. procede de synthese de ces materiaux. capteurs chimiques comprenant ces materiaux |
EP1034196B1 (en) | 1998-10-05 | 2005-01-12 | Promerus LLC | Catalyst and methods for polymerizing cycloolefins |
US6350832B1 (en) | 1998-12-09 | 2002-02-26 | The B. F. Goodrich Company | Mold addition polymerization of norbornene-type monomers using group 10 metal complexes |
JP2002533318A (ja) | 1998-12-22 | 2002-10-08 | ニューロサーチ、アクティーゼルスカブ | イオンチャネル調節剤 |
AU2871900A (en) | 1999-02-04 | 2000-08-25 | Millennium Pharmaceuticals, Inc. | G-protein coupled heptahelical receptor binding compounds and methods of use thereof |
GB9904933D0 (en) | 1999-03-04 | 1999-04-28 | Glaxo Group Ltd | Compounds |
US6316503B1 (en) | 1999-03-15 | 2001-11-13 | Tularik Inc. | LXR modulators |
EP1212065A4 (en) * | 1999-07-08 | 2004-02-11 | Tularik Inc | COMPILATIONS AND METHODS FOR INCREASING THE HDL CHOLESTEROL LEVEL |
DE60219595T2 (de) | 2001-01-26 | 2008-01-10 | Chugai Seiyaku K.K. | Verfahren zur behandlung von erkrankungen mit malonyl coa-decarboxylase-inhibitoren |
EP1377290B1 (en) | 2001-01-26 | 2006-10-04 | Chugai Seiyaku Kabushiki Kaisha | Malonyl-coa decarboxylase inhibitors useful as metabolic modulators |
JP4539565B2 (ja) | 2006-01-13 | 2010-09-08 | 株式会社ジェイ・エム・エス | 血液浄化回路 |
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AU2002245294B2 (en) | 2005-09-22 |
KR100637564B1 (ko) | 2006-10-20 |
CA2735267A1 (en) | 2002-08-01 |
ES2362270T3 (es) | 2011-06-30 |
CN100528154C (zh) | 2009-08-19 |
US7524969B2 (en) | 2009-04-28 |
JP2008007510A (ja) | 2008-01-17 |
WO2002058698A8 (en) | 2005-06-30 |
KR20030070609A (ko) | 2003-08-30 |
WO2002058698A2 (en) | 2002-08-01 |
US8119819B2 (en) | 2012-02-21 |
CA2435067A1 (en) | 2002-08-01 |
JP2004527475A (ja) | 2004-09-09 |
CA2435067C (en) | 2011-11-15 |
EP1411929A2 (en) | 2004-04-28 |
US20040082576A1 (en) | 2004-04-29 |
CA2735478A1 (en) | 2002-08-01 |
JP2010065054A (ja) | 2010-03-25 |
CA2735267C (en) | 2013-05-07 |
CN1537001A (zh) | 2004-10-13 |
US20100016259A1 (en) | 2010-01-21 |
WO2002058698A3 (en) | 2004-02-12 |
CN101596191A (zh) | 2009-12-09 |
ATE509014T1 (de) | 2011-05-15 |
EP1411929B1 (en) | 2011-05-11 |
HK1138521A1 (en) | 2010-08-27 |
CA2735478C (en) | 2014-07-08 |
HK1068285A1 (en) | 2005-04-29 |
CN101596191B (zh) | 2011-06-15 |
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