TWI612962B - 乙炔基衍生物 - Google Patents
乙炔基衍生物 Download PDFInfo
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- TWI612962B TWI612962B TW105122266A TW105122266A TWI612962B TW I612962 B TWI612962 B TW I612962B TW 105122266 A TW105122266 A TW 105122266A TW 105122266 A TW105122266 A TW 105122266A TW I612962 B TWI612962 B TW I612962B
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- Prior art keywords
- phenyl
- compound
- difluoro
- formula
- spiro
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- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 239000000203 mixture Substances 0.000 claims abstract description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 37
- 239000002253 acid Substances 0.000 claims abstract description 26
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 26
- 230000003287 optical effect Effects 0.000 claims abstract description 24
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 13
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 11
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 10
- 230000036506 anxiety Effects 0.000 claims abstract description 9
- 206010003805 Autism Diseases 0.000 claims abstract description 7
- 208000020706 Autistic disease Diseases 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims abstract description 7
- 206010047700 Vomiting Diseases 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 7
- 230000008673 vomiting Effects 0.000 claims abstract description 7
- 230000004112 neuroprotection Effects 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 46
- -1 2-phenylethynyl Chemical group 0.000 claims description 26
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 12
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- VQFAUHJPOOWPCF-SANMLTNESA-N (6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-methylspiro[1,3-diazinane-6,4'-5,6,7,8-tetrahydro-1H-cyclohepta[c]pyrazole]-2,4-dione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N([C@]2(CC1=O)CCCCC=1NN=CC=12)C)=O VQFAUHJPOOWPCF-SANMLTNESA-N 0.000 claims description 6
- JQTTVBBQZKSMKH-SANMLTNESA-N (3S)-3'-[2,6-difluoro-4-(2-pyridin-3-ylethynyl)phenyl]-1'-methylspiro[1,2-dihydroindene-3,6'-1,3-diazinane]-2',4'-dione Chemical compound FC1=C(C(=CC(=C1)C#CC=1C=NC=CC=1)F)N1C(N([C@@]2(CCC3=CC=CC=C23)CC1=O)C)=O JQTTVBBQZKSMKH-SANMLTNESA-N 0.000 claims description 4
- FXLNLNIFGVNEBK-SANMLTNESA-N (6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-methylspiro[1,3-diazinane-6,5'-6,7-dihydrocyclopenta[b]pyridine]-2,4-dione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N([C@]2(CC1=O)CCC1=NC=CC=C12)C)=O FXLNLNIFGVNEBK-SANMLTNESA-N 0.000 claims description 4
- CMFHEUJVSQXEFR-SANMLTNESA-N (6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-methylspiro[1,3-diazinane-6,5'-7,8-dihydro-6H-quinazoline]-2,4-dione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N([C@@]2(CC1=O)C=1C=NC=NC=1CCC2)C)=O CMFHEUJVSQXEFR-SANMLTNESA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- ZOLJSTICBXZCNS-MHZLTWQESA-N (6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-methylspiro[1,3-diazinane-6,5'-7,8-dihydro-6H-quinoline]-2,4-dione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N([C@@]2(CC1=O)C=1C=CC=NC=1CCC2)C)=O ZOLJSTICBXZCNS-MHZLTWQESA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
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- DCRVMPKANCNANZ-VWLOTQADSA-N (4S)-1-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3-methylspiro[1,3-diazinane-4,4'-1,5,6,7-tetrahydroindazole] Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN([C@@]2(CC1)C=1C=NNC=1CCC2)C DCRVMPKANCNANZ-VWLOTQADSA-N 0.000 claims 1
- HDTHDHFLPUXEHH-MHZLTWQESA-N (4S)-1-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3-methylspiro[1,3-diazinane-4,5'-7,8-dihydro-6H-isoquinoline] Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN([C@@]2(CC1)C=1C=CN=CC=1CCC2)C HDTHDHFLPUXEHH-MHZLTWQESA-N 0.000 claims 1
- CMDXNYZKLDDLAX-MHZLTWQESA-N (4S)-1-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3-methylspiro[1,3-diazinane-4,8'-6,7-dihydro-5H-isoquinoline] Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1CN([C@]2(CC1)CCCC=1C=CN=CC=12)C CMDXNYZKLDDLAX-MHZLTWQESA-N 0.000 claims 1
- GCTGBTIYBHWYFT-MHZLTWQESA-N (6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,1'-dimethylspiro[1,3-diazinane-6,4'-5,6,7,8-tetrahydrocyclohepta[c]pyrazole]-2,4-dione Chemical compound FC1=C(C(=CC(=C1)C#CC1=CC=CC=C1)F)N1C(N([C@]2(CC1=O)CCCCC=1N(N=CC=12)C)C)=O GCTGBTIYBHWYFT-MHZLTWQESA-N 0.000 claims 1
- CCMLHTFXYPZVCA-SANMLTNESA-N CN1CN(CC[C@]12CCCC3=C2C=NN3C)C4=C(C=C(C=C4F)C#CC5=CC=CC=C5)F Chemical compound CN1CN(CC[C@]12CCCC3=C2C=NN3C)C4=C(C=C(C=C4F)C#CC5=CC=CC=C5)F CCMLHTFXYPZVCA-SANMLTNESA-N 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
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- 210000004027 cell Anatomy 0.000 description 11
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 5
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Abstract
本發明係關於式I化合物
其中R1為低碳數烷基;R2為苯基或吡啶基,其中吡啶基中之N原子可處於不同位置;n為0、1或2;V/U彼此獨立地為O或CH2,其中V與U不能同時為O;L為五或六員雜芳基,其選自
或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體。
該等化合物可用於治療帕金森氏病(Parkinson's disease)、焦慮症、嘔吐、強迫症、自閉症、神經保護、癌症、抑鬱症及2型糖尿病。
Description
其中R1為低碳數烷基;R2為苯基或吡啶基,其中吡啶基中之N原子可處於不同位置;n為0、1或2;V/U彼此獨立地為O或CH2,其中V與U不能同時為O;L為五或六員雜芳基,其選自
或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體。
已出人意料地發現,通式I化合物為代謝型麩胺酸受體4(mGluR4)之正向異位調節劑(PAM)。
代謝型麩胺酸受體4為人體內由GRM4基因編碼之蛋白質。
連同GRM6、GRM7及GRM8,其屬於代謝型麩胺酸受體家族之第III組,且其經由G α i/o蛋白質之活化而與腺苷酸環化酶不利地偶合。其主要表現在突觸前末梢上,充當自受體或異受體,且其活化導致自突觸前末梢釋放的遞質減少。mGluR4主要基於其獨特分佈及此受體之活化在多個CNS及非CNS路徑中發揮關鍵調節作用之最近證據(Celanire S,Campo B,Expert Opinion in Drug Discovery,2012),目前受到許多關注。
雖然在此領域中已取得一些進展,但第III組mGluR之配體結合域之類似性導致鑑別此受體之選擇性正位性促效劑之難題。然而,以正向異位調節劑(PAM)而非正位性促效劑為目標為在mGluR之間鑑別具有專一選擇性的分子提供更廣的機會。
經由非多巴胺激導性途徑,mGluR4 PAM作為用於治療運動(及非運動)症狀之有前景的治療劑以及帕金森氏病(Parkinson's disease)之疾病調節劑出現。
帕金森氏病為導致黑質(SN)中之多巴胺激導性神經元丟失之進行性神經退化性疾病。在此疾病中,多巴胺耗竭的一種結果為一系列運動障礙,包括運動徐緩、運動不能、震顫、步態障礙及平衡問題。雖然存在許多其他與該疾病相關之非運動症狀,但此等運動紊亂形成PD之標誌。在該疾病早期,使用多巴胺D2受體促效劑、左旋多巴或單胺氧化酶B抑制劑,可藉由多巴胺替換或加強來有效地治療PD症狀。然而,隨著疾病發展,此等藥劑控制運動症狀之效力變小。此外,包括由多巴胺促效劑誘發之運動困難之不良作用的出現限制其用途。因此,仍存在對改善運動症狀之控制效力的用於治療PD之新方法的需要。
已提出將代謝型麩胺酸受體4(mGluR4)之活化作為帕金森氏病之
潛在治療方法。第III組mGluR之成員mGluR4主要為在控制動作之基底神經節迴路中若干關鍵位置表現的突觸前麩胺酸受體。用偏好第III組之促效劑活化mGluR4可能藉由分別減少GABA及麩胺酸之釋放而降低抑制性及興奮性後突觸電位。
備受關注的是,尋求減輕帕金森氏症之運動症狀同時緩解黑質紋狀體神經元之持續退化的新穎藥物。正位性mGluR4促效劑L-AP4已在PD之6-OHDA嚙齒動物模型中證明神經保護作用且第一正向異位調節劑(-)-PHCCC減少經1-甲基-4-苯基-1,2,3,6-四氫吡啶(MPTP)治療之小鼠中的黑質紋狀體退化。此等研究提供有說服力的臨床前跡象,其表明mGluR4活化劑構成一種有效方法,其不僅用於PD之症狀性治療,亦可潛在地作為此適應症之疾病調節劑。
Neuroreport,19(4),475-8,2008,Proc.Natl.Acad.Sci,USA,100(23),13668-73,2003及J.Neurosci.26(27),7222-9,2006及Mol.Pharmacol.74(5),1345-58,2008中亦描述了選擇性mGluR4調節劑之神經保護作用。
焦慮症為世界上最普遍的精神病症之一,且與帕金森氏病併發(Prediger R等人Neuropharmacology 2012;62:115-24)。過度麩胺酸激導性神經傳遞為焦慮症病理生理學之一個重要特徵。基於焦慮症及情緒障礙所涉及之大腦區域中之mGluR4之突觸前位置及抑制過度大腦興奮性,mGluR4活化劑可代表新一代抗焦慮劑療法(Eur.J.Pharmacol.,498(1-3),153-6,2004)。
Addex已在2010年報導,ADX88178對焦慮症之兩種臨床前嚙齒動物模型有效:小鼠之大理石埋入測試及小鼠與大鼠之EPM。在大鼠EPM測試中,在經口給藥後,ADX88178亦顯示出類似抗焦慮劑之特徵。
mGluR4調節劑亦顯示發揮抗抑鬱作用(Neuropharmacology, 46(2),151-9,2004)。
此外,mGluR4調節劑亦顯示參與升糖素分泌抑制(Diabetes,53(4),998-1006,2004)。因此,mGluR4之正位性或正向異位調節劑具有經由其降血糖作用治療2型糖尿病之潛能。
此外,已顯示mGluR4表現於前列腺癌細胞株中(Anticancer Res.29(1),371-7,2009)或結腸直腸癌中(Cli.Cancer Research,11(9)3288-95,2005)。因此,mGluR4調節劑亦可具有治療癌症之潛在作用。
mGluR4 PAM之其他提出的作用可預期用於治療嘔吐、強迫症、厭食症及自閉症。
式I化合物因其具有可貴的治療性質而著稱。其可用於治療或預防與mGluR4受體之異位調節劑有關的病症。
作為mGluR4受體之異位調節劑之化合物的最佳適應症為帕金森氏病、焦慮症、嘔吐、強迫症、厭食症、自閉症、神經保護、癌症、抑鬱症及2型糖尿病。
本發明係關於式I化合物及關於其醫藥學上可接受之鹽,關於作為醫藥學活性物質之此等化合物,關於其製造方法以及關於其用於治療或預防與mGluR4受體之異位調節劑有關之病症(諸如帕金森氏病、焦慮症、嘔吐、強迫症、自閉症、神經保護、癌症、抑鬱症及2型糖尿病)的用途及關於含有式I化合物的醫藥組合物。
本發明之另一目標為用於治療或預防帕金森氏病、焦慮症、嘔吐、強迫症、厭食症、自閉症、神經保護、癌症、抑鬱症及2型糖尿病之方法,該方法包含向有需要之哺乳動物投與有效量之式I化合物。
此外,本發明包括所有外消旋混合物、所有其相對應的對映異構體及/或光學異構體、或含有氫、氟、碳、氧或氮之同位素的類似物。
無論所討論之術語係單獨出現或組合出現,本說明書中所使用之一般術語之以下定義均適用。
如本文中所使用,術語「低碳數烷基」表示含有1至7個碳原子之飽和直鏈或分支鏈基團,例如甲基、乙基、丙基、異丙基、正丁基、異丁基、2-丁基、第三丁基及其類似者。較佳烷基為具有1至4個碳原子之基團。
術語「醫藥學上可接受之酸加成鹽」包涵與諸如鹽酸、硝酸、硫酸、磷酸、檸檬酸、甲酸、反丁烯二酸、順丁烯二酸、乙酸、丁二酸、酒石酸、甲磺酸、對甲苯磺酸及其類似酸之無機酸及有機酸所成的鹽。
其中R1為低碳數烷基;R2為苯基或吡啶基,其中吡啶基中之N原子可處於不同位置;L為五或六員雜芳基,其選自
或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,例如以下化合物:(8S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[6,7-二氫-5H-異喹啉-8,6'-六氫嘧啶]-2',4'-二酮
(6S)-3-[2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯基]-1-甲基-螺[六氫嘧啶-6,1'-四氫萘]-2,4-二酮
(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[7,8-二氫-6H-喹啉-5,6'-六氫嘧啶]-2',4'-二酮
(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[7,8-二氫-6H-異喹啉-5,6'-六氫嘧啶]-2',4'-二酮
(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[7,8-二氫-6H-喹唑啉-5,6'-六氫嘧啶]-2',4'-二酮
(8S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-乙基-螺[6,7-二氫-5H-異喹啉-8,6'-六氫嘧啶]-2',4'-二酮
(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[1,5,6,7-四氫吲唑-4,6'-六氫嘧啶]-2',4'-二酮
(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1',2-二甲基-螺[6,7-二氫-5H-吲唑-4,6'-六氫嘧啶]-2',4'-二酮或(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1,1'-二甲基-螺[6,7-二氫-5H-吲唑-4,6'-六氫嘧啶]-2',4'-二酮。
其中R1為低碳數烷基;R2為苯基或吡啶基,其中吡啶基中之N原子可處於不同位置;L為五或六員雜芳基,其選自
或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,例如以下化合物:(6S)-3-[2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯基]-1-甲基-螺[六氫嘧啶-6,1'-茚滿]-2,4-二酮或(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[6,7-二氫環戊并[b]吡啶-5,6'-六氫嘧啶]-2',4'-二酮。
其中R1為低碳數烷基;R2為苯基或吡啶基,其中吡啶基中之N原子可處於不同位置;L為五或六員雜芳基,其選自
或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相
對應的對映異構體及/或光學異構體及/或立體異構體,例如以下化合物:(4S)-3'-[2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯基]-1'-甲基-螺[烷-4,6'-六氫嘧啶]-2',4'-二酮或(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[2,3-二氫哌喃并[2,3-b]吡啶-4,6'-六氫嘧啶]-2',4'-二酮。
其中R1為低碳數烷基;R2為苯基或吡啶基,其中吡啶基中之N原子可處於不同位置;L為五或六員雜芳基,其選自
或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,例如以下化合物:(6S)-3-[2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯基]-1-甲基-螺[六氫嘧啶-6,4'-異烷]-2,4-二酮。
其中R1為低碳數烷基;R2為苯基或吡啶基,其中吡啶基中之N原子可處於不同位置;L為五或六員雜芳基,其選自
或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,例如以下化合物:(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[5,6,7,8-四氫-1H-環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮
(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1,1'-二甲基-螺[5,6,7,8-四氫環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮或(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1',2-二甲基-螺[5,6,7,8-四氫環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮。
本發明式I化合物之製備可以依序或彙集合成途徑進行。本發明化合物之合成顯示於以下流程1中。進行反應及所得產物之純化所需之技能為熟習此項技術者所知。以下製程說明中所用之取代基及指數具有本文之前所給出之意義。
可藉由以下給出之方法,藉由實例中給出之方法或藉由類似方法來製造式I化合物。個別反應步驟之適當反應條件為熟習此項技術者所知。反應順序不限於流程中所呈現之順序,然而,視起始物質及其各別反應性而定,反應步驟之順序可自由改變。起始物質可購得或可藉由與以下所給出之方法類似之方法、藉由發明內容或實例中所引用之參考文獻中所述之方法、或藉由此項技術中已知之方法來製備。
本發明之式I化合物及其醫藥學上可接受之鹽可藉由此項技術中已知之方法,例如藉由下文所描述之方法變體來製備,該方法包含
a)用R1-I將式之化合物於DMF中在
NaH或Cs2CO3存在下烷基化成式之化合
物,其中R1為低碳數烷基且其餘取代基上文已有描述,或視需要,將所獲得之化合物轉化成醫藥學上可接受之酸加成鹽。
在流程1中及實例1至17中進一步更詳細地描述式I化合物的製備。
通式I化合物可例如藉由以下獲得:使經適當取代之苯胺或胺基吡啶1與經適當取代之芳基乙炔2進行薗頭偶合(Sonogashira coupling),得到所要式3之乙炔基化合物。在諸如三光氣或羰基二咪唑(CDI)之光氣或光氣等效物存在下,在諸如DMF、甲苯或二噁烷之溶劑中,在諸如三乙胺之鹼存在或不存在下,使式3之乙炔基化合物與式4之經適當取代之胺基酯反應,形成所要式5之脲類似物。5在如THF或DMF之溶劑中在諸如NaH或KOtBu之強鹼存在下發生閉環,形成所要式I-1之嘧啶-2,4-二酮化合物。經由烷基化引入R2取代基(R2=低碳數烷基),形成所要通式I之經乙炔基-苯基、乙炔基-吡啶基或乙
炔基-異噻唑基取代之嘧啶-2,4-二酮化合物(流程1)。
一般而言,用於合成式I化合物之步驟的順序在某些情況下亦可修改。
產生經編碼人類mGlu4受體之cDNA穩定轉染的單株HEK-293細胞株;對於關於mGlu4正向異位調節劑(PAM)之操作,選擇具有低受體表現量及低組成性受體活性的細胞株以區分促效活性與PAM活性。根據標準方案(Freshney,2000),在補充有1mM麩醯胺酸、10%(vol/vol)熱不活化小牛血清、青黴素/鏈黴素、50μg/ml潮黴素及15μg/ml殺稻瘟菌素之高葡萄糖達爾伯克氏改良伊格爾培養基(Dulbecco's Modified Eagle Medium)中培養細胞(所有細胞培養試劑及抗生素來自Invitrogen,Basel,Switzerland)。
在實驗前約24小時,將5×104個細胞/孔接種於塗佈有聚-D-離胺酸之黑色/透明底96孔盤。在37℃下,在加樣緩衝液(1×HBSS,20mM HEPES)中,給細胞加載2.5μM Fluo-4AM,持續1小時,且用加樣緩衝液洗滌五次。將細胞轉移至功能性藥物篩選系統7000(Hamamatsu,Paris,France),且在37℃下添加測試化合物之11次半對數連續稀釋液且培養細胞達10至30分鐘,同時線上記錄螢光。在此預培育步驟之後,將促效劑(2S)-2-胺基-4-膦醯基丁酸(L-AP4)以與EC20相對應之濃度添加至細胞中,同時線上記錄螢光;為了慮及細胞反應性之逐日變化,在各實驗即將進行之前藉由記錄L-AP4之完整劑量反應曲線來確定L-AP4之EC20。
反應按螢光峰增值減去基線(亦即,不添加L-AP4之螢光),針對用飽和濃度之L-AP4獲得的最大刺激效應標準化來量測。使用XLfit用
最大刺激%繪製曲線圖,XLfit為使用Levenburg Marquardt算法迭代繪製資料之曲線擬合程式。所使用之單一位點競爭分析方程為y=A+((B-A)/(1+((x/C)D))),其中y為最大刺激效應%,A為y之最小值,B為y之最大值,C為EC50,x為競爭化合物之濃度的log10,且D為曲線的斜率(希爾係數(Hill Coefficient))。自此等曲線計算EC50(達到50%之最大受體活化時之藥物濃度)、希爾係數以及用飽和濃度之L-AP4獲得的以最大刺激效應%計之最大反應(參見圖1)。
在用PAM測試化合物預培育期間(亦即,在施加EC20濃度之L-AP4之前)獲得的正信號指示促效活性,缺少該等信號則證明缺乏促效活性。在添加EC20濃度之L-AP4之後觀察到的信號減弱指示測試化合物之抑制活性。
圖1:mGlu4 PAM Ca2+移動篩選分析及EC50與Emax%值之測定的實驗概述的說明。
式(I)化合物及其醫藥學上可接受之鹽可用作藥劑,例如呈醫藥製劑形式。醫藥製劑可經口投與,例如以錠劑、包衣錠劑、糖衣藥丸、硬及軟明膠膠囊、溶液、乳液或懸浮液之形式。然而,投藥亦可例如以栓劑形式經直腸,或例如以注射溶液形式非經腸實現。
式(I)化合物及其醫藥學上可接受之鹽可經醫藥學上惰性的無機或有機載劑處理以用於製備醫藥製劑。舉例而言,乳糖、玉米澱粉或其衍生物、滑石、硬脂酸或其鹽及其類似者可用作錠劑、包衣錠劑、糖衣藥丸及硬明膠膠囊之此類載劑。用於軟明膠膠囊之適合載劑為例如植物油、蠟、脂肪、固態及液態多元醇及其類似者;然而,視活性物質之性質而定,通常在軟明膠膠囊之情況下不需要載劑。用於製備溶液及糊漿之適合載劑為例如水、多元醇、蔗糖、轉化糖、葡萄糖及
其類似者。諸如醇類、多元醇、甘油、植物油及其類似者之佐劑可用於式(I)化合物之水溶性鹽的水性注射溶液,但通常並非為必要的。栓劑之適合載劑為例如天然油或硬化油、蠟、脂肪、半液態或液態多元醇及其類似者。
此外,醫藥製劑可含有防腐劑、增溶劑、穩定劑、濕潤劑、乳化劑、甜味劑、著色劑、調味劑、用於改變滲透壓之鹽、緩衝劑、掩蔽劑或抗氧化劑。其亦可還含有其他治療學上有價值之物質。
如先前所提及,含有式(I)化合物或其醫藥學上可接受之鹽及治療上惰性之賦形劑的藥劑與用於製造此類藥劑之方法一樣亦為本發明之目標,該方法包含將一或多種式I化合物或其醫藥學上可接受之鹽及視需要一或多種其他有治療價值的物質連同一或多種治療上惰性之載劑一起引入至蓋倫(galenical)劑型中。
如先前所進一步提及,使用式(I)化合物以製備適用於預防及/或治療上文所述疾病之藥劑亦為本發明之一個目標。
劑量可在較寬界限內變化,且當然,在各特定情況下將配合個人需求。一般而言,經口或非經腸投藥之有效劑量在0.01至20mg/kg/天之間,就所有所述適應症而言,較佳為0.1至10mg/kg/天之劑量。體重為70kg之成年人之日劑量相應地介於每天0.7至1400mg之間,較佳介於每天7與700mg之間。
1.將成分1、2、3及4混合且用純化水造粒。
2.在50℃下乾燥該等顆粒。
3.使顆粒通過適合之研磨設備。
4.添加成分5且混合3分鐘;在適合壓力機上壓縮。
1.在適合混合器中混合成分1、2及3持續30分鐘。
2.添加成分4及5且混合3分鐘。
3.填充至適合膠囊中。
首先在混合器中且接著在粉碎機中混合式I化合物、乳糖及玉米澱粉。使混合物返回至混合器;將滑石添加至其中且充分混合。藉由機器將混合物填充至適合膠囊(例如硬明膠膠囊)中。
使式I化合物溶解於聚乙二醇400及注射用水(部分)之混合物中。藉由乙酸將pH調整至5.0。藉由添加剩餘量之水將體積調整至1.0ml。過濾溶液,適當過量填充至小瓶中且滅菌。
將雙-(三苯基膦)-二氯化鈀(II)(826mg,1.18mmol,0.02當量)溶解於100ml THF中。在室溫下添加2,6-二氟-4-碘苯胺(15g,58.8mmol)及苯基乙炔(7.2g,7.8ml,70.6mmol,1.2當量)。添加三乙胺(29.8g,41ml,0.29mol,5當量)、三苯膦(617mg,2.35mmol,0.04當量)及碘化銅(I)(112mg,0.58mmol,0.01當量)且在60℃下攪拌混合物1小時。冷卻反應混合物且用飽和NaHCO3溶液萃取且用乙酸乙酯萃取兩次。有機層用水洗滌三次,經硫酸鈉乾燥且蒸發至乾燥。藉由在矽膠管柱上急驟層析,用梯度為0:100至40:60之乙酸乙酯:庚烷溶離來純化粗產物。獲得呈黃色固體狀之所要2,6-二氟-4-苯基乙炔基-苯胺(12.6g,93%產率),MS:m/e=230.1(M+H+)。
將6,7-二氫異喹啉-8(5H)-酮(1g,6.79mmol)溶解於10ml THF中。添加(R)-2-甲基丙烷-2-亞磺醯胺(CAS 196929-78-9)(1.24g,10.2mmol,1.5當量)及乙醇鈦(IV)(4.65g,4.23ml,20.4mmol,3.0當量)且在65℃下攪拌混合物3小時。冷卻反應混合物且添加飽和NaHCO3溶液及乙酸乙酯。經由矽藻土過濾所形成之懸浮液且用乙酸乙酯萃取濾液兩次。有機層用鹽水洗滌,經硫酸鈉乾燥且蒸發至乾燥。藉由在矽
膠管柱上急驟層析,用梯度為10:90至100:0之乙酸乙酯:庚烷溶離來純化粗產物。獲得呈黃色固體狀之所要(R,E)-N-(6,7-二氫異喹啉-8(5H)-亞基)-2-甲基丙烷-2-亞磺醯胺(1.02g,60%產率),MS:m/e=251.2(M+H+)。
將乙酸甲酯(0.6g,0.375ml,8.15mmol,2當量)溶解於10ml無水THF中且冷卻溶液至-70℃。在-75℃至-65℃下逐滴添加LDA(2.0M於THF/庚烷/乙苯中)(4.07ml,8.15mmol,2當量)且在-70℃下攪拌混合物30分鐘。在-75℃至-65℃下逐滴添加溶解於10ml無水THF中的三異丙醇氯鈦(4.25g,16.3mmol,4當量)且在-70℃下攪拌混合物30分鐘。在-75℃至-65℃下逐滴添加溶解於10ml無水THF中之(R,E)-N-(6,7-二氫異喹啉-8(5H)-亞基)-2-甲基丙烷-2-亞磺醯胺(實例1,步驟2)(1.02g,4.07mmol)且在-70℃下攪拌混合物1小時。添加飽和NaHCO3溶液且攪拌混合物10分鐘。添加乙酸乙酯至所形成之懸浮液且攪拌混合物10分鐘。經由矽藻土過濾所形成之懸浮液且用乙酸乙酯萃取濾液兩次。有機層用鹽水洗滌,經硫酸鈉乾燥且蒸發至乾燥。藉由在矽膠管柱上急驟層析,用梯度為100:0至90:10之二氯甲烷:甲醇溶離來純化粗產物。獲得呈黃色油狀物的所要2-((S)-8-((R)-1,1-二甲基乙基亞磺醯胺基)-5,6,7,8-四氫異喹啉-8-基)乙酸甲酯(0.92g,70%產率),MS:m/e=325.2(M+H+)。
將2-((S)-8-((R)-1,1-二甲基乙基亞磺醯胺基)-5,6,7,8-四氫異喹啉-8-基)乙酸甲酯(實例1,步驟3)(920mg,2.84mmol)溶解於10ml MeOH中且添加HCl(4N於二噁烷中)(7.1ml,28.4mmol,10當量)。在室溫下攪拌混合物2小時。蒸發反應混合物且用飽和NaHCO3溶液萃
取且用二氯甲烷萃取兩次。合併有機層,經硫酸鈉乾燥且蒸發至乾燥。藉由在矽膠管柱上急驟層析,用梯度為0:100至20:80之甲醇:二氯甲烷溶離來純化粗產物。獲得呈黃色油狀物的所要(S)-2-(8-胺基-5,6,7,8-四氫異喹啉-8-基)乙酸甲酯(340mg,54%產率),MS:m/e=221.2(M+H+)。
在室溫下將2,6-二氟-4-苯基乙炔基-苯胺(實例1,步驟1)(360mg,1.57mmol,1.0當量)溶解於DMF(4.0ml)中且添加CDI(255mg,1.57mmol,1.0當量)。在100℃下攪拌混合物1小時。向混合物中添加(S)-2-(8-胺基-5,6,7,8-四氫異喹啉-8-基)乙酸甲酯(實例1,步驟4)(100mg,0.50mmol,1.0當量)且在室溫下攪拌1小時。用isolute®蒸發反應混合物。藉由急驟層析,用梯度為20:80至100:0之乙酸乙酯:庚烷溶離來純化粗產物。獲得呈白色固體狀的所要(S)-2-(8-(3-(2,6-二氟-4-(苯基乙炔基)苯基)脲基)-5,6,7,8-四氫異喹啉-8-基)乙酸甲酯(300mg,40%產率),MS:m/e=476.3(M+H+)。
在室溫下將(300mg,0.63mmol)(S)-2-(8-(3-(2,6-二氟-4-(苯基乙炔基)苯基)脲基)-5,6,7,8-四氫異喹啉-8-基)乙酸甲酯(實例1,步驟5)溶解於THF(3ml)中且添加氫化鈉(60%於礦物油中)(38mg,0.946mmol,1.5當量)。在室溫下攪拌混合物1小時。用飽和NaHCO3溶液萃取反應混合物且用乙酸乙酯萃取兩次。有機層用水及鹽水洗滌,經硫酸鈉乾燥且蒸發至乾燥。獲得呈淡黃色固體狀的所要(S)-1'-(2,6-二氟-4-(苯基乙炔基)苯基)-6,7-二氫-1'H,5H-螺[異喹啉-8,4'-嘧啶]-2',6'(3'H,5'H)-二酮(240mg,86%產率),MS:m/e=444.2(M+H+)。
在室溫下將(240mg,0.54mmol)(S)-1'-(2,6-二氟-4-(苯基乙炔基)苯基)-6,7-二氫-1'H,5H-螺[異喹啉-8,4'-嘧啶]-2',6'(3'H,5'H)-二酮(實例1,步驟6)溶解於DMF(2ml)中且添加碳酸銫(265mg,0.81mmol,1.5當量)及碘甲烷(115mg,51μl,0.81mmol,1.5當量)。在室溫下攪拌混合物1小時。用isolute®蒸發反應混合物。藉由在矽膠管柱上急驟層析,用梯度為30:70至100:0之乙酸乙酯:庚烷溶離來純化粗產物。獲得呈淡黃色油狀的所要(8S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[6,7-二氫-5H-異喹啉-8,6'-六氫嘧啶]-2',4'-二酮(37mg,15%產率),MS:m/e=458.3(M+H+)。
使用類似於實例1,步驟2、3及4中所述之化學方法,以3,4-二氫萘-1(2H)-酮為起始物質,獲得呈黃色液體狀之標題化合物,MS:m/e=220.1(M+H+)。
使用類似於實例1,步驟1中所述之化學方法,以2,6-二氟-4-碘苯胺及3-乙炔基吡啶為起始物質,獲得呈淡棕色固體狀之標題化合物,MS:m/e=231.1(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯胺(實例2,步驟2)及(S)-2-(1-胺基-1,2,3,4-四氫萘-1-基)乙酸甲酯(實例2,步驟1)為起始物質,獲得呈淡黃色固體狀之標題化合物,MS:m/e=458.2(M+H+)。
使用類似於實例1,步驟2、3及4中所述之化學方法,以2,3-二氫-1H-茚-1-酮為起始物質,獲得呈黃色液體狀之標題化合物,MS:m/e=206.1(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯胺(實例2,步驟2)及(S)-2-(1-胺基-2,3-二氫-1H-茚-1-基)乙酸甲酯(實例3,步驟1)為起始物質,獲得呈淡黃色固體狀之標題化合物,MS:m/e=444.2(M+H+)。
使用類似於實例1,步驟2、3及4中所述之化學方法,以6,7-二氫-5H-環戊并[b]吡啶-5-酮為起始物質,獲得呈棕色油狀物之標題化合物,MS:m/e=207.1(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-苯基乙炔基-苯胺(實例1,步驟1)及(S)-2-(5-胺基-6,7-二氫-5H-環戊并[b]吡啶-5-基)乙酸甲酯(實例4,步驟1)為起始物質,獲得呈淡棕色固體狀之標題化合物,MS:m/e=444.2(M+H+)。
使用類似於實例1,步驟2、3及4中所述之化學方法,以7,8-二氫喹啉-5(6H)-酮為起始物質,獲得呈黃色油狀物之標題化合物,MS:m/e=221.2(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-
4-苯基乙炔基-苯胺(實例1,步驟1)及(S)-2-(5-胺基-5,6,7,8-四氫喹啉-5-基)乙酸甲酯(實例5,步驟1)為起始物質,獲得呈白色固體狀之標題化合物,MS:m/e=458.3(M+H+)。
使用類似於實例1,步驟2、3及4中所述之化學方法,以7,8-二氫異喹啉-5(6H)-酮為起始物質,獲得呈黃色油狀物之標題化合物,MS:m/e=221.2(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-苯基乙炔基-苯胺(實例1,步驟1)及(S)-2-(5-胺基-5,6,7,8-四氫異喹啉-5-基)乙酸甲酯(實例6,步驟1)為起始物質,獲得呈棕色泡沫狀之標題化合物,MS:m/e=458.3(M+H+)。
使用類似於實例1,步驟2、3及4中所描述之化學方法,以7,8-二氫-6H-喹唑啉-5-酮為起始物質,獲得呈黃色固體狀之標題化合物,MS:m/e=222.2(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-苯基乙炔基-苯胺(實例1,步驟1)及(S)-2-(5-胺基-5,6,7,8-四氫喹唑啉-5-基)乙酸甲酯(實例7,步驟1)為起始物質,獲得呈白色固體狀之標題化合物,MS:m/e=459.3(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-碘苯胺及(S)-2-(4-胺基烷-4-基)乙酸甲酯(實例8,步驟1)為起始物質,獲得呈淡棕色固體狀之標題化合物,MS:m/e=485.2(M+H+)。
使用類似於實例1,步驟1中所述之化學方法,以(S)-1'-(2,6-二氟-4-碘苯基)-3'-甲基-1'H-螺[烷-4,4'-嘧啶]-2',6'(3'H,5'H)-二酮(實例8,步驟2)及3-乙炔基吡啶為起始物質,獲得呈黃色固體狀之標題化合物,MS:m/e=460.3(M+H+)。
使用類似於實例1,步驟2、3及4中所述之化學方法,以2H-哌喃并[2,3-b]吡啶-4(3H)-酮為起始物質,獲得呈淡黃色油狀物之標題化合物,MS:m/e=223.2(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-苯基乙炔基-苯胺(實例1,步驟1)及(S)-2-(4-胺基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-4-基)乙酸甲酯(實例9,步驟1)為起始物質,獲得呈白色固體狀之標題化合物,MS:m/e=460.3(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯胺(實例2,步驟2)及(S)-2-(4-胺基異烷-4-基)乙酸甲酯(實例10,步驟1)為起始物質,獲得呈白色固體狀之標題化合物,MS:m/e=460.3(M+H+)。
使用類似於實例1,步驟7中所述之化學方法,以(S)-1'-(2,6-二氟-4-(苯基乙炔基)苯基)-6,7-二氫-1'H,5H-螺[異喹啉-8,4'-嘧啶]-2',6'(3'H,5'H)-二酮(實例1,步驟6)及碘乙烷為起始物質,獲得呈黃色油狀物之標題化合物,MS:m/e=472.3(M+H+)。
將6,7-二氫-2H-吲唑-4(5H)-酮(CAS 912259-10-0)(1.46g,10.7mmol)溶解於THF(15ml)中且冷卻至0至5℃。小心地逐份添加氫化鈉(60%於礦物油中之分散液)(450mg,11.3mmol,1.05當量)且在室溫下攪拌混合物60分鐘。將反應混合物再次冷卻至0至5℃且添加(2-(氯甲氧基)乙基)三甲基矽烷(2.28ml,2.15g,12.9mmol,1.2當量)且在室溫下攪拌混合物2小時。小心地用飽和NaHCO3溶液萃取反應混合物且用乙酸乙酯萃取兩次。有機層用鹽水洗滌,經硫酸鈉乾燥且蒸發至乾燥。獲得呈黃色油狀物的所要2-((2-(三甲基矽烷基)乙氧基)甲基)-6,7-二氫-2H-吲唑-4(5H)-酮(定量產率),MS:m/e=267.2(M+H+)。
使用類似於實例1,步驟2、3及4中所述之化學方法,以2-((2-(三甲基矽烷基)乙氧基)甲基)-6,7-二氫-2H-吲唑-4(5H)-酮(實例12,步驟1)為起始物質,藉由用HCl攪拌裂解步驟僅10分鐘而非1小時,獲得呈黃色油狀物之標題化合物,MS:m/e=341.2(M+H+)。
使用類似於實例1,步驟5、6及7中所述之化學方法,以2,6-二氟-4-苯基乙炔基-苯胺(實例1,步驟1)及(S)-2-(4-胺基-2-((2-(三甲基矽烷基)乙氧基)甲基)-4,5,6,7-四氫-2H-吲唑-4-基)乙酸甲酯(實例12,步驟2)為起始物質,獲得呈白色泡沫狀之標題化合物,MS:m/e=577.2(M+H+)。
使用類似於實例1,步驟4中所述之化學方法,藉由在室溫下攪拌反應物16小時,以(S)-1'-(2,6-二氟-4-(苯基乙炔基)苯基)-3'-甲基-2-((2-(三甲基矽烷基)乙氧基)甲基)-2,5,6,7-四氫-1'H-螺[吲唑-4,4'-嘧啶]-2',6'(3'H,5'H)-二酮(實例12,步驟3)為起始物質,獲得呈白色泡沫狀之標題化合物,MS:m/e=447.2(M+H+)。
使用類似於實例1,步驟7中所述之化學方法,以(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[1,5,6,7-四氫吲唑-4,6'-六氫嘧啶]-2',4'-二酮(實例12)及碘甲烷為起始物質,使用Reprosil Chiral NR®柱,以60:40之庚烷:乙醇作為溶劑來分離所形成之兩種異構體,獲得呈黃色固體狀之標題化合物,MS:m/e=461.2(M+H+)。
使用類似於實例1,步驟7中所述之化學方法,以(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[1,5,6,7-四氫吲唑-4,6'-六氫嘧啶]-2',4'-二酮(實例12)及碘甲烷為起始物質,使用Reprosil Chiral
NR®柱,以60:40之庚烷:乙醇作為溶劑來分離所形成之兩種異構體,獲得呈淡黃色固體狀之標題化合物,MS:m/e=461.2(M+H+)。
使用類似於實例12中所述之化學方法,以5,6,7,8-四氫-1H-環庚并[c]吡唑-4-酮(CAS 115215-89-9)而非6,7-二氫-2H-吲唑-4(5H)-酮為起始物質,獲得呈白色固體狀之標題化合物,MS:m/e=461.3(M+H+)。
使用類似於實例1,步驟7中所述之化學方法,以(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[5,6,7,8-四氫-1H-環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮(實例15)及碘甲烷為起始物質,使用對掌性管柱(Reprosil Chiral NR,以60:40之庚烷:乙醇作為溶劑)分離所形成之兩種異構體,獲得呈白色固體狀之標題化合物,MS:m/e=475.2(M+H+)。
使用類似於實例1,步驟7中所述之化學方法,以(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[5,6,7,8-四氫-1H-環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮(實例15)及碘甲烷為起始物質,使用對掌性管柱(Reprosil Chiral NR,以60:40之庚烷:乙醇作為溶劑)分離所形成之兩種異構體,獲得呈白色泡沫狀之標題化合物,MS:m/e=475.2(M+H+)。
圖1:mGlu4 PAM Ca2+移動篩選分析及EC50與Emax%值之測定的實驗概述的說明。
Claims (16)
- 如請求項1或2之式I化合物或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,其中該化合物為(8S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[6,7-二氫-5H-異喹啉-8,6'-六氫嘧啶]-2',4'-二酮(6S)-3-[2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯基]-1-甲基-螺[六氫嘧啶-6,1'-四氫萘]-2,4-二酮(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[7,8-二氫-6H-喹啉-5,6'-六氫嘧啶]-2',4'-二酮(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[7,8-二氫-6H-異喹啉-5,6'-六氫嘧啶]-2',4'-二酮(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[7,8-二氫- 6H-喹唑啉-5,6'-六氫嘧啶]-2',4'-二酮(8S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-乙基-螺[6,7-二氫-5H-異喹啉-8,6'-六氫嘧啶]-2',4'-二酮(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[1,5,6,7-四氫吲唑-4,6'-六氫嘧啶]-2',4'-二酮(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1',2-二甲基-螺[6,7-二氫-5H-吲唑-4,6'-六氫嘧啶1-2',4'-二酮或(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1,1'-二甲基-螺[6,7-二氫-5H-吲唑-4,6'-六氫嘧啶]-2',4'-二酮。
- 如請求項1或4之式I化合物或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,其中該化合物為(6S)-3-[2,6-二氟-4-[2-(3-吡啶基)乙炔基]苯基]-1-甲基-螺[六氫嘧啶-6,1'-茚滿]-2,4-二酮或(5S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[6,7-二氫環戊并[b]吡啶-5,6'-六氫嘧啶]-2',4'-二酮。
- 如請求項1或10之式I化合物或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,該化合物為(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1'-甲基-螺[5,6,7,8-四氫-1H-環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1,1'-二甲基-螺[5,6,7,8-四氫環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮或(4S)-3'-[2,6-二氟-4-(2-苯基乙炔基)苯基]-1',2-二甲基-螺 [5,6,7,8-四氫環庚并[c]吡唑-4,6'-六氫嘧啶]-2',4'-二酮。
- 如請求項1、2、4、6、8及10中任一項之式I化合物或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,其用作治療活性物質。
- 如請求項1、2、4、6、8及10中任一項之式I化合物或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體,其用於治療帕金森氏病(Parkinson's disease)、焦慮症、嘔吐、強迫症、自閉症、神經保護、癌症、抑鬱症及2型糖尿病。
- 一種醫藥組合物,其包含如請求項1至11中任一項之式I化合物或 其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體及醫藥學上可接受之賦形劑。
- 一種如請求項1至11中任一項之式I化合物或其醫藥學上可接受之鹽或酸加成鹽、外消旋混合物、或其相對應的對映異構體及/或光學異構體及/或立體異構體的用途,其用於製備供治療帕金森氏病、焦慮症、嘔吐、強迫症、自閉症、神經保護、癌症、抑鬱症及2型糖尿病用之藥物。
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Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL3176170T3 (pl) | 2012-06-13 | 2019-05-31 | Incyte Holdings Corp | Podstawione związki tricykliczne jako inhibitory fgfr |
CA2909207C (en) | 2013-04-19 | 2021-11-02 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
EP3617205B1 (en) | 2015-02-20 | 2021-08-04 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
EP3322701B1 (en) | 2015-07-15 | 2019-05-01 | H. Hoffnabb-La Roche Ag | Ethynyl derivatives as metabotropic glutamate receptor modulators |
SI3484889T1 (sl) * | 2016-07-18 | 2020-11-30 | F. Hoffmann-La Roche Ag | Derivati etinila |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
WO2019213506A1 (en) | 2018-05-04 | 2019-11-07 | Incyte Corporation | Salts of an fgfr inhibitor |
CA3099287A1 (en) | 2018-05-04 | 2019-11-07 | Incyte Corporation | Solid forms of an fgfr inhibitor and processes for preparing the same |
IL280213B2 (en) | 2018-07-26 | 2024-06-01 | Domain Therapeutics | Altered quinazolinone derivatives and their use as positive allosteric modulators of MGLUR4 |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
KR20220100879A (ko) | 2019-10-14 | 2022-07-18 | 인사이트 코포레이션 | Fgfr 저해제로서의 이환식 헤테로사이클 |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
MX2022006691A (es) | 2019-12-04 | 2022-09-19 | Incyte Corp | Derivados de un inhibidor de receptores del factor de crecimiento de fibroblastos (fgfr). |
EP4069696A1 (en) | 2019-12-04 | 2022-10-12 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
US12012409B2 (en) | 2020-01-15 | 2024-06-18 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
WO2022261160A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201136924A (en) * | 2010-04-13 | 2011-11-01 | Hoffmann La Roche | Arylethynyl derivatives |
TW201524963A (zh) * | 2013-09-25 | 2015-07-01 | Hoffmann La Roche | 乙炔基衍生物 |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6875433B2 (en) | 2002-08-23 | 2005-04-05 | The United States Of America As Represented By The Secretary Of The Army | Monoclonal antibodies and complementarity-determining regions binding to Ebola glycoprotein |
JP5567268B2 (ja) | 2005-05-24 | 2014-08-06 | メルク セローノ ソシエテ アノニム | Crth2の調節剤としての三環系スピロ誘導体 |
JP2010502617A (ja) | 2006-08-31 | 2010-01-28 | シェーリング コーポレイション | 抗菌物質として有用なヒダントイン誘導体 |
JP5622568B2 (ja) | 2007-06-03 | 2014-11-12 | バンダービルト ユニバーシティ | ベンズアミドmGluR5の正のアロステリック調節因子ならびにその作製および使用方法 |
EP3572125A3 (en) | 2008-02-01 | 2019-12-18 | Her Majesty The Queen In Right of Canada as represented by The Minister of Health | Monoclonal antibodies for ebola and marburg viruses |
JP5518899B2 (ja) | 2009-01-19 | 2014-06-11 | フォンダツィオネ・イルクス・カ’グランダ−オスペダレ・マジョーレ・ポリクリニコ | 抗微生物活性を有するメラノコルチンアナログ |
WO2011071574A2 (en) | 2009-09-02 | 2011-06-16 | United States Deparment Of The Army, As Represented By The Secretary Of The Army | Monoclonal antibodies against glycoprotein of ebola sudan boniface virus |
EP2473055A4 (en) | 2009-09-04 | 2013-02-13 | Univ Vanderbilt | ALLOSTERIC MGLUR4 POTENTIATORS, COMPOSITIONS, AND METHODS OF TREATING NEUROLOGICAL DYSFUNCTIONS |
US8389536B2 (en) | 2009-10-27 | 2013-03-05 | Hoffmann-La Roche Inc. | Positive allosteric modulators (PAM) |
US8759377B2 (en) | 2009-11-23 | 2014-06-24 | Vanderbilt University | Substituted dioxopiperidines and dioxopyrrolidines as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction |
US8586581B2 (en) | 2009-12-17 | 2013-11-19 | Hoffmann-La Roche Inc | Ethynyl compounds useful for treatment of CNS disorders |
US8772300B2 (en) | 2011-04-19 | 2014-07-08 | Hoffmann-La Roche Inc. | Phenyl or pyridinyl-ethynyl derivatives |
MY165141A (en) | 2011-04-26 | 2018-02-28 | Hoffmann La Roche | Pyrazolidin-3-one derivatives |
ES2534090T3 (es) | 2011-04-26 | 2015-04-17 | F. Hoffmann-La Roche Ag | Derivados de etinilo como moduladores alostéricos positivos del mGluR5 |
WO2012162635A1 (en) | 2011-05-26 | 2012-11-29 | Sunovion Pharmaceuticals Inc. | Metabotropic glutamate receptors 5 modulators and methods of use thereof |
US20130123254A1 (en) | 2011-09-30 | 2013-05-16 | Barbara Biemans | Pharmaceutically acceptable mglur5 positive allosteric modulators and their methods of identification |
UA110862C2 (uk) | 2011-10-07 | 2016-02-25 | Ф. Хоффманн-Ля Рош Аг | Похідні етинілу як алостеричні модулятори метаботропного рецептора глутамату mglur 5 |
UA110995C2 (uk) | 2011-10-07 | 2016-03-10 | Ф. Хоффманн-Ля Рош Аг | Етинільні похідні як модулятори метаботропного глутаматного рецептора |
MY167810A (en) | 2012-07-17 | 2018-09-26 | Hoffmann La Roche | Arylethynyl derivatives |
EP2909179B1 (en) | 2012-10-18 | 2016-10-05 | F. Hoffmann-La Roche AG | Ethynyl derivatives as modulators of mglur5 receptor activity |
PE20150733A1 (es) | 2012-10-18 | 2015-05-17 | Hoffmann La Roche | Derivados de etinilo como moduladores de la actividad del receptor mglur5 |
CN105121424B (zh) | 2013-02-18 | 2019-01-22 | 华领医药技术(上海)有限公司 | mGluR调节剂 |
UY35400A (es) | 2013-03-15 | 2014-10-31 | Novartis Ag | Compuestos y composiciones para el tratamiento de enfermedades parasitarias |
JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
TWI649310B (zh) * | 2014-01-10 | 2019-02-01 | 赫孚孟拉羅股份公司 | 乙炔基衍生物 |
CA2939034A1 (en) | 2014-02-19 | 2015-08-27 | Cangene Corporation | Methods of modulating an immune response |
CN104860941B (zh) | 2014-02-25 | 2017-03-22 | 上海海雁医药科技有限公司 | 2,4‑二取代苯‑1,5‑二胺衍生物及其应用以及由其制备的药物组合物和药用组合物 |
MA39305A3 (fr) | 2014-02-25 | 2018-05-31 | Hoffmann La Roche | Dérivés d'éthynyle |
CN106999566B (zh) | 2014-10-03 | 2022-01-28 | 麻省理工学院 | 结合埃博拉病毒糖蛋白的抗体及其用途 |
JP6539749B2 (ja) | 2015-03-19 | 2019-07-03 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | mGluR4のモジュレーターとしての3−(4−エチニルフェニル)ヘキサヒドロピリミジン−2,4−ジオン誘導体 |
EP3322701B1 (en) | 2015-07-15 | 2019-05-01 | H. Hoffnabb-La Roche Ag | Ethynyl derivatives as metabotropic glutamate receptor modulators |
SI3484889T1 (sl) | 2016-07-18 | 2020-11-30 | F. Hoffmann-La Roche Ag | Derivati etinila |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201136924A (en) * | 2010-04-13 | 2011-11-01 | Hoffmann La Roche | Arylethynyl derivatives |
TW201524963A (zh) * | 2013-09-25 | 2015-07-01 | Hoffmann La Roche | 乙炔基衍生物 |
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