CN1473045A - 制备地那普林的方法 - Google Patents
制备地那普林的方法 Download PDFInfo
- Publication number
- CN1473045A CN1473045A CNA018166903A CN01816690A CN1473045A CN 1473045 A CN1473045 A CN 1473045A CN A018166903 A CNA018166903 A CN A018166903A CN 01816690 A CN01816690 A CN 01816690A CN 1473045 A CN1473045 A CN 1473045A
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- Prior art keywords
- hydrogen
- chemical compound
- formula
- alkyl
- solution
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- 238000000034 method Methods 0.000 title claims abstract description 49
- 230000008569 process Effects 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 19
- ZQTSNGJHMUKLOM-ZDUSSCGKSA-N dinapsoline Chemical compound C1NCC2=CC=CC3=C2[C@@H]1C1=CC=C(O)C(O)=C1C3 ZQTSNGJHMUKLOM-ZDUSSCGKSA-N 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical group BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 230000029936 alkylation Effects 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229960003638 dopamine Drugs 0.000 claims description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
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- -1 isoquinolines chemical compound Chemical class 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 23
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- 239000007787 solid Substances 0.000 description 11
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- 239000002585 base Substances 0.000 description 10
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
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- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- CYJZJGYYTFQQBY-UHFFFAOYSA-N 5-bromoisoquinoline Chemical compound N1=CC=C2C(Br)=CC=CC2=C1 CYJZJGYYTFQQBY-UHFFFAOYSA-N 0.000 description 3
- KLYCPFXDDDMZNQ-UHFFFAOYSA-N Benzyne Chemical compound C1=CC#CC=C1 KLYCPFXDDDMZNQ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 108050004812 Dopamine receptor Proteins 0.000 description 3
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- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
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Abstract
本发明涉及制备式(IX)化合物的新方法,其中R1、R2、R4、R5、R6和A的定义见说明书,并且涉及式(IX)的某些衍生物,它们可用于治疗运动疾病。
Description
技术领域
本发明涉及制备在运动疾病治疗中用作多巴胺受体激动剂的地那普林(dinapsoline)及其某些衍生物的方法。
背景技术
多巴胺已在许多神经疾病中涉及到。通常认识到,在中枢和/或外周神经系统中功能性多巴胺能活性过量或不足可引起高血压、发作性睡眠病和其他行为性、神经病学、生理学和运动疾病包括帕金森氏病、以无力控制随意运动系统为特征的慢性进行性疾病。
1997年2月27日出版的国际专利WO 97/06799中描述了许多用于治疗与多巴胺有关的中枢和外周神经系统机能不良的配位体,它们具有以下所描述的四氢-1H-萘[1,2,3-de]异喹啉一般化学结构。
尤其,国际申请中具体地描述了在本说明书中称作“地那普林”的(±)-8,9-二羟基-2,3,7,11b-四氢-1H-萘[1,2,3-de]异喹啉的合成和应用。在图1和2以及实验部分描述了地那普林的合成。D.Ghosh等人在J.Med.Chem.,Vol.39,pp.549-555(1996)中进一步描述了地那普林的合成和药理学评价。
尽管现有技术方法在小范围内使用,但整个方法是一个多达14步才能完成的长合成路线,包括保护和脱保护步骤。发现接近合成结束时的环化步骤是有问题的并且如果有任何产物生成,那么收率也是根本无法重现的。因此,需要一种简单、方便、经济和大规模的制备地那普林及其衍生物的方法。本发明已发现一种适宜的可避免有问题的环化步骤的方法,该方法使用异喹啉系统和区域选择性碳-碳键形成技术通过几个简单的步骤来建立整个四环骨架。
发明概述
发明详述
本发明涉及一种新的制备治疗运动性疾病并且具有下式结构的地那普林及其衍生物的方法,其中R1和R2各自独立地为氢或羟基保护基;或者R1和R2可以连接在一起形成-(CH2)n-;n为1-3;A为CH2、CHOR1或C=O;并且R4、R5和R6各自独立地为氢、C1-4烷基、C1-4烷氧基、羟基或卤素。在反应方案4中举例说明该新的和改善的方法。
本发明也提供某些用于治疗运动性疾病的式IX地那普林衍生物。
本文和权利要求(除非上下文另外说明)中所使用的术语“C1-4烷基”是指直链或支链烷基如甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基。本文和权利要求中所使用的术语“C1-4烷氧基”是指直链或支链烷氧基如甲氧基、乙氧基、丙氧基和丁氧基。优选地,这些基团包含1-2个碳原子。除非另外说明,本文和权利要求中所使用的术语“卤素”包括溴、氯、碘和氟,而术语“卤化物”包括溴化物、氯化物和碘化物的阴离子。本文和权利要求中所使用的术语“A”独立地选自亚甲基(-CH2-)、羟基或羟基保护的亚甲基(-CHOR1)或羰基(C=O)。
术语“羟基保护基”是指本领域技术人员公知的、可在本发明中用于封闭或保护羟基的那些基团。优选地,如果需要,所述基团可通过不导致所述分子其余部分任何明显破坏的方法,例如通过化学或酶水解、在温和条件下用化学还原剂处理、用紫外线照射或催化氢化方法除去。
适宜的羟基保护基包括酰基如乙酰基、丙酰基、丁酰基、氯代乙酰基、二氯乙酰基和三氯乙酰基、苯氧基羰基、苄氧基羰基、二苯甲氧基羰基、三苯甲氧基羰基、对硝基-苄氧基羰基和2,2,2-三氯乙氧基羰基;芳酰基如苯甲酰基和取代的苯甲酰基,例如甲氧基苯甲酰基、硝基苯甲酰基、甲基苯甲酰基等;烷基如甲氧基甲基、苄氧基甲基、烷基;芳烷基如苄基、二苯甲基、三苯甲基或对-硝基苄基;或三有机硅烷基如三(C1-C6)烷基甲硅烷基(三甲基甲硅烷基、三乙基甲硅烷基、三丙基甲硅烷基、异丙基二甲基甲硅烷基、叔丁基二甲基甲硅烷基、甲基二异丙基甲硅烷基或甲基二叔丁基甲硅烷基)、三芳基甲硅烷基(例如三苯基甲硅烷基、三-对-二甲苯基甲硅烷基)或三芳烷基甲硅烷基(例如三苄基甲硅烷基)。这些和其他适宜的羟基保护基的实例及其形成和除去方法是本领域公知的,例如参见Protective Groups inOrganic Synthesis,T.W.Greene,John Wiley & Sons,New York,1991,第2章及其参考。
优选的羟基保护基是酰基如乙酰基、丙酰基和氯代丙酰基;芳酰基如苯甲酰基和取代的苯甲酰基以及芳基如苄基和取代的苄基。最优选地,当R1和R2连接在一起形成亚甲基(-CH2-)时获得的羟基保护基。
本领域技术人员应该理解,最后的脱封闭帮助将依赖于取代基R1和R2中所存在的保护基改变。脱封闭步骤如反应方案4步骤(g)中所描述的产生其中R1和R2为氢的式IX化合物的脱封闭步骤通过常规方法如水解、化学还原、氢化等完成,并且包括除去其中R1和R2连接在一起形成亚甲基(-CH2-)的羟基保护基的方法。
式IX化合物可通过各种方法如本文在实施例、在反应方案所描述的方法及其本领域技术人员显而易见的改变方法制备。优选地,式IX稠合异喹啉可通过还原方法,由式VII苯并苯并异喹啉化合物制备,然后如反应方案4所述除去羟基保护基。优选地,各种式VII苯并苯并异喹啉化合物可如反应方案3所述,利用游离基碳-碳键形成,由式VI芳基异喹啉制备,而式V芳基异喹啉可通过反应方案1中所描述的方法和反应方案2中所描述的其他方法,由式I异喹啉和适当取代的苯基衍生物制备。反应方案1
试剂:(a)Br2/AlCl3/纯品;(b)n-BuLi然后DMF,(c)LDA然后III
如反应方案1所述,式V化合物可由取代的或未取代的式I异喹啉制备,通常已知,优选地在5-位进行亲电子取代得到式II 5-溴-异喹啉。溴化反应(a)可以纯品形式和在路易斯酸催化剂如无水氯化铝存在下进行,或者溴化反应可在惰性有机溶剂如二氯甲烷中进行。在两种情况下,总收率是彼此可比较的,并且优选地,循环反应以产品形式进行,因为这避免了另外的溶剂蒸发步骤。是II 5-溴-异喹啉化合物可在适宜的惰性有机溶剂如THF中利用正丁基锂进行金属转移得到相应的5-锂-异喹啉并且优选地,该反应在低于-50℃--80℃的温度下进行。该通用的5-锂-异喹啉可烷基化、酰基化为各种5-取代的异喹啉。向所述5-锂-异喹啉中加入DMF,然后温热至室温并用等量的无机酸中和后,该5-锂-异喹啉产生收率极好的式III 5-甲酰基-异喹啉。利用近期公开的由R.Mattson等人在ACS Organic Division,1998,Boston Abstract No.059中描述的方法,优选地,式III醛可与由相应的式IV烃前体衍生的4-溴-3-锂-1,2-(亚甲基二氧基)苯反应得到所需要的式V二苯基甲醇结晶。反应方案2
试剂:(a)Br2/AlCl3/纯品;(b)LDA然后IVa;(c)n-BuLi然后DMF
或者,所需要的式V化合物可通过类似的但与反应方案2所描述的形成步骤不同的途径制备。
以上所描述的和在反应方案1中所显示的将式II化合物转化为式III化合物的形成反应可用4-溴-3-锂-1,2-(亚甲基二氧基)苯进行,得到相应的式IVa 2-溴-5,6-(亚甲基二氧基)苯甲醛。然后IVa醛很容易与锂化5-溴-异喹啉反应产生完全相同的式V二苯基甲醇。提供这些补充的和汇集方法来适应本发明不同对的异喹啉和4-溴-1,2-(亚甲基二氧基)苯。反应方案3
试剂:(a)MnO2/苯;(b)n-Bu3SnH/AlBN;(d)Et3SiH/THF;(e)n-Bu3SnH/AlBN
式V二苯甲醇可以很容易地转化为用作制备地那普林及其衍生物中间体的式VIa、VIb和VIc芳基异喹啉。本领域技术人员应该理解,式V醇可以很容易地按照常规方法,用氧化剂如二氧化锰氧化为相应的式VIa酮。式V醇可以很容易地用羟基保护基保护,得到还原后提供式VIb化合物的式VIc化合物。
将式VIa、VIb和VIc化合物环化为相应的式VIIa、VIIb和VIIc化合物的反应可以很容易地通过本领域公知的反应条件开始。然而发现,最好的结果是通过自由基引发的碳-碳键形成反应获得的,因为该方法对所选择前体的电子环境最不敏感。优选地,碳-碳键反应可在质子源如无机酸例如硫酸和盐酸,或有机酸例如乙酸、三氟乙酸和对甲苯磺酸存在下,用氢自由基源如三烷基氢化锡、三芳基氢化锡、三烷基硅烷、三芳基硅烷等和自由基引发剂如2,2′-偶氮双异丁腈、日光、可控制的电势阴极(Pt)等进行。在式VIb化合物向式VIIb环化化合物的转化中,在乙酸存在下使用三丁基氢化锡和各种公知的引发剂并且特别是2,2′-偶氮双异丁腈是有利的和优选的。反应方案4
试剂:(f)NaBH3CN/HCl/THF;(g)BBr3/CH2Cl2;(h)Pd/C/二甲苯
当环化时,式VIIa、VIIb和VIIc中间体用作各种衍生物的起始物,所述衍生物仅在反应方案4所述的取代基A一个位置上不同。式VIIIb化合物在带有杂环的氮上选择性还原得到相应的式VIIIb四氢异喹啉,它是式IXb地那普林的直接前体。选择性环还原可以通过许多不同的还原方法如在THF和酸性介质中的氰基硼氢化钠进行,可使用氢化物还原剂如L-Selectride或Superhydride并且优选地,在升高的压力下催化氢化。本领域技术人员应该理解,或者,与所述环还原相反做法可通过在升高的温度下,在有机溶剂如沸腾的二甲苯中使用钯催化的脱氢进行。式VIIIb保护化合物转化为式IXb二醇的反应可通过在二氯甲烷中,在低温如-60℃--80℃下使用三溴化硼完成并且终产物可以以氢溴酸盐的形式分离出来,相应的盐酸盐可通过用三氯化硼代替三溴化硼有利地制备。如果要制备其中R为C1-4烷基的式IXb化合物,那么利用常规方法,在除去保护基前,将式VIIIb化合物烷基化有利于得到所需要的式IXb二醇。
如反应方案4所述,当要制备其中A为羟基(IXc)或羰基(IXa)的式IX化合物时,可将接近的VIIIa前体转化为所需要的式IXa化合物,而适当地保护的式VIIIc可有利地脱保护以便提供所需要的IXc醇化合物。本领域技术人员应该理解,转化和修饰式IX化合物中的A取代基可很容易地通过公知的常规方法,将一个化合物转化为另一个化合物,如反应方案4中关于式IXa、IXb和IXc化合物的描述。
在本发明优选的具体实例中,式VI化合物具有下式结构其中R1和R2各自独立地为氢或羟基保护基;或者R1和R2可以连接在一起形成-(CH2)n-;n为1-3;R3为氯、溴或碘;A为CH2、CHOR1或C=O;并且R4、R5和R6各自独立地为氢、C1-4烷基、C1-4烷氧基、羟基或卤素。最优选地,R1和R2连接在一起形成-(CH2)n-,其中n为1;R3为溴;A为CH2并且R4、R5和R6为氢。
在本发明另一优选的具体实例中,式VII化合物具有下式结构其中R1和R2各自独立地为氢或羟基保护基;或者R1和R2可以连接在一起形成-(CH2)n-;A为CH2、CHOR1或C=O;n为1-3;并且R4、R5和R6各自独立地为氢、C1-4烷基、C1-4烷氧基、羟基或卤素。最优选地,R1和R2连接在一起形成-(CH2)n-,其中n为1;A为CH2并且R4、R5和R6为氢。在本发明另一优选的具体实例中,式IX化合物具有下式结构其中R1和R2各自独立地为氢或羟基保护基;或者R1和R2可以连接在一起形成-(CH2)n-;n为1-3;A为CHOR1或C=O;R为氢或C1-4烷基;并且R4、R5和R6各自独立地为氢、C1-4烷基、C1-4烷氧基、羟基或卤素。最优选地,R1和R2连接在一起形成-(CH2)n-,其中n为1;A为CH2并且R4、R5和R6为氢。
另一方面,本发明提供制备式IX化合物的方法其中R1和R2各自独立地为氢;A为CH2、CHOH或C=O;R为氢或C1-4烷基;并且R4、R5和R6各自独立地为氢、C1-4烷基、C1-4烷氧基、羟基或卤素,所述方法包括步骤(a)用还原剂还原式VII化合物其中R1和R2各自独立地为羟基保护基;或者R1和R2可以连接在一起形成-(CH2)n-,其中n为1-3并且R4、R5、R6和A如上定义;(b)将所得到的还原产物脱保护得到式IX化合物,其中R1和R2为氢和(c)将步骤(a)或(b)的产物烷基化或不烷基化得到式IX化合物,其中R为C1-4烷基。优选地,在本发明方法中,R1形成-(CH2)n-,其中n为1;R3为溴,A为CH2并且R4、R5和R6为氢,R2被连接在一起形成-(CH2)-,A为CH2并且R、R4、R5和R6为氢。
与多巴胺受体的结合:
多巴胺受体通过刺激其在细胞膜上的受体产生室温下反应。利用C.P.Manik,P.B.Monlinoff和P.McGonigle在J.ofNeurochemistry,Vol.51,pp.391-397(1988)和K.D.Burris等人在Neuropsychopharmacology,Vol.12,pp.335-345(1995)中描述的体外结合测定方法,在大鼠中进行D1和D2受体亲和力的测定。另外,使用由HEK-293细胞制备的膜,所述细胞表达转染的人D21受体和用D2受体激动剂[125I]-7-OH-PIPAT标记的部位,并且结果显示本发明化合物在这些试验中是有活性的。
在另一具体实施方案中,本发明包括药物组合物,所述组合物含有至少一种式IX化合物和药物助剂、载体或稀释剂。
再一实施方案中,本发明涉及一种治疗哺乳动物运动疾病的方法,该方法包括给予所述哺乳动物治疗有效量的式IX化合物或其无毒可药用盐、溶剂化物或水合物。
再一实施方案中,本发明涉及一种治疗哺乳动物帕金森氏病的方法,该方法包括给予所述哺乳动物治疗有效量的式IX化合物或其无毒可药用盐、溶剂化物或水合物。
为了治疗使用,式IX的药理活性化合物通常会作为药物组合物来给药,所述组合物包含作为必要活性组分的至少一种该化合物和固体或液体可药用载体以及可有可无的标准和常规技术中采用的可药用助剂和赋型剂。
药物组合物包括适于口服、非胃肠道(包括皮下、肌内、皮内和静脉内)、支气管或鼻腔给药的剂量形式。因此,如果使用固体载体,制剂可以被压片,以粉剂或丸剂形式放置在硬明胶胶囊中,或者是锭剂或糖锭的形式。固体载体可包含常规的赋型剂如粘合剂、填充剂、制片润滑剂、崩解剂、湿润剂等。如果需要,片剂可通过常规技术进行膜包衣。如果采用液体载体,制剂可以是糖浆、乳剂、软明胶胶囊、注射用灭菌载体、水性或非水性液体混悬剂形式,或者可以是使用前用水或者其他合适载体重新配制的干燥产品。液体制剂可以包含常规添加剂如悬浮剂、乳化剂、湿润剂、非水性载体(包括食用油)、防腐剂以及芳香剂和/或着色剂。为了非胃肠道给药,载体通常包含灭菌水,至少占大部分,尽管盐水溶液、葡萄糖溶液等也可以使用。也可以使用可注射混悬液,这时可以使用常规悬浮剂。常规防腐剂、缓冲剂等也可以被加到非胃肠道给药的剂型中。特别有用的是以非胃肠道制剂形式给予式IX化合物。通过适于所需制剂的常规技术制备药物组合物,所述制剂包含合适量的活性组分,即本发明化合物。例如,参见Remington’s Pharmaceutical Sciences,Mack PublishingCompany,Easton,PA,17th edition,1985。
式IX化合物实现治疗作用的剂量不仅取决于患者的年龄、体重和性别以及给药方式等因素,也取决于所需钾通道激活活性的程度和用于特定疾病的具体化合物的作用强度。也期待具体化合物的治疗和剂量以单位剂量形式进行并且该单位剂量形式由本领域技术人员依据活性的相对水平来调节。临床医生可以确定所使用的特定剂量(和每天给药的次数),并且可以随本发明特定情况下剂量的确定而变化以产生所需的治疗效果。
用于患有本文所述任何疾病的哺乳动物包括人的式IX化合物或其药物组合物的合适剂量是活性组分的量从约0.1μg/kg体重到100mg/kg体重。对于非胃肠道给药来说,静脉给药的剂量范围可以是1μg/kg体重到10mg/kg体重。优选地,每天1-4次以相等剂量给予活性组分。然而,通常先给予小剂量,然后逐渐增加剂量直到测定治疗情况时使宿主达到最佳剂量。
然而,可以理解的是实际给予化合物的量是由临床医生根据相关情况来决定的,所述情况包括被治疗的疾病、所给化合物的选择、给药途径的选择、患者个体的年龄、体重和反应、患者症状的严重程度。
下列实施例是以举例说明的方式给出的并且不以任何方式对本发明构成限定,因为本发明的许多变化在本发明范围之内是可能的。
具体实施方案的描述
所报道的所有新化合物都显示与其指定结构一致的光谱特征(IR、MS、1H和13C NMR)。NMR是利用Brucker ACP 300光谱计,在指定溶剂[氘代氯仿(CDCl3)或全氘代二甲基亚砜(DMSO-d5)]中,在300MHz下进行的。所报道的数据包括如下:以PPM表示的与四甲基硅烷(TMS)计算值相比的化学位移(δ);多重性(s=单峰、d=双峰、t=三重峰、q=四重峰、p=五重峰并且br=宽峰);整合和偶联常数(以Hz表示)。熔点是利用Thomas Hoover毛细管装置获得的并且是未经校正的。
实施例15-溴异喹啉
实验装置包括安装有冷凝器的500ml三颈烧瓶、滴液漏斗和终端为刚性新月形特氟隆聚四氟乙烯浆的搅拌器。向装有异喹啉(57.6g,447mmol)的烧瓶中加入AlCl3(123g,920mmol)。将该混合物加热至75-85℃。利用滴液漏斗经4小时的时间滴加溴(48.0g,300ml)。所得到的混合物在75℃下搅拌1小时。将几乎为黑色的混合物倾入碎冰中并用手充分搅拌。该冷却的混合物用氢氧化钠水溶液(10N)处理以便将所有的铝盐溶解成为铝酸钠并用乙醚提取油层。用Na2SO4干燥并浓缩后,乙醚提取液在0.3mm下蒸馏。从大约125℃下的馏分中获得白色固体(16.3g,78mmol)(26%收率)。产物进一步通过重结晶(戊烷或己烷)纯化:mp:80-81℃;
1H NMR(DMSO-d6)δ9.34(s,1H),8.63(d,1H,J=9.0Hz),8.17(d,1H,J
=7.5Hz),8.11(d,1H,J=6.6Hz),7.90(d,1H,J=6.0Hz),7.60(t,1H,J=
7.5Hz);
13C NMR(DMSO-d6)δ153.0,144.7,134.3,134.0,129.3,128.5,128.0,
120.3,和118.6.C9H6BrN分析的计算值:C,51.96;H,2.91;N,6.73。
实测值:C,51.82;H,2.91;N,6.64。
实施例25-异喹啉甲醛(isoquinolinecarboxaldehyde)
在-78℃下,向正丁基锂(19.3ml 2.5M正己烷溶液,48mmol)的乙醚(80ml)和THF(80ml)混合物溶液中滴加溴代异喹啉(5.0g,24mmol)的THF(10ml)溶液。反应混合物在-78℃ 环境下加热30分钟。按照Pearson等人在J.Heterocycl.Chem.Vol.6(2),pp.243-245(1969)中描述的一般方法,将DMF(3.30g,45mmol)的THF(10ml)溶液冷却至-78℃并迅速加到异喹啉锂溶液中。混合物在-78℃下搅拌15分钟。加入乙醇(20ml),然后加入NH4Cl溶液。所悬浮液温热至室温。与乙醚提取液合并的有机层用Na2SO4干燥。淡黄色固体(2.4g,15mmol,64%收率)通过层析法获得(SiO2 Type-H,50%EtOAc/己烷)并重结晶(乙醇):mp 114-116℃;
1H NMR(DMSO-d6)δ10.40(s,1H),9.44(s,1H),8.85(d,1H,J=6.0Hz),
8.69(d,1H,J=6.0Hz),8.45(m,2H),7.90(t,1H,J=7.2Hz);
13C NMR(DMSO-d6))δ194.23,153.5,146.2,140.2,135.2,132.6,130.2,
128.6,127.5,和117.2.C10H7NO·0.05H2O分析的计算值:C,75.99;H,4.53;N,8.86。
实测值:C,75.98;H,4.66;N,8.68。
实施例34-溴-1,2-(亚甲基二氧基)-3-苯甲醛
在-78℃下,向4-溴-1,2-(亚甲基二氧基)苯(24.9mmol)的THF(52ml)溶液中缓慢地加入二异丙基酰胺锂的环己烷(1.5M,27.4mmol)溶液并将所得到的溶液搅拌15分钟。然后滴加DMF(4.15ml),反应溶液在室温下温热1小时。该溶液用饱和NH4Cl洗涤,浓缩有机层并真空干燥。黄色的固体产物用乙酸异丙酯重结晶得到标题化合物的黄色针状结晶(69%收率)。mp 158-159℃;
1H NMR(CDCl3)δ10.29(s,1H),7.08(d,1H,J=8.25Hz),6.83(d,1H,
J=8.22.Hz),6.17(s,2H);
13C NMR CDCl3)δ190.8,149.8,149.1,126.5,117.7,115.9,113.9,
103.8.C8H5BrO3分析的计算值:C,41.95;H,2.20;Br,34.89。
实测值:C,41.91;H,2.09;Br,34.56。
实施例4α-(5-溴-1,3-苯并二氧戊环-4-基)-5-异喹啉甲醇
在-78℃下,向4-溴-1,2-(亚甲基二氧基)苯(3.01g,15mmol)的THF(20ml)溶液中滴加二异丙基酰胺锂(10.6ml 1.5M环己烷溶液,16mmol)。反应混合物在-78℃环境下搅拌20分钟。形成棕色的溶液。滴加5-异喹啉甲醛(1.90g,12mmol)d THF(4ml)溶液。所得到的混合物在-78℃下搅拌10分钟并温热至室温。在室温下继续搅拌30分钟,然后混合物用饱和NH4Cl溶液猝灭。产物用EtOAc提取并减压除去溶剂。残渣通过色谱层析(SiO2 Type-H,35%EtOAc/己烷)纯化得到黄色的固体(2.8g,7.8mmol,65%收率):mp173-175℃;
1H NMR(DMSO-d6)δ9.32(s,1H),8.47(d,1H,J=6.OHz),8.05(d,1H,
J=8.1Hz),7.96(d,1H,J=7.2Hz),7.76(d,1H,J=6.0Hz),7.66(t,1H,J
=7.8Hz),7.14(d,1H,J=8.1Hz),6.84(d,1H,J=8.1Hz),6.58(d,1H,J=
8.1Hz),6.28(d,1H,J=5.4Hz),5.95(s,1H),5.80(s,1H);
13C NMR(DMSO-d6)δ153.1,147.6,147.0,142.9,136.9,132.7,128.9,
128.3,127.3,126.7,125.6,124.4,116.3,114.0,109.3,101.6,和69.0.C17H12BrNO3分析的计算值:C,57.01;H,3.38;N,3.91。
实测值:C,57.04;H,3.51;N,3.89。
实施例5α-(5-溴-1,3-苯并二氧戊环-4-基)-5-异喹啉甲醇
在-78℃环境下,向5-溴异喹啉(0.5g,2.4mmol)的乙醚(8ml)溶液中滴加叔丁基锂(3.6ml 1.7M戊烷溶液,6.0mmol)。混合物在-78℃ 环境下搅拌30分钟,然后在干冰丙酮浴上,在烧瓶中继续搅拌15分钟。在-78℃环境下一次加入4-溴-1,2-(亚甲基二氧基)-3-苯甲醛(0.524g,2.4mmol)。混合物在-78℃下搅拌5分钟并利用水浴温热至室温。在室温下继续搅拌20分钟,然后混合物用饱和NH4Cl溶液猝灭,用EtOAc提取并用Na2SO4干燥。色谱层析(SiO2 35%EtOAc/己烷)得到标题化合物的黄色固体(0.18g,0.50mmol,21%收率),它与实施例4化合物相同。
实施例65-[(5-溴-1,3-苯并二氧戊环-4-基)甲基]异喹啉
向仲醇α-(5-溴-1,3-苯并二氧戊环-4-基)-5-异喹啉甲醇(8.37mmol)的三氟乙酸(100ml)溶液中加入三乙基硅烷(83.7mmol),所得到的溶液在70-75℃下回流1小时并在室温下搅拌过夜。真空除去溶剂,残渣溶解在乙酸乙酯中,用饱和NH4Cl溶液洗涤,用Na2SO4干燥,过滤并浓缩。通过柱色谱层析进行纯化,得到标题化合物三氟乙酸盐的白色结晶固体(67%收率):mp 138-140℃;
1H NMR(CDCl3)δ9.64(s,1H),8.63(d,1H,J=6.59Hz),8.45(d,1H,J=
6.62Hz),8.14(d,1H,J=8.22Hz),7.77(t,1H,J=7.39Hz),7.64(d,1H,
J=7.29Hz),7.13(d,1H,J=8.33Hz),6.71(d,1H,J=8.31Hz),5.94(s,
2H),4.53(s,2H);
13C NMR(CDCl3)δ147.8,147.7,147.1,137.2,135.1,134.7,133.4,
130.3,128.6,128.3,125.9,120.7,119.4,116.3,109.1,101.9和31.7.
C17H12BrNO2·C2HF3O2分析的
计算值:C,50.02;H,2.87;Br,17.51;N,3.07。
实测值:C,49.91;H,3.02;Br,17.95;N,3.04。
实施例712H-苯并[d,e][1,3]苯并二氧戊烷环[4,5-h]异喹啉方法A:
将5-[(5-溴-1,3-苯并二氧戊环-4-基)甲基]异喹啉(0.357g,1.0mmol)和2,2′-偶氮双异丁腈(0.064g,0.39mmol)的苯(10ml)溶液冷却至-78℃,用N2脱气4次,然后在氩气下加热至80℃。在2小时内加入三丁基氢化锡(1.14g,3.9mmol)的脱氢苯(10ml)溶液。分4次(每半小时加入1/4)加入TFA(0.185g,1.6mmol)。加入TFA后,反应混合物在80℃ 环境下搅拌6小时。另外滴加三丁基氢化锡(0.228g,0.80mmol)。连续搅拌过夜(16小时)。一次加入另一部分2,2′-偶氮双异丁腈(0.064g,0.39mmol)和TFA(0.093g,0.80mmol)。在2小时内也加入三丁基氢化锡(1.14g,3.9mmol)的脱氢苯(10ml)溶液。分4次(每半小时加入1/4)加入更多的TFA(0.185g,1.6mmol)。再连续搅拌6小时并滴加三丁基氢化锡(0.456g,1.6mmol)。反应混合物搅拌过夜(16小时)。减压除去溶剂。残渣中加入戊烷(100ml),所得到的混合物冷却至-78℃。形成棕色树胶并过滤。滤液用MeCN提取。将MeCN层与棕色树胶合并。蒸发MeCN得到的粗品通过色谱层析(SiO2 Type-H,15%EtOAc/己烷)纯化。分离的化合物溶解在CH2Cl2中并用HCl(1N)提取。水层用10N NaOH溶液碱化至pH~10并再次用CH2Cl2提取。有机层用Na2SO4干燥。蒸发溶剂得到标题化合物的橙色固体(0.068g,0.26mmol,25%收率):mp194-197℃;
1H NMR(DMSO-d6)δ9.12(s,1H),9.06(s,1H),7.93(d,1H,J=6.9Hz),
7.83(d,1H,J=8.1Hz),7.73(dd,1H,J=7.2,1.5Hz),7.66(t,1H,J=
7.8Hz),6.96(d,1H,J=8.4Hz),6.14(s,2H),4.44(s,2H);
13C NMR(DMSO-d6)δ150.6,147.0,145.2,135.6,130.6,129.3,129.1,
127.7,127.5,125.0,123.6,117.2,116.1,107.5,101.6,and 26.6.
C17H11NO2·0.12CH2Cl2分析的计算值:C,75.75;H,4.17;N,5.16。
实测值:C,75.75;H,4.03;N,4.83。
方法B:
将5-[(5-溴-1,3-苯并二氧戊环-4-基)甲基]异喹啉(12.6g,36.8mmol)和2,2′-偶氮双异丁腈(5.92g,36.0mmol)的苯(1500ml)溶液冷却至-78℃,用氮气脱气/冲洗4次,然后在氩气下加热至80℃。在3小时内滴加三丁基氢化锡(39.9g,137mmol)的脱氢苯(30ml)溶液。在加入氢化锡前一次加入乙酸(12.6g,210mmol)。反应混合物在80℃环境下搅拌16小时。加入过量的三乙胺来中和残留的乙酸组分。减压除去溶剂。加入二氯甲烷(250ml)来溶解半固体。然后加入己烷至该混合物刚好开始变混浊。将该溶液倾入短硅胶柱上并通过用己烷洗涤除去三正丁基乙酸锡,直至通过TLC不再能检测到。然后用己烷和乙酸乙酯洗脱产物得到所需要的标题化合物(6.1g,23.4mmol,63.5%收率),它与通过方法A制备的产物相同。
实施例8
(±)-8,9-亚甲基二氧基-2,3,7,11b-四氢-1H-萘[1,2,3-de]异喹啉
方法A:
向12H-苯并[d,e][1,3]苯并二氧戊烷环[4,5-h]异喹啉(0.085g,0.33mmol)的THF(43ml)溶液中加入2N HCl(1.7ml,3.4mmol),形成橙色沉淀。一次加入氰基硼氢化钠(0.274g,4.4mmol)。所得到的悬浮液在室温下搅拌2小时。加入HCl(2N,10ml)并连续搅拌5分钟。加入饱和NaHCO3溶液(pH~7-8)。所得到的混合物用EtOAc提取,用Na2SO4干燥并减压除去溶剂。残渣进行色谱层析(SiO2 Type-H,5%MeOH/CH2Cl2)得到标题化合物的黄色树胶(0.066g,0.25mmol,75%收率):
1H NMR(CDCl3)δ7.15(m,2H),6.97(d,1H,J=6.9Hz),6.83(br,s,1H),
6.68(d,1H,J=8.1Hz),6.59(d,1H,J=8.1Hz),6.01(d,1H,J=1.4Hz),
5.91(d,1H,J=1.4Hz),4.40-4.00(m,5H),3.55(dd,1H,J=17.7,3.0Hz),
3.10(t,1H,J=12.0Hz);
13C NMR(CDCl3)δ146.1,144.8,136.0,132.2,130.4,128.6,127.1,
127.0,124.5,118.5,116.2,106.2,101.2,45.8,35.1,34.3,和28.9.
C17H15NO2·0.52HCN·1.8H2O分析的
计算值:C,67.49;H,6.18;N,6.83。
实测值:C,67.45;H,5.96;N,6.75。
方法B:
在将与1-L Parr“弹式反应器”装配在一起的适宜的玻璃套筒中,将12H-苯并[d,e][1,3]苯并二氧戊烷环[4,5-h]异喹啉(11.26g)溶解到500ml冰醋酸中。向该暗琥珀色溶液中加入480mg PtO2和磁搅拌块。通常的冲洗周期在-78℃重复3次。最后,将氢气充入140 PSI压力下的钢瓶中同时仍保持其中的组分在-78℃下。让反应器在2小时内温热至室温同时使内压增至195 PSI。在室温下大约4小时后,气体吸收更快。24小时后,内压重新回到165 PSI,粗略地表明在化学计量水平摄入氢气。解除压力后倒出黑色悬浮液,在硅胶上过滤,用乙酸冲洗并减压浓缩得到大约19g粘稠物。粗品用碳酸氢钠溶液中和,然后用二氯甲烷提取得到11.6g标题化合物,其1H NMR与通过方法A制备的上述纯品物质难以区别。
实施例9
5-溴-1,3-苯并二氧戊环-4-基)-(5-异喹啉基)甲酮
向仲醇α-(5-溴-1,3-苯并二氧戊环-4-基)-5-异喹啉甲醇(1.39mmol)的苯(200ml)溶液中加入二氧化锰(28.0mmol),反应混合物在室温下充分搅拌过夜。过量的MnO2通过硅藻土过滤,用EtOAc洗涤(×2),合并滤液洗涤液并浓缩得到黄色产品固体产物(定量收率)。产物用EtOAc/己烷重结晶得到标题化合物:mp193-195℃;
1H NMR(CDCl3)δ9.33(s,1H),8.86(d,1H,J=6.09Hz),8.71(d,1H,J=
6.06Hz),8.19(d,1H,J=8.16Hz),7.97(d,1H,J=38Hz),7.61(t,1H,J=
8.13Hz),7.10(d,1H,J=8.28Hz),6.81(d,1H,J=8.28Hz),5.97(s,2H);
13C NMR(CDCl3)δ192.8,153.0,147.7,146.2,136.6,134.3,133.9,
131.9,129.1,126.2,126.1,123.4,118.8,110.9,110.7,102.7.
C17H10BrNO3分析的计算值:C,57.33;H,2.83;Br,22.43;N,3.93。
实测值:C,57.3;H,2.76;Br,22.73;N,3.82。
实施例10
12H-苯并[d,e][1,3]苯并二氧戊烷环[4,5-h]异喹啉-12-酮
向酮(5-溴-1,3-苯并二氧戊环-4-基)-(5-异喹啉基)甲酮(0.56mmol)的苯(12ml)溶液中加入三丁基氢化锡(0.06mmol)和2,2′-偶氮双异丁腈(0.035mmol),所得到的混合物在氮气下回流40小时。真空除去溶剂,残渣溶解在乙腈中并用己烷洗涤(×3)。真空浓缩提取液并进行柱色谱层析(EtOAc/己烷)。分离产物得到黄色荧光固体。产物用EtOAc/己烷重结晶(10%收率)得到标题化合物:MS(ESI)m/e275。
1H NMR(DMSO-d6)δ9.59(s,1H),9.47(s,1H),8.69(dd,1H,J=7.50,
1.20Hz),8.61(dd,1H,J=8.10,1.20Hz),8.26(d,1H,J=8.40),8.02(t,
1H,J=7.50Hz),7.43(d,1H,J=8.40Hz),6.33(s,2H).
实施例11
(±)-8,9-二羟基-2,3,7,11b-四氢-1H-萘[1,2,3-de]异喹啉
将BBr3(25.0ml 1M CH2Cl2溶液,25.0mmol)加到如实施例8制备的亚甲基二氧基地那普林(1.4g,5.3mmol)的CH2Cl2冷却(-78℃)溶液中。混合物在-78℃氮环境下搅拌3小时,然后在室温下搅拌过夜。混合物冷却至-78℃后,滴加甲醇(50ml)并减压除去溶剂。残渣溶解在甲醇(100ml)中,溶液在氮环境下回流2小时。除去溶剂后,残渣进行色谱层析(SiO2,10%MeOH/CH2Cl2)得到标题化合物的暗棕色固体(1.65g,4.94mmol,93%收率)。MS(ESI) m/z 254(MH+);
1H NMR(DMSO-d6)δ9.50(br,s,2H),9.28(s,1H),8.54(s,1H),7.32
(d,1H,J=8.3Hz),7.23(t,1H,J=8.3Hz),7.12(d,1H,J=8.5Hz),6.70
(d,1H,J=9.3Hz),6.54(d,1H,J=6.7Hz),4.37(s2H),4.30-4.23(m,2H),
3.97(m,1H),3.45-3.31(m,2H);
13C NMR(DMSO-d6)δ143.8,142.0,136.9,132.1,127.6,127.0,126.6,
124.1,123.7,114.0,112.7,48.6,44.0,32.9,和28.5.
C16H15NO2·1.28HBr·0.59H2O分析的
计算值:C,52.34;H,4.79;N,3.82。
实测值:C,52.29;H,4.92;N,4.14。
实施例12
12H-苯并[d,e][1,3]苯并二氧戊烷环[4,5-h]异喹啉
将样品(±)-8,9-亚甲基二氧基-2,3,7,11b-四氢-1H-萘[1,2,3-de]异喹啉(651mg)溶解到250ml试剂级二甲苯中。向该溶液中加入40mg 5%披钯炭催化剂,悬浮液在氮环境下温热回流。24小时后,取出少量等份试样并通过LC/MC分析,结果显示完全氧化。通过在短硅胶(Type-H)床上过滤除去催化剂,橙色滤液减压浓缩得到640mg暗橙色结晶。该标题化合物样品的NMR与实施例7制备的样品难以区别。
实施例13
(±)-N-甲基-8,9-二羟基-2,3,7,11b-四氢-1H-萘[1,2,3-de]异喹啉
步骤A N-甲基-12H-苯并[d,e][1,3]苯并二氧戊烷环[4,5-h]异喹啉
向12H-苯并[d,e][1,3]苯并二氧戊烷环[4,5-h]异喹啉(0.38mmol)的温热二氯乙烷(4ml)溶液中加入碘甲烷(12.8mmol),几分钟后观察到黄色悬浮液。反应物在搅拌下温热至40℃ 20分钟。所有的起始物消失后,将氮气吹入该系统中以便除去溶剂和过量Mel,然后进一步在高真空下干燥。所得到的黄色残渣再悬浮在THF中,然后加入三乙酰氧基硼氢化钠(0.4g)和氰基硼氢化钠(0.12g)。几分钟后,该悬浮液变成橙色,继续搅拌20分钟。将饱和氯化铵和盐酸(2N)加到该悬浮液中形成两层。然后加入羟基硼氢化钠(0.12g)并搅拌30分钟。分离两次,蒸发有机层并真空干燥。通过重结晶使产物部分分离和纯化,得到标题化合物(0.047g),母液通过柱过滤纯化得到更多的产物(0.04g,82%收率):
1H NMR(DMSO-d6)δ7.39(d,1H,J=7.35Hz),7.28(t,1H,J=7.47Hz),
7.13(d,1H,J=7.29Hz),6.86(d,1H,J=8.04Hz),6.72(d,1H,J=
7.95Hz),6.09(s,1Hz),6.02(s,1H),4.60-4.25(m,3H),4.20-4.03(m,2H),
3.75-3.68(m,1H),3.60-3.40(m,1H),3.02(s,3H);
C18H17NO2的LCMC计算值(M+):279.13。
实测值(MH+):280.13。
步骤B (±)-N-甲基-8,9-二羟基-2,3,7,11b-四氢-1H-萘[1,2,3-de]异喹啉
向冷却至-78℃下步骤A化合物(0.16mmol)的二氯甲烷(4ml)溶液中加三溴化硼(1M二氯甲烷溶液,0.77mmol)。反应溶液在-78℃下搅拌2小时并温热至室温过夜。将该溶液冷却至-78℃并加入无水甲醇使反应猝灭。搅拌10分钟后,除去溶剂并加入无水甲醇。该过程重复3次。通过用MeOH/CH2Cl2重结晶进行纯化得到标题化合物(0.035g):
1H NMR(MeOD-d3)δ7.37(d,1H,J=7.26Hz),7.29(t,1H,J=7.35Hz),
7.11(d,1H,J=7.32Hz),6.72(d,1H,J=8.19Hz),6.59(d,1H,J=8.49),
4.7-4.39(m,3H),4.20-4.05(m,1H)3.70-3.40(m,2H),3.20(s,3H);
C17H17NO2的LCMC计算值(M+):267.13。
实测值(MH+):268.16。
Claims (13)
2.权利要求1的方法,其中A为CH2。
3.权利要求2的方法,其中R1和R2结合形成-(CH2)n-,这里n为1。
4.权利要求3的方法,其中R4、R5和R6为氢。
5.权利要求1的方法,其中所述还原剂为氰基硼氢化钠。
6.权利要求1的方法,其中所述脱保护剂是三溴化硼。
8.权利要求7的化合物,其中R1和R2为氢并且A为CHOR1,这里R1为氢。
9.权利要求7的化合物,其中R1和R2为氢并且A为C=O。
10.权利要求8的化合物,其中R4、R5和R6为氢。
11.权利要求10的化合物,其中R为氢。
12.一种治疗多巴胺相关疾病的药物组合物,该组合物包含治疗有效量的权利要求7所定义的化合物和可药用载体或稀释剂。
13.一种治疗哺乳动物多巴胺相关疾病的方法,该方法包括给予所述哺乳动物治疗有效量的权利要求7所定义的化合物。
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US11168056B2 (en) | 2019-05-20 | 2021-11-09 | H. Lundbeck A/S | Process for the manufacturing of (6aR,10aR)-7-propyl-6,6a,7,8,9,10,10a,11-octahydro-[1,3]dioxolo[4′,5′:5,6]benzo[1,2-G]quinoline and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[G]quinoline-6,7-diol |
US11111263B2 (en) | 2019-05-20 | 2021-09-07 | H. Lundbeck A/S | Process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid |
US11130775B2 (en) | 2019-05-20 | 2021-09-28 | H. Lundbeck A/S | Solid forms of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid |
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- 2001-08-10 BR BR0113170-2A patent/BR0113170A/pt not_active Application Discontinuation
- 2001-08-10 AU AU2001288242A patent/AU2001288242B2/en not_active Ceased
- 2001-08-10 CA CA002417807A patent/CA2417807A1/en not_active Abandoned
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2003
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105980361A (zh) * | 2014-02-21 | 2016-09-28 | 法国施维雅药厂 | 用于治疗心血管疾病的5-苄基异喹啉衍生物 |
CN105980361B (zh) * | 2014-02-21 | 2019-05-21 | 法国施维雅药厂 | 用于治疗心血管疾病的5-苄基异喹啉衍生物 |
Also Published As
Publication number | Publication date |
---|---|
MXPA03001272A (es) | 2004-04-02 |
JP2004506014A (ja) | 2004-02-26 |
US6645975B1 (en) | 2003-11-11 |
EP1320367A1 (en) | 2003-06-25 |
BR0113170A (pt) | 2004-01-06 |
EP1320367A4 (en) | 2007-01-17 |
AU2001288242B2 (en) | 2005-11-17 |
KR20030027020A (ko) | 2003-04-03 |
NO20030515L (no) | 2003-03-31 |
NZ524212A (en) | 2004-07-30 |
NO20030515D0 (no) | 2003-02-03 |
CA2417807A1 (en) | 2002-02-21 |
WO2002013827A1 (en) | 2002-02-21 |
AU8824201A (en) | 2002-02-25 |
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