CN1535957A - 新的异喹啉化合物、它们的制备方法和含有它们的药物组合物 - Google Patents
新的异喹啉化合物、它们的制备方法和含有它们的药物组合物 Download PDFInfo
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- CN1535957A CN1535957A CNA2004100310343A CN200410031034A CN1535957A CN 1535957 A CN1535957 A CN 1535957A CN A2004100310343 A CNA2004100310343 A CN A2004100310343A CN 200410031034 A CN200410031034 A CN 200410031034A CN 1535957 A CN1535957 A CN 1535957A
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- BNARPIVTQPOTFL-UHFFFAOYSA-N n-[2-(6-methoxy-2-phenyl-3,4-dihydro-1h-isoquinolin-4-yl)ethyl]acetamide Chemical compound C1C(CCNC(C)=O)C2=CC(OC)=CC=C2CN1C1=CC=CC=C1 BNARPIVTQPOTFL-UHFFFAOYSA-N 0.000 claims 1
- PAEOENNQTFVPNO-UHFFFAOYSA-N n-[2-(6-methoxyisoquinolin-4-yl)ethyl]acetamide Chemical compound C1=NC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 PAEOENNQTFVPNO-UHFFFAOYSA-N 0.000 claims 1
- PKVSSRCSSWCMMX-UHFFFAOYSA-N n-[2-(6-methoxyisoquinolin-4-yl)ethyl]butanamide Chemical compound C1=C(OC)C=C2C(CCNC(=O)CCC)=CN=CC2=C1 PKVSSRCSSWCMMX-UHFFFAOYSA-N 0.000 claims 1
- LKEGKWOWRPHYAP-UHFFFAOYSA-N n-[2-(6-methoxyisoquinolin-4-yl)ethyl]cyclopropanecarboxamide Chemical compound C12=CC(OC)=CC=C2C=NC=C1CCNC(=O)C1CC1 LKEGKWOWRPHYAP-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A45—HAND OR TRAVELLING ARTICLES
- A45F—TRAVELLING OR CAMP EQUIPMENT: SACKS OR PACKS CARRIED ON THE BODY
- A45F5/00—Holders or carriers for hand articles; Holders or carriers for use while travelling or camping
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
本发明涉及式(I)化合物,其中:n是1、2或3,A代表基团(见右下式),X代表N或NR1,R2代表烷氧基、环烷基氧基或环烷基烷氧基。药物。
Description
本发明涉及新的异喹啉化合物、它们的制备方法和含有它们的药物组合物。
由文献已知:异喹啉化合物可用作血管舒张剂(US 4880817、US 4843071、US 4822800),或可用于植物的生长(Czasopismo Techniezne(Krakow),1992,89(1),7-12)、作为酪氨酸磷酸酶调节剂(WO 9946268)或还可用于合成(Tetrahedron Letters,2002,43(19),3557-3560;Heterocycles,2000,52(3),1371-1383)。
鉴于它们的原始结构,本发明化合物是新化合物且具有与褪黑激素能受体密切相关的药理学性质。
最近十年,大量研究已经证明:褪黑激素(N-乙酰基-5-甲氧基色胺)在大量生理病理学现象中和昼夜节律控制中扮演重要角色,但是褪黑激素具有相当短的半衰期,这是由于它被迅速代谢的缘故。因此关注的焦点在于获得临床褪黑激素类似物的可能性,所述类似物在代谢上更为稳定、具有激动剂或拮抗剂特征且可预期它们的治疗效果优于激素本身。
除了它们在昼夜节律障碍(J.Neurosurg.1985,63,321-341页)和睡眠障碍(Psychopharmacology,1990,100,222-226页)方面的有益作用外,褪黑激素能系统的配体还相对中枢神经系统具有宝贵的药理学性质,尤其是抗焦虑与抗精神病性质(Neuropharmacology of Pineal Secretions,1990,8(3-4),264-272页)和镇痛性质(Pharmacopsychiat.,1987,20,222-223页),还用于治疗帕金森氏病(J.Neurosurg.1985,63,321-341页)和阿尔茨海默氏病(Brain Research,1990,528,170-174页)。这些化合物在某些癌症(Melatonin-Clinical Perspectives,牛津大学出版社,1988,164-165页)、排卵(Science,1987,227,714-720页)、糖尿病(Clinical Endocrinology,1986,24,359-364页)和治疗肥胖(International Journal of Eating Disorders,1996,20(4),443-446页)方面的活性也已得到证明。这些各种各样的效果经由特异性褪黑激素受体的介导而发挥。分子生物学研究已经证明存在大量能够与该激素结合的受体亚型(Trends Pharmacol.Sci.,1995,16,50页;WO 9704094)。对于不同的物种、包括哺乳动物而言,已经有可能对一些这样的受体进行定位和鉴别。为了能够更好地理解这些受体的生理功能,获得选择性配体是非常有利的。而且,这类化合物通过选择性地与一种或另一种这些受体相互作用,可以在治疗与褪黑激素能系统有关的病变中成为医师的优选药物,有些病变已在上文中提及。
除了是新化合物以外,本发明的化合物可显示非常强的对褪黑激素受体的亲合性和/或对一种或另一种褪黑激素能受体亚型的选择性。
更特别的是,本发明涉及式(I)化合物、它们的对映异构体和非对映异构体,还涉及它们与可药用酸或碱的加成盐:
其中:
◆n是1、2或3,
其中:
●Z代表硫原子或氧原子,
●R和R”可以相同或不同,各自代表氢原子或直链或支链(C1-C6)烷基,
●且R’代表直链或支链(C1-C6)烷基、直链或支链(C2-C6)链烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C3-C8)环烷基-(C1-C6)烷基——其中的烷基部分是直链或支链的、芳基、芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的、杂芳基或杂芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的,
◆X代表氮原子或基团N-R1,其中R1代表氢原子或直链或支链(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烷基-(C1-C6)烷基——其中的烷基部分是直链或支链的、芳基、芳酰基、芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的、杂芳基、杂芳酰基或杂芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的,
◆R2代表直链或支链(C1-C6)烷氧基、(C3-C8)环烷基氧基或(C3-C8)环烷基-(C1-C6)烷氧基——其中的烷氧基部分是直链或支链的,
其中:
“芳基”应被理解为意指苯基或萘基,这些基团是未取代的或被一至三个相同或不同的基团取代,取代基选自直链或支链(C1-C6)烷基、直链或支链(C1-C6)烷氧基、OH、COOH、烷氧基羰基——其中的烷氧基部分是直链或支链的、甲酰基、硝基、氰基、羟甲基、氨基——任选被一或两个直链或支链(C1-C6)烷基取代,和卤原子,
“杂芳基”应被理解为意指任何单-或双-环基团,其含有5至10个环成员且可含有1至3个选自氧、硫和氮的杂原子,如呋喃基、噻吩基、吡咯基、咪唑啉基、吡啶基、喹啉基、异喹啉基、苯并二氢吡喃基、吲哚基、苯并噻吩基或苯并呋喃基,这些基团有可能是部分氢化的、未取代的或被一至三个相同或不同的基团取代,取代基选自直链或支链(C1-C6)烷基、直链或支链(C1-C6)烷氧基、OH、COOH、烷氧基羰基——其中的烷氧基部分是直链或支链的、甲酰基、硝基、氰基、氨基——任选被一或两个直链或支链(C1-C6)烷基取代、羟甲基和卤原子。
在可药用的酸中,可不加任何限制地提及盐酸、氢溴酸、硫酸、磷酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、柠檬酸、抗坏血酸、甲磺酸、樟脑酸等。
在可药用的碱中,可不加任何限制地提及氢氧化钠、氢氧化钾、三乙胺、叔丁胺等。
优选的n值是2和3。
优选的本发明化合物是这样的式(I)化合物,其中:
●n是2且A代表-NHCOR’基团,更特别地代表这样的-NHCOR’基团:其中R’代表直链或支链(C1-C6)烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基或己基,或(C3-C8)环烷基,例如环丙基、环丁基、环戊基或环己基,
●n是3且A代表-CONHR’基团、更特别地代表这样的-CONHR’基团:其中R’代表直链或支链(C1-C6)烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基或己基,或(C3-C8)环烷基,例如环丙基、环丁基、环戊基或环己基。
优选的R2基团是烷氧基、更特别地是甲氧基。
X优选代表氮原子或NR1基团,其中R1代表环烷基烷基、未取代或取代的苯基、或苄基——其中的苯基部分是取代的或未取代的。
进而更优选地,本发明涉及下列式(I)化合物:
-N-[2-(6-甲氧基-4-异喹啉基)乙基]乙酰胺,
-N-[2-(6-甲氧基-4-异喹啉基)乙基]丁酰胺,
-N-[2—(6-甲氧基-4-异喹啉基)乙基]丙酰胺,
-N-[2-(6-甲氧基-4-异喹啉基)乙基]环丙烷酰胺,
-4-(6-甲氧基-4-异喹啉基)-N-甲基丁酰胺,
-N-[2-(6-甲氧基-2-苯基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺,
-N-[2-(2-苄基-6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺,
-N-{2-[2-(环丙基甲基)-6-甲氧基-1,2,3,4-四氢-4-异喹啉基]乙基}乙酰胺。
优选的本发明化合物的对映异构体、非对映异构体和与可药用酸或碱的加成盐构成本发明的主要部分。
本发明还涉及式(I)化合物的制备方法,该方法的特征在于使用式(II)化合物作为起始物质:
其中R2和n如式(I)所定义且Ra代表直链或支链(C1-C6)烷基,
使其受到POCl3的作用,得到式(III)化合物:
其中R2、n和Ra如上所定义,
—将其置于披钯碳存在下,得到式(IV)化合物:
其中R2、n和Ra如上所定义,
—或在披钯碳存在下对其进行氢化,得到式(V)化合物:
其中R2、n和Ra如上所定义,
使该式(V)化合物与式G-R’1化合物缩合,其中G代表离去基团如卤原子或叔丁氧基羰基,且R’1可具有R1所给出的任何含义,氢原子除外,得到式(VI)化合物:
其中R2、R’1、n和Ra如上所定义,
式(III)至(VI)化合物构成式(VII)化合物:
其中R2、n和Ra如上所定义,且X和符号
如式(I)所定义,使其与式HNRR’的胺缩合,其中R和R’如式(I)所定义,得到式(I/a)化合物,为式(I)化合物的一个特例:
或使该式(VII)化合物进行有机化学中常规的反应序列,得到式(VIII)化合物:
其中R2、X、n和符号
如上所定义,使其:
—与酰氯ClCOR’或对应的混合或对称的酐反应,其中R’如上所定义,得到式(I/b)化合物,为式(I)化合物的一个特例:
其中R2、R’、X、n和符号
如上所定义,
任选地继之以式R’a-J化合物的作用,其中R’a可以具有R’的任何含义且J代表离去基团如卤原子或甲苯磺酰基,得到式(I/c)化合物,为式(I)化合物的一个特例:
其中R2、R’、R’a、X、n和符号
如上所定义,
—或者受到式(IX)化合物的作用:
其中R’如上所定义,任选地继之以如上所定义的式R’a-J化合物的作用,得到式(I/d)化合物,为式(I)化合物的一个特例:
式(I/a)至(I/d)化合物有可能受到硫化剂、例如Lawesson试剂的作用,得到式(I/e)化合物,为式(I)化合物的一个特例:
其中R2、n和符号
如上所定义且B代表C(S)NRR’、N(R)C(S)R’或N(R)C(S)NR’R”基团,其中R、R’和R”如上所定义,
式(I/a)至(I/e)化合物构成式(I)化合物的全体,这些化合物可按照常规分离技术加以纯化,如果需要将其转化为与可药用酸或碱的加成盐,并且任选地按照常规分离技术分离为异构体。
起始化合物(II)是市售可得的,或者本领域技术人员借助常规化学反应或文献所述化学反应可容易地获得。
本发明化合物和含有它们的药物组合物经证明可用于治疗褪黑激素能系统的障碍。
本发明化合物的药理学研究事实上已经证明:它们是无毒的、对褪黑激素受体具有高亲合性且就中枢神经系统和微循环而言具有实质性活性,从而能够确定:本发明的产物可用于治疗紧张状态、睡眠障碍、焦虑、严重抑郁、季节性情感障碍、心血管病变、消化系统病变、由飞行时差引起的失眠与疲劳、精神分裂症、恐慌发作、忧郁、食欲障碍、肥胖、失眠、疼痛、精神病性精神障碍、癫痫、糖尿病、帕金森氏病、老年性痴呆、与正常或病理性衰老有关的各种障碍、偏头痛、记忆丧失、阿尔茨海默氏病和脑循环障碍。在活性的另一领域,本发明产物似乎可用于治疗性功能障碍、具有抑制排卵和免疫调节性质且可用于治疗癌症。
这些化合物将优选用于治疗严重抑郁、季节性情感障碍、睡眠障碍、心血管病变、由飞行时差引起的失眠与疲劳、食欲障碍和肥胖。
例如,这些化合物可用于治疗季节性情感障碍和睡眠障碍。
本发明还涉及药物组合物,其包含至少一种式(I)化合物本身或其与一种或多种可药用赋形剂的组合。
在本发明的药物组合物中,特别地可提及那些适合于口服、肠胃外、鼻、经皮或透皮、直肠、经舌、眼或呼吸施用的组合物,特别是片剂或糖衣丸、舌下片、药囊剂、paquet、明胶胶囊剂、glossette、锭剂、栓剂、霜剂、软膏剂、皮肤凝胶剂和可饮用或可注射的安瓿剂。
剂量根据患者的性别、年龄与体重、施用途径、治疗适应症的属性或任何有关的治疗而异,每24小时0.01mg至1g,分一次或多次施用。
下列实施例阐述本发明而非以任何方式对其进行限制。下列制备例生成本发明化合物或用于制备本发明化合物的合成中间体。
制备例1:4-(6-甲氧基-3,4-二氢-4-异喹啉基)丁酸乙酯盐酸盐
步骤A:5-氰基-5-(3-甲氧基苯基)戊酸乙酯
在0℃下,将2g(3-甲氧基苯基)乙腈和1.5ml 4-溴丁酸乙酯溶于50ml二甲基甲酰胺中。向该溶液逐渐加入600mg 60%氢化钠(600mg,15mmol)。将反应混合物在环境温度下搅拌4小时、加入100ml酸性水并用醚萃取。然后将有机相经硫酸镁干燥,过滤并在减压下蒸发。所得油经柱纯化(洗脱剂:醚/环己烷4/6),得到黄色油形式的标题产物。
步骤B:6-氨基-5-(3-甲氧基苯基)己酸乙酯盐酸盐
将步骤A所得化合物(11.2g,43mmol)预先溶于150ml乙醇中,倒入高压釜内,然后加入阮内镍(以重量计10%)。然后将混合物置于氢压下(10巴)并在50℃下加热48小时,同时搅拌。过滤除去阮内镍后,在减压下蒸发有机相。将醚加入所得残余物中,向该溶液通入HCl气,然后搅拌直至沉淀出现。然后抽吸滤出所得沉淀并从甲苯中重结晶,得到白色固体形式的标题产物。
熔点:104-106℃
步骤C:6-(甲酰氨基)-5-(3-甲氧基苯基)己酸乙酯
将碱形式的步骤B所得的胺(6.4g,27mmol)溶于60ml甲酸乙酯中。将反应混合物在回流下加热6小时,同时搅拌,然后在减压下蒸发。将醚加入所得残余物中。然后连续用酸性水(1N HCl)、水和10%碳酸氢盐溶液洗涤有机相,随后经硫酸镁干燥,过滤并在减压下蒸发,得到黄色油形式的标题产物。
步骤D:4-(6-甲氧基-3,4-二氢-4-异喹啉基)丁酸乙酯盐酸盐
将步骤C所得的甲醛(6.8g,23mmol)溶于100ml乙腈中,然后将反应混合物加热至约60℃。向该溶液加入磷酰氯(7ml),在回流下加热6小时,同时搅拌,然后在减压下蒸发。将乙醇加入所得残余物中、再于减压下蒸发,重复两次,然后加入水。用二氯甲烷洗涤水相,然后用饱和碳酸氢钠溶液使其呈碱性并用二氯甲烷萃取。将有机相经硫酸镁干燥,过滤并在减压下蒸发。将用HCl气饱和的醚加入所得油中,然后在减压下蒸发。在加热状态下将甲苯加入残余物中并搅拌直至沉淀出现。然后抽吸滤出所得沉淀,得到白色固体形式的标题产物。
熔点:97-99℃
制备例2:4-(2-氨基乙基)-6-甲氧基-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
步骤A:氰基(3-甲氧基苯基)乙酸甲酯
在锥形圆口烧瓶内,将25g(3-甲氧基苯基)乙腈溶于200ml无水THF中。向该溶液加入60%氢化钠(8.88g,0.37mol)并将反应混合物在回流下加热30分钟,同时搅拌。然后在半小时内滴加碳酸二甲酯(58ml,0.6814mol),随后将反应混合物在回流下加热2小时,同时搅拌。将反应混合物倒入微酸性冷水中。水相用醚萃取,然后用水洗涤醚相,再蒸发。向上述所得油中加入碳酸钾(47.15g,0.34mol)溶液。搅拌后,混合物用醚洗涤。将所得醚相重新用碳酸钾(12.02g,0.08mol)溶液洗涤。合并两份水相,立即酸化并用醚萃取。将如此得到的有机相用10%碳酸氢钠溶液洗涤、经硫酸镁干燥并在减压下蒸发,得到橙黄色油形式的标题产物。
步骤B:3-氨基-2-(3-甲氧基苯基)丙酸甲酯盐酸盐
将步骤A所得化合物(34.32g,0.1672mol)溶于150ml甲醇中。将该溶液倒入高压釜内,然后向溶液加入50ml氯仿和氧化铂(以重量计10%)。将高压釜置于氢压(60巴)和环境温度下,磁力搅拌24小时。过滤除去催化剂后,在减压下蒸发溶液。将醚加入所得的油中。抽吸滤出所生成的沉淀并从乙腈中重结晶,得到白色固体形式的标题产物。
熔点:170-172℃
步骤C:3-(甲酰氨基)-2-(3-甲氧基苯基)丙酸甲酯
将碱形式的步骤B所得化合物(20.25g,0.08mol)溶于130ml甲酸乙酯(1.81mol)中。将反应混合物在回流下加热6小时,然后在减压下蒸发。将乙酸乙酯加入所得的油中。将有机相用碱性水(NaHCO3)洗涤,经硫酸镁干燥,过滤并蒸发,得到黄色油形式的标题产物。
步骤D:6-甲氧基-3,4-二氢-4-异喹啉甲酸甲酯盐酸盐
将步骤C所得化合物(8.03g,0.03mol)溶于100ml乙腈中,然后将反应混合物加热至大约60℃。向该溶液加入磷酰氯(16ml,0.17mol),然后在回流下加热6小时,同时搅拌,随后在减压下蒸发。将甲醇加入所得残余物、再于减压下蒸发,重复两次,然后加入最少量的丙酮。随后抽吸滤出所生成的沉淀,得到白色固体形式的标题产物。
熔点:212-215℃
步骤E:6-甲氧基-1,2,3,4-四氢-4-异喹啉甲酸甲酯盐酸盐
将碱形式的步骤D所得化合物(9.21g)溶于150ml甲醇中,然后向该溶液加入披钯碳(900mg)。将反应混合物在环境温度和氢气下搅拌4小时。过滤除去披钯碳后,在减压下蒸发有机相。将用HCl饱和的醚加入所得的油中。抽吸滤出所生成的沉淀并从乙腈中重结晶,得到白色固体形式的标题产物。
熔点:191-193℃
步骤F:6-甲氧基-3,4-二氢-2,4(1H)-异喹啉二甲酸叔丁基4-甲基酯
将步骤E所得化合物(4.02g,15mmol)悬浮于100ml二氯甲烷中,然后加入三乙胺(6.6ml)。当溶解完全时,加入二碳酸二叔丁酯(4g,18mmol)并将反应混合物在环境温度下搅拌30分钟。将溶液倒入100ml水中,用酸性水(0.1N HCl)中和过量的三乙胺。分离后,水相用二氯甲烷萃取,合并的有机溶液经硫酸镁干燥,过滤并在减压下蒸发。经硅胶色谱法纯化标题产物。
无色的油。
步骤G:4-(羟甲基)-6-甲氧基-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
将氢化铝锂(5.62g,148mmol)悬浮于50ml无水四氢呋喃中。然后滴加预先溶于50ml无水四氢呋喃的步骤F所得化合物(11.9g,37mmol)的溶液。然后将反应混合物在环境温度下搅拌2小时。向反应混合物加入最少量的氢氧化钠溶液(2N NaOH),直至气体的生成停止,以便生成锂与铝的氢氧化物沉淀。然后滤出沉淀,用四氢呋喃洗涤。在减压下蒸发有机相。经硅胶色谱法纯化标题产物。
澄清的黄色油。
步骤H:6-甲氧基-4-{[(甲基磺酰基)氧基]甲基}-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
将步骤G所得化合物(10.5g,36mmol)溶于150ml二氯甲烷中,然后加入三乙胺(8.5ml)。将该溶液冷却至0℃并滴加甲磺酰氯(4.8ml,62mmol)。将反应混合物在环境温度下搅拌2小时,然后倒入150ml水中。将溶液用二氯甲烷萃取,经硫酸镁干燥,过滤并于减压下蒸发。经硅胶色谱法纯化标题化合物。
黄色的油。
步骤I:4-(氰基甲基)-6-甲氧基-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
将氰化钾(5.52g,85mmol)悬浮于50ml DMSO中,将该溶液加热至80℃。向该溶液逐渐加入预先溶于50ml DMSO的步骤H所得化合物(6.3g,17mmol),然后将反应混合物再次于80℃下加热30分钟。将溶液倒入150ml水中并用二氯甲烷萃取三次。然后将有机相经硫酸镁干燥、过滤并蒸发。所得暗红色油经硅胶色谱法纯化(洗脱剂:环己烷,逐渐加入乙酸乙酯,直至比例达到8/2),使所得固体从环己烷中重结晶,得到白色固体形式的标题产物。
熔点:75-77℃
步骤J:4-(2-氨基乙基)-6-甲氧基-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
将步骤I所得化合物(6.3g,21mmol)溶于150ml用NH3气饱和的甲醇中。将该溶液倒入高压釜内,加入阮内镍(600mg)。然后将反应混合物在60℃和50巴氢压下搅拌6小时。过滤除去催化剂后,在减压下蒸发溶液,得到无色油形式的标题化合物。
制备例3:(6-甲氧基-4-异喹啉基)乙腈盐酸盐
步骤A:6-甲氧基-4-异喹啉甲酸甲酯盐酸盐
将碱形式的制备例2步骤D所得化合物(1.56g,0.006mol)溶于10ml十氢化萘中,然后加入活性披钯碳(以重量计10%)。将反应混合物在130℃下加热24小时,同时搅拌。在加热状态中滤出催化剂并用乙酸乙酯洗涤。在减压下蒸发后,将用HCl气饱和的醚溶液加入所得油中。抽吸滤出所生成的沉淀并从乙腈中重结晶,得到白色固体形式的标题产物。
熔点:178-180℃
步骤B:(6-甲氧基-4-异喹啉基)甲醇盐酸盐
将碱形式的步骤A所得化合物(0.395g,0.0015mol)溶于200ml醚中。然后逐渐加入氢化铝锂(0.14g,0.004mol),同时使烧瓶在冰中冷却。将反应混合物在环境温度下搅拌一周。向反应混合物加入最少量30%氢氧化钠溶液(几滴),以生成锂与铝的氢氧化物沉淀。然后滤出沉淀并用乙酸乙酯洗涤。将有机相经硫酸镁干燥,过滤并在减压下蒸发。将用HCl气饱和的醚加入所得油中。抽吸滤出所生成的沉淀并从乙腈中重结晶,得到白色固体形式的标题产物。
熔点:250-252℃
步骤C:4-(氯甲基)-6-甲氧基异喹啉
将步骤B所得化合物的盐酸盐(1.09g,0.005mol)悬浮于50ml氯仿中。加入亚硫酰氯(2.80ml,0.04mol),然后将反应混合物在回流下加热24小时,同时搅拌。在减压下蒸发后,将乙醚加入所得残余物中。抽吸滤出所生成的沉淀并从乙腈中重结晶,得到白色固体形式的标题化合物。
熔点:256-257℃
步骤D:(6-甲氧基-4-异喹啉基)乙腈盐酸盐
将步骤C所得化合物的盐酸盐(0.60g,0.0024mol)溶于10ml饱和碳酸钾水溶液和40ml二氯甲烷中。然后向前述溶液加入四丁基溴化铵(2g,0.006mol)和氰化钾(0.80g,0.012mol)。将反应混合物在环境温度下搅拌24小时。用二氯甲烷萃取溶液,将有机相用水洗涤,经硫酸镁干燥,过滤并蒸发。向所得的油加入丙酮和用HCl气饱和的醚。抽吸滤出所生成的沉淀并从甲苯/环己烷5/5中重结晶,得到黄色固体形式的标题化合物。
熔点:114-115℃
制备例4:4-(氨基甲基)-6-甲氧基-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
步骤A:6-甲氧基-4-{[(甲基磺酰基)氧基]甲基}-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
工艺同制备例2步骤A至H。
步骤B:4-(叠氮基甲基)-6-甲氧基-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
将叠氮化钠(1.12g)悬浮于40ml DMF中,将该溶液加热至80℃。向前述溶液逐渐加入预先溶于10ml DMF的步骤A所得化合物(1.6g),然后将反应混合物再次于80℃下加热2至3小时。将溶液倒入150ml水中并用乙酸乙酯萃取三次。然后将有机相经硫酸镁干燥,过滤并蒸发。所得暗红色油经硅胶色谱法纯化(洗脱剂:环己烷,逐渐加入乙酸乙酯,直至比例达到5/5),得到无色油形式的标题产物。
步骤C:4-(氨基甲基)-6-甲氧基-3,4-二氢-2(1H)-异喹啉甲酸叔丁酯
将步骤B所得化合物(1.14g)溶于100ml甲醇中,然后向该溶液加入披钯碳(120mg)。将反应混合物在环境温度和氢下搅拌3小时。过滤除去披钯碳后,在减压下蒸发有机相。所得残余物经硅胶色谱法纯化(洗脱剂:环己烷,逐渐加入乙酸乙酯,直至比例达到5/5),得到无色油形式的标题产物。
实施例1:4-(6-甲氧基-3,4-二氢-4-异喹啉基)-N-甲基丁酰胺
将碱形式的制备例1所得化合物(41mmol)溶于10ml乙醇中。加入60ml含水甲胺,并将反应混合物在环境温度下搅拌12小时。在减压下蒸发后,将50ml水加入滤液中并用二氯甲烷萃取。将有机相用水洗涤,经硫酸镁干燥,过滤并在减压下蒸发。所得油经硅胶色谱法纯化后,得到标题产物。
黄色油。
实施例2:4-(6-甲氧基-1,2,3,4-四氢-4-异喹啉基)-N-甲基丁酰胺
将碱形式的实施例1所得化合物(54mmol)溶于50ml甲醇中,然后向该溶液加入披钯碳(150mg)。将反应混合物在环境温度和氢下搅拌4小时。过滤除去披钯碳后,在减压下蒸发有机相。所得油经硅胶色谱法纯化,得到黄色油形式的标题产物。
实施例3:4-(6-甲氧基-4-异喹啉基)-N-甲基丁酰胺
步骤A:4-(6-甲氧基-4-异喹啉基)丁酸乙酯盐酸盐
在加热条件下,将制备例1所得化合物(1.6g,5mmol)溶于20ml含有三乙胺(0.9ml)和无水乙醇(2ml)的甲苯中。向反应混合物加入披钯碳(300mg),然后在回流下加热24小时,同时搅拌。过滤除去披钯碳后,在减压下蒸发有机相。所得残余物经硅胶色谱法纯化(洗脱剂:二氯甲烷,逐渐加入甲醇)。将所得油转化为盐酸盐形式,然后使所生成的沉淀从乙腈中重结晶。
熔点:190-192℃
步骤B:4-(6-甲氧基-4-异喹啉基)-N-甲基丁酰胺
将步骤A所得化合物(2.2g,7mmol)溶于30ml甲胺(40%水溶液),将混合物在回流下加热3小时,同时搅拌。将50ml水加入反应混合物并用醚萃取。将有机相用水洗涤,经硫酸镁干燥,过滤并在减压下蒸发。所得油经硅胶色谱法纯化(洗脱剂:二氯甲烷,逐渐加入甲醇)。在减压下蒸发所得油,使所生成的沉淀从甲苯中重结晶,得到白色固体形式的标题产物。
熔点:117-119℃
元素微量分析:
C% | H% | N% | |
计算值 | 69.74 | 7.02 | 10.84 |
实测值 | 69.64 | 7.22 | 10.83 |
实施例4:N-[2-(6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺盐酸盐
将制备例2步骤I所得化合物(6g,20mmol)溶于100ml乙酸酐中,然后将该溶液倒入高压釜内。随后向该溶液加入阮内镍(600mg),将反应混合物在60℃和50巴氢压下搅拌6小时。过滤除去催化剂后,在减压下蒸发溶液。向所得橙色残余物加入10%氢氧化钠溶液并搅拌15分钟,然后用乙酸乙酯萃取(3次)。将有机相用水洗涤一次,经硫酸镁干燥,过滤并在减压下蒸发。将50ml甲醇加入所得油中。将氯化氢气通入溶液中,然后搅拌24小时,用CaCl2隔水。在减压下蒸发溶液并使所得沉淀从乙腈中重结晶,得到白色固体形式的标题产物。
熔点:182-184℃
实施例5:N-[2-(6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]丙酰胺盐酸盐
将制备例2所得化合物和2当量碳酸钾溶于3/2乙酸乙酯/水混合物中。然后向该溶液滴加丙酰氯(2当量)。将反应混合物在环境温度下搅拌1小时。分离各相后,将有机相用水洗涤,经硫酸镁干燥,过滤并在减压下蒸发。所得油经硅胶色谱法纯化(洗脱剂:乙酸乙酯/环己烷5/5)。将甲醇加入所得油中。将氯化氢气通入溶液中,然后搅拌24小时,用CaCl2各隔水。在减压下蒸发溶液,得到白色固体形式的标题化合物。
熔点:161-163℃
实施例6:N-[2-(6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]丁酰胺盐酸盐
用丁酰氯代替丙酰氯,通过与实施例5相同的工艺得到标题化合物。
吸湿性非常强的白色固体。
实施例7:N-[2-(6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]环丙烷酰胺盐酸盐
用环丙基碳酰氯代替丙酰氯,通过与实施例5相同的工艺得到标题化合物。
白色固体。
熔点:215-217℃
实施例8:N-[2-(6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]环丁烷酰胺盐酸盐
用环丁基碳酰氯代替丙酰氯,通过与实施例5相同的工艺得到标题化合物。
白色固体。
熔点:130-132℃
实施例9:N-[2-(6-甲氧基-4-异喹啉基)乙基]乙酰胺盐酸盐
将碱形式的制备例3所得化合物(0.30g,0.0015mol)预先溶于10ml乙酸酐,倒入高压釜内,然后加入阮内镍(以重量计10%)。然后将混合物置于氢压(60巴)下并于60℃下加热6小时,同时搅拌。过滤除去阮内镍后,在环境温度下向有机相加入10%氢氧化钠溶液并磁力搅拌15分钟。溶液用乙酸乙酯萃取,将有机相用盐水洗涤,经硫酸镁干燥,过滤并在减压下蒸发。所得油经柱纯化(洗脱剂:二氯甲烷,逐渐加入甲醇,直至比例达到9/1)。将用HCl气饱和的醚加入纯化油中。抽吸滤出所生成的沉淀并从乙醇中重结晶,得到白色固体形式的标题产物。
熔点:212-214℃
实施例10:N-[2-(6-甲氧基-4-异喹啉基)乙基]丙酰胺盐酸盐
在加热条件下,将实施例5的化合物溶于最少量的甲醇中,然后用甲苯稀释。继而向该溶液加入1.5当量三乙胺,随后在披钯碳(以重量计10%)存在下将反应混合物在回流下加热3小时。过滤除去催化剂后,在减压下蒸发溶液。所得油经硅胶色谱法纯化(洗脱剂:二氯甲烷/甲醇9/1)。将用HCl气饱和的醚加入纯化油中,搅拌直至得到沉淀。抽吸滤出所生成的沉淀,置于真空干燥器内。得到白色固体形式的标题产物。
熔点:233-235℃
实施例11:N-[2-(6-甲氧基-4-异喹啉基)乙基]丁酰胺盐酸盐
从实施例6所得化合物开始,按照与实施例10相同的工艺得到标题化合物。
熔点:195-197℃
实施例12:N-[2-(6-甲氧基-4-异喹啉基)乙基]环丙烷酰胺盐酸盐
从实施例7所得化合物开始,按照与实施例10相同的工艺得到标题化合物。
熔点:226-228℃
实施例13:N-[2-(6-甲氧基-2-苯基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺盐
酸盐
将碱形式的实施例4所得化合物(460mg,1.8mmol)悬浮于30ml二氯甲烷中。然后加入三苯基铋(900mg,2mmol)和乙酸铜Cu(OAc)2(190mg,0.95mmol)。将反应混合物置于氩气下并在环境温度下磁力搅拌18小时。将混合物过滤,加入水并用乙酸乙酯萃取。将有机相经硫酸镁干燥,过滤并在减压下蒸发。所得残余物经硅胶色谱法纯化(洗脱剂:乙酸乙酯/环己烷2/8)。将用HCl气饱和的醚加入纯化油中,搅拌直至得到沉淀,然后抽吸滤出该沉淀,置于真空干燥器内,得到白色固体形式的标题产物。
熔点:83-85℃
实施例14:N-[2-(2-苄基-6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺
将实施例4所得化合物(740mg,2.5mmol)和碳酸钾(720mg,5mmol)悬浮于20ml DMF中,然后向该溶液加入苄基溴(0.37ml,3mmol)。将反应混合物在125℃下加热4小时,同时搅拌。将溶液倒入50ml水中,用6N HCl酸化并用乙酸乙酯洗涤。然后用碳酸钾使水相呈碱性并用二氯甲烷萃取。将有机相经硫酸镁干燥,过滤并在减压下蒸发。所得残余物经硅胶色谱法纯化(洗脱剂:二氯甲烷,逐渐加入甲醇,直至比例达到9/1)。纯化的油生成沉淀。使所生成的沉淀从7/3甲苯/环己烷混合物中重结晶,得到白色固体形式的标题产物。
熔点:123-125℃
实施例15:N-{2-[2-(3-甲酰基苯基)-6-甲氧基-1,2,3,4-四氢-4-异喹啉基]乙基}
乙酰胺
将乙酸铜Cu(OAc)2(960mg,5mmol)和三乙胺(1.5ml,10.5mmol)悬浮于60ml二氯甲烷中。然后向该溶液接连逐渐加入实施例4化合物(1g,3.5mmol)、3-甲酰基苯基硼酸(1.05g,7mmol)和分子筛。将反应混合物在环境温度下搅拌2小时。将混合物过滤,用水洗涤,经硫酸镁干燥,过滤并在减压下蒸发。所得残余物经硅胶色谱法纯化(洗脱剂:二氯甲烷,逐渐加入甲醇,直至比例达到9/1),得到黄色油形式的标题产物。
实施例16:N-[2-(6-甲氧基-2-甲基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺盐
酸盐
在0℃下,向碱形式的实施例4所得化合物(1.8g,7.2mmol)加入甲酸(0.55ml)和37%甲醛(0.6ml)。将反应混合物在80℃下加热24小时,同时搅拌。反应混合物冷却至0℃后,加入10ml 6N HCl。然后将混合物用醚洗涤,用2N NaOH使其呈碱性并用醚萃取。将有机相经硫酸镁干燥,过滤并在减压下蒸发。所得黄色的油经硅胶色谱法纯化(洗脱剂:二氯甲烷,逐渐加入甲醇,直至比例达到9/1)。将用HCl气饱和的醚加入纯化油中,搅拌直至得到沉淀,然后抽吸滤出该沉淀并置于真空干燥器内,得到吸湿性非常强的白色固体形式的标题产物。
熔点:59-61℃
实施例17:N-{2-[2-(环丙基甲基)-6-甲氧基-1,2,3,4-四氢-4-异喹啉基]乙基}
乙酰胺盐酸盐
将实施例4所得化合物(1.03g)和碳酸钾(1.25g)悬浮于50ml丙酮中。将该溶液在环境温度下搅拌10分钟,然后向溶液加入溴代甲基环丙烷(0.36ml)。将反应混合物在环境温度下搅拌12小时。滤出碳酸钾并蒸发所回收的溶液。将水加入残余物中,水相用醚萃取。将有机相经硫酸镁干燥,过滤并在减压下蒸发。所得残余物经硅胶色谱法纯化(洗脱剂:二氯甲烷,逐渐加入甲醇,直至比例达到9/1)。将用HCl气饱和的醚加入纯化油中,搅拌直至得到沉淀,然后抽吸滤出该沉淀并置于真空干燥器内,得到吸湿性白色固体形式的标题产物。
熔点:<50℃
实施例18:N-[(6-甲氧基-1,2,3,4-四氢-4-异喹啉基)甲基]乙酰胺盐酸盐
将制备例4所得化合物(0.77g)和碳酸钾(1.8g)溶于50ml 1/1二氯甲烷/水混合物中。然后向该溶液滴加乙酰氯(0.47ml)。将反应混合物在环境温度下搅拌2小时。分离各相后,将有机相用水洗涤,经硫酸镁干燥,过滤并在减压下蒸发。将甲醇加入所得油中。将氯化氢气通入该溶液,然后利用CaCl2护罩搅拌24小时,为脱保护时间。在减压下蒸发溶液并使所得沉淀从乙腈中重结晶,得到白色固体形式的标题产物。
熔点:246-248℃
药理学研究
实施例A:急性毒性研究
每8只小鼠(26±2g)为一组,在口服给药后评价急性毒性。在第一天中定时观察动物,并于处置后两周内每天观察。对LD50(导致50%动物死亡的剂量)进行了评价证明了本发明化合物的低毒性。
实施例B:强迫游泳试验
在行为模型、即强迫游泳试验中测试本发明化合物。
装置为充满水的Plexiglas圆筒。动物逐个试验6分钟。在每次试验开始时,将动物置于圆筒中心。记录不动时间。当每只动物停止挣扎并在水表面上保持不动、只作出使头露出水面的动作时,判断为不动。
在试验开始前给药40分钟后,本发明化合物显著地减少了不动时间,证明了本发明化合物的抗抑郁活性。确切而言,实施例9的化合物以2.5mg/kg经口给药,导致不动持续时间从102秒(对照)减少至57秒。实施例3的化合物以25mg/kg经口给药,导致不动持续时间从129秒(对照)减少至60秒。
实施例C:与褪黑激素受体MT1和MT2结合的研究
使用2-[125I]-碘褪黑激素作为参照放射性配体,进行MT1或MT2受体结合实验。使用液体闪烁计数器测定所保留的放射性。
然后使用不同的供试化合物进行竞争性结合实验,一式三份。就每种化合物而言测试不同的浓度范围。从结果可确定供试化合物的结合亲合性(Ki)。
由此,所发现的本发明化合物的Ki值显示了对一种或另一种受体亚型MT1或MT2的结合,这些值≤10μM。确切而言,实施例9的化合物的Ki(MT1)为9.12×10-9M,Ki(MT2)为2.16×10-9M;实施例3的化合物的Ki(MT1)为3.8×10-9M,Ki(MT2)为2.6×10-9M;实施例10的化合物的Ki(MT1)为4.26×10-9M,Ki(MT2)为1.14×10-9M。
实施例D:本发明化合物对大鼠运动活动昼夜节律的作用
褪黑激素在借助昼/夜交替影响大部分生理、生化与行为昼夜节律中的牵连已使得有可能建立供探究褪黑激素能配体的药理模型。
相对于众多参数、尤其是相对于运动活动的昼夜节律,即内源性昼夜节律钟活动的可靠指标,测试了化合物的效果。
本研究中,评价了这类化合物对特定实验模型,即置于暂时隔离(永久性黑暗)的大鼠的效果。
实验方案
一月龄雄性大鼠一旦到达实验室,立即接受每24小时光照12小时的光照周期(LD 12:12)。
适应2至3周后,将它们置于装有轮子的笼内,轮子与记录系统连接,以便检测运动活动阶段,从而监测昼(LD)或夜(DD)节律。
一旦所记录的节律于光照周期LD 12:12下显示稳定模式,立即将大鼠置于永久性黑暗中(DD)。
2至3周后,当已明确建立自由期(反映内源性时钟的节律)时,向大鼠每日施用供试化合物。
通过目视观察活动的节律:
-光照节律对活动节律的影响,
-对永久性黑暗中节律的影响的消失,
-每日施用化合物的影响;暂时的或持久的效果。
利用软件包有可能:
-测量自由期和处置期间动物活动的持续时间与强度和节律期,
-如果有的话,通过光谱分析证明昼夜与非昼夜(例如次昼夜)成分的存在。
结果
本发明化合物明确显示经由褪黑激素能系统对昼夜节律具有强大的作用。
实施例E:明/暗笼试验
在行为模型、即明/暗笼试验中测试本发明化合物,该试验可揭示化合物的抗焦虑活性。
设备包括两个聚乙烯箱子,用Plexiglas覆盖。其中一个箱子处于黑暗中。另一个箱子上方装有灯,在箱子中心产生大约4000勒克斯的光强度。一条不透明塑料通道将明箱与暗箱分开。动物逐个试验5分钟。在每次试验期间清扫每个箱子的地面。在每次试验开始时,将小鼠置于通道内,面向暗箱。记录小鼠在第一次进入暗箱之后于明箱内度过的时间和穿过通道的次数。
在试验开始前施用化合物30分钟后,本发明化合物显著地增加了在明笼内度过的时间和穿过通道的次数,这证明了本发明化合物的抗焦虑活性。
实施例F:本发明化合物对大鼠尾动脉的活性
体外测试了本发明化合物对大鼠尾动脉的活性。在这些血管中存在褪黑激素能受体,因而为研究褪黑激素能配体的活性提供了相关的药理模型。刺激受体能够诱导血管收缩或舒张,这依赖于所研究的动脉节段。
方案
在2至3周内,使一月龄大鼠习惯于12h/12h的明/暗周期。
处死后,分离尾动脉,供养在高氧培养基中。然后在动脉两端插管,垂直悬挂在器官室内适合的培养基中,经由其近端灌注。灌注流的压力变化能够评价化合物的血管收缩或血管舒张效果。
在预先已被苯福林(1μM)收缩的节段上评价化合物的活性。向预收缩的节段加入一定浓度的供试化合物,以非积分方式测定浓度/响应曲线。当所观察的效果达到平衡时,改变培养基,使制备物留置20分钟,然后加入相同浓度的苯福林和另一浓度的供试化合物。
结果
本发明化合物显著地改变了预先被苯福林收缩的尾动脉的直径。
实施例G:药物组合物:片剂
1000片,每片剂量为5mg N-[2-(6-甲氧基-4-异喹啉基)乙基]乙酰胺盐
酸盐(实施例9) 5g
小麦淀粉 20g
玉米淀粉 20g
乳糖 30g
硬脂酸镁 2g
二氧化硅 1g
羟丙基纤维素 2g
Claims (18)
1、式(I)化合物、它们的对映异构体和非对映异构体,以及其与可药用酸或碱的加成盐:
其中:
◆n是1、2或3,
其中:
●Z代表硫原子或氧原子,
●R和R”可以相同或不同,各自代表氢原子或直链或支链(C1-C6)烷基,
●且R’代表直链或支链(C1-C6)烷基、直链或支链(C2-C6)链烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C3-C8)环烷基-(C1-C6)烷基——其中的烷基部分是直链或支链的、芳基、芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的、杂芳基或杂芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的,
◆X代表氮原子或基团N-R1,其中R1代表氢原子或直链或支链(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烷基-(C1-C6)烷基——其中的烷基部分是直链或支链的、芳基、芳酰基、芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的、杂芳基、杂芳酰基或杂芳基-(C1-C6)烷基——其中的烷基部分是直链或支链的,
◆R2代表直链或支链(C1-C6)烷氧基、(C3-C8)环烷基氧基或(C3-C8)环烷基-(C1-C6)烷氧基——其中的烷氧基部分是直链或支链的,
其中:
-“芳基”应被理解为意指苯基或萘基,这些基团是未取代的或被一至三个相同或不同的基团取代,取代基选自直链或支链(C1-C6)烷基、直链或支链(C1-C6)烷氧基、OH、COOH、烷氧基羰基——其中的烷氧基部分是直链或支链的、甲酰基、硝基、氰基、羟甲基、氨基——任选地被一或两个直链或支链(C1-C6)烷基取代,和卤原子,
-“杂芳基”应被理解为意指任何单-或双-环基团,其含有5至10个环成员且可含有1至3个选自氧、硫和氮的杂原子,如呋喃基、噻吩基、吡咯基、咪唑啉基、吡啶基、喹啉基、异喹啉基、苯并二氢吡喃基、吲哚基、苯并噻吩基或苯并呋喃基,这些基团有可能是部分氢化的、未取代的或被一至三个相同或不同的基团取代,取代基选自直链或支链(C1-C6)烷基、直链或支链(C1-C6)烷氧基、OH、COOH、烷氧基羰基——其中的烷氧基部分是直链或支链的、甲酰基、硝基、氰基、氨基——任选地被一或两个直链或支链(C1-C6)烷基取代、羟甲基和卤原子。
2、根据权利要求1的式(I)化合物,其中n是2且A代表-NHCOR’基团,它们的对映异构体和非对映异构体,以及它们与可药用酸或碱的加成盐。
3、根据权利要求1的式(I)化合物,其中n是3且A代表-CONHR’基团,它们的对映异构体和非对映异构体,以及它们与可药用酸或碱的加成盐。
4、根据权利要求1的式(I)化合物,其中R2代表甲氧基,它们的对映异构体和非对映异构体,以及它们与可药用酸或碱的加成盐。
5、根据权利要求1的式(I)化合物,其中X代表氮原子,它们的对映异构体和非对映异构体,以及它们与可药用酸或碱的加成盐。
6、根据权利要求1的式(I)化合物,其中X代表NPh或NBz基团,它们的对映异构体和非对映异构体,以及它们与可药用酸或碱的加成盐。
7、根据权利要求1的式(I)化合物,其为N-[2-(6-甲氧基-4-异喹啉基)乙基]乙酰胺,以及其与可药用酸的加成盐。
8、根据权利要求1的式(I)化合物,其为N-[2-(6-甲氧基-4-异喹啉基)乙基]丁酰胺,以及其与可药用酸的加成盐。
9、根据权利要求1的式(I)化合物,其为N-[2-(6-甲氧基-4-异喹啉基)乙基]丙酰胺,以及其与可药用酸的加成盐。
10、根据权利要求1的式(I)化合物,其为N-[2-(6-甲氧基-4-异喹啉基)乙基]环丙烷酰胺,以及其与可药用酸的加成盐。
11、根据权利要求1的式(I)化合物,其为4-(6-甲氧基-4-异喹啉基)-N-甲基丁酰胺,以及其与可药用酸的加成盐。
12、根据权利要求1的式(I)化合物,其为N-[2-(6-甲氧基-2-苯基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺,以及其与可药用酸的加成盐。
13、根据权利要求1的式(I)化合物,其为N-[2-(2-苄基-6-甲氧基-1,2,3,4-四氢-4-异喹啉基)乙基]乙酰胺,以及其与可药用酸的加成盐。
14、根据权利要求1的式(I)化合物,其为N-{2-[2-(环丙基甲基)-6-甲氧基-1,2,3,4-四氢-4-异喹啉基]乙基}乙酰胺,以及其与可药用酸的加成盐。
15、制备权利要求1的式(I)化合物的方法,其特征在于使用式(II)化合物作为起始物质:
其中R2和n如式(I)所定义且Ra代表直链或支链(C1-C6)烷基,
使其受到POCl3的作用,得到式(III)化合物:
其中R2、n和Ra如上所定义,
—将其置于披钯碳存在下,得到式(IV)化合物:
其中R2、n和Ra如上所定义,
—或在披钯碳存在下对其进行氢化,得到式(V)化合物:
其中R2、n和Ra如上所定义,
使该式(V)化合物与式G-R’1化合物缩合,其中G代表离去基团且R’1可具有R1所给出的任何含义,氢原子除外,得到式(VI)化合物:
其中R2、R’1、n和Ra如上所定义,
式(III)至(VI)化合物构成式(VII)化合物:
使其与式HNRR’的胺缩合,其中R和R’如式(I)所定义,得到式(I/a)化合物,为式(I)化合物的一个特例:
或使该式(VII)化合物进行有机化学中常规的反应序列,得到式(VIII)化合物:
—与酰氯ClCOR’或对应的混合或对称的酐反应,其中R’如上所定义,得到式(I/b)化合物,为式(I)化合物的一个特例:
其中R2、R’、X、n和符号
如上所定义,
任选地继之以式R’a-J化合物的作用,其中R’a可具有R’的任何含义且J代表离去基团如卤原子或甲苯磺酰基,得到式(I/c)化合物,为式(I)化合物的一个特例:
—或者受到式(IX)化合物的作用:
O=C=N-R’ (IX)
其中R’如上所定义,任选地继之以如上所定义的式R’a-J化合物的作用,得到式(I/d)化合物,为式(I)化合物的一个特例:
式(I/a)至(I/d)化合物有可能受到硫化剂、例如Lawesson试剂的作用,得到式(I/e)化合物,为式(I)化合物的一个特例:
其中R2、n和符号
如上所定义且B代表C(S)NRR’、N(R)C(S)R’或N(R)C(S)NR’R”基团,其中R、R’和R”如上所定义,
式(I/a)至(I/e)化合物构成式(I)化合物的全体,这些化合物可按照常规分离技术加以纯化,如果需要将其转化为与可药用酸或碱的加成盐,并且任选地按照常规分离技术分离为异构体。
16、药物组合物,其包含根据权利要求1至14任意一项的式(I)化合物或其与可药用酸或碱的加成盐与一种或多种可药用赋形剂的组合。
17、根据权利要求16的药物组合物,其用于制备用来治疗褪黑激素能系统障碍的药物。
18、根据权利要求16的药物组合物,其用于制备药物,所述药物用于治疗睡眠障碍、紧张状态、焦虑、季节性情感障碍或严重的抑郁、心血管病变、消化系统病变、由飞行时差引起的失眠与疲劳、精神分裂症、恐慌发作、忧郁、食欲障碍、肥胖、失眠、精神病性精神障碍、癫痫、糖尿病、帕金森氏病、老年性痴呆、与正常或病理性衰老有关的各种障碍、偏头痛、记忆丧失、阿尔茨海默氏病、脑循环障碍以及性功能障碍,也作为排卵抑制剂、免疫调节剂,以及治疗癌症。
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CN100386319C (zh) * | 2005-12-05 | 2008-05-07 | 中国人民解放军第二军医大学 | 具有抗生育和抗真菌活性的四氢异喹啉类化合物或其盐类 |
WO2022022542A1 (zh) * | 2020-07-28 | 2022-02-03 | 上海翰森生物医药科技有限公司 | 双环类衍生物调节剂、其制备方法和应用 |
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FR2881138B1 (fr) * | 2005-01-27 | 2007-03-02 | Servier Lab | Nouveaux derives d'oximes heterocycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
EP1731507A1 (en) | 2005-04-26 | 2006-12-13 | Institut National des Sciences Appliquees de Rouen (INSA) | New heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-alzheimer agents |
WO2008092292A1 (en) * | 2007-01-17 | 2008-08-07 | The Hong Kong University Of Science And Technology | Isoquinolone compounds as subtype-selective agonists for melatonin receptors mt1 and mt2 |
WO2009118765A2 (en) * | 2008-03-28 | 2009-10-01 | Panacea Biotec Limited | Novel monoamine re-uptake inhibitor |
ES2580702B1 (es) | 2015-02-25 | 2017-06-08 | Palobiofarma, S.L. | Derivados de 2-aminopiridina como antagonistas del receptor A2b de adenosina y ligandos del receptor MT3 de melatonina |
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HU189764B (en) * | 1983-10-25 | 1986-07-28 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for preparing 1-(bis (substituted methyl)-methyl)-isoquinoline-derivatives |
US4584379A (en) * | 1985-01-22 | 1986-04-22 | Merrell Dow Pharmaceuticals Inc. | Isoquinoline thromboxane synthetase inhibitors |
DE3640641A1 (de) * | 1986-11-28 | 1988-07-14 | Thomae Gmbh Dr K | Neue heteroaromatische aminderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
DE3718570A1 (de) * | 1987-06-03 | 1988-12-15 | Boehringer Ingelheim Kg | Benzo- und thieno-3,4-dihydro-1- pyridinylessigsaeurederivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
FR2658818B1 (fr) * | 1990-02-27 | 1993-12-31 | Adir Cie | Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
SI0736012T1 (en) * | 1993-12-21 | 2001-02-28 | Boehringer Ingelheim Pharma | Anellated dihydropyridines and their use in the production of pharmaceutical preparations |
FR2729147A1 (fr) * | 1995-01-11 | 1996-07-12 | Adir | Nouveaux composes (hetero) cycliques alkyles, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
DE69633289T2 (de) * | 1995-06-27 | 2006-01-12 | Takeda Pharmaceutical Co. Ltd. | 4-acylamino(halogen)alkyl-chinolin derivate, deren herstellung und deren verwendung als melatonin-agonisten |
FR2778662B1 (fr) * | 1998-05-12 | 2000-06-16 | Adir | Nouveaux composes cycliques substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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CN100386319C (zh) * | 2005-12-05 | 2008-05-07 | 中国人民解放军第二军医大学 | 具有抗生育和抗真菌活性的四氢异喹啉类化合物或其盐类 |
WO2022022542A1 (zh) * | 2020-07-28 | 2022-02-03 | 上海翰森生物医药科技有限公司 | 双环类衍生物调节剂、其制备方法和应用 |
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