CN102238948B - 作为酪氨酸酶抑制剂的新颖的4-(杂环烷基)苯-1,3-二酚化合物,其制备方法及其在人类药物及化妆品中的应用 - Google Patents
作为酪氨酸酶抑制剂的新颖的4-(杂环烷基)苯-1,3-二酚化合物,其制备方法及其在人类药物及化妆品中的应用 Download PDFInfo
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- CN102238948B CN102238948B CN200980148286.5A CN200980148286A CN102238948B CN 102238948 B CN102238948 B CN 102238948B CN 200980148286 A CN200980148286 A CN 200980148286A CN 102238948 B CN102238948 B CN 102238948B
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Abstract
本发明涉及以下通式(I)的新颖的4-(杂环烷基)苯-1,3-二酚化合物,含有它们的组合物,其制备方法及其在用于治疗或预防色素性病变的药物或化妆品组合物中的应用。<CNIPR:IMG <CNIPR:IMG wi="117.74" he="64.29" file="2009801482865100004dest_path_image002.GIF" img-format="jpg"
Description
本发明涉及作为工业及有用产品的新颖的4-(杂环烷基)苯-1,3-二酚化合物。还涉及其制备方法及其作为酪氨酸酶抑制剂在用于治疗或预防色素性病变的药物或化妆品组合物中的应用。
皮肤色素沉着,特别是人类皮肤色素沉着,是树突细胞—黑素细胞合成黑素的结果。黑素细胞含有称作黑素体的细胞器,它将黑素转移到角质形成细胞的上层中,后者随后通过表皮的分化被转运到皮肤的表面(Gilchrest BA,
Park HY, Eller MS, Yaar M, Mechanisms of ultraviolet light-induced
pigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing VJ, Tsukamoto K,
Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909)。
酪氨酸酶是黑素发生中起关键作用的酶,它催化黑素合成的头两步。酪氨酸酶的纯合突变引起I型眼皮肤白化病,其特征是完全缺乏黑素合成(Toyofuku K,
Wada I, Spritz RA, Hearing VJ, The molecular basis of oculocutaneous albinism
type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in
a lack of pigmentation. Biochem J 2001; 355: 259-269)。
对于由黑素的产生增多造成的色素沉着病,现在还没有能满足患者和皮肤科医师的全部期望的治疗方法。为了治疗色素沉着病,发展新的治疗手段很重要。
大多数已知的皮肤美白化合物是酚类或氢醌衍生物。这些化合物抑制酪氨酸酶,但是它们大都因为形成醌而对黑素细胞有细胞毒性。这种毒性作用有造成皮肤永久性脱色素的危险。特别希望得到能够抑制黑素发生,同时对于黑素细胞的毒性很弱或没有毒性的化合物。
在文献中已描述的化合物中,专利申请WO 99/15148公开了4-环烷基间苯二酚作为脱色素剂的应用。
专利FR 2704428公开了4-卤-间苯二酚作为脱色素剂的应用。
专利申请WO 2006/097224和WO 2006/097223公开了4-环烷基甲基间苯二酚作为脱色素剂的应用。
专利申请WO 2005/085169公开了3-(2,4-二羟基苯基)丙酸烷基酯作为脱色素剂的应用。
专利申请WO 2004/017936公开了3-(2,4-二羟基苯基)丙烯酰胺作为脱色素剂的应用。
专利申请WO 2004/052330公开了4-[1,3]二噻烷-2-基间苯二酚作为脱色素剂的应用。
特别是,专利EP 0341664公开了4-烷基间苯二酚作为脱色素剂的应用,其中的4-正丁基间苯二酚也称作rucinol,是以IKlen®的名称销售的脱色霜的成分的一部分。
申请人现已出乎意料和令人惊奇地发现,有4-(杂环烷基)苯-1,3-二酚结构的新颖化合物具有很好的酪氨酸酶抑制活性和很低的细胞毒性。另外,这些化合物的酪氨酸酶抑制活性大于rucinol,与此同时,其对黑素细胞的细胞毒性小于rucinol。
这些化合物可用于人类药物,特别是皮肤病药物,以及化妆品领域。
因此,本发明涉及以下通式(I)化合物,以及通式(I)化合物的盐,及其异构体和对映异构体形式:
其中:
R1、R2、R3和R4可以相同或不同,代表:
- 氢,
- C1-C4烷基,
- 羟甲基,羟乙基,
- (C1-C4烷氧基)羰基,
- C1-C4烷氧基,
- 羟基,
或者
R1和R2彼此连接,与它们所连接的碳原子一起形成一个含5或6个碳原子的碳环,而R3和R4可以相同或不同,代表:
- 氢,
- C1-C4烷基
或者
R1和R4彼此连接,形成一个-(CH2)2-或-(CH2)3-链,而R2和R3可以相同或不同,代表:
- 氢,
- C1-C4烷基;
X代表氧原子或硫原子;
Y代表氢、氯原子或氟原子;
m可以是1或2,n可以是0或1,并且当n=0时,m为1或2,而当n=1时,则m=1。
在通式(I)化合物与可药用的碱形成的盐中,优选的是与有机碱或与无机碱形成的盐。
合适的无机碱是,例如,氢氧化钾、氢氧化钠或氢氧化钙。
合适的有机碱是,例如,吗啉,哌嗪或赖氨酸。
通式(I)化合物也可以以水合物或溶剂化物的形式存在。
适合形成溶剂化物的溶剂是,例如,醇类,比如乙醇或异丙醇。
根据本发明,术语“C1-C4烷基”代表含1至4个碳原子的直链或支链的饱和烃基链。
根据本发明,术语“(C1-C4烷氧基)羰基”代表被含1至4个碳原子的烷基取代的羧基。
根据本发明,术语“C1-C4烷氧基”代表被含有1至4个碳原子的直链或支链的饱和烃基取代的氧原子。
根据本发明,术语“异构体”代表以该苯-1,3-二酚的4位处的杂环烷基上的取代基为基础的顺式和反式。
根据本发明,特别优选的通式(I)化合物是这样的化合物,其中:
- R1代表氢,C1-C4烷基或羟甲基,
- R2代表氢,
- R3代表氢,
- R4代表氢,
- X代表氧原子,
- Y代表氢或氟原子,
- m=1和n=1,
以及这些通式(I)化合物的盐,及其异构体和对映异构体形式。
在属于本发明范围的式(I)化合物中,特别可以提到以下化合物:
1:4-(四氢吡喃-4-基)苯-1,3-二酚
2:4-(四氢噻喃-4-基)苯-1,3-二酚
3:4-(顺-2,6-二甲基四氢吡喃-4-基)苯-1,3-二酚
4:反-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚
5:顺-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚
6:反-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚
7:顺-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚
8:反-4-(2-羟甲基四氢吡喃-4-基)苯-1,3-二酚
9:4-(2,2,6,6-四甲基四氢吡喃-4-基)苯-1,3-二酚
10:4-(四氢呋喃-3-基)苯-1,3-二酚
11:4-(四氢噻吩-3-基)苯-1,3-二酚
12:4-(6-氧杂螺[4.5]癸-9-基)苯-1,3-二酚
13:4-氯-6-(四氢吡喃-4-基)苯-1,3-二酚
14:4-氟-6-(四氢吡喃-4-基)苯-1,3-二酚
15:4-(2,2-二乙基四氢吡喃-4-基)苯-1,3-二酚
16:4-(四氢吡喃-3-基)苯-1,3-二酚
17:反-4-(5-羟甲基四氢呋喃-3-基)苯-1,3-二酚
18:顺-4-(5-羟甲基四氢呋喃-3-基)苯-1,3-二酚
19:反-4-氟-6-(5-羟甲基四氢呋喃-3-基)苯-1,3-二酚
20:顺-4-氟-6-(5-羟甲基四氢呋喃-3-基)苯-1,3-二酚
21:反-4-氟-6-(2-羟甲基四氢吡喃-4-基)苯-1,3-二酚
22:顺-4-氟-6-(2-羟甲基四氢吡喃-4-基)苯-1,3-二酚
23:顺-4-(8-氧杂双环[3.2.1]辛-3-基)苯-1,3-二酚
24:反-4-(8-氧杂双环[3.2.1]辛-3-基)苯-1,3-二酚
25:4-氟-6-(四氢噻喃-4-基)苯-1,3-二酚
通式(I)化合物按照图1中所示的一般反应方案1-4制备。
图1的方案1相应于通式(I)化合物的制备,其中m=n=1,X=O,R1、R2、R3、R4和Y具有与以上相同的定义。
根据图1的这一反应方案1,2,4-二苄氧基溴苯(1)在丁基锂存在下与通式(2)的杂环烷酮反应,得到通式(3)的苄醇,通式(2)的杂环烷酮是市售商品,或者按照常规的合成方法制备(W.D. Langley,
Org, Synth. I, 122(1932))。
通式(3)的苄醇在酸(例如樟脑磺酸)存在下于非质子溶剂(例如甲苯)中脱水,从而得到通式(4)化合物。
通式(5)化合物:
由通式(3)化合物出发,或由通式(4)化合物出发,通过在溶剂(例如甲醇)中在氢和钯基催化剂(例如碳载钯)存在下氢化得到:
通式(6)化合物:
由通式(5)化合物用卤化剂,例如N-氯代琥珀酰亚胺(Y=Cl)或者Selectfluor®(Y=F),经卤化作用得到。
图1的方案2相应于通式(I)化合物的制备,其中m=n=1,X=O或S,R1、R2、R3、R4和Y具有和以上相同的定义。
根据图1的方案2,2,4-二(甲氧基甲氧基)溴苯(7)在碱(例如丁基锂)存在下与例如通式(2)的杂环烷酮反应,得到通式(8)的苄醇,其中通式(2)的杂环烷酮是市售商品或根据常规方法制备(W.D. Langley,Org. Synth. I,
122(1932))。
通式(8)的苄醇在溶剂(例如甲苯)中于酸(例如樟脑磺酸)存在下脱水,得到通式(9)化合物。
通式(10)化合物由通式(9)化合物在溶剂(例如甲醇)中于氢和钯基催化剂(例如碳载钯)存在下氢化得到。
通式(5)化合物由通式(10)化合物出发,在甲醇中于盐酸存在下得到。
图1的方案3相应于通式(I)化合物的制备,其中m=1,n=0,X=O,R1=R2=H,R3、R4和Y具有和以上相同的定义。
采用图1的反应方案3,2,4-二苄氧基溴苯(1)在丁基锂存在下与通式(11)的杂环烷酮反应,以便得到通式(12)化合物,其中通式(11)的杂环烷酮是市售商品或者按照常规合成方法制备(W.D. Langley,
Org. Synth. I, 122 (1932))。
通式(13)化合物由通式(12)化合物出发,通过在溶剂(例如甲醇)中于氢和钯基催化剂(例如碳载钯)存在下氢化得到。
通式(16)化合物:
由通式(13)化合物用卤化剂,例如N-氯代琥珀酰亚胺(Y=Cl)或Selectfluor®
(Y=F),进行卤化反应得到。
图1的方案4相应于通式(I)化合物的制备,其中m=1,n=0,X=O或S,R1=R2=H,R3、R4和Y具有和以上相同的定义。
采用图1的反应方案4,2,4-二(甲氧基甲氧基)溴苯(7)在丁基锂存在下与通式(11)的杂环烷酮反应,以便得到通式(14)的苄醇,其中通过(11)的杂环烷酮是市售商品或按照常规的合成方法制备(W.D. Langley,
Org. Synth. I, 122(1932))。
通式(14)的苄醇随后在溶剂(例如甲醇)中于酸(例如盐酸)存在下脱水,得到通式(15)化合物。
通式(13)化合物由通式(15)化合物在溶剂(例如甲醇)中于氢和钯基催化剂(例如碳载钯)存在下氢化得到。
因此,本发明涉及至少一种如上定义的通式(I)化合物作为药物的应用。
本发明还涉及至少一种如上定义的通式(I)化合物作为药物的应用,其中该化合物具有酪氨酸酶抑制活性。
本发明还涉及至少一种如上定义的通式(I)化合物用于制备药物或化妆品组合物的应用,其中该化合物具有酪氨酸酶抑制活性。
有利的是,本发明化合物对于酪氨酸酶的IC50值(抑制酶催活性的50%的剂量)小于或等于10 μM,特别是小于或等于1 μM。
本发明还涉及用于治疗和/或预防色素性病变的通式(I)化合物。
实际上,本发明的通式(I)化合物特别适合用于治疗或预防色素性病变,例如,黄褐斑、褐黄斑、着色斑、老年斑、与光照老化有关的不规则的色素沉着过度、雀斑、由擦伤造成的炎后色素沉着过度、烧伤、瘢痕、皮肤病、接触性变态反应;痣,遗传性色素沉着过度,代谢或药物原因的色素沉着过度,黑素瘤或任何其它的色素沉着过度性病变。
本发明的一个主题还在于特别是用于治疗上述病症的药物组合物,其特征在于,它在与对该组合物选定的给药方法相适应的可药用的载体中含有通式(I)化合物,该化合物为其异构体和对映异构体形式之一,或是它与可药用的碱形成的盐。
术语“可药用的载体”是指与皮肤、粘膜及皮肤附件相容的介质。
本发明的组合物可以局部给药。优选的是,将组合物包装成适合局部施用的形式。
当局部施用时,本发明的药物组合物特别是用于治疗皮肤和粘膜,它可以是液体、糊状或固体形式,尤其是软膏剂、霜剂、溶液剂或凝胶剂的形式。
用于局部施用的组合物含有的本发明化合物的浓度,以组合物的总重量为基础,一般为0.001-10%重量,优选为0.01-5%重量。
本发明的通式(I)化合物还可用于化妆品领域,特别是用于防止阳光的有害作用,防止和/或抵抗皮肤和皮肤附件的光诱发老化或时间性老化。
因此,本发明的又一个主题是一种组合物,它在化妆品可接受的载体中含有至少一种通式(I)化合物。术语“化妆品可接受的介质”是指与皮肤、粘膜和皮肤附件相容的介质。
本发明的另一主题是含有至少一种通式(I)化合物的组合物用于防止和/或治疗皮肤老化迹象的化妆品用途。
本发明的再一主题是含有至少一种通式(I)化合物的组合物用于身体和头发卫生的化妆品用途。
本发明的化妆品组合物在化妆品可接受的载体中含有通式(I)化合物,或其异构体和对映异构体形式之一,或其与化妆品可接受的碱形成的盐,它特别可以是霜剂、乳剂、凝胶剂、微球或纳米球或脂质或聚合囊泡的混悬剂、浸渍垫、溶液剂、喷雾剂、泡沫剂、条棒、皂、洗涤基料或香波等形式。
通式(I)化合物在化妆品组合物中的浓度优选为组合物总重量为0.001-10%重量。
上述的药物和化妆品组合物还可含有惰性添加剂,或者在药物组合物的情形还含有药效活性添加剂,或这些添加剂的组合,特别是:
润湿剂;
增香剂;
防腐剂,例如对羟基苯甲酸酯;
稳定剂;
水分调节剂;
pH调节剂;
渗透压调节剂;
乳化剂;
UV-A和UV-B屏蔽剂;
抗氧化剂,例如α-生育酚、丁基化羟基苯甲醚或丁基化羟基甲苯、超氧化物歧化酶、二氢泛醌、焦亚磷酸钠;
润肤剂;
湿润剂,例如甘油、PEG 400、硫吗啉酮及其衍生物,或尿素;
抗皮脂溢剂或抗痤疮剂,例如S-羧甲基半胱氨酸、S-苄基半胱胺、它们的盐或衍生物,或过氧化苯甲酰。
当然,本领域技术人员会小心地选择加到这些组合物中的任选的化合物,使得本发明固有的优越性不会,或基本上不会因为所设想的加入而受损。
现在将以示例说明而不是任何限制的方式给出本发明通式(I)化合物的几个制备实施例,这些化合物的生物活性结果,以及以这些化合物为基础的各种制剂。
实施例 1:4-(四氢吡喃-4-基)苯-1,3-二酚
a). 4-(2,4-二(苄氧基)苯基)四氢吡喃-4-醇
向冷却至-70℃的1.85 g 2,4-二(苄氧基)-1-溴苯在20 ml四氢呋喃中的溶液加入2.4 ml 2.5 M正丁基锂/己烷溶液。将反应混合物在-70℃搅拌1小时,加入555 μl四氢-4H-吡喃-4-酮。将反应混合物在-70℃搅拌1小时,然后放置过夜,回到环境温度。将反应混合物倒入其中加有2 ml 2M盐酸的15 ml氯化铵饱和溶液中,然后用乙酸乙酯萃取。将有机相合并,用硫酸镁干燥后蒸发。残留物在硅胶上色谱分离,用70:30的庚烷:乙酸乙酯洗脱。
得到820 mg白色固体形式的4-(2,4-二(苄氧基)苯基)四氢吡喃-4-醇。收率=42%。
b). 4-(四氢吡喃-4-基)苯-1,3-二酚
将815 mg 4-(2,4-二(苄氧基)苯基)四氢吡喃-4-醇在10 ml乙酸乙酯中的混合物在244 mg钯/碳(10%)存在下于环境温度和5巴的氢气压力下搅拌17小时。将反应混合物过滤,然后蒸发滤液。残留物(394 mg)自乙酸乙酯中结晶。
得到275 mg白色晶状固体形式的4-(四氢吡喃-4-基)苯-1,3-二酚。收率=68%。
实施例 2:4-(四氢噻喃-4-基)苯-1,3-二酚
a) 1-溴-2,4-二(甲氧基甲氧基)苯
将42.56 g碳酸钾加到20.0 g 4-溴间苯二酚(97%)在200 ml丙酮中的溶液里。在5℃搅拌反应混合物10分钟,然后逐滴加入23.4 ml氯甲基·甲基醚。将反应混合物在环境温度下搅拌3小时。蒸发溶剂,残留物溶在水-乙酸乙酯混合物中。水相用乙酸乙酯萃取,将有机相合并,用氯化钠饱和溶液洗,用硫酸镁干燥,过滤和蒸发。残留物在硅胶上色谱分离,用90:10的庚烷:乙酸乙酯洗脱。
得到27.94 g无色油状的1-溴-2,4-二(甲氧基甲氧基)苯。收率=99%。
b). 4-(2,4-二(甲氧基甲氧基)苯基)四氢噻喃-4-醇
向5.54 g 1-溴-2,4-二(甲氧基甲氧基)苯在80 ml四氢呋喃中的溶液加入6.35 ml四甲基乙二胺。将该混合物冷却至-70℃,加入16.8 ml 2.5 M的正丁基锂/己烷溶液。将反应混合物在-70℃搅拌1小时,加入2.79 g四氢噻喃-4-酮在30 ml四氢呋喃中的溶液。将反应混合物在-70℃搅拌1小时后于环境温度下放置过夜。加入50 ml 2M盐酸,将反应混合物激烈搅拌15分钟,然后用乙酸乙酯萃取。将有机相合并,用氯化钠饱和溶液洗,用硫酸镁干燥后蒸发。残留物在硅胶上色谱分离,用75:25的庚烷:乙酸乙酯混合物洗脱。
得到黄色油状形式的2.97 g 4-(2,4-二(甲氧基甲氧基)苯基)四氢噻喃-4-醇。收率=47%。
C). 5-(2,4-二(甲氧基甲氧基)苯基)-3,6-二氢-2H-噻喃
向2.96 g 4-(2,4-二(甲氧基甲氧基)苯基)四氢噻喃-4-醇在60 ml甲苯中的溶液加入22 mg樟脑磺酸。将该混合物回流1小时,蒸发溶剂,残留物在硅胶上色谱分离,用80:20的庚烷:乙酸乙酯洗脱。
得到黄色油状的1.90 g 5-(2,4-二(甲氧基甲氧基)苯基)-3,6-二氢-2H-噻喃。收率=68%。
d) 4-(2,4-二(甲氧基甲氧基)苯基)四氢噻喃
将1.89 g 4-(2,4-二(甲氧基甲氧基)苯基)-3,6-二氢-2H-噻喃在20 ml乙酸乙酯中的混合物于1.89 g钯/碳(10%)存在下在50℃和80巴的氢气压力下搅拌8小时。反应混合物经硅藻土过滤,将滤液蒸发。
得以1.48 g油状的4-(2,4-二(甲氧基甲氧基)苯基)四氢噻喃。收率=77%。
e) 4-(四氢噻喃-4-基)苯-1,3-二酚
向1.47 g 4-(2,4-二(甲氧基甲氧基)苯基)四氢噻喃在18 ml甲醇和3 ml乙酸乙酯中的溶液加入18 ml 1 M盐酸。将混合物在环境温度下搅拌3小时,在50℃加热17小时。向反应混合物中加入12.0 ml碳酸氢钠饱和溶液,将其激烈搅拌20分钟,然后沉降分离。水相用乙酸乙酯萃取,将有机相合并,用氯化钠饱和溶液洗,用硫酸镁干燥,过滤后蒸发。残留物在硅胶上色谱分离,用70:30的庚烷:乙酸乙酯洗脱。得到的固体溶于乙醚和庚烷中,过滤和干燥。
将得到的固体自乙醚中结晶,过滤和干燥。
得到30 mg 4-(四氢噻喃-4-基)苯-1,3-二酚,为白色粉末形式。收率=3%。
实施例 3:顺-4-(2,6-二甲基四氢吡喃-4-基)苯-1,3-二酚
a) 顺-2,6-二甲基四氢吡喃-4-酮
10 g 2,6-二甲基-γ-吡喃酮溶在200 ml甲醇中,然后加入0.8 g钯/碳(10%)。将反应混合物在25个气压的氢气下搅拌24小时。将反应混合物过滤后蒸除溶剂,回收到8.81 g顺-2,6-二甲基四氢吡喃-4-酮。收率=88%。
b) 4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基四氢吡喃-4-醇
向2.65 g 1-溴-2,4-二(甲氧基甲氧基)苯在40 ml四氢呋喃中的溶液加入3.0 ml四甲基乙二胺。将该混合物冷却至-70℃,加入8.0 ml 2.5 M正丁基锂/己烷。反应混合物在-70℃搅拌1小时,加入1.47 g顺-2,6-二甲基四氢吡喃-4-酮在15 ml四氢呋喃中的溶液。将反应混合物在-70℃搅拌1小时,然后在环境温度下放置过夜。加入25 ml 2M盐酸,将反应混合物激烈搅拌15分钟,然后用乙酸乙酯萃取。将有机相合并,用饱和氯化钠溶液洗,用硫酸镁干燥后蒸发。残留物在硅胶上色谱分离,用75:25的庚烷:乙酸乙酯洗脱。
得到562 mg黄色油状的4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基四氢吡喃-4-醇。收率=18%。
c) 4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基-3,6-二氢-2H-吡喃
向247 mg 4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基四氢吡喃-4-醇在5 ml甲苯中的溶液加入2 mg樟脑磺酸。将该混合物回流2小时。蒸发溶剂,残留物在硅胶上色谱分离,用80:20的庚烷:乙酸乙酯混合物洗脱。
得到132 mg黄色油状形式的4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基-3,6-二氢-吡喃。收率=57%。
d) 顺-4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基四氢吡喃
将132 mg顺-4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基-3,6-二氢-2H-吡喃在10 ml甲醇中的混合物于28 mg钯/碳(10%)存在下在环境温度和3巴的氢气压力下搅拌5小时。将反应混合物过滤,滤液蒸发。
得到125 mg白色粉末形式的顺-4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基四氢吡喃。收率=94%。
e) 顺-4-(2,6-二甲基四氢吡喃-4-基)苯-1,3-二酚
向120 mg顺-4-(2,4-二(甲氧基甲氧基)苯基)-2,6-二甲基四氢吡喃在2.5 ml甲醇中的溶液加入1.9 ml 1N盐酸。将混合物在环境温度下搅拌过夜,然后回流1小时。加入1.5 ml碳酸氢钠饱和溶液,将反应混合物激烈搅拌20分钟后沉降分离。水相用乙酸乙酯萃取,将有机相合并,用氯化钠饱和溶液洗,用硫酸镁干燥,过滤和蒸发。残留物在硅胶上色谱分离,用95:5的二氯甲烷:甲醇洗脱。得到40 mg白色粉末状的顺-4-(2,6-二甲基四氢吡喃-4-基)苯-1,3-二酚,收率=46%。
实施例 4:反-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚
a) 2-甲基-2,3-二氢吡喃-4-酮
向2.07 g Danishefsky二烯(((E)-3-甲氧基-1-亚甲基烯丙氧基)三甲基硅烷)和581 mg乙醛在25 ml乙醚中的冷却至-70℃的溶液加入1.7 ml BF3·Et2O。将混合物在-70℃搅拌1小时。加入10 ml碳酸氢钠饱和溶液,反应混合物用乙醚萃取。将有机相合并,用硫酸镁干燥,过滤和冷蒸发。
得到1.35 g橙色油状的2-甲基-2,3-二氢吡喃-4-酮。收率=100%。
b) 2-甲基四氢吡喃-4-酮
1.35 g 2-甲基-2,3-二氢吡喃-4-酮在15 ml乙酸乙酯中,于270 mg钯/碳(10%)存在下,在环境温度和氢气氛下搅拌3天。将反应混合物经滤纸过滤,蒸发滤液。残留物在硅胶上色谱分离,用60:40的戊烷:乙醚洗脱。
得到787 mg黄色油状的2-甲基四氢吡喃-4-酮。收率=57%。
c) 4-(2,4-二(苄氧基)苯基)-2-甲基四氢吡喃-4-醇
向2.06 g 2,4-二(苄氧基)-1-溴苯在20 ml四氢呋喃中的冷却至-70℃的溶液加入2.7 ml 2.5 M正丁基锂/己烷溶液。将反应混合物在-70℃搅拌10分钟,加入766 mg 2-甲基四氢吡喃-4-酮在7 ml四氢呋喃中的溶液。将反应混合物在-70℃搅拌1小时,然后放置3小时回到环境温度。将其倒入已加入3 ml 2 M盐酸的20 ml氯化钠饱和溶液中,用乙酸乙酯萃取。将有机相合并,用硫酸镁干燥后蒸发。残留物在硅胶上色谱分离,用70:30的庚烷:乙酸乙酯洗脱。
得到838 mg黄色油状的4-(2,4-二(苄氧基)苯基)-2-甲基四氢吡喃-4-醇。收率=37%。
d) 反-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚
将830 mg 4-(2,4-二(苄氧基)苯基)-2-甲基四氢吡喃-4-醇在12 ml乙酸乙酯中于415 mg钯/碳(10%)存在下在环境温度和5巴的氢气压力下搅拌3小时。将反应混合物过滤,滤液蒸发。残留物(516 mg)在硅胶上色谱分离,用80:20的庚烷:乙酸乙酯洗脱。
得到37 mg白色粉末状的反-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚。收率=8%。
实施例 5:顺-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚
在先前的纯化步骤中,分离出又一极性级分:得到57 mg白色粉末状的顺-4-(2-甲基四氢吡喃-4-基)苯-1,3-二醇。收率=13%。
实施例 6:反-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚
按照与实施例4相似的方式,但是在第4a步使用丙醛,然后以类似的方式重复步骤4b、4c和4d,得到反-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚。
实施例 7:顺-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚
按照与实施例5相似的方式,通过将实施6合成得到的产物纯化,得到又一个极性级分顺-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚。
实施例 8:反-4-(2-羟甲基四氢吡喃-4-基)苯-1,3-二酚
按照与实施例4相似的方式,但是在第4a步使用苄氧基乙醛,然后以类似的方式重复步聚4b、4c和4d,得到反-4-(2-羟甲基四氢吡喃-4-基)苯-1,3-二酚。
实施例 9:4-(2,2,6,6-四甲基四氢吡喃-4-基)苯-1,3-二酚
a) 2,2,6,6-四甲基四氢吡喃-4-酮
将5 g商品佛尔酮溶于36 ml 1 M盐酸溶液中,在40℃加热2天。将反应混合物蒸馏(63-65℃),得到3.0 g浅黄色油状物。收率=53%。
b) 4-(2,2,6,6-四甲基四氢吡喃-4-基)苯-1,3-二醇
按照与实施例4相似的方式,但是在步骤4c使用2,2,6,6-四甲基四氢吡喃-4-酮,然后以类似的方式重复步骤4d,得以4-(2,2,6,6-四甲基四氢吡喃-4-基)苯-1,3-二酚。
实施例 10:4-(四氢呋喃-3-基)苯-1,3-二酚
a) 二氢呋喃-3-酮
将16.8 g氧化铬(VI)在50 ml水与15.6 ml 95%硫酸中的溶液逐滴加到4.9 g 3-羟基四氢呋喃在450 ml丙酮中的溶液里。将反应混合物在0℃搅拌40分钟。加入450 ml水,用乙醚萃取。将有机相合并,用氯化钠饱和溶液洗,用硫酸镁干燥,过滤和蒸发。残留物在硅胶上色谱分离,用60:40的戊烷:乙醚洗脱。得到1.78 g无色油状的二氢呋喃-3-酮。收率=28%。
b) 3-(2,4-二(苄氧基)苯基)-2,5-二氢呋喃
向4.74 g 2,4-二(苄氧基)-1-溴苯在50 ml四氢呋喃中的冷却至-70℃的溶液加入2 ml 2.5 M正丁基锂/己烷溶液。反应混合物在-70℃搅拌10分钟,加入1.77 g二氢呋喃-3-酮在15 ml四氢呋喃中的溶液,将反应混合物在-70℃搅拌1小时,然后放置过夜回到环境温度。将反应混合物倒入35 ml氯化铵饱和溶液中,该溶液中已加有6.5 ml 2M盐酸,然后用乙酸乙酯萃取。将有机相合并,用硫酸镁干燥后蒸发。残留物在硅胶上色谱分离,用60:40的庚烷:乙酸乙酯洗脱。
得到1.57 g黄色油状的3-(2,4-二(苄氧基)苯基)-2,5-二氢呋喃。收率=34%。
c) 4-(四氢呋喃-3-基)苯-1,3-二酚
将1.56 g 3-(2,4-二(苄氧基)苯基)四氢呋喃-3-醇在25 ml乙酸乙酯中的混合物于780 mg钯/碳(10%)存在下在环境温度和5巴氢气压力下搅拌7小时。将反应混合物过滤,滤液蒸发。残留物在硅胶上色谱分离,用50:50的庚烷:乙酸乙酯洗脱。得到的固体从二氯甲烷/庚烷中结晶。得到285 mg白色粉末形式的4-(四氢呋喃-3-基)苯-1,3-二酚。收率=36%。
实施例 11:4-(四氢噻吩-3-基)苯-1,3-二酚
a) 3-(2,4-二(甲氧基甲氧基)苯基)四氢噻吩-3-醇
向冷却至-70℃的13.10 g 1-溴-2,4-二(甲氧甲氧基)苯在200 ml四氢呋喃中的溶液加入23.0 ml 2.5 M的正丁基锂/己烷溶液。将反应混合物在-70℃搅拌20分,加入4.90 ml四氢噻吩-3-酮。将反应混合物在-70℃搅拌1小时,然后放置过夜以便回到环境温度。将反应混合物倒入已加有30 ml 2M盐酸的150 ml氯化铵饱和溶液中,然后用乙酸乙酯萃取。将有机相合并,用硫酸镁干燥后蒸发。残留物在硅胶上色谱分离,用85:15的庚烷:乙酸乙酯洗脱。
得到4.10 g橙色油状的3-(2,4-二(甲氧基甲氧基)苯基)四氢噻吩-3-醇。收率=29%。
b) 4-(4,5-二氢噻吩-3-基)苯-1,3-二酚
向4.10 g 3-(2,4-二(甲氧基甲氧基)苯基)四氢噻吩-3-醇在50 ml甲醇和8 ml乙酸乙酯中的溶液加入50 ml 1N盐酸。将此混合物在50℃加热4小时。加入40 ml碳酸氢钠饱和溶液,将反应混合物激烈搅拌20分钟,然后沉降分离。水相用乙酸乙酯萃取,将有机相合并,用氯化钠饱和溶液洗,用硫酸镁干燥,过滤和蒸发。残留物在硅胶上色谱分离,用80:20的庚烷:乙酸乙酯洗脱。
得到400 ml黄色油状的4-(4,5-二氢噻吩-3-基)苯-1,3-二酚。收率=15%。
c) 4-(四氢噻吩-3-基)苯-1,3-二酚
将400 mg 4-(4,5-二氢噻吩-3-基)苯-1,3-二酚在10 ml乙酸乙酯中的混合物,于400 mg钯/碳(10%)存在下,在环境温度和6巴的氢气压力下搅拌4天。将反应混合物过滤,然后蒸发滤液。残留物在硅胶上色谱分离,用80:20的庚烷:乙酸乙酯洗脱。得到的固体从二氯甲烷/庚烷中结晶。
得到232 mg奶油色固体形式的4-(四氢噻吩-3-基)苯-1,3-二醇。收率=57%。
实施例 12:4-(6-氧杂螺[4.5]癸-9-基)苯-1,3-二酚
a) 6-氧杂螺[4.5]癸-9-酮
在环境温度下将5 g (E)-3-[(叔丁基二甲基硅烷基氧)丁-1,3-二烯基]二甲胺加到3.9 g环戊酮在11 ml 2-丁醇中的溶液里。将反应混合物在环境温度下搅拌18小时,蒸发溶剂,然后将残留物溶在100 ml乙醚中。将该混合物冷却至-78℃,然后慢慢加入1.9 ml乙酰氯。将混合物在-78℃搅拌10分钟,然后加入100 ml氯化铵饱和溶液使反应停止。形成的混合物用200 ml乙醚萃取,将有机相合并,用无水硫酸钠干燥。蒸发后残留物在硅胶上色谱分离(8:2的庚烷:乙酸乙酯)。残留物溶在50 ml甲醇中,然后加入200 mg钯/碳(10%)。将反应混合物在氢气氛下搅拌2小时,过滤,然后蒸除甲醇。得到600 mg 6-氧杂螺[4.5]癸-9-酮。收率=18%。
b) 4-(6-氧杂螺[4.5]癸-9-基)苯-1,3-二酚
按照与实施例1相似的方式,但是在步骤1a中使用6-氧杂螺[4.5]癸-9-酮,然后以类似方式重复步骤1b,得到4-(6-氧杂螺[4.5]癸-9-基)苯-1,3-二酚。
实施例 13:4-氯-6-(四氢吡喃-4-基)苯-1,3-二酚
在0℃下向2 g 4-(四氢吡喃-4-基)苯-1,3-二酚(实施例1)在30 ml二氯甲烷中的溶液加入2.4 g N-氯代琥珀酰亚胺。将反应混合物在环境温度下搅拌16小时,用二氯甲烷萃取,然后用水洗。将有机相合并,用硫酸钠干燥。蒸发后残留物在硅胶上色谱分离(75:25的庚烷:乙酸乙酯)。得到400 mg 4-氯-6-(四氢吡喃-4-基)苯-1,3-二酚。收率=17%。
实施例 14:4-氟-6-(四氢吡喃-4-基)苯-1,3-二酚
在0℃下向2 g 4-(四氢吡喃-4-基)苯-1,3-二酚(实施例1)在20 ml乙腈中的溶液加入3.65 g N-氟-N’-(氯甲基)三亚乙基二胺二(四氟硼酸盐)。将反应混合物在环境温度下搅拌16小时,然后用乙酸乙酯萃取,有机相洗后用硫酸钠干燥。蒸发后的残留物在硅胶上色谱分离(9:1的庚烷:乙酸乙酯)。得到200 mg 4-氟-6-(四氢吡喃-4-基)苯-1,3-二酚。收率=10%。
实施例 15:4-(2,2-二乙基四氢吡喃-4-基)苯-1,3-二酚
按照与实施例12a相似的方式,但是使用二乙基酮,然后以类似的方式重复步骤12b,得到4-(2,2-二乙基四氢吡喃-4-基)苯-1,3-二酚。
实施例 16:4-(四氢吡喃-3-基)苯-1,3-二酚
按照与实施例1相似的方式,但是使用二氢吡喃-3-酮,得到4-(四氢吡喃-3-基)苯-1,3-二酚。
实施例 17:酪氨酸酶活性抑制试验
使用B16F1细胞(鼠黑素瘤细胞系)的裂解物测定抑制剂的活性。在L-酪氨酸底物存在下,这些细胞内存在的酪氨酸酶对于L-酪氨酸通过羟基化变成L-DOPA和随后L-DOPA被氧化成多巴醌的反应起催化作用。在MBTH(3-甲基-2-苯并噻唑啉酮腙)存在下,多巴醌被捕获,从而形成在520 nm处吸收的粉红色复合物。
将B16F1细胞在DMEM培养基+10%胎牛血清+10-9
M α-MSH中在7% CO2下于37℃培养4天。将其用胰蛋白酶处理,在PBS中洗,计数和粒化。将小粒以107细胞/ml置于裂解缓冲液(10 mM磷酸钠,pH 6.8-1%
Igepal)中,该悬浮液用超声处理10秒钟。在4000 rpm下离心30分后,得到的上清液构成在酶催化试验中作为酪氨酸酶源的细胞裂解物。
试验在384孔板中以50 μl的总体积用双重试样进行。每个孔内含有:
40 μl溶液,在缓冲液B(62.25 mM磷酸钠、pH 6.8, 2.5%二甲基甲酰胺)中含有1.25 mM L-酪氨酸、6.25 mM L-DOPA(辅因子)和3.75 mM MBTH;
5 μl的抑制剂在DMSO中的稀释液;
在50 mM Tris HCl缓冲液、pH 7.5中稀释一半的5 μl细胞裂解液。
将板在37℃温育,6小时后在520 nM进行光谱分析读数。为避免任何可能的产物吸收,系统采用校正过的吸光度(6小时后的吸光度-零时刻的吸光度)。
将抑制剂按照剂量-响应方式进行试验,以计算IC50(抑制50%酶活性的剂量)。
对每次试验加入几个内部对照:
-用于100%活性的对照:5 μl的抑制剂用5 μl DMSO代替,
-用于50%活性的对照:5 μl的抑制剂用5 μl的苯基硫脲/DMSO(300 μM)代替,
-用于0%活性的对照:L-酪氨酸底物用缓冲液B代替。
对于本发明化合物得到的结果示于表A中:
表
A
实施例 18:黑素发生的抑制试验
黑素发生的抑制按照根据Reigner等,Cell Mol. Biol
(1999) 45:969-980的方法修改的方案在MNT1人黑素瘤细胞中测定。此试验的根据是2个放射性标记的示踪物的伴行掺入:14C-硫脲嘧啶掺入到新合成的黑素中,反映了黑素发生;而3H-亮氨酸掺入到蛋白质中,反映了细胞存活,因而反映了试验化合物的毒性。
将MNT1细胞在试验化合物和放射性同位素存在下接种到96孔板中。在37℃温育24小时后,洗涤细胞并测定2种放射性同位素的数量。试验化合物按照剂量-响应的方式进行评价,以便根据14C的掺入率计算对于抑制黑素发生的IC50,而14C掺入率要通过3H掺入率进行规一化。还根据3H掺入率计算了对于细胞毒性的IC50。
这一试验因此有可能将特异地抑制黑素发生的产物与对黑素细胞有细胞毒性的产物区分开来。
实施例 19:制剂
此实施例示例说明了以本发明化合物为基础的各种制剂。
局部用制剂
(a) 软膏剂
化合物1
0.020 g
十四烷酸异丙酯
81.700 g
流态液体凡士林
9.100 g
硅胶(Aerosil
200)
9.180 g
(b) 软膏剂
化合物6
0.300 g
白凡士林,药品级
适量至100 g
(c) 非离子型水/油霜剂
化合物1
0.100 g
乳化的羊毛脂醇、蜡和油的
混合物(无水优色林(eucerin)) 39.900 g
对羟基苯甲酸甲酯
0.075 g
对羟基苯甲酸丙酯
0.075 g
无菌的软化水
适量至100 g
(d) 洗剂
化合物6
0.100 g
聚乙二醇(PEG 400)
69.900 g
95%乙醇
30.000 g
(e) 疏水性软膏剂
化合物2
0.300 g
十四烷酸异丙酯
36.400 g
硅油(Rhodorsil 47
V
300)
36.400 g
蜂蜡
13.600 g
硅油(Abil 300 000
cst)
适量至100 g
(f) 非离子型油/水霜剂
化合物4
1.000 g
十六醇
4.000 g
甘油单硬脂酸酯
2.500 g
硬脂酸聚乙二醇(50)酯
2.500 g
乳木果油
9.200 g
丙二醇
2.000 g
对羟基苯甲酸甲酯
0.075 g
对羟基苯甲酸丙酯
0.075 g
无菌的软化水
适量至100 g
Claims (7)
1.以下通式(I)化合物及通式(I)化合物的盐,和其异构体和对映异构体形式:
其中:
R1代表氢、 C1-C4烷基或羟甲基,
R2、R3和R4代表:
- 氢,
X代表氧原子或硫原子;
Y代表氢或氟原子;
m=1,n=1。
2.权利要求1的化合物,其特征在于,它是与选自有机碱和无机碱的一种碱形成的盐的形式。
3.权利要求1或2的化合物,其特征在于:
X代表氧原子。
4.权利要求1的化合物,其特征在于,它选自以下化合物:
1:4-(四氢吡喃-4-基)苯-1,3-二酚
2:4-(四氢噻喃-4-基)苯-1,3-二酚
4:反-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚
5:顺-4-(2-甲基四氢吡喃-4-基)苯-1,3-二酚
6:反-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚
7:顺-4-(2-乙基四氢吡喃-4-基)苯-1,3-二酚
8:反-4-(2-羟甲基四氢吡喃-4-基)苯-1,3-二酚
14:4-氟-6-(四氢吡喃-4-基)苯-1,3-二酚。
5.权利要求1-4中任一项的化合物在制备治疗或预防色素性病变的药物中的应用。
6.权利要求5的应用,其特征在于,所述的色素性病变选自:黄褐斑、褐黄斑、着色斑、老年斑、与光照老化有关的不规则的色素沉着过度、雀斑、由擦伤、烧伤、瘢痕、接触性变态反应造成的炎后色素沉着过度;痣、遗传性色素沉着过度、代谢或药物原因的色素沉着过度、黑素瘤或任何其它的色素沉着过度性病变。
7.根据权利要求1至4中任一项的化合物在制备用于防止阳光的有害作用,防止和/或抵抗皮肤和皮肤附件的光诱发老化或时间性老化,及用于身体和头发卫生的化妆品中的应用。
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FR0858206 | 2008-12-02 | ||
FR0858206A FR2939136B1 (fr) | 2008-12-02 | 2008-12-02 | Nouveaux composes 4-(heterocycloalkyl)-benzene-1,3-diol comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
US20212809P | 2009-01-30 | 2009-01-30 | |
US61/202128 | 2009-01-30 | ||
US61/202,128 | 2009-01-30 | ||
PCT/EP2009/066267 WO2010063773A1 (en) | 2008-12-02 | 2009-12-02 | Novel 4-(heterocycloalkyl)benzene-1,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and also in cosmetics |
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US (1) | US8372879B2 (zh) |
EP (2) | EP2529735B1 (zh) |
JP (1) | JP5395188B2 (zh) |
KR (1) | KR101290504B1 (zh) |
CN (1) | CN102238948B (zh) |
AR (1) | AR074454A1 (zh) |
AU (1) | AU2009324080B2 (zh) |
BR (1) | BRPI0916504B8 (zh) |
CA (1) | CA2742703C (zh) |
DK (1) | DK2373310T3 (zh) |
ES (2) | ES2506265T3 (zh) |
FR (1) | FR2939136B1 (zh) |
HR (1) | HRP20120954T1 (zh) |
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PL (2) | PL2529735T3 (zh) |
PT (1) | PT2373310E (zh) |
RU (1) | RU2482116C2 (zh) |
SI (1) | SI2373310T1 (zh) |
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WO (1) | WO2010063773A1 (zh) |
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FR2939135B1 (fr) * | 2008-12-02 | 2010-12-03 | Galderma Res & Dev | Nouveaux composes 4-(azacycloalkyl)-benzene-1,3-diol comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
EP2688403B1 (en) * | 2011-03-23 | 2017-05-31 | Trevena, Inc. | Opioid receptor ligands and methods of using and making same |
EP2956449B1 (fr) | 2013-02-14 | 2017-06-28 | Galderma Research & Development | Procede de synthese de composes 4-(heterocycloalkyl)-benzene-1,3-diol |
WO2014139080A1 (en) * | 2013-03-12 | 2014-09-18 | Boehringer Ingelheim International Trading (Shanghai) Co., Ltd. | Novel process for the manufacture of 3-oxo-tetrahydrofuran |
FR3030249B1 (fr) * | 2014-12-22 | 2018-11-02 | L'oreal | Composition aqueuse comprenant un compose 4-(heterocycloalkyl)-benzene-1,3-diol, un polymere et un glycol |
FR3030252B1 (fr) * | 2014-12-22 | 2018-11-02 | L'oreal | Composition aqueuse comprenant un compose 4-(heterocycloalkyl)-benzene-1,3-diol, un monoalcool en c2-c4 et un glycol |
FR3030250B1 (fr) * | 2014-12-22 | 2018-11-02 | L'oreal | Composition aqueuse comprenant un compose 4-(heterocycloalkyl)-benzene-1,3-diol et un hydrotrope |
FR3030251B1 (fr) * | 2014-12-22 | 2018-11-02 | L'oreal | Composition comprenant un compose 4-(heterocycloalkyl)-benzene-1,3-diol et un solvant particulier |
JP6873598B2 (ja) * | 2015-12-22 | 2021-05-19 | ロレアル | 活性成分のための改善された局所送達系 |
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