CN116496205A - 一种卡瑞斯汀的盐及其用途 - Google Patents
一种卡瑞斯汀的盐及其用途 Download PDFInfo
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- CN116496205A CN116496205A CN202310400947.0A CN202310400947A CN116496205A CN 116496205 A CN116496205 A CN 116496205A CN 202310400947 A CN202310400947 A CN 202310400947A CN 116496205 A CN116496205 A CN 116496205A
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- Prior art keywords
- salt
- acid
- karostigma
- ebastine
- salts
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- 150000003839 salts Chemical class 0.000 title claims abstract description 63
- -1 inter alia Chemical class 0.000 claims abstract description 41
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- 208000026935 allergic disease Diseases 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 11
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- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 claims abstract description 7
- 239000011734 sodium Substances 0.000 claims abstract description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 5
- 239000011591 potassium Substances 0.000 claims abstract description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract 2
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims description 4
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 3
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- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明公开了一种卡瑞斯汀的盐及用途,涉及药物化学领域,解决现有技术中卡瑞斯汀固体形态差、杂质多、不稳定、不易提纯、不易放大合成,不适用于药用等问题。本发明的卡瑞斯汀盐包括但不限于酸盐或碱盐,尤其包括钾盐、钠盐、甲磺酸盐和对甲苯磺酸盐。本发明的卡瑞斯汀的盐具备制备组胺H1受体拮抗剂的药物中的用途。本发明的卡瑞斯汀盐,容易提纯、稳定性高、工艺简单且易工业化生产等特点,并且具有较好的引湿性特征,方便储存;同时本发明的盐可快速进入体内发挥药效作用,口服吸收好,安全性及个体差异均优于依巴斯汀,是一种很有发展前途的抗过敏性疾病的药物。
Description
本申请主张2022年5月6日申请的发明名称为“一种卡瑞斯汀的盐及其用途”、专利号为CN202210486129.2的发明专利的优先权,特此以引用的方式明确并入本文中。
技术领域
本发明涉及药物化学技术领域,具体涉及一种卡瑞斯汀的盐及用途。
背景技术
过敏性疾病(anaphylactia)又称变态反应性疾病,指由接触致敏物质引起过敏反应或变态反应的疾病。目前临床上常见的过敏性疾病主要包括过敏性鼻炎、哮喘、荨麻疹、特应性皮炎、过敏性眼结膜炎,以及过敏性的胃肠道疾病等等。过敏反应是指已产生免疫的机体在再次接受相同抗原刺激时所发生的组织损伤或功能紊乱的反应。近年来,中国过敏性疾病的发病率呈持续上升趋势,我国过敏性疾病的发病率接近40%。以过敏性鼻炎为例,过敏性鼻炎是发病率最高的疾病,截止目前不完全统计全球患病人数已超过5亿。过敏性鼻炎主要表现为鼻塞、鼻痒、流鼻涕、打喷嚏等。过敏性疾病症状长期、反复发作,如未能及时预防或干预治疗,可能影响患者的睡眠、社交、工作等生活质量。
组胺H1受体拮抗剂是预防和治疗过敏性疾病常用的一类药物,从发展历程上分,主要分为三代。第一代如氯苯那敏、异丙嗪、苯海拉明、赛庚啶,药物作用时间短、同时具有中枢抑制和镇静作用,表现出嗜睡、癫痫、皮疹、过敏性休克等不良反应。第二代如氯雷他定、西替利嗪、依巴斯汀、阿司咪唑和特非那定,具有长效、非镇静作用;其中阿司咪唑和特非那定已被发现可延长 QTc 间期,并且在极少数情况下会在过量或其他特定条件下引起心律失常,现监管机构已撤销对它们的批准。第三代以咪唑斯汀、地氯雷他定、左西替利嗪为代表,其中咪唑斯汀具有独特的抗组胺和抗其它炎症介质的双重作用;地氯雷他定为氯雷他定的活性代谢物,解决了氯雷他定个体差异大的问题;左西替利嗪是西替利嗪的单一异构体。
依巴斯汀片属于第二代组胺H1受体拮抗剂,是一种强效、长效、高选择性的组胺H1受体阻断剂,并且对中枢神经系统的胆碱能受体没有拮抗作用,能选择性地阻断组胺H1受体,且无镇静作用,用于治疗各种过敏性疾病:荨麻疹、过敏性鼻炎、湿疹、皮炎、痒疹、皮肤瘙痒症等。口服给药后,依巴斯汀被快速吸收,大部分经强烈的肝首过效应而代谢。其主要经过两条路线代谢,一条是在CYP3A酶的作用下脱烷基,生成脱烷基依巴斯汀代谢产物;另一条代谢路线是在CYP2J2酶的作用下生成羟基依巴斯汀代谢产物,羟基依巴斯汀再通过CYP2J2和CYP3A4酶的氧化作用生成一种酸性代谢产物卡瑞斯汀(Carebastine)。依巴斯汀及其代谢物卡瑞斯汀,均不进入中枢,无不良中枢神经作用和抗胆碱能作用。
尚未报道,并且没有证据表明与依巴斯汀治疗相关的 QTc 间期延长。因此,每日一次依巴斯汀为目前用于季节性和常年性过敏性鼻炎和慢性特发性荨麻疹的一线治疗的其他第二代抗组胺药提供了一种有效且耐受良好的替代品。与第一代H1受体拮抗剂相比,依巴斯汀未见明显的心脏及精神运动系统异常。但是,由于依巴斯汀口服起效时间在1~4小时,故不适用于急性过敏性疾病如急性寻麻疹、哮喘等的紧急治疗。
目前临床上起效较快的组胺H1受体拮抗剂仅有左西替利嗪和西替利嗪。左西替利嗪和西替利嗪相较依巴斯汀更易进入中枢,临床上表现出嗜睡、头痛。因此,临床上急需可用于急性过敏性疾病患者如急性寻麻疹、哮喘患者的无镇静作用的、起效快的组胺H1受体拮抗剂。
卡瑞斯汀是依巴斯汀的体内活性代谢产物,其结构式如式I所示:
。
同依巴斯汀一样,卡瑞斯汀对组胺H1受体具有很强的选择性拮抗作用,能抑制组胺释放,对中枢神经系统的H1受体拮抗作用和抗胆碱作用很弱。以卡瑞斯汀直接入药,可以有效解决依巴斯汀口服起效时间慢的问题。但卡瑞斯汀没有很好的固体形态,导致卡瑞斯汀无法满足药学要求:固体形态差制剂无法稳定使用,不易纯化、无法放大生产,质量不可控,不适合药用,故目前还没有卡瑞斯汀上市药品。
发明内容
本发明的目的之一在于,提供一种卡瑞斯汀的盐,解决现有技术中卡瑞斯汀固体形态差、杂质多、不稳定、不易提纯、不易放大合成,不适用于药用等问题。
本发明的目的之二在于,提供一种卡瑞斯汀的盐的用途。
本发明的目的之三在于,提供一种包含卡瑞斯汀的盐的组合物。
为实现上述目的,本发明采用的技术方案如下:
一方面,本发明提供一种卡瑞斯汀药学上可接受的盐,所述盐为卡瑞斯汀与酸所形成的酸盐,或与碱所形成的碱盐。
本发明的部分实施方案中,上述酸盐为无机酸盐或有机酸盐。
进一步地,上述无机酸盐选自硫酸盐、硫酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、碳酸盐、碳酸氢盐、亚硫酸盐、亚硫酸氢盐、焦硫酸盐、磷酸一氢盐、磷酸二氢盐、高氯酸盐、过硫酸盐、半硫酸盐、重硫酸盐、硫氰酸盐、磷酸盐、焦磷酸盐或偏磷酸盐。
进一步地,上述有机酸盐选自甲酸盐、乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、丙酮酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、柠檬酸盐、4-硝基苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、丙炔酸盐、2-丁炔酸盐、2-羟基-乙烷磺酸盐、乙烯基乙酸盐、酒石酸盐、L-酒石酸盐、富马酸盐、羟乙基磺酸盐、马来酸盐、乳酸盐、乳糖酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚糖酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、草酸盐、三氟乙酸盐、三氟甲磺酸盐、己二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、羟基乙酸盐、藻酸盐、抗坏血酸盐、异抗坏血酸盐、天冬氨酸盐、L-天冬氨酸盐、谷氨酸盐、L-谷氨酸盐、2-苯氧基苯甲酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、乙酰乙酸盐、2-羟基乙磺酸盐、硼酸盐、氯代苯甲酸盐、樟脑酸盐、衣康酸盐、樟脑磺酸盐、左旋樟脑磺酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、氨基磺酸盐、乳糖醛酸盐、半乳糖醛酸盐、环戊基丙酸盐、十二烷基硫酸盐、丙烯酸盐、环戊烷丙酸盐、甘油磷酸盐、甲氧基苯甲酸盐、二葡萄糖酸盐、葡萄糖酸盐、庚酸盐、己酸盐、2-羟基-乙磺酸盐、三甲基乙酸盐、葡糖醛酸盐、月桂酸盐、邻苯二甲酸盐、苯乙酸盐、月桂基硫酸盐、2-乙酰氧基苯甲酸盐、烟酸盐、肉桂酸盐、油酸盐、棕榈酸盐、果胶酸盐、苯二甲酸盐、戊二酸盐、羟基马来酸盐、羟基苯甲酸盐、苯乙酸盐、3-羟基-2-萘甲酸盐、3-苯基丙酸盐、异丁酸盐、新戊酸盐、苦味酸盐、硬脂酸盐、2 ,2-二氯乙酸盐、酰化氨基酸盐、海藻酸盐、4-乙酰氨基苯磺酸盐、葵酸盐、胆酸盐、辛酸盐、壬酸盐、环拉酸盐、酞酸盐、盐酸半胱氨酸盐、山梨酸盐、帕莫酸盐、粘酸盐、盐酸甘氨酸盐、萘二磺酸盐、二甲苯磺酸盐、二盐酸胱氨酸盐、十一酸盐、聚乙烯磺酸盐、磺基水杨酸盐、苯基丁酸盐、4-羟基丁酸盐、聚乙烯硫酸盐、萘-1-磺酸盐、萘-2-磺酸盐或戊酸盐。
本发明的部分实施方案中,上述有机酸盐选自甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、萘二磺酸盐、萘-1-磺酸盐或萘-2-磺酸盐。
进一步地,上述有机酸盐选自甲磺酸盐、苯磺酸盐或对甲苯磺酸盐。
本发明的部分实施方案中,上述碱盐选自碱金属盐、取代或未取代的铵盐、胺盐、碱性氨基酸盐、或取代或未取代的吡啶盐。
进一步地,上述金属碱盐选自锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铁盐、或锌盐;优选钾盐或钠盐。
进一步地,上述取代或未取代的铵盐选自铵盐、四甲基铵盐、四乙基铵盐或胆碱盐。
进一步地,上述胺盐选自甲胺盐、二甲胺盐、三甲胺盐、乙胺盐、二乙胺盐、三乙胺盐、异丙胺盐、叔丁胺盐、二异丙胺盐、2-乙氨基乙醇盐、氨丁三醇盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、哌啶盐、哌嗪盐、吗啉盐、葡甲胺盐、N-甲基葡糖胺盐、二甲基葡糖胺盐、乙基葡糖胺盐、二环己基胺盐、1,6-己二胺盐、半乳糖胺盐、葡糖胺盐、三羟基甲基氨基甲烷盐、氨基丙二醇盐、1-氨基-2,3,4-丁三醇盐或丝氨醇盐。
进一步地,上述碱性氨基酸盐选自赖氨酸盐、精氨酸盐、L-精氨酸盐、组氨酸盐、L-组氨酸盐、肌氨酸盐、L-赖氨酸盐或鸟氨酸盐。
进一步地,上述取代或未取代的吡啶盐选自吡啶盐、甲基吡啶盐、乙基吡啶盐或丙基吡啶盐。
本发明的部分实施方案中,上述卡瑞斯汀的盐为单盐或者复盐,单盐中卡瑞斯汀和盐根的摩尔比为1:1~2:1,复盐中卡瑞斯汀和盐根的摩尔比为1:4~4:1。
进一步地,在一些实施例中,上述卡瑞斯汀的盐选自:
、/>、
、/>、
、/>、
或/>。
另一方面,本发明提供上述任意一项卡瑞斯汀的盐的制备方法,包括如下步骤:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸与酸或碱在有机溶剂条件下加热反应成盐。
进一步地,上述酸包括有机酸或无机酸;优选地,所述有机酸包括但不限于对甲苯磺酸、甲磺酸、苯磺酸或萘-2-磺酸。
进一步地,上述碱包括金属碱;优选地,所述金属碱包括但不限于氢氧化钠、氢氧化钾、氢氧化钙或氢氧化镁。
进一步地,上述有机溶剂包括但不限于醇类、酯类或腈类;优选地,所述醇类包括但不限于甲醇、乙醇或异丙醇;所述酯类包括但不限于乙酸乙酯;所述腈类包括但不限于乙腈。
进一步地,上述加热的温度选自30~100℃;优选50~60℃。
第三方面,本发明提供上述任一项卡瑞斯汀的盐的药物组合物,所述药物组合物还包含药学上可接受的载体。
上述“药学上可接受的载体”:是指与活性成分一同给药的稀释剂、辅剂、赋形剂或媒介物,并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
第四方面,本发明提供上述任一项卡瑞斯汀的盐在制备组胺H1受体拮抗剂中的用途。
进一步地,上述用途包含上述任一项卡瑞斯汀的盐在制备治疗和/或预防过敏性疾病的药物中的用途。
进一步地,上述过敏性疾病为急性过敏性疾病。
进一步地,上述过敏性疾病选自荨麻疹、过敏性鼻炎、湿疹、皮炎或皮肤瘙痒症。
进一步优选地,上述急性过敏性疾病选自急性过荨麻疹或急性过敏性鼻炎。
本发明中英文缩写代表的名称为:
DMAC:乙酰胺
EA:乙酸乙酯
DMSO:二甲基亚砜
CMC-Na:羧甲基纤维素钠。
与现有技术相比,本发明具有以下有益效果:
本发明的卡瑞斯汀盐为白色粉末状固体,具有良好的药用固体形态、纯度和稳定性高。卡瑞斯汀是依巴斯汀的活性代谢产物,进入体内后无需经酶的代谢就可产生药效作用,起效时间快,避免了酶的基因多态性导致个体用药差异而引起的安全性风险、以及无效引起的过敏持续的危及生命的风险。本发明的卡瑞斯汀盐为临床过敏性患者提供了一个新的选择。
卡瑞斯汀是酸碱两性化合物,申请人经过大量试验,系统研究了卡瑞斯汀的盐,发现卡瑞斯汀可形成的盐有限,且酸盐的纯度及稳定性均优于碱盐,如对甲苯磺酸盐的纯度及稳定性优于钾盐的纯度及稳定性,但本发明人发现卡瑞斯汀酸盐存在较严重的引湿性,相比而言,本发明的钾盐及对甲苯磺酸盐具有更好的引湿性特征。
另一方面本发明的对甲苯磺酸盐溶解度不如游离态的卡瑞斯汀,但是,从大鼠的药代动力学研究中,申请人惊奇地发现,同摩尔给药,卡瑞斯汀对甲苯磺酸盐和钾盐均有优于依巴斯汀和游离态的卡瑞斯汀的药代动力学性质,如AUC比较,卡瑞斯汀对甲苯磺酸盐组和钾盐组的体内卡瑞斯汀的AUC明显大于依巴斯汀组和游离的卡瑞斯汀组,且生成的卡瑞斯汀的Tmax小于依巴斯汀的Tmax,说明本发明的卡瑞斯汀盐起效更快,相同摩尔给药,具有更好的药代动力学性质。另外,小鼠急性毒性研究发现,卡瑞斯汀对甲苯磺酸盐和钾盐的急性毒性均低于依巴斯汀。
附图说明
附图1为卡瑞斯汀(游离态)0天 HPLC图;
附图2为卡瑞斯汀(游离态)光照(12天)HPLC图;
附图3为卡瑞斯汀对甲苯磺酸盐0天 HPLC图;
附图4为卡瑞斯汀对甲苯磺酸盐光照(12天)HPLC图。
具体实施方式
以下将结合实施例和实验例对本发明作进一步的详细描述,本发明的实施例和实验例仅用于说明本发明的技术方案,并非对本发明的限制,凡依照本发明公开的内容所作的任何本领域的等同置换,均属于本发明的保护范围。
化合物的结构是核磁共振(1H NMR)或液质联用(LC~MS)来确定的。
液质联用仪(LC~MS)为安捷伦G6120B(与液相Agilent 1260配用);核磁共振仪(1HNMR)为Bruker AVANCE~400或Bruker AVANCE~800,核磁共振(1H NMR)位移(δ)以百万分之一(ppm)的单位给出,内标为四甲基硅烷(TMS),化学位移是以10~6(ppm)作为单位给出。
本发明的术语“室温”是指温度处于10~30℃之间。
实施例1:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸钾(卡瑞斯汀钾盐)的制备
步骤1: 2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸甲酯的制备
25ml单口瓶加入4-(二苯甲氧基)哌啶盐酸盐(473mg,1.77mmol),DMAC(4.5ml),K3PO4(1.13g,5.3mmol),KI(29mg,0.177mmol),搅拌加热至100℃。称取2-[4-(4-氯-1-丁酰基)苯基]-2-甲基丙酸甲酯(600mg,2.12mmol)溶于DMAC 1ml,缓慢滴加入反应液,保温反应4~6h,TLC检测原料反应完毕。降温至室温,加入醋酸异丙酯、水,搅拌分层。水相再加入醋酸异丙酯萃取,合并有机相,水洗二次,无水硫酸钠干燥,过滤,浓缩,过硅胶柱,得到标题产物500mg,收率45%,纯度:97.3%。
ESI-MS: m/z = 514.3(M+H) +。
1H NMR (400 MHz, CDCl3) δ: 7.93 (d, J=8.3Hz, 2H), 7.47 (m, 4H), 7.42(d, J=8.3Hz, 2H), 7.30 (m, 4H), 7.18 (m, 2H), 3.64 (s, 3H),2.98 (m, 4H), 2.42– 2.40 (m, 4H), 1.96 (m, 4H), 1.62 (s, 6H), 1.42 (m, 4H)。
步骤2:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸(卡瑞斯汀)的制备
25ml三口烧瓶加入(5-甲基-2-氧-1,3-二氧-4-基)甲基-2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)-丁酰基)苯基)-2-甲基丙酸甲酯(320mg,0.62mmol),甲醇1.5ml,10%NaOH2ml,加热至60℃反应2h,TLC原料反应完毕。反应结束,冷却至室温,浓缩干,加入EA,加盐酸调节pH至2~3,分层,水洗一次,有机相干燥,浓缩干得到标题产物300mg。收率:95%,纯度95.0%。
ESI-MS: m/z = 500.3(M+H) +。
1H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m,12H), 5.48(s,1H),3.73 (m, 1H), 3.05–3.02 (m, 2H), 2.77–2.66 (m, 6H), 2.20–2.07 (m, 2H),2.00–1.81 (m,4H), 1.58 (s, 6H)。
步骤3:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸钾(卡瑞斯汀钾盐)的制备
25ml三口烧瓶加入2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸(499mg,1mmol),乙腈3.5ml,加热至60℃,加入氢氧化钾(56mg,1mmol)搅拌,降温,析出白色固体,过滤,烘干得到卡瑞斯汀钾盐500mg,收率90%,纯度98.67%。
ESI-MS: m/z = 500.3(M+H) +。
1H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m,12H), 5.48(s,1H),3.73 (m, 1H), 3.05–3.02 (m, 2H), 2.77–2.66 (m, 6H), 2.20–2.07 (m, 2H),2.00–1.81 (m,4H), 1.58 (s, 6H)。
实施例2:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸钠(卡瑞斯汀钠盐)的制备
本实施例中2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸的制备方法同实施例1。
25ml三口烧瓶加入2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸(499mg,1mmol),乙腈3.5ml,加热至60℃,加入氢氧化钠(40mg,1mmol)搅拌1h,浓缩干,加入甲基叔丁醚搅拌,过滤,烘干得到卡瑞斯汀钠盐458mg,收率85%,纯度96.98%。
ESI-MS: m/z = 500.3(M+H) +。
1H NMR (400 MHz, CDCl3) δ:7.75-7.63 (m, 2H), 7.57–7.24 (m,12H), 5.48(s,1H),3.73 (m, 1H), 3.05–3.02 (m, 2H), 2.77–2.66 (m, 6H), 2.20–2.07 (m, 2H),2.00–1.81 (m,4H), 1.58 (s, 6H)。
实施例3:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸对甲苯磺酸盐(卡瑞斯汀对甲苯磺酸盐)的制备
本实施例中2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸的制备方法同实施例1。
25ml三口烧瓶加入2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸(500mg,0.1mmol),异丙醇1ml,加热至60℃,加入对甲苯磺酸(172mg,1mmol)搅拌,降温,析出白色固体,过滤,烘干得到卡瑞斯汀对甲苯磺酸盐585mg,收率87%,纯度99.99%。
ESI-MS: m/z = 500.3(M+H) +。
1H NMR (400 MHz, CDCl3) δ:7.94 (d, 2H), 7.49 (dd, 4H), 7.36 (dt, 8H),7.29 – 7.21 (m, 2H), 7.11 (d, 2H), 5.48 (s,1H),3.73 (m, 1H), 3.05–3.02 (m,2H), 2.77–2.66 (m, 6H), 2.41(s,3H),2.20–2.07 (m, 2H), 2.00–1.81 (m,4H), 1.58(s, 6H)。
实施例4:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸甲磺酸盐(卡瑞斯汀甲磺酸盐)的制备
本实施例中2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸的制备方法同实施例1。
25ml三口烧瓶加入2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸(499mg,1mmol),EA3.5ml,加热至60℃,加入甲磺酸(96mg,1mmol)搅拌1h,浓缩干,加入甲基叔丁醚搅拌,过滤,烘干得到白色固体,卡瑞斯汀甲磺酸盐482mg,收率81%,纯度96.81%。
ESI-MS: m/z = 500.3(M+H) +。
1H NMR (400 MHz, CDCl3) δ: δ:7.75-7.63 (m, 2H), 7.57–7.24 (m,12H),5.48 (s,1H),3.73 (m, 1H), 3.29(s,3H),3.09 (s, 1H),3.05–3.02 (m, 2H), 2.77–2.66 (m, 6H), 2.20–2.07 (m, 2H), 2.00–1.81 (m,4H), 1.58 (s, 6H)。
实施例5:卡瑞斯汀对甲苯磺酸盐的制备
25ml三口烧瓶加入2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸(500mg,0.1mmol),异丙醇1 ml,加热至80℃,加入对甲苯磺酸(172mg,1mmol)搅拌反应完全,降温,析晶,过滤,烘干得到卡瑞斯汀对甲苯磺酸盐565 mg,收率84%,纯度97.91%。
ESI-MS: m/z = 500.3(M+H) +。
1H NMR (400 MHz, CDCl3) δ:7.94 (d, 2H), 7.49 (dd, 4H), 7.36 (dt, 8H),7.29 – 7.21 (m, 2H), 7.11 (d, 2H), 5.48 (s,1H),3.73 (m, 1H), 3.05–3.02 (m,2H), 2.77–2.66 (m, 6H), 2.41(s,3H),2.20–2.07 (m, 2H), 2.00–1.81 (m,4H), 1.58(s, 6H)。
说明:本发明各试验例中“依巴斯汀(对比例1组,购买)”表示该组所用试验样品为市售购买的依巴斯汀(对比例1);“卡瑞斯汀对甲苯磺酸盐(实施例3组)”表示该组所用试验样品为实施例3制备的卡瑞斯汀对甲苯磺酸盐;类似记载做类似解释。
试验例1:组胺所致豚鼠休克试验
1. 试验样品:依巴斯汀(对比例1组,购买)、卡瑞斯汀钾盐(实施例1组)、卡瑞斯汀钠盐(实施例2组)、卡瑞斯汀对甲苯磺酸盐(实施例3组)、卡瑞斯汀甲磺酸盐(实施例4组)。
2. 试验方法:取豚鼠60只,体重220g左右,随机分成6组:空白对照组、实施例1组、实施例2组、实施例3组、实施例4组、依巴斯汀组。除空白对照组外,其余各组按1.00 mg/kg的依巴斯汀等摩尔剂量换算,分别灌胃给予相应药物,空白组给予等体积的0.5%CMC-Na溶液,给药容积均为10ml/kg。用药后1小时,豚鼠后足掌外侧静脉注射0.125wt.%磷酸组胺生理盐水溶液2ml/kg,10s内注射完毕后,立即秒表计时,观察动物出现呼吸加快及惊厥倒下的潜伏期。
3. 试验结果:
与空白对照组比较: ∗ p <0.01;与依巴斯汀组(对比例1组)比较:▲p<0.01。
与空白对照组相比,组胺静脉注射后,实施例化合物和依巴斯汀均显著延长了豚鼠对组胺致敏出现呼吸加快的潜伏期和惊厥潜伏期(p<0.01),且未出现动物死亡;与依巴斯汀给药组相比,实施例1、2、3、4组化合物延长豚鼠呼吸加快潜伏期和惊厥潜伏期更为明显(p<0.01)。
试验例2:大鼠药代动力学试验
1. 试验样品:依巴斯汀(对比例1组)、卡瑞斯汀(对比例2组)、卡瑞斯汀钾盐(实施例1组)、卡瑞斯汀对甲苯磺酸盐(实施例3组)。
2. 试验方法:
取SD大鼠24只,体重180~200g左右,随机分为4组,每组6只,雌雄各半,口服灌胃给予相应的药物。大鼠给药前禁食12 h,饮水自由。每组均以10mg/kg的依巴斯汀等摩尔剂量给药。组别和剂量分别为:
对比例1组:依巴斯汀, 10 mg/kg;
对比例2组:卡瑞斯汀, 10.63 mg/kg;
实施例1组:卡瑞斯汀钾盐, 11.11 mg/kg;
实施例3组:卡瑞斯汀对甲苯磺酸盐, 14.39 mg/kg。
受试物的配制:受试物的配制均在配制室的常规工作台进行。采用DMSO为溶剂分别配置1.00 mg/mL的依巴斯汀、卡瑞斯汀、实施例1和实施例3储备液。大鼠给药溶液采用0.5%CMC-Na溶液分别配置成10 mg/mL的依巴斯汀溶液、10 mg/mL的卡瑞斯汀溶液和11.11mg/kg的实施例1溶液、14.39 mg/mL的实施例3溶液。
给药前采集空白血,给药后按预定时间点采血:0.25h,0.5h,0.75h,1h,2h,3h,4h,6h,8h,10h,24h。采血约0.5mL,置EDTA-K2管中,离心分离血浆,并置于-80℃保存。用液相-质谱联用分析系统(LC-MS/MS)检测分析血浆样品中的原型和代谢产物卡瑞斯汀,并计算药代参数。
3. 试验结果:
SD大鼠单次给予实施例1、实施例3和依巴斯汀、卡瑞斯汀化合物后,依巴斯汀组中原型的含量均低于3ng/mL,说明依巴斯汀进入体内后,能快速代谢。
SD大鼠单次给予实施例1、实施例3和依巴斯汀、卡瑞斯汀化合物后,各组中代谢产生的卡瑞斯汀的平均药代动力学参数见下表:
。
由上表可知,大鼠口服给予实施例1组、实施例3组化合物后,实施例1组、实施例3组大鼠体内血浆中卡瑞斯汀的量AUClast明显优于依巴斯汀组、卡瑞斯汀组;但是实施例1组、实施例3组卡瑞斯汀达峰时间Tmax小于依巴斯汀组、卡瑞斯汀组,说明本发明的实施例1组、实施例3组可快速进入体内,抑制组胺H1受体,具有用于临床上急性过敏性疾病患者如急性寻麻疹的治疗潜力。
另外,在大鼠药代动力学研究过程还发现,依巴斯汀组中3只雌性大鼠的AUC和Cmax小于3只雄性大鼠AUC和Cmax,具有明显的差别,说明依巴斯汀给药后,在SD大鼠中,依巴斯汀表现出了性别差异。而本发明实施例化合物,未表现出性别差异。
结果表明,在等摩尔剂量给药的情况下,本发明实施例化合物与依巴斯汀相比达峰时间(Tmax)更快,特别是实施例3化合物,起效非常快,并且没有表现出性别差异,具有用于临床上急性过敏性疾病患者如急性寻麻疹的治疗的潜力,且能减少个体用药差异。
试验例3:小鼠急性毒性研究
1. 试验样品:依巴斯汀(对比例1)、卡瑞斯汀钾盐、卡瑞斯汀对甲苯磺酸盐。
2. 试验方法:
取健康成年KM小鼠70只,18-22g,雌雄各半,随机分成7组:空白对照组、实施例1高剂量组、实施例1低剂量组、实施例3高剂量组、实施例3低剂量组、依巴斯汀高剂量组、依巴斯汀低剂量组。
实施例1高剂量组、实施例3高剂量组、依巴斯汀高剂量组为同摩尔给药,分别为5.38 g/kg、6.72 g/kg、5 g/kg;实施例1低剂量组、实施例3低剂量组、依巴斯汀低剂量组为同摩尔给药,分别为2.69 g/kg、3.36 g/kg、2.5 g/kg;所有药物均通过灌胃方式给予,空白组给予等体积的0.5%CMC-Na溶液,给药前所有动物禁食12h,不禁水。
给药后连续饲养观察14天,每天观察小鼠毒性反应(如死亡等)情况并记录,观察期结束后对所有存活动物进行解剖,大体观察各脏器有无明显病变。
3. 试验结果:
单次灌胃给予低剂量的实施例1、3化合物和依巴斯汀后,所有动物整个观察阶段未见明显异常,解剖动物大体解剖观察未见明显异常,MDT>2.5 g/kg。单次灌胃给予高剂量的实施例1、3化合物和依巴斯汀后,依巴斯汀组死亡率高于实施例1、3组,提示本发明实施例1、3化合物与依巴斯汀相比,安全性更高。
。
试验例4:稳定性研究
1. 试验样品:卡瑞斯汀(对比例2、对比例2’)、卡瑞斯汀钾盐(实施例1)、卡瑞斯汀对甲苯磺酸盐(实施例3、实施例5)。
2. 试验方法:
称取样品卡瑞斯汀(对比例2)、卡瑞斯汀精制品(对比例2’)、卡瑞斯汀钾盐(实施例1)、卡瑞斯汀对甲苯磺酸盐(实施例3)、卡瑞斯汀对甲苯磺酸盐(实施例5)各3份分别放置于称量瓶中,每组样品分别放置于高温(60℃),高湿(RH80%),光照(5000Lux)条件,12天后取样检测。说明:上述卡瑞斯汀精制品对比例2’可通过本领域常规技术手段将对比例2进行柱层析制备。
检测方法:取各样品适量,精密称定,加乙腈溶解并定量稀释成每1ml约含0.08mg的溶液。采用高效液相色谱法,用十八烷基硅烷键合硅胶为填充剂,以水-乙腈(1:1)为流动相,检测波长为256nm,柱温35℃,进样体积10ul;各样品溶液分别注入液相色谱仪,记录色谱图。
3. 试验结果:
如下表结果显示,卡瑞斯汀对甲苯磺酸盐在高温、高湿、光照条件下稳定,卡瑞斯汀钾盐与卡瑞斯汀对甲苯磺酸盐相比,光照下稳定性略有所下降,但游离态卡瑞斯汀(对比例2)在光照条件下很不稳定,杂质增加,纯度下降明显。附图1~4也示出了游离态卡瑞斯汀(对比例2)和卡瑞斯汀对甲苯磺酸盐0天和12天光照的HLPC图,证明卡瑞斯汀(游离态)在光照下降解多,稳定性存在问题,且产生较多大于0.1%的杂质,不适合药用。
。
试验例5:引湿性研究
1. 试验样品:卡瑞斯汀(对比例2)、卡瑞斯汀盐酸盐(对比例3)、卡瑞斯汀钾盐(实施例1)、卡瑞斯汀对甲苯磺酸盐(实施例3)。其中卡瑞斯汀盐酸盐的制备参照专利US6340761的描述,纯度99%以上。
2. 试验方法:
(1)取干燥的具塞玻璃称量瓶(外径为50mm,高为15mm),于试验前一天置于适宜的25℃±1℃恒温干燥器(下部放置氯化铵或硫酸铵饱和溶液)或人工气候箱(设定温度为25℃±1℃,相对湿度为80%±2%)内,精密称定重量(m1);
(2)取供试品适量,平铺于上述称量瓶中,供试品厚度一般约为1mm,精密称定重量(m2);
(3)将称量瓶敞口,并与瓶盖同置于上述恒温恒湿条件下24h;
(4)盖好称量瓶盖子,精密称定重量(m3);
(5)增重百分率=(m3-m2)/(m2-m1)×100%。
3. 试验结果:
引湿性结果如下表所示:结果说明,本发明的卡瑞斯汀钾盐、卡瑞斯汀对甲苯磺酸盐具有比游离态卡瑞斯汀及卡瑞斯汀盐酸盐更好的引湿性特征。
。
上述结果按照药典界定,即“有引湿性”表示引湿增重小于15%但不小于2%;“极具引湿性”表示引湿增重不小于15%;“无或几乎无引湿性”表示引湿增重小于0.2%;“略有引湿性”表示引湿增重小于2%但不小于0.2%。
试验例6:溶解度测试
1. 试验样品:卡瑞斯汀(对比例2)、卡瑞斯汀对甲苯磺酸盐(实施例3)。
2. 试验方法:
pH1.2盐酸溶液:取7.65ml 盐酸,加水稀释至1000ml,摇匀即得。
pH4.5磷酸盐缓冲液:称取KH2PO4 3.40278g,用水溶解并稀释至500ml, 摇匀即得。
pH6.8磷酸盐缓冲液:称取KH2PO4 3.40353g,氢氧化钠0.4428g,用水溶解并稀释至500ml,摇匀即得。
取适量实施例3、对比例2化合物分别至装有50ml水、50ml pH1.2盐酸溶液、50mlpH4.5磷酸盐缓冲液、50ml pH6.8磷酸盐缓冲液的锥形瓶中,使溶液呈过饱合状态,能明显看到不溶物。
将锥形瓶放入水浴恒温中,温度37℃,振荡速率:120转/min,分别于24h、48h、72h取样,用液相色谱仪检测。
3. 试验结果:
结果如上表所示:在所有测试的介质中,不同时间上,实施例3的溶解度均低于对比例2的溶解度。但是,实施例3的化合物在大鼠药代动力学试验中,均表现出更优的药代动力学性质。
上述实施例仅为本发明的优选实施方式之一,不应当用于限制本发明的保护范围,但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色,其所解决的技术问题仍然与本发明一致的,均应当包含在本发明的保护范围之内。
Claims (10)
1.一种卡瑞斯汀的盐,其特征在于,所述盐为卡瑞斯汀与酸所形成的酸盐或卡瑞斯汀与碱所形成的碱盐。
2.根据权利要求1所述的卡瑞斯汀的盐,其特征在于,所述酸盐包含无机酸盐或有机酸盐;优选地,所述有机酸盐选自甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、萘二磺酸盐、萘-1-磺酸盐、或萘-2-磺酸盐。
3.根据权利要求2所述的,卡瑞斯汀的盐,其特征在于,所述酸盐选自甲磺酸盐、苯磺酸盐或对甲苯磺酸盐。
4.根据权利要求1所述的卡瑞斯汀的盐,其特征在于,所述碱盐包含碱金属盐、取代或未取代的铵盐、胺盐、碱性氨基酸盐、或取代或未取代的吡啶盐;优选地,所述碱盐选自锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铁盐或锌盐。
5.根据权利要求4所述的卡瑞斯汀的盐,其特征在于,所述碱盐选自钾盐或钠盐。
6.根据权利要求1~5任意一项所述的卡瑞斯汀的盐,其特征在于,所述卡瑞斯汀的盐为单盐或者复盐,单盐中卡瑞斯汀和盐根的摩尔比为1:1~2:1,复盐中卡瑞斯汀和盐根的摩尔比为1:4~4:1。
7.根据权利要求1~6任意一项所述的卡瑞斯汀的盐,其特征在于,所述卡瑞斯汀的盐选自:
、/>、
、/>、
、/>、
或/>。
8.权利要求1~7任意一项所述的卡瑞斯汀的盐的制备方法,其特征在于,所述制备方法包括如下步骤:2-(4-(4-(4-(二苯甲氧基)哌啶-1-基)丁酰基)苯基)-2-甲基丙酸与酸或碱在有机溶剂条件下加热反应成盐。
9.一种含有权利要求1~7任意一项所述的卡瑞斯汀的盐的药物组合物,其特征在于,所述药物组合物还包含药学上可接受的载体。
10.权利要求1~7任意一项所述的卡瑞斯汀的盐在制备组胺H1受体拮抗剂的药物中的用途;优选地,所述用途包含在制备治疗和/或预防过敏性疾病的药物中的用途;进一步优选地,所述过敏性疾病为急性过敏性疾病;进一步优选地,所述过敏性疾病选自荨麻疹、过敏性鼻炎、湿疹、皮炎或皮肤瘙痒症;更进一步优选地,所述急性过敏性疾病为急性荨麻疹或急性过敏性鼻炎。
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