CN114436945B - 一种苯磺酰胺类化合物、制备方法及应用 - Google Patents
一种苯磺酰胺类化合物、制备方法及应用 Download PDFInfo
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- CN114436945B CN114436945B CN202111657898.6A CN202111657898A CN114436945B CN 114436945 B CN114436945 B CN 114436945B CN 202111657898 A CN202111657898 A CN 202111657898A CN 114436945 B CN114436945 B CN 114436945B
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- compound
- benzenesulfonamide
- acetamide
- amine
- chloride
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- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 22
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- 239000000594 mannitol Substances 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 150000003248 quinolines Chemical class 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 238000010025 steaming Methods 0.000 description 1
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- 230000004936 stimulating effect Effects 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—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
- 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明涉及一种苯磺酰胺类化合物,具有通式(I)或通式(II)的结构形式:或所述化合物式(I)化合物或式(II)化合物的药学上可接受的盐;其中,通式I中,R1为单取代或双取代吸电子、供电子或中性基团,R2为有取代基或无取代基的碱性含氮五元、六元、七元脂肪杂环,n1=0‑5;或,通式II中,R1为单取代或双取代吸电子、供电子或中性基团,R2为单取代或双取代吸电子、供电子或中性基团,n1=0‑3。本发明所述苯磺酰胺类化合物能够抑制NFAT(为活化T细胞核因子的简称)入核,对CRAC通道的抑制具有高活性,是一类结构新颖的CRAC通道抑制剂,可作为CRAC通道抑制剂的先导化合物加以利用。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种苯磺酰胺类化合物、制备方法及应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
钙激活释放钙通道(Ca2+release activated Ca2+,CRAC)抑制剂作为免疫抑制剂可用于自身免疫性疾病、器官移植的免疫排斥、以及感染性疾病的治疗;同时钙激活释放钙通道功能异常还与多种疾病的发生密切相关,如肿瘤等,因此,CRAC通道抑制剂还可用于与CRAC通道功能异常相关疾病的治疗。虽然目前报道了一些不同结构类型的CRAC通道抑制剂,但因种种原因,仍未有CRAC通道抑制剂应用于临床,因此仍需积极探索发现结构新颖、拥有自主知识产权、更安全有效的CRAC通道抑制剂,以满足应用需求。
发明内容
为了克服上述问题,本发明设计了一种苯磺酰胺类化合物,对CRAC通道具有高抑制活性。
基于上述研究成果,本公开提供以下技术方案:
本公开第一方面,提供一种苯磺酰胺类化合物,具有通式(I)或通式(II)的结构形式:
,
或所述化合物式(I)化合物或式(II)化合物的药学上可接受的盐。
其中,通式I中,R1为单取代或双取代吸电子、供电子或中性基团,R2为有取代基或无取代基的碱性含氮五元、六元、七元脂肪杂环,n1=0-5;或,通式II中,R1为单取代或双取代吸电子、供电子或中性基团,R2为单取代或双取代吸电子、供电子或中性基团,n1=0-3。
本公开第二方面,提供上述通式I或通式II所述化合物的制备方法,包括以下步骤:
以苯胺为起始原料,依次与酰氯(优选为氯乙酰氯)、脂肪胺或芳香胺、苯磺酰氯或对位取代的苯磺酰氯(优选为4-溴甲基苯磺酰氯)反应制备得到。
本公开第三方面,提供一种组合物,其包括通式I或II所示化合物或其药学上可接受的盐。
本公开第四方面,提供一种药学制剂,其包括通式I或II所示化合物或其药学上可接受的盐或上述组合物,与至少一种药学载体和/或赋形剂。
本公开第五方面,提供上述通式I或II所示化合物或其药学上可接受的盐、或组合物或药学制剂在制备CRAC通道抑制剂或与CRAC通道功能异常相关疾病药物中的应用,优选的,所述疾病为自身免疫性疾病、肿瘤或感染类疾病。
本发明一个或多个具体实施方式至少取得了以下技术效果:
本发明所述苯磺酰胺类化合物能够抑制NFAT(为活化T细胞核因子的简称)入核,对CRAC通道的抑制具有高活性,是一类结构新颖的CRAC通道抑制剂,可作为CRAC通道抑制剂的先导化合物加以利用。
附图说明
构成本公开的一部分的说明书附图用来提供对本公开的进一步理解,本公开的示意性实施例及其说明用于解释本公开,并不构成对本公开的不当限定。
图1为本发明实施例1和2部分化合物对CRAC通道的抑制活性图。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本公开提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本公开所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本公开的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
正如背景技术所介绍的,现有的抑制剂化合物但因种种原因,仍未有CRAC通道抑制剂应用于临床,因此仍需积极探索发现结构新颖、拥有自主知识产权、更安全有效的CRAC通道抑制剂,以满足应用需求。因此,本公开提出了一种结构新颖的苯磺酰胺类化合物,对CRAC通道具有高抑制活性。
本公开第一方面,提供一种苯磺酰胺类化合物,具有通式(I)或通式(II)的结构形式:
,
或所述化合物式(I)化合物或式(II)化合物的药学上可接受的盐。
其中,通式I中,R1为单取代或双取代吸电子、供电子或中性基团,R2为有取代基或无取代基的碱性含氮五元、六元、七元脂肪杂环,n1=0-5;或,通式II中,R1为单取代或双取代吸电子、供电子或中性基团,R2为单取代或双取代吸电子、供电子或中性基团,n1=0-3。
在一种典型实施方式中,通式I中,R1优选为氢、卤素、烷基、烷氧基、烷氧酯基、2-4-二氯基,R2优选为N-甲基哌啶-4-基、吗啉-4-基、吡咯-1-基、哌啶-1-基、1-甲基哌嗪-4-基, n1=0-5;或,通式II中,R1优选为氢、卤素、烷基、烷氧基、烷氧酯基、硝基、2-4-二氯基,R2优选为烷基、卤素、烷氧基, n1=0-3。
优选的,通式I和II中,R1选自C1-6烷基、C1-6烷氧基、C1-6烷氧脂基;或,通式II中,R2选自C1-6烷基、C1-6烷氧基;更优选的,通式I,R1选自氯、甲基、甲氧基,R2选自N-甲基哌啶-4-基、吡咯-1-基、2-(哌啶-1-基)乙基;或,通式II中,R1选自氯、甲基,R2选自氟。
举例而言,“药学上可接受的盐”的例子可以包括无机酸盐,例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐和硝酸盐;有机酸盐,例如醋酸盐、丙酸盐、草酸盐、琥珀酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、马来酸盐、延胡索酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐和抗坏血酸盐;无机碱盐,例如钠盐、钾盐、钙盐、锌盐、镁盐和铝盐;以及有机碱盐,例如精氨酸盐、苄星盐、胆碱盐、二乙胺盐、二醇胺盐、甘氨酸盐、赖氨酸盐、葡甲胺盐、乙醇胺盐和氨基丁三醇盐。
在一种典型实施方式中,所述苯磺酰胺类化合物选自以下结构:
N-(4-氯苯基)-2-(N-(1-甲基哌啶-4-基)苯磺酰胺基)乙酰胺(LI1)
N-(4-甲基苯基)-2-(N-(1-甲基哌啶-4-基)苯磺酰胺基)乙酰胺的合成N-(4-氯苄基)-N-[2-[(4-甲基苯基)氨基]-2-氧乙基]苯磺酰胺(LI2)
N-(4-甲氧基苯基)-2-(N-(1-甲基哌啶-4-基)苯磺酰胺基)乙酰胺的合成(LI3)
N-(2, 4-二氯苯基)-2-(N-(1-甲基哌啶-4-基)苯磺胺基)乙酰胺的合成(LI4)
N-(4-氯苯基)-2-(N-(3-(吡咯-1-基)丙基)苯磺酰胺基)乙酰胺(LI5)
N-(4-甲基苯基)-2-(N-(3-(吡咯-1-基)丙基)苯磺酰胺基)乙酰胺(LI6)
N-(4-甲氧基苯基)-2-(N-(3-(吡咯-1-基)丙基)苯磺酰胺基)乙酰胺(LI7)
N-(4-甲基苯基)-2-(N-(2-(哌啶 -1-基)乙基) 苯磺酰胺基)乙酰胺(LI8)
N-(4-氯苯基)-2-((4-((二甲氨基)甲基)-N-(4-氟苄基)苯基)磺酰胺)乙酰胺(LII1)
N-(4-甲基苯基)-2-((4-((二甲氨基)甲基)-N-(4-氟苄基)苯基)磺酰胺)乙酰胺(LII2)
N-(4-氯苯基)-2-(4-((二甲氨基)甲基)-N-苯丙基苯磺酰胺)乙酰胺(LII3)
本公开第二方面,提供上述通式I或通式II所述化合物的制备方法,包括以下步骤:
以苯胺为起始原料,依次与酰氯(优选为氯乙酰氯)、脂肪胺或芳香胺、苯磺酰物(优选为苯磺酰氯)或对位取代的苯磺酰物(优选为4-溴甲基苯磺酰氯)反应制备得到,
优选的,具体步骤为:在苯胺中加入氯乙酰氯、CH2Cl2和K2CO3反应制备得到中间体酰胺,优选的,所述苯胺、氯乙酰氯、K2CO3的摩尔比为1:(1.5-3):(1-2);
进一步,在苯胺中加入CH2Cl2及无水K2CO3制备得到反应液,将氯乙酰氯溶于CH2Cl2中,在冰浴下缓慢滴加至反应液中,室温反应至 TLC 检测无原料胺,随后萃取、干燥、过滤、重结晶后得中间体酰胺;
中间体酰胺与脂肪胺或芳香胺反应制备得到中间体仲胺,进一步,中间体酰胺中先加入乙腈及无水K2CO3,再加入脂肪胺或芳香胺加热回流;萃取、过滤、干燥和纯化后得到中间体仲胺;优选的,中间体酰胺、K2CO3和脂肪胺或芳香胺的摩尔比为1:(2-4):(1-2),加热回流时间为6-24 h,温度为65-90℃;
在中间体仲胺中加入苯磺酰氯或对溴甲基取代的苯磺酰氯制备得到通式I目标化合物及通式II中间体溴甲基取代的苯磺酰胺,优选为在冰浴条件下加入对溴甲基取代的苯磺酰氯;
优选为,还需要加入CH2Cl2和无水碳酸钾制备得到通式I目标化合物及通式II中间体溴甲基取代的苯磺酰胺;优选的,中间体仲胺、无水碳酸钾、苯磺酰氯或对溴甲基取代的苯磺酰氯的摩尔比为:1:(1.5-2.5):(1.0-1.5);在冰浴条件下反应20-40min,撤去冰浴后常温下反应10-14h;
进一步,中间体溴甲基取代的苯磺酰胺回流反应、萃取、干燥、重结晶即可制备得到通式II化合物;
优选的,向中间体溴甲基取代的苯磺酰胺中加入二甲胺、乙腈,回流反应至原料反应完毕。优选的,中间体溴甲基取代的苯磺酰胺与二甲胺的摩尔比为1:(2-5),反应时间为4-6 h,反应温度为65-80℃。
在一种典型实施方式中,所述苯胺选自2,4-二氯苯胺、4-氯苯胺、4-甲基苯胺、4-甲氧基苯胺,所述脂肪胺与芳香胺选自1-(3-氨基丙基)吡咯烷、4-氨基-1-甲基哌啶、1-(2氨乙基)哌啶、对氟苄胺、苯丙胺。
具体反应过程如下:
(1)结构通式I的合成路线
(2)结构通式II的合成路线
1、中间体 Ib所述化合物的制备
以胺Ia为起始原料,向其中加入CH2Cl2及无水K2CO3,然后将氯乙酰氯溶于CH2Cl2中,在冰浴下缓慢滴加至反应液中,室温反应至 TLC 检测无原料胺。向反应液中加入蒸馏水,用CH2Cl2萃取,合并有机层,用无水MgSO4或Na2SO4干燥。滤去 MgSO4或Na2SO4,滤液减压蒸干,乙醇重结晶,得中间体Ib。
2、中间体Id和IId所述化合物的制备
向中间体Ib中加入乙腈及无水K2CO3,再加入胺Ic或IIc,加热回流6-24 h,。向反应液中加入蒸馏水,用CH2Cl2萃取,合并有机层,用无水 MgSO4或Na2SO4干燥。滤去 MgSO4或Na2SO4,滤液减压旋蒸,柱层析纯化,得中间体Id或IId。
3、通式I目标化合物及中间体IIf的制备
向中间体Id、IId中加入CH2Cl2及无水K2CO3,然后将苯磺酰氯或者对位取代的苯磺酰氯溶于CH2Cl2中,在冰浴下缓慢滴加至反应液中,滴毕,室温反应至 TLC 检测无原料胺。向反应液中加入蒸馏水,用CH2Cl2萃取,合并有机层,用无水 MgSO4或Na2SO4干燥。滤去无水MgSO4或Na2SO4,滤液减压旋蒸,柱层析纯化,得到通式I目标化合物及中间体IIf。
4、通式II目标化合物的制备
向中间体IIf中加入二甲氨基、乙腈,回流反应至原料IIf反应完毕。向反应液中加入蒸馏水,用CH2Cl2萃取,合并有机层,用无水 MgSO4或Na2SO4干燥,滤去无水 MgSO4或Na2SO4,滤液减压旋蒸,粗产品用正己烷及乙酸乙酯混合溶剂重结晶。
本公开第三方面,提供一种组合物,其包括通式I或II所示化合物或其药学上可接受的盐。
本公开第四方面,提供一种药学制剂,其包括通式I或II所示化合物或其药学上可接受的盐或上述组合物,与至少一种药学载体和/或赋形剂。
本发明的化合物可形成水合物或溶剂合物。本领域技术人员已知将化合物与水一起冻干时所形成的水合物或在溶液中与合适的有机溶剂浓缩时形成溶剂合物的方法。
本发明的化合物或含有本发明化合物的药物组合物可以为多种药物剂型,并以单位剂量形式给药。所述药物剂型或给药剂型可以是液体剂型、固体剂型、外用制剂、喷剂等等。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混旋剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明的药物组合物或药物制剂中还可以含有常用的载体,这里所述可药用载体包括如盐水,缓冲盐水,葡萄糖,水,甘油,乙醇和它们的结合物,下文更详细地论述。如果需要,该组合物还可以包含较小量的润湿剂或乳化剂,或pH 缓冲剂。该组合物可以是液体,悬浮液,乳剂,片剂,丸剂,胶囊,持续释放制剂或粉末。该组合物可以用传统的薪合剂和载体如三酸甘油酯配制成栓剂。口服制剂可以包括标准载体如药物品级的甘露糖醇,乳糖,淀粉,硬脂酸镁,糖精钠,纤维素和碳酸镁等等。视需要制剂而定,配制可以设计混合、制粒和压缩或溶解成分。在另一个途径中,该组合物可以配制成纳米颗粒。
使用的药物载体可以为,例如,固体或者液体。
典型的固体载体包括乳糖,石膏粉,蔗糖,滑石,凝胶,琼脂,果胶,阿拉伯胶,硬脂酸镁,硬脂酸等等。固体载体可以包括一种或多种可能同时作为增香剂,润滑剂,增溶剂,悬浮剂,填料,助流剂,压缩助剂,粘合剂或片剂-崩解剂的物质;它还可以是包封材料。在粉末中,载体为精细粉碎的固体,它与精细粉碎的活性成分的混合。在片剂中活性成分与具有必要的压缩性质的载体以合适的比例混合,以需要的形状和大小压缩。粉末和片剂优选包含至多99%活性成分。合适的固体载体包括,例如,磷酸钙、硬脂酸镁、滑石粉、糖、乳糖、糊精、淀粉、凝胶、纤维素、甲基纤维素、羧甲基纤维素钠盐、聚乙烯吡咯烷酮烷酮、低熔点蜡和离子交换树脂。
典型的液体载体包括糖浆、花生油、橄榄油、水等。液体载体用于制备溶液、悬浮剂、乳剂、糖浆、酊剂和密封的组合物。活性成分可以溶解或悬浮于药学上可接受的液体载体如水、有机溶剂、二者的混合物或药学上可接受的油类或脂肪。液体载体可以包含其他合适的药物添加剂如增溶剂、乳化剂、缓冲剂、防腐剂、增甜剂、增香剂、悬浮剂、增稠剂、颜料、粘度调节剂、稳定形或渗透压-调节剂。用于口服和肠胃外给药的液体载体的合适的例子包括水(部分地包含如同上述的添加剂,例如纤维素衍生物,优选羧甲基纤维素钠盐溶液)、醇(包括一元醇和多元醇,例如乙二醇)和它们的衍生物、油类(例如分馏椰子油和花生油)。用于肠胃外给药的载体还可以为油脂如油酸乙酯和异丙基肉豆蔻酸盐。无菌的液体载体用于肠胃外给药的无菌的液态组合物。用于加压组合物的液体载体可以为卤代烃或其他药学上可接受的推进剂。无菌溶液或悬浮溶液液体药物组合物可以用来注射,例如,静脉内、肌内、腹膜内或皮下注射。注射时可单次推入或逐渐注入,如静脉滴注。该化合物还可以液体或者固体组合物的形式口服给药。
载体或赋形剂可以包括本领域已知的时间延迟材料,如单硬脂酸甘油酯或二硬脂酸甘油酯,还可包括蜡、乙基纤维素、轻丙基甲基纤维素、异丁烯酸甲酯等。当制剂用于口服时,公认PHOSALPG-50中的0.01%吐温80 用于其他化合物的可接受的口服制剂的配制,可以适应于本发明各种化合物的配制。给予本发明化合物时可以使用各式各样的药物形式。如果使用固体载体,制剂可以为片剂、被放入硬胶囊中的粉末或小药丸形式或锭剂或糖锭形式。固体载体的量在很大程度上变化,但是优选从约 25mg 到约 1.0g 。如果使用液体载体,制剂可以为糖浆,乳剂,软胶囊,或者为在安瓶、小瓶或非水的液体悬浮液中的无菌注射溶液或悬浮液。
为了获得稳定的水溶性的剂型,可以将化合物或其药学上可接受的盐溶于有机或无机酸的水溶液,0.3M琥珀酸或柠檬酸溶液。如果得不到可溶形式,可将化合物溶于合适的共溶剂或它们的结合。这样的合适的共溶剂的例子包括,但是不局限于,浓度范围从0-60%总体积的乙醇、丙二醇、聚乙二醇300、聚山梨酸酯80、甘油、聚氧乙烯脂肪酸酯、脂肪醇或甘油轻脂肪酸酯等。
各种释放系统是已知的并且可以用于化合物或其他各种制剂的给药,这些制剂包括片剂、胶囊、可注射的溶液、脂质体中的胶囊、微粒、微胶囊等。引入的方法包括但是不局限于皮肤的、皮内、肌内、腹膜内、静脉内、皮下、鼻腔内、肺、硬膜外、眼睛和(通常优选的)口服途径。化合物可以通过任何方便的或者其它适当的途径给药,例如通过上皮或粘膜途径(例如,口腔粘膜、直肠和肠粘膜等)吸收或通过负载药物的支架以及可以与其他生物活性剂一起给药。可以全身或局部给药。用于鼻,支气管或肺疾病的治疗或预防时,优选的给药途径为口服,鼻给药或支气管烟雾剂或喷雾器。
本公开第五方面,提供上述通式I或II所示化合物或其药学上可接受的盐、或组合物或药学制剂在制备CRAC通道抑制剂或与CRAC通道功能异常相关疾病药物中的应用,优选的,所述疾病为自身免疫性疾病、肿瘤或感染类疾病。
为了使得本领域技术人员能够更加清楚地了解本公开的技术方案,以下将结合具体的实施例与对比例详细说明本公开的技术方案。
实施例1:N-(4-氯苯基)-2-(N-(1-甲基哌啶-4-基)苯磺胺基)乙酰胺的合成(LI1)
(1)中间体2-氯-N-(4-氯苯基)乙酰胺的合成
将对氯苯胺(2.00 g,15.68 mmol)及干燥的碳酸钾粉末(3.25 g,23.52 mmol)依次加入到20 mL二氯甲烷中,搅拌后呈白色混浊液。将氯乙酰氯(4.43 g,39.19 mmol,3.05mL)溶于6 mL二氯甲烷中,在冰浴下缓慢滴加入反应液中。滴毕,室温下反应约2h,TLC检测无原料胺出现。向反应液中加入40 mL蒸馏水,用二氯甲烷(40 mL×3)萃取,合并有机层,无水硫酸钠干燥过夜。滤去无水硫酸钠,滤液减压蒸干得白色固体。所得白色固体置于20 mL无水乙醇(依固体量增减),加热至沸腾并保持一会,趁热抽滤,冷却结晶,将结晶出固体抽滤洗涤)得白色固体约1.09 g,产率34.07%。
ESI-MS:[M+H]+:203.9975。
1HNMR(400MHz, CDCl3) δ4.13(s, 2H), 7.26(d, J=8Hz, 2H), 7.45(d, J=12Hz,2H)。
(2)中间体N-(4-氯苯基)-2-((1-甲基哌啶-4-基)氨基)乙酰胺的合成
将2-氯-N-(4-氯苯基)乙酰胺(0.5 g,2.53 mmol)及碳酸钾粉末(1.02 g,7.38mmol)溶于12 mL乙腈中,搅拌后呈白色混浊液。将4-氨基-1-甲基哌啶(0.42 g,3.68 mmol,462μL)加至混浊液中,75℃下回流反应8-12 h。反应完成后,反应液减压蒸干后加入40 mL蒸馏水,用二氯甲烷(40 mL×3)萃取,合并有机层,用无水硫酸钠干燥过夜。滤去无水硫酸钠,滤液减压蒸至2-3 mL,柱层析分离得粗产物,粗产物加石油醚固化,抽滤,置于干燥器干燥得白色固体0.28 g,产率41.12%。
ESI-MS:[M+H]+:282.1402。
1HNMR(400MHz, DMSO) δ1.34(m, 2H), 1.76(d, 12Hz, 2H), 1.91(t,J=12Hz,2H), 2.15(s, 3H),2.37(m,J=4Hz, 1H), 2.51(t,J=4Hz, 2H), 2.72(d,J=12Hz, 2H),7.36 (d,J=4Hz, 2H),7.66 (d,J=8Hz, 2H), 9.95(s, 1H)。
(3)目标化合物N-(4-氯苯基)-2-(N-(1-甲基哌啶-4-基)苯磺胺基)乙酰胺的合成
取上一步产物N-(4-氯苯基)-2-((1-甲基哌啶-4-基)氨基)乙酰胺(101.94 mg,0.36 mmol)及碳酸钾(100 mg,0.72 mmol)溶于24 mL二氯甲烷中,取苯磺酰氯(83.07 mg,0.47 mmol,l60 μL)加入前述反应液中,室温下反应5-7 h,之后转移到39℃下回流反应1h。反应完成后,反应液中加入20 mL蒸馏水,用二氯甲烷(30 mL×3)萃取,合并有机层,用无水硫酸钠干燥过夜。滤去无水硫酸钠,减压蒸干,得淡黄色固体,所得淡黄色固体用乙醇重结晶,抽滤洗涤,干燥得白色絮状固体约0.024 g,产率15.79%。
ESI-MS: [M+Na]+: 444.1065。
1HNMR(400MHz, CDCl3) δ1.18(m,J=4Hz, 8Hz, 2H), 1.73(m,J=8Hz, 2H), 1.99(t,J=12Hz, 2H), 2.20(s, 3H), 2.82(d,J=12Hz, 2H), 3.66(m,J=8Hz, 1H), 3.83(s,2H), 7.23(d,J=8Hz, 2H), 7.44(d,J=8Hz, 2H), 7.49(t,J=8Hz, 2H), 7.58(t,J=8Hz,2H),7.83(d,J=8Hz, 2H),8.43(s,1H)。
实施例2:N-(4-氯苯基)-2-((4-((二甲氨基)甲基)-N-(4-氟苄基)苯基)磺酰胺)乙酰胺(LII1)的合成
(1)中间体N-(4-氯苯基)-2-((4-氟苄基)氨基)乙酰胺
取前述实施例1中合成的2-氯-N-(4-氯苯基)乙酰胺(0.8 g,3.92 mmol)和碳酸钾(1.63 g,11.76 mmol)溶于25 mL乙腈中,加入对氟苄胺(0.74 g,5.88 mmol, 672μL),75℃下回流8-12 h。反应完毕,向反应液中加入40 mL蒸馏水,二氯甲烷(40 mL×3)萃取,有机层用无水Na2SO4干燥。过滤,滤液减压蒸干得白色絮状固体。乙醇重结晶得固体0.26 g,产率22.76%。
ESI-MS:[M+H]+=293.0850。
1HNMR(400MHz, CDCl3)δ 3.35(s, 2H), 3.75(s, 2H), 8.98(t,J=8Hz, 2H),7.21(t,J=4Hz, 2H), 7.23(t,J=4Hz, 2H), 7.44(d,J=8Hz, 2H), 9.15(s, 1H)。
(2)中间体2-((4-(溴甲基)-N-(4-氟苄基)苯基)磺胺基)-N-(4-氯苯基)乙酰胺
将产物N-(4-氯苯基)-2-((4-氟苄基)氨基)乙酰胺(100 mg,0.34 mmol)和无水碳酸钾(88 mg,0.64 mmol)溶于20 mL无水二氯甲烷中,冰浴下加入4-溴甲基苯磺酰氯(102.4mg,0.38 mmol),反应半小时,撤去冰浴,常温下反应12 h左右。反应完毕,反应液中加入20 mL蒸馏水,用二氯甲烷(40 mL×3)萃取,合并有机层,用无水硫酸钠干燥过夜。滤去无水硫酸钠,减压蒸干,得白色固体,干法柱层析(洗脱剂正己烷:乙酸乙酯=2:1),减压蒸干并干燥得产物0.095 g,产率52.78%。
ESI-MS:[M+Na]+:546.9876。
1HNMR (400MHz, CDCl3) δ 3.97(s, 2H), 4.46(s, 2H), 4.78(s, 2H),7.14(t,J=8Hz,2H), 7.33(d,J=8Hz, 2H), 7.44(d,J=8Hz, 2H), 7.64(d,J=8Hz, 2H), 7.87(d,J=8Hz, 2H)。
(3)中间体N-(4-氯苯基)-2-((4-((二甲氨基)甲基)-N-(4-氟苄基)苯基)磺酰胺)乙酰胺
取产物2-((4-(溴甲基)-N-(4-氟苄基)苯基)磺胺基)-N-(4-氯苯基)乙酰胺(0.06g,0.11mmol)和二甲胺(0.02 g,0.46 mmol,590μL)依次加入到4 mL无水乙腈中,75℃下反应5 h。反应完毕,反应液中加入30 mL蒸馏水,用二氯甲烷(30 mL×3)萃取,合并有机层,用无水硫酸钠干燥过夜。滤去无水硫酸钠,减压蒸干,得白色固体。加入正己烷3 mL和数滴乙酸乙酯,固体部分溶解,68℃加热回流,趁热过滤,滤液置于-20℃冰箱冷却结晶,所得固体抽滤洗涤干燥得白色固体0.019 g,产率33.99%。
ESI-MS:[M+H]+=490.1334。
1HNMR(400MHz, CDCl3)δ 2.14s, 6H), 3.45(s, 2H), 3.95(s, 2H), 4.48(s,2H), 7.13(t,J=8Hz, 2H), 7.31(m,J=4Hz, 4H), 7.45(t,J=12Hz, 8Hz, 4H), 7.82(d,J=8Hz, 2H), 10.03(s, 1H)。
生物活性测定:
1、目标化合物对CRAC通道抑制活性的测定
毒胡萝卜素(Thapsigargin,TG)可有效抑制ER上Ca2+- ATP酶(SERCA),引起ER中原有存储的Ca2+被动消耗直至耗竭,从而触发CRAC通道的开放和随后的NFAT核易位。因此,本专利利用稳定转染NFAT1-GFP的HeLa细胞系,通过TG诱导的NFAT核转位实验测试所合成化合物对CRAC通道的抑制活性,具体步骤如下:
将20000/mL 密度的NFAT1-GFP稳定转染的HeLa细胞 (1 mL)接种到35 mm的玻底小皿中,培养过夜。将待测试的化合物以200 μM的终浓度添加到每个培养皿中,在37℃条件下,与细胞共孵育30 min。随后,每个培养皿中加入10 μM TG和1 mM Ca2+,并与细胞再一起孵育20分钟,刺激NFAT入核。最后,将培养皿用PBS缓缓清洗3次,并用4%多聚甲醛(PFA)溶液(1000μL/皿)在黑暗环境中固定10分钟,然后用PBS缓缓清洗2次。向每个培养皿中添加1000 μL PBS,并在Lecia SP8激光共聚焦扫描显微镜系统(物镜:63倍)上成像。实验结果如表一及图1所示
表一:苯磺酰胺类化合物的结构及对CRAC通道的抑制活性(通过TG诱导的NFAT入核活性进行表征)
注:“+”代表完全抑制NFAT入核,“±”代表部分抑制NFAT入核,“-”代表不能抑制NFAT入核。对NFAT入核的抑制活性越高,化合物对CRAC通道的抑制活性越高。
由表一可知,在化合物的苯磺酰胺的氨基位引入含氮碱性基团,对CRAC通道的抑制活性要更好,碱性脂肪环的链越长对活性相对有利。
图1展示了部分化合物对CRAC通道的抑制活性,从中可以看出,LI1对NFAT信号通路有部分活性,LII1对NFAT信号通路无活性。
活性研究表明,上述苯磺酰胺类化合物,是一类结构新颖的CRAC通道抑制剂,可作为CRAC通道抑制剂的先导化合物加以利用。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (12)
1.一种苯磺酰胺类化合物的制备方法,其特征在于,以苯胺为起始原料,依次与酰氯、脂肪胺、苯磺酰物反应制备得到;
具体反应过程如下:
所制备的苯磺酰胺类化合物,具有通式I的结构形式:
或所述化合物式(I)化合物的药学上可接受的盐;
所述通式1所指的苯磺酰胺类化合物选自以下结构:
N-(4-氯苯基)-2-(N-(1-甲基哌啶-4-基)苯磺酰胺基)乙酰胺(LI1)
N-(4-甲基苯基)-2-(N-(1-甲基哌啶-4-基)苯磺酰胺基)乙酰胺(LI2)
N-(4-甲氧基苯基)-2-(N-(1-甲基哌啶-4-基)苯磺酰胺基)乙酰胺(LI3)
N-(2, 4-二氯苯基)-2-(N-(1-甲基哌啶-4-基)苯磺胺基)乙酰胺(LI4)
N-(4-甲基苯基)-2-(N-(2-(哌啶 -1-基)乙基) 苯磺酰胺基)乙酰胺(LI8)。
2.根据权利要求1所述的制备方法,其特征在于,包括以下步骤:酰氯为氯乙酰氯,苯磺酰物为苯磺酰氯。
3.根据权利要求2所述的制备方法,其特征在于,包括以下步骤:在苯胺中加入氯乙酰氯、CH2Cl2和K2CO3反应制备得到中间体酰胺。
4.根据权利要求3所述的制备方法,其特征在于,包括以下步骤:所述苯胺、氯乙酰氯、K2CO3的摩尔比为1:1.5-3:1-2。
5.根据权利要求3所述的制备方法,其特征在于,包括以下步骤:
在苯胺中加入CH2Cl2及无水K2CO3制备得到反应液,将氯乙酰氯溶于CH2Cl2中,在冰浴下缓慢滴加至反应液中,室温反应至 TLC 检测无原料胺,随后萃取、干燥、过滤、重结晶后得中间体酰胺。
6.根据权利要求1所述的制备方法,其特征在于,所述中间体酰胺与脂肪胺反应制备得到中间体仲胺。
7.根据权利要求1所述的制备方法,其特征在于,中间体酰胺中先加入乙腈及无水K2CO3,再加入脂肪胺加热回流;萃取、过滤、干燥和纯化后得到中间体仲胺。
8.根据权利要求7所述的制备方法,其特征在于,中间体酰胺、K2CO3和脂肪胺或芳香胺的摩尔比为1:2-4:1-2,加热回流时间为6-24 h,温度为65-90℃。
9.根据权利要求8所述的制备方法,其特征在于,在中间体仲胺中加入苯磺酰氯制备得到通式I化合物。
10.根据权利要求9所述的制备方法,其特征在于,还需要加入CH2Cl2和无水碳酸钾制备得到通式I化合物。
11.根据权利要求1所述的制备方法,其特征在于,所述苯胺选自2,4-二氯苯胺、4-氯苯胺、4-甲基苯胺、4-甲氧基苯胺,所述脂肪胺选自4-氨基-1-甲基哌啶、1-(2氨乙基)哌啶。
12.权利要求1所述的制备方法所制备的苯磺酰胺类化合物或其药学上可接受的盐在制备CRAC通道抑制剂或与CRAC通道功能异常相关疾病药物中的应用。
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