KR20250063463A - Cationic lipid and method for preparing the same - Google Patents
Cationic lipid and method for preparing the same Download PDFInfo
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Abstract
본 발명은 양이온성 지질 및 이의 제조방법에 관한 것으로, 보다 구체적으로는, 특정 구조로 인해 음이온성 약물과 복합체를 형성하여, 약물 전달에 유용한 양이온성 지질 및 이를 제조하는 방법에 관한 것이다.The present invention relates to a cationic lipid and a method for producing the same, and more specifically, to a cationic lipid useful for drug delivery by forming a complex with an anionic drug due to a specific structure, and a method for producing the same.
Description
본 발명은 양이온성 지질 및 이의 제조방법에 관한 것으로, 보다 구체적으로는, 특정 구조로 인해 음이온성 약물과 복합체를 형성하여, 약물 전달에 유용한 양이온성 지질 및 이를 제조하는 방법에 관한 것이다.The present invention relates to a cationic lipid and a method for producing the same, and more specifically, to a cationic lipid useful for drug delivery by forming a complex with an anionic drug due to a specific structure, and a method for producing the same.
핵산을 비롯한 음이온성 약물을 이용한 치료에 있어서, 안전하고 효율적인 약물 전달기술은 오랫동안 연구되어 왔으며, 다양한 전달체 및 전달기술이 개발되어 왔다. 전달체는 크게 아데노바이러스나 레트로바이러스 등을 이용한 바이러스성 전달체와 양이온성 지질 및 양이온성 고분자 등을 이용한 비바이러스성 전달체로 나뉜다. 바이러스성 전달체의 경우 비특이적 면역 반응 등의 위험성에 노출되어 있으며 생산 공정이 복잡하여 상용화하는 데 많은 문제점이 있는 것으로 알려져 있다. 따라서, 최근 연구 방향은 비바이러스성 전달체를 이용하여 그 단점을 개선하는 방향으로 진행되고 있다. 비바이러스성 전달체는, 바이러스성 전달체에 비하여 생체 내 안전성의 측면에서 부작용이 적고, 경제성 측면에서 생산 가격이 저렴하다는 장점을 가지고 있다.In the treatment using anionic drugs including nucleic acids, safe and efficient drug delivery technology has been studied for a long time, and various carriers and delivery technologies have been developed. Carriers are largely divided into viral carriers using adenovirus or retrovirus, and non-viral carriers using cationic lipids and cationic polymers. In the case of viral carriers, they are exposed to the risk of non-specific immune responses, etc., and it is known that there are many problems in commercialization due to the complex production process. Therefore, recent research is being conducted in the direction of improving the shortcomings using non-viral carriers. Non-viral carriers have the advantage of less side effects in terms of in vivo safety compared to viral carriers, and are inexpensive to produce in terms of economic efficiency.
핵산 물질의 전달에 이용되는 비바이러스성 전달체로서 대표적인 것은 양이온성 지질을 이용한 양이온성 지질과 핵산의 복합체(lipoplex) 및 폴리양이온성(polycation) 고분자와 핵산의 복합체(polyplex)이다. 이러한 양이온성 지질 혹은 폴리양이온성 고분자는, 음이온성 약물과 정전기적 상호 작용을 통해 복합체를 형성함으로써 음이온성 약물을 안정화시키고, 세포 내 전달을 증가시킨다는 점에서 많은 연구가 진행되어 왔다(De Paula D, Bentley MV, Mahato RI, Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting, RNA 13 (2007) 431-56; Gary DJ, Puri N, Won YY, Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery, J Control release 121 (2007) 64-73).Representative nonviral vectors used for the delivery of nucleic acid materials include complexes of cationic lipids and nucleic acids (lipoplexes) and polycationic polymers and nucleic acids (polyplexes). Many studies have been conducted on cationic lipids or polycationic polymers because they form complexes with anionic drugs through electrostatic interactions, thereby stabilizing the anionic drugs and increasing their intracellular delivery (De Paula D, Bentley MV, Mahato RI, Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting, RNA 13 (2007) 431-56; Gary DJ, Puri N, Won YY, Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery, J Control release 121 (2007) 64-73).
그러나 폴리양이온성(polycation) 고분자는 다가 양이온 전하에 기인한 세포독성이 있어 실제 사용하기에는 문제점이 있고, 핵산-양이온성 지질 복합체는 혈중에서의 안정성이 낮아 실제 생체 내에서의 사용이 어렵다. 또한, 양이온성 지질, 중성 지질 및 용해성 지질(fusogenic lipid)을 포함하는 이온성 리포좀은 사용되는 양이온성 지질의 합성 방법이 복잡하고, 세포 독성이 있으며, 세포내 핵산 전달 효율이 낮다는 단점이 있다.However, polycation polymers have problems in practical use due to cytotoxicity caused by multiple cationic charges, and nucleic acid-cationic lipid complexes have low stability in the blood, making them difficult to use in vivo. In addition, ionic liposomes containing cationic lipids, neutral lipids, and fusogenic lipids have the disadvantages of complicated synthesis methods for cationic lipids used, cytotoxicity, and low efficiency of intracellular nucleic acid delivery.
본 발명의 목적은 음이온성 약물과 복합체를 용이하게 형성할 수 있어 약물 전달에 유용한 특정 구조의 양이온성 지질 및 이의 제조방법을 제공하는 것이다.The purpose of the present invention is to provide a cationic lipid having a specific structure that can easily form a complex with an anionic drug and is useful for drug delivery, and a method for producing the same.
본 발명의 제1 측면은, 하기 화학식 1로 표시되는 구조를 갖는 지질을 제공한다:A first aspect of the present invention provides a lipid having a structure represented by the following chemical formula 1:
[화학식 1][Chemical Formula 1]
여기에서,Here,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
R은 수소 원자(H) 또는 이고, 여기서 R4는 치환되거나 비치환된 알킬기, 알케닐기, 또는 알키닐기이고, R5는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고, *는 질소 원자에의 부착점(point of attachment)을 나타낸다.R is a hydrogen atom (H) or , wherein R 4 is a substituted or unsubstituted alkyl group, alkenyl group, or alkynyl group, R 5 is a substituted or unsubstituted alkylene group, alkenylene group, or alkynylene group, and * represents a point of attachment to a nitrogen atom.
보다 구체적으로, 상기 화학식 1에서,More specifically, in the chemical formula 1,
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C1-30 알킬기, 치환되거나 비치환된 C2-30 알케닐기, 또는 치환되거나 비치환된 C2-30 알키닐기이고,R 1 and R 4 are each independently a substituted or unsubstituted C 1-30 alkyl group, a substituted or unsubstituted C 2-30 alkenyl group, or a substituted or unsubstituted C 2-30 alkynyl group,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C1-15 알킬렌기, 치환되거나 비치환된 C2-15 알케닐렌기, 또는 치환되거나 비치환된 C2-15 알키닐렌기이고,R 2 and R 5 are each independently a substituted or unsubstituted C 1-15 alkylene group, a substituted or unsubstituted C 2-15 alkenylene group, or a substituted or unsubstituted C 2-15 alkynylene group,
R3는 비치환된 C2-9 알킬렌기이다.R 3 is an unsubstituted C 2-9 alkylene group.
보다 더 구체적으로, 상기 화학식 1에서,More specifically, in the chemical formula 1,
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C1-20 알킬기, 치환되거나 비치환된 C2-20 알케닐기, 또는 치환되거나 비치환된 C2-20 알키닐기이고,R 1 and R 4 are each independently a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 2-20 alkenyl group, or a substituted or unsubstituted C 2-20 alkynyl group,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C1-12 알킬렌기, 치환되거나 비치환된 C2-12 알케닐렌기, 또는 치환되거나 비치환된 C2-12 알키닐렌기이고,R 2 and R 5 are each independently a substituted or unsubstituted C 1-12 alkylene group, a substituted or unsubstituted C 2-12 alkenylene group, or a substituted or unsubstituted C 2-12 alkynylene group,
R3는 비치환된 C2-7 알킬렌기이다.R 3 is an unsubstituted C 2-7 alkylene group.
보다 더 구체적으로, 상기 화학식 1에서,More specifically, in the chemical formula 1,
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C5-20 알킬기, 치환되거나 비치환된 C5-20 알케닐기, 또는 치환되거나 비치환된 C5-20 알키닐기이고,R 1 and R 4 are each independently a substituted or unsubstituted C 5-20 alkyl group, a substituted or unsubstituted C 5-20 alkenyl group, or a substituted or unsubstituted C 5-20 alkynyl group,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C3-12 알킬렌기, 치환되거나 비치환된 C3-12 알케닐렌기, 또는 치환되거나 비치환된 C3-12 알키닐렌기이고,R 2 and R 5 are each independently a substituted or unsubstituted C 3-12 alkylene group, a substituted or unsubstituted C 3-12 alkenylene group, or a substituted or unsubstituted C 3-12 alkynylene group,
R3는 비치환된 C2-5 알킬렌기이다.R 3 is an unsubstituted C 2-5 alkylene group.
더욱 더 구체적으로, 상기 지질은 하기 화학식 A 내지 L로부터 선택되는 어느 하나의 구조를 갖는 것일 수 있다: More specifically, the lipid may have any one structure selected from the following chemical formulas A to L:
본 발명의 제2 측면은, (1) 화학식 a의 화합물을 화학식 b의 화합물과 반응시켜 화학식 c의 화합물을 얻는 단계; (2) 화학식 c의 화합물을 화학식 d의 화합물과 반응시켜 화학식 e의 화합물을 얻는 단계; 및 (3) 화학식 e의 화합물을 화학식 f의 화합물과 반응시켜 화학식 1-1의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법을 제공한다:A second aspect of the present invention provides a method for preparing a lipid, comprising: (1) reacting a compound of formula a with a compound of formula b to obtain a compound of formula c; (2) reacting a compound of formula c with a compound of formula d to obtain a compound of formula e; and (3) reacting a compound of formula e with a compound of formula f to obtain a compound of formula 1-1.
[화학식 a][chemical formula a]
HOC(=O)-R2-NH2 HOC(=O)-R 2 -NH 2
[화학식 b][chemical formula b]
R1-OHR 1 -OH
[화학식 c][chemical formula c]
R1-OC(=O)-R2-NH2 R 1 -OC(=O)-R 2 -NH 2
[화학식 d][chemical formula d]
[화학식 e][chemical formula e]
R1-OC(=O)-R2-NH-C(=O)-CH=CH2 R 1 -OC(=O)-R 2 -NH-C(=O)-CH=CH 2
[화학식 f][chemical formula f]
tBu-OC(=O)-NH-R3-NH2 tBu-OC(=O)-NH-R 3 -NH 2
[화학식 1-1][Chemical Formula 1-1]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-NH-R3-NH-C(=O)O-tBuR 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -NH-R 3 -NH-C(=O)O-tBu
상기에서,In the above,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
tBu는 tert-부틸기이고,tBu is tert-butyl group,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.X is selected from the group consisting of F, CI, Br, and I.
본 발명의 제3 측면은, (1) 화학식 a의 화합물을 화학식 b의 화합물과 반응시켜 화학식 c의 화합물을 얻는 단계; (2) 화학식 c의 화합물을 화학식 d의 화합물과 반응시켜 화학식 e의 화합물을 얻는 단계; 및 (3) 화학식 e의 화합물을 화학식 f의 화합물과 반응시켜 화학식 1-2의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법을 제공한다:A third aspect of the present invention provides a method for preparing a lipid, comprising: (1) reacting a compound of formula a with a compound of formula b to obtain a compound of formula c; (2) reacting a compound of formula c with a compound of formula d to obtain a compound of formula e; and (3) reacting a compound of formula e with a compound of formula f to obtain a compound of formula 1-2.
[화학식 a][chemical formula a]
HOC(=O)-R2-NH2 HOC(=O)-R 2 -NH 2
[화학식 b][chemical formula b]
R1-OHR 1 -OH
[화학식 c][chemical formula c]
R1-OC(=O)-R2-NH2 R 1 -OC(=O)-R 2 -NH 2
[화학식 d][chemical formula d]
[화학식 e][chemical formula e]
R1-OC(=O)-R2-NH-C(=O)-CH=CH2 R 1 -OC(=O)-R 2 -NH-C(=O)-CH=CH 2
[화학식 f][chemical formula f]
tBu-OC(=O)-NH-R3-NH2 tBu-OC(=O)-NH-R 3 -NH 2
[화학식 1-2][Chemical Formula 1-2]
[R1-OC(=O)-R2-NH-C(=O)-CH2-CH2]2-N-R3-NH-C(=O)O-tBu[R 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 ] 2 -NR 3 -NH-C(=O)O-tBu
상기에서,In the above,
R1은 각각 독립적으로 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is each independently a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 각각 독립적으로 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is each independently a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
tBu는 tert-부틸기이고,tBu is tert-butyl group,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.X is selected from the group consisting of F, CI, Br, and I.
본 발명의 제4 측면은, 본 발명의 제2 측면에서 얻어진 화학식 1-1의 화합물을 화학식 g의 화합물과 반응시켜 화학식 1-3의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법을 제공한다:The fourth aspect of the present invention provides a method for producing a lipid, comprising the step of reacting the compound of formula 1-1 obtained in the second aspect of the present invention with a compound of formula g to obtain a compound of formula 1-3:
[화학식 1-1][Chemical Formula 1-1]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-NH-R3-NH-C(=O)O-tBuR 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -NH-R 3 -NH-C(=O)O-tBu
[화학식 g][chemical formula g]
R4-OC(=O)-R5-NH-C(=O)-CH=CH2 R 4 -OC(=O)-R 5 -NH-C(=O)-CH=CH 2
[화학식 1-3][Chemical Formula 1-3]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-N(A)-R3-NH-C(=O)O-tBuR 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -N(A)-R 3 -NH-C(=O)O-tBu
상기에서,In the above,
R1은 각각 독립적으로 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is each independently a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 각각 독립적으로 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is each independently a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
A는 -CH2-CH2-C(=O)-NH-R5-C(=O)O-R4이고, 여기서 R4는 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고, R5는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,A is -CH 2 -CH 2 -C(=O)-NH-R 5 -C(=O)OR 4 , where R 4 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group, R 5 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
tBu는 tert-부틸기이고,tBu is tert-butyl group,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.X is selected from the group consisting of F, CI, Br, and I.
본 발명의 제5 측면은, 본 발명에 따른 지질을 포함하는 약물 전달용 조성물을 제공한다.A fifth aspect of the present invention provides a drug delivery composition comprising a lipid according to the present invention.
본 발명에 따른 특정 구조의 지질은 음이온성 약물과 복합체를 용이하게 형성할 수 있고, 이 복합체를 활용하면 약물을 목표한 생체 조직 내에 효율적으로 전달할 수 있다.A lipid having a specific structure according to the present invention can easily form a complex with an anionic drug, and utilizing this complex, the drug can be efficiently delivered into a target biological tissue.
도 1은 실시예 1에서 수행된 지질 합성 과정에 대한 반응 개략도이다.
도 2는 실시예 2에서 수행된 지질 합성 과정에 대한 반응 개략도이다.
도 3은 실시예 3에서 수행된 지질 합성 과정에 대한 반응 개략도이다.
도 4는 실시예 4에서 수행된 지질 합성 과정에 대한 반응 개략도이다.Figure 1 is a reaction schematic diagram for the lipid synthesis process performed in Example 1.
Figure 2 is a reaction schematic diagram for the lipid synthesis process performed in Example 2.
Figure 3 is a reaction schematic diagram for the lipid synthesis process performed in Example 3.
Figure 4 is a reaction schematic diagram for the lipid synthesis process performed in Example 4.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 제1 측면에 따라 제공되는 지질은 하기 화학식 1로 표시되는 구조를 갖는다:The lipid provided according to the first aspect of the present invention has a structure represented by the following chemical formula 1:
[화학식 1][Chemical Formula 1]
여기에서,Here,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
R은 수소 원자(H) 또는 이고, 여기서 R4는 치환되거나 비치환된 알킬기, 알케닐기, 또는 알키닐기이고, R5는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고, *는 질소 원자에의 부착점(point of attachment)을 나타낸다.R is a hydrogen atom (H) or , wherein R 4 is a substituted or unsubstituted alkyl group, alkenyl group, or alkynyl group, R 5 is a substituted or unsubstituted alkylene group, alkenylene group, or alkynylene group, and * represents a point of attachment to a nitrogen atom.
본 발명의 제1 측면에 따라 제공되는 지질의 범위에는 상기 화학식 1의 구조를 갖는 것은 물론 그의 양이온화 형태도 포함된다.The range of lipids provided according to the first aspect of the present invention includes those having the structure of the above chemical formula 1 as well as their cationic forms.
본 명세서에서, 임의의 기가 “치환 또는 비치환된” 것이라는 표현은, 달리 특정되지 않는 한, 그 기가 치환되지 않거나, -OH, 할로겐 원자, C1-6 알킬기, C1-6 알콕시기, C1-6 할로겐화알킬기, C1-6 할로겐화알콕시기, C3-20 사이클로알킬기, C3-20 헤테로사이클로알킬기, C6-20 아릴기 또는 C3-20 헤테로아릴기 중에서 선택된 하나 이상의 치환기로 치환된 것임을 의미한다.As used herein, the expression “substituted or unsubstituted” of any group means, unless otherwise specified, that the group is unsubstituted or substituted with one or more substituents selected from —OH, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 halogenated alkyl group, a C 1-6 halogenated alkoxy group, a C 3-20 cycloalkyl group, a C 3-20 heterocycloalkyl group, a C 6-20 aryl group, or a C 3-20 heteroaryl group.
본 명세서에서, “알킬”, “알케닐”, “알키닐”, “알킬렌” “알케닐렌” 및 “알키닐렌”은 각각 독립적으로 분지형 또는 비분지형, 또는 환상 또는 비환상일 수 있다.In this specification, “alkyl”, “alkenyl”, “alkynyl”, “alkylene”, “alkenylene” and “alkynylene” can each independently be branched or unbranched, or cyclic or acyclic.
본 발명의 일 구체예에 따르면, 상기 화학식 1에서,According to one specific example of the present invention, in the chemical formula 1,
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C1-30 알킬기, 치환되거나 비치환된 C2-30 알케닐기, 또는 치환되거나 비치환된 C2-30 알키닐기일 수 있고,R 1 and R 4 can each independently be a substituted or unsubstituted C 1-30 alkyl group, a substituted or unsubstituted C 2-30 alkenyl group, or a substituted or unsubstituted C 2-30 alkynyl group,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C1-15 알킬렌기, 치환되거나 비치환된 C2-15 알케닐렌기, 또는 치환되거나 비치환된 C2-15 알키닐렌기일 수 있고,R 2 and R 5 can each independently be a substituted or unsubstituted C 1-15 alkylene group, a substituted or unsubstituted C 2-15 alkenylene group, or a substituted or unsubstituted C 2-15 alkynylene group,
R3는 비치환된 C2-9 알킬렌기일 수 있다.R 3 may be an unsubstituted C 2-9 alkylene group.
보다 더 구체적으로, 상기 화학식 1에서,More specifically, in the chemical formula 1,
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C1-20 알킬기, 치환되거나 비치환된 C2-20 알케닐기, 또는 치환되거나 비치환된 C2-20 알키닐기일 수 있고,R 1 and R 4 can each independently be a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 2-20 alkenyl group, or a substituted or unsubstituted C 2-20 alkynyl group,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C1-12 알킬렌기, 치환되거나 비치환된 C2-12 알케닐렌기, 또는 치환되거나 비치환된 C2-12 알키닐렌기일 수 있고,R 2 and R 5 can each independently be a substituted or unsubstituted C 1-12 alkylene group, a substituted or unsubstituted C 2-12 alkenylene group, or a substituted or unsubstituted C 2-12 alkynylene group,
R3는 비치환된 C2-7 알킬렌기일 수 있다.R 3 may be an unsubstituted C 2-7 alkylene group.
보다 더 구체적으로, 상기 화학식 1에서,More specifically, in the chemical formula 1,
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C5-20 알킬기, 치환되거나 비치환된 C5-20 알케닐기, 또는 치환되거나 비치환된 C5-20 알키닐기일 수 있고,R 1 and R 4 can each independently be a substituted or unsubstituted C 5-20 alkyl group, a substituted or unsubstituted C 5-20 alkenyl group, or a substituted or unsubstituted C 5-20 alkynyl group,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C3-12 알킬렌기, 치환되거나 비치환된 C3-12 알케닐렌기, 또는 치환되거나 비치환된 C3-12 알키닐렌기일 수 있고,R 2 and R 5 can each independently be a substituted or unsubstituted C 3-12 alkylene group, a substituted or unsubstituted C 3-12 alkenylene group, or a substituted or unsubstituted C 3-12 alkynylene group,
R3는 비치환된 C2-5 알킬렌기일 수 있다.R 3 may be an unsubstituted C 2-5 alkylene group.
더욱 더 구체적으로, 상기 지질은 하기 화학식 A 내지 L로부터 선택되는 어느 하나의 구조를 갖는 것일 수 있다: More specifically, the lipid may have any one structure selected from the following chemical formulas A to L:
본 발명의 제2 측면은, (1) 화학식 a의 화합물을 화학식 b의 화합물과 반응시켜 화학식 c의 화합물을 얻는 단계; (2) 화학식 c의 화합물을 화학식 d의 화합물과 반응시켜 화학식 e의 화합물을 얻는 단계; 및 (3) 화학식 e의 화합물을 화학식 f의 화합물과 반응시켜 화학식 1-1의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법을 제공한다:A second aspect of the present invention provides a method for preparing a lipid, comprising: (1) reacting a compound of formula a with a compound of formula b to obtain a compound of formula c; (2) reacting a compound of formula c with a compound of formula d to obtain a compound of formula e; and (3) reacting a compound of formula e with a compound of formula f to obtain a compound of formula 1-1.
[화학식 a][chemical formula a]
HOC(=O)-R2-NH2 HOC(=O)-R 2 -NH 2
[화학식 b][chemical formula b]
R1-OHR 1 -OH
[화학식 c][chemical formula c]
R1-OC(=O)-R2-NH2 R 1 -OC(=O)-R 2 -NH 2
[화학식 d][chemical formula d]
[화학식 e][chemical formula e]
R1-OC(=O)-R2-NH-C(=O)-CH=CH2 R 1 -OC(=O)-R 2 -NH-C(=O)-CH=CH 2
[화학식 f][chemical formula f]
tBu-OC(=O)-NH-R3-NH2 tBu-OC(=O)-NH-R 3 -NH 2
[화학식 1-1][Chemical Formula 1-1]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-NH-R3-NH-C(=O)O-tBuR 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -NH-R 3 -NH-C(=O)O-tBu
상기에서,In the above,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
tBu는 tert-부틸기이고,tBu is tert-butyl group,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.X is selected from the group consisting of F, CI, Br, and I.
본 발명의 제3 측면은, (1) 화학식 a의 화합물을 화학식 b의 화합물과 반응시켜 화학식 c의 화합물을 얻는 단계; (2) 화학식 c의 화합물을 화학식 d의 화합물과 반응시켜 화학식 e의 화합물을 얻는 단계; 및 (3) 화학식 e의 화합물을 화학식 f의 화합물과 반응시켜 화학식 1-2의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법을 제공한다:A third aspect of the present invention provides a method for preparing a lipid, comprising: (1) reacting a compound of formula a with a compound of formula b to obtain a compound of formula c; (2) reacting a compound of formula c with a compound of formula d to obtain a compound of formula e; and (3) reacting a compound of formula e with a compound of formula f to obtain a compound of formula 1-2.
[화학식 a][chemical formula a]
HOC(=O)-R2-NH2 HOC(=O)-R 2 -NH 2
[화학식 b][chemical formula b]
R1-OHR 1 -OH
[화학식 c][chemical formula c]
R1-OC(=O)-R2-NH2 R 1 -OC(=O)-R 2 -NH 2
[화학식 d][chemical formula d]
[화학식 e][chemical formula e]
R1-OC(=O)-R2-NH-C(=O)-CH=CH2 R 1 -OC(=O)-R 2 -NH-C(=O)-CH=CH 2
[화학식 f][chemical formula f]
tBu-OC(=O)-NH-R3-NH2 tBu-OC(=O)-NH-R 3 -NH 2
[화학식 1-2][Chemical Formula 1-2]
[R1-OC(=O)-R2-NH-C(=O)-CH2-CH2]2-N-R3-NH-C(=O)O-tBu[R 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 ] 2 -NR 3 -NH-C(=O)O-tBu
상기에서,In the above,
R1은 각각 독립적으로 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is each independently a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 각각 독립적으로 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is each independently a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
tBu는 tert-부틸기이고,tBu is tert-butyl group,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.X is selected from the group consisting of F, CI, Br, and I.
본 발명의 제2 및 제3 측면에 따른 지질 제조방법의 일 구체예에서, 상기 (1)단계의 반응은 용매(예컨대, 사이클로헥산) 내에서 촉매(예컨대, p-톨루엔설폰산 일수화물(p-TsOH)) 존재 하에서 환류(reflux) 하에 수행될 수 있고, 상기 (2)단계의 반응은 용매(예컨대, 염화메틸렌(MC)) 내에서 촉매(예컨대, 트리에틸아민(TEA)) 존재 하에서 저온(예컨대, -10°C 내지 10°C) 또는 상온(예컨대, 20°C 내지 30°C) 조건하에 수행될 수 있으며, 상기 (3)단계의 반응은 용매(예컨대, n-부탄올(n-BuOH)) 내에서 환류(reflux) 하에 수행될 수 있으나, 이에 한정되지 않는다.In one specific example of the lipid production method according to the second and third aspects of the present invention, the reaction of step (1) can be performed under reflux in a solvent (e.g., cyclohexane) in the presence of a catalyst (e.g., p-toluenesulfonic acid monohydrate (p-TsOH)), the reaction of step (2) can be performed under conditions of low temperature (e.g., -10°C to 10°C) or room temperature (e.g., 20°C to 30°C) in a solvent (e.g., methylene chloride (MC)) in the presence of a catalyst (e.g., triethylamine (TEA)), and the reaction of step (3) can be performed under reflux in a solvent (e.g., n-butanol (n-BuOH)), but is not limited thereto.
본 발명의 제4 측면은, 본 발명의 제2 측면에서 얻어진 화학식 1-1의 화합물을 화학식 g의 화합물과 반응시켜 화학식 1-3의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법을 제공한다:The fourth aspect of the present invention provides a method for producing a lipid, comprising the step of reacting the compound of formula 1-1 obtained in the second aspect of the present invention with a compound of formula g to obtain a compound of formula 1-3:
[화학식 1-1][Chemical Formula 1-1]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-NH-R3-NH-C(=O)O-tBuR 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -NH-R 3 -NH-C(=O)O-tBu
[화학식 g][chemical formula g]
R4-OC(=O)-R5-NH-C(=O)-CH=CH2 R 4 -OC(=O)-R 5 -NH-C(=O)-CH=CH 2
[화학식 1-3][Chemical Formula 1-3]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-N(A)-R3-NH-C(=O)O-tBuR 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -N(A)-R 3 -NH-C(=O)O-tBu
상기에서,In the above,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R3는 비치환된 알킬렌기이고,R 3 is an unsubstituted alkylene group,
A는 -CH2-CH2-C(=O)-NH-R5-C(=O)O-R4이고, 여기서 R4는 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고, R5는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,A is -CH 2 -CH 2 -C(=O)-NH-R 5 -C(=O)OR 4 , where R 4 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group, R 5 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
tBu는 tert-부틸기이고,tBu is tert-butyl group,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.X is selected from the group consisting of F, CI, Br, and I.
본 발명의 제4 측면에 따른 지질 제조방법의 일 구체예에서, 상기 반응은 용매(예컨대, n-부탄올(n-BuOH)) 내에서 환류(reflux) 하에 수행될 수 있으나, 이에 한정되지 않는다.In one specific example of the lipid production method according to the fourth aspect of the present invention, the reaction may be performed under reflux in a solvent (e.g., n-butanol (n-BuOH)), but is not limited thereto.
본 발명에 따른 특정 구조의 지질은 음이온성 약물과 복합체를 용이하게 형성할 수 있어 약물 전달에 유용하다.The lipid having a specific structure according to the present invention can easily form a complex with anionic drugs, making it useful for drug delivery.
따라서, 본 발명의 제5 측면에 따르면, 본 발명의 지질을 포함하는 약물 전달용 조성물이 제공된다.Therefore, according to the fifth aspect of the present invention, a drug delivery composition comprising the lipid of the present invention is provided.
일 구체예에서, 상기 약물은 핵산, 폴리펩티드, 바이러스 또는 이들의 조합으로부터 선택된 것일 수 있고, 바람직하게는 핵산일 수 있다.In one specific embodiment, the drug may be selected from a nucleic acid, a polypeptide, a virus or a combination thereof, and preferably may be a nucleic acid.
상기 “핵산”은, 예를 들어, DNA, RNA, siRNA, shRNA, miRNA, mRNA, 앱타머, 안티센스 올리고뉴클레오티드, 또는 이들의 조합일 수 있으나, 이에 제한되지 않는다. The above “nucleic acid” may be, but is not limited to, DNA, RNA, siRNA, shRNA, miRNA, mRNA, aptamer, antisense oligonucleotide, or a combination thereof.
상기 “폴리펩티드”는 항체 또는 이의 절편, 시토킨, 호르몬 또는 그 유사체와 같은 체내에 활성을 갖는 단백질, 또는 항원, 이의 유사체 또는 전구체의 폴리펩티드 서열을 포함하여, 체내에서 일련의 과정을 통해 항원으로 인식될 수 있는 단백질을 의미할 수 있다.The above “polypeptide” may mean a protein that is active in the body, such as an antibody or a fragment thereof, a cytokine, a hormone or an analogue thereof, or a protein that can be recognized as an antigen through a series of processes in the body, including a polypeptide sequence of an antigen, an analogue or a precursor thereof.
일 구체예에서, 본 발명의 지질은 약물과 복합체를 형성하고, 이 복합체가 양친성 블록 공중합체가 형성하는 나노입자 구조체 내부에 봉입될 수 있다.In one specific embodiment, the lipid of the present invention forms a complex with a drug, and the complex can be encapsulated within a nanoparticle structure formed by an amphiphilic block copolymer.
일 구체예에서, 상기 양친성 블록 공중합체는, 친수성 A 블록 및 소수성 B 블록을 포함하는 A-B 형 블록 공중합체일 수 있다. 상기 A-B 형 블록 공중합체는, 수용액 상에서, 소수성 B 블록이 코어(내벽)를 형성하고 친수성 A 블록이 쉘(외벽)을 형성하는 코어-쉘 타입의 고분자 나노입자를 형성한다. In one specific example, the amphiphilic block copolymer may be an A-B type block copolymer including a hydrophilic A block and a hydrophobic B block. The A-B type block copolymer forms, in an aqueous solution, a core-shell type polymer nanoparticle in which the hydrophobic B block forms a core (inner wall) and the hydrophilic A block forms a shell (outer wall).
일 구체예에서, 상기 친수성 A 블록은 폴리알킬렌글리콜, 폴리비닐알콜, 폴리비닐피롤리돈, 폴리아크릴아미드 및 그 유도체로 구성된 군으로부터 선택되는 하나 이상일 수 있다. In one specific embodiment, the hydrophilic A block may be at least one selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide and derivatives thereof.
보다 구체적으로, 상기 친수성 A 블록은 모노메톡시폴리에틸렌클리콜(mPEG), 모노아세톡시폴리에틸렌글리콜, 폴리에틸렌글리콜, 폴리에틸렌과 프로필렌글리콜의 공중합체 및 폴리비닐피롤리돈으로 구성된 군으로부터 선택되는 하나 이상일 수 있다. More specifically, the hydrophilic A block may be at least one selected from the group consisting of monomethoxypolyethylene glycol (mPEG), monoacetoxypolyethylene glycol, polyethylene glycol, a copolymer of polyethylene and propylene glycol, and polyvinylpyrrolidone.
또한, 필요에 따라, 상기 친수성 A 블록의 말단에 특정 조직이나 세포에 도달할 수 있는 작용기, 리간드, 또는 세포내 전달을 촉진할 수 있는 작용기를 화학적으로 결합시켜 나노입자 전달체의 체내 분포를 조절하거나 상기 나노입자 전달체가 세포 내로 전달되는 효율을 높일 수 있다. 일 구체예에서, 상기 작용기나 리간드는 단당류, 다당류, 비타민, 펩타이드, 단백질 및 세포 표면 수용체에 대한 항체로 이루어진 군에서 선택된 1종 이상일 수 있다. 보다 구체적으로, 상기 작용기나 리간드는 아니사마이드(anisamide), 비타민 B9(엽산), 비타민 B12, 비타민A, 갈락토오스, 락토오스, 만노오스, 히알루론산, RGD 펩타이드, NGR 펩타이드, 트랜스페린, 트랜스페린 수용체에 대한 항체 등으로 이루어진 군에서 선택된 1종 이상일 수 있다.In addition, if necessary, a functional group, a ligand, or a functional group capable of promoting intracellular delivery that can reach a specific tissue or cell may be chemically bonded to the terminal of the hydrophilic A block to control the distribution of the nanoparticle carrier in the body or to increase the efficiency of delivery of the nanoparticle carrier into a cell. In one specific example, the functional group or ligand may be at least one selected from the group consisting of a monosaccharide, a polysaccharide, a vitamin, a peptide, a protein, and an antibody to a cell surface receptor. More specifically, the functional group or ligand may be at least one selected from the group consisting of anisamide, vitamin B9 (folic acid), vitamin B12, vitamin A, galactose, lactose, mannose, hyaluronic acid, RGD peptide, NGR peptide, transferrin, an antibody to a transferrin receptor, and the like.
상기 소수성 B 블록은 생체적합성 생분해성 고분자로서, 일 구체예에서, 이는 폴리에스테르, 폴리언하이드라이드, 폴리아미노산, 폴리오르소에스테르 및 폴리포스파진으로 구성된 군으로부터 선택되는 하나 이상일 수 있다. The above hydrophobic B block is a biocompatible biodegradable polymer, and in one specific example, it may be at least one selected from the group consisting of polyester, polyanhydride, polyamino acid, polyorthoester and polyphosphazine.
보다 구체적으로, 상기 소수성 B 블록은 폴리락타이드(PLA), 폴리글리콜라이드, 폴리카프로락톤, 폴리디옥산-2-온, 폴리락타이드와 글리콜라이드의 공중합체, 폴리락타이드와 폴리디옥산-2-온의 공중합체, 폴리락타이드와 폴리카프로락톤의 공중합체 및 폴리글리콜라이드와 폴리카프로락톤의 공중합체로 구성된 군으로부터 선택되는 하나 이상일 수 있다. More specifically, the hydrophobic B block may be at least one selected from the group consisting of polylactide (PLA), polyglycolide, polycaprolactone, polydioxan-2-one, a copolymer of polylactide and glycolide, a copolymer of polylactide and polydioxan-2-one, a copolymer of polylactide and polycaprolactone, and a copolymer of polyglycolide and polycaprolactone.
또한, 일 구체예에서, 상기 소수성 B 블록은, 소수성 B 블록의 소수성을 증가시켜 나노입자의 안정성을 향상시키기 위하여, 소수성 B 블록 말단의 히드록시기에 토코페롤, 콜레스테롤, 또는 탄소수 10 내지 24개의 지방산을 화학적으로 결합시키는 것에 의하여 수식된 것일 수 있다. Additionally, in one specific embodiment, the hydrophobic B block may be modified by chemically bonding tocopherol, cholesterol, or a fatty acid having 10 to 24 carbon atoms to a hydroxyl group at the terminal of the hydrophobic B block to increase the hydrophobicity of the hydrophobic B block and thereby improve the stability of the nanoparticle.
이하, 본 발명을 하기 실시예에 의거하여 보다 자세하게 설명하나, 이들은 본 발명을 설명하기 위한 것일 뿐 이들에 의하여 본 발명의 범위가 어떤 식으로든 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples, but these are only intended to explain the present invention and the scope of the present invention is not limited in any way by these examples.
[실시예][Example]
실시예 1Example 1
1-1. 도 1에 나타낸 합성 개요에 따라 하기 화학식 A의 화합물을 제조하였다.1-1. A compound of chemical formula A was prepared according to the synthetic outline shown in Fig. 1.
[화학식 A][Chemical Formula A]
1-2. 2-옥틸도데실 6-아크릴아미도헥사노에이트(2-octyldodecyl 6-acrylamidohexanoate)의 합성1-2. Synthesis of 2-octyldodecyl 6-acrylamidohexanoate
250 mL 3-neck 둥근 바닥 플라스크(RBF)에 6-아미노헥산산(6-aminohexanoic acid)(1.05 g, 8.04 mmol, 1.20 eq), 2-옥틸도데칸-1-올(2-octyldodecan-1-ol)(2.00 g, 6.70 mmol, 1.00eq), p-톨루엔술폰산 일수화물(p-toluenesulfonic acid monohydrate, p-TsOH)(2.29 g, 12.06 mmol, 1.80 eq), 사이클로헥산(cyclohexane)(100 mL)을 첨가하고, 딘-스타크 트랩과 컨덴서를 설치하여 교반 및 환류하였다. 24시간 후, 상온으로 냉각하여 진공으로 농축하고, 염화메틸렌(methylene chloride 또는 dichloromethane, MC)과 NaOH 수용액으로 추출한 후, 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하여 낮은 순도의 2-옥틸도데실 6-아미노헥사노에이트(2-octyldodecyl 6-aminohexanoate)를 얻었다. 추가적인 정제 없이, 100 mL 3-neck RBF에 앞서 얻은 2-옥틸도데실 6-아미노헥사노에이트, 염화메틸렌(33 mL), 트리에틸아민(triethylamine, TEA)(1.49 g, 14.74 mmol, 2.20 eq)을 넣고 0 ℃로 냉각한 후, 아크릴로일 클로라이드(acryloyl chloride)(0.67 g, 7.37 mmol, 1.10 eq)를 한 방울씩 떨어뜨려 주입하였다. 반응기의 온도를 상온(20~25℃)으로 올려 교반하였다. 18시간 후, 반응기 안의 혼합물을 HCl 수용액으로 추출하고, 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하고 에틸 아세테이트(ethyl acetate):헥산(hexane)=1:2로 실리카 컬럼을 이용하여 정제하여 2-옥틸도데실 6-아크릴아미도헥사노에이트(1928.20 mg, 수율: 62 %)를 얻었다.A 250 mL 3-neck round bottom flask (RBF) was added with 6-aminohexanoic acid (1.05 g, 8.04 mmol, 1.20 eq), 2-octyldodecan-1-ol (2.00 g, 6.70 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (p-TsOH) (2.29 g, 12.06 mmol, 1.80 eq), and cyclohexane (100 mL), and a Dean-Stark trap and a condenser were installed to stir and reflux. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, extracted with methylene chloride (or dichloromethane, MC) and an aqueous NaOH solution, and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to obtain low purity 2-octyldodecyl 6-aminohexanoate. Without additional purification, the previously obtained 2-octyldodecyl 6-aminohexanoate, methylene chloride (33 mL), and triethylamine (TEA) (1.49 g, 14.74 mmol, 2.20 eq) were added to a 100 mL 3-neck RBF, cooled to 0 ℃, and acryloyl chloride (0.67 g, 7.37 mmol, 1.10 eq) was injected dropwise. The temperature of the reactor was raised to room temperature (20~25℃) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo and purified using a silica column with ethyl acetate: hexane = 1:2 to obtain 2-octyldodecyl 6-acrylamidohexanoate (1928.20 mg, yield: 62%).
1H-NMR (400 MHz, CDCl3) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.64 (d, 1H), 3.97 (d, 2H), 3.37 (t, 2H), 2.14 (t, 2H), 1.68 - 1.26 (m, 41H), 0.90 (t, 6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.64 (d, 1H), 3.97 (d, 2H), 3.37 (t, 2H), 2.14 (t, 2H), 1.68 - 1.26 (m, 41H), 0.90 (t, 6H)
1-3. 화학식 A의 화합물의 합성1-3. Synthesis of the compound of chemical formula A
100 mL 3-neck RBF에 2-옥틸도데실 6-아크릴아미도헥사노에이트(120.00 mg, 2.58 mmol, 2.40 eq), tert-부틸 N-(2-아미노에틸)카바메이트(tert-butyl N-(2-aminoethyl)carbamate)(171.99 mg, 1.07 mmol, 1.00 eq), n-부탄올(n-BuOH)(10 mL)을 넣고 교반 및 환류하였다. 48 시간 후, 80℃에서 진공으로 농축하고 염화메틸렌:메탄올:수산화암모늄(ammonium hydroxide)=20:1:0.1로 실리카 컬럼을 이용하여 정제하여 화학식 A의 화합물을 얻었다.A 100 mL 3-neck RBF was charged with 2-octyldodecyl 6-acrylamidohexanoate (120.00 mg, 2.58 mmol, 2.40 eq), tert-butyl N-(2-aminoethyl)carbamate (171.99 mg, 1.07 mmol, 1.00 eq), and n-butanol (n-BuOH) (10 mL), stirred and refluxed. After 48 h, the mixture was concentrated in vacuo at 80 °C and purified using a silica column with methylene chloride:methanol:ammonium hydroxide = 20:1:0.1 to obtain the compound of formula A.
1H-NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 4.93 (s, 1H), 3.96 (d, 2H), 3.24 (q, 4H), 2.89 (t, 2H), 2.75 (t, 2H), 2.30-2.36 (m, 4H), 1.62-1.68 (m, 3H), 1.44-1.56 (m, 2H), 1.47 (s, 9H), 1.20-1.39 (m, 35H), 0.90 (t, 6H) 1 H-NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 4.93 (s, 1H), 3.96 (d, 2H), 3.24 (q, 4H), 2.89 (t, 2H), 2.75 (t, 2H), 2.30-2.36 (m, 4H), 1.62-1.68 (m, 3H), 1.44-1.56 (m, 2H), 1.47 (s, 9H), 1.20-1.39 (m, 35H), 0.90 (t, 6H)
실시예 2Example 2
2-1. 도 2에 나타낸 합성 개요에 따라 하기 화학식 B의 화합물을 제조하였다.2-1. A compound of chemical formula B was prepared according to the synthetic outline shown in Fig. 2.
[화학식 B][Chemical Formula B]
2-2. 2-헥실옥틸 6-아크릴아미도헥사노에이트(2-hexyloctyl 6-acrylamidohexanoate)의 합성2-2. Synthesis of 2-hexyloctyl 6-acrylamidohexanoate
500 mL 3-neck RBF에 6-아미노헥산산(1.84 g, 13.99 mmol, 1.20 eq), 2-헥실-1-n-옥탄올(2-hexyl-1-n-octanol)(2.50 g, 11.66 mmol, 1.00 eq), p-톨루엔술폰산 일수화물(3.99 g, 20.99 mmol, 1.80 eq), 사이클로헥산(120 mL)을 첨가하고, 딘-스타크 트랩과 컨덴서를 설치하여 교반 및 환류하였다. 24시간 후, 상온으로 냉각하여 진공으로 농축하고, 염화메틸렌과 NaOH 수용액으로 추출한 후, 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하여 낮은 순도의 2-헥실옥틸 6-아미노헥사노에이트(2-hexyloctyl 6-aminohexanoate)를 얻었다. 추가적인 정제 없이, 250 mL 3-neck RBF에 앞서 얻은 2-헥실옥틸 6-아미노헥사노에이트, 염화메틸렌(60 mL), 트리에틸아민(2.60 g ,25.65 mmol, 2.20 eq)을 넣고 0 ℃로 냉각한 후, 아크릴로일 클로라이드(1.16 g, 12.83 mmol, 1.10 eq)를 한 방울씩 떨어뜨려 주입하였다. 반응기의 온도를 상온(20~25℃)으로 올려 교반하였다. 18시간 후, 반응기 안의 혼합물을 HCl 수용액으로 추출하고 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하고 에틸 아세테이트:헥산=1:2로 실리카 컬럼을 이용하여 정제하여 2-헥실옥틸 6-아크릴아미도헥사노에이트(3.63 g, 수율: 82 %)를 얻었다.A 500 mL 3-neck RBF was added 6-Aminohexanoic acid (1.84 g, 13.99 mmol, 1.20 eq), 2-hexyl-1-n-octanol (2.50 g, 11.66 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (3.99 g, 20.99 mmol, 1.80 eq), and cyclohexane (120 mL), and a Dean-Stark trap and a condenser were installed, followed by stirring and refluxing. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and NaOH aqueous solution. The organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to obtain low purity 2-hexyloctyl 6-aminohexanoate. Without further purification, the previously obtained 2-hexyloctyl 6-aminohexanoate, methylene chloride (60 mL), and triethylamine (2.60 g, 25.65 mmol, 2.20 eq) were put into a 250 mL 3-neck RBF, cooled to 0 °C, and acryloyl chloride (1.16 g, 12.83 mmol, 1.10 eq) was added dropwise. The temperature of the reactor was raised to room temperature (20–25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl solution, and the organic layer was dried over Na 2 SO 4 and filtered. The residue was concentrated in vacuo and purified using a silica column with ethyl acetate:hexane = 1:2 to obtain 2-hexyloctyl 6-acrylamidohexanoate (3.63 g, yield: 82%).
1H-NMR (400 MHz, CDCl3) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.64 (d, 1H), 3.97 (d, 2H), 2.33 (t, 2H), 1.68 - 1.54 (m, 5H), 1.41 (m, 2H), 1.30 (m, 20H), 0.90 (t, 6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.64 (d, 1H), 3.97 (d, 2H), 2.33 (t, 2H), 1.68 - 1.54 (m, 5H), 1.41 (m, 2H), 1.30 (m, 20H), 0.90 (t, 6H)
2-3. 화학식 B의 화합물의 합성2-3. Synthesis of the compound of chemical formula B
100 mL 3-neck RBF에 2-헥실옥틸 6-아크릴아미도헥사노에이트(1429.07 mg, 3.74 mmol, 2.40 eq), tert-부틸 N-(2-아미노에틸)카바메이트(250.00 mg, 1.56 mmol, 1.00 eq), n-부탄올(10 mL)을 넣고 교반 및 환류하였다. 48 시간 후, 80℃에서 진공으로 농축하고 염화메틸렌:메탄올:수산화암모늄=15:1:0.1로 실리카 컬럼을 이용하여 정제하여 화학식 B의 화합물을 얻었다.A 100 mL 3-neck RBF was charged with 2-hexyloctyl 6-acrylamidohexanoate (1429.07 mg, 3.74 mmol, 2.40 eq), tert-butyl N-(2-aminoethyl)carbamate (250.00 mg, 1.56 mmol, 1.00 eq), and n-butanol (10 mL), stirred and refluxed. After 48 h, the mixture was concentrated in vacuo at 80 °C and purified using a silica column with methylene chloride:methanol:ammonium hydroxide = 15:1:0.1 to obtain the compound of formula B.
1H-NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 4.96 (s, 1H), 3.96 (d, 2H), 3.24 (q, 4H), 2.90 (t, 2H), 2.76 (t, 2H), 2.37 (t, 2H), 2.31 (t, 2H), 1.60-1.80 (m, 3H), 1.47-1.57 (m, 2H), 1.51 (s, 9H), 1.20-1.39 (m, 24H), 0.90 (t, 6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 7.09 (s, 1H), 4.96 (s, 1H), 3.96 (d, 2H), 3.24 (q, 4H), 2.90 (t, 2H), 2.76 (t, 2H), 2.37 (t, 2H), 2.31 (t, 2H), 1.60-1.80 (m, 3H), 1.47-1.57 (m, 2H), 1.51 (s, 9H), 1.20-1.39 (m, 24H), 0.90 (t, 6H)
실시예 3Example 3
3-1. 도 3에 나타낸 합성 개요에 따라 하기 화학식 C의 화합물을 제조하였다.3-1. A compound of the following chemical formula C was prepared according to the synthetic outline shown in Fig. 3.
[화학식 C][Chemical Formula C]
3-2. 2-헥실옥틸 8-아크릴아미도옥타노에이트(2-hexyloctyl 8-acrylamidooctanoate)의 합성3-2. Synthesis of 2-hexyloctyl 8-acrylamidooctanoate
250 mL 3-neck RBF에 8-아미노옥탄산(8-aminooctanoic acid)(1.78 g, 11.19 mmol, 1.20 eq), 2- 헥실옥탄-1-올(hexyloctan-1-ol)(2.00 g, 9.33 mmol, 1.00 eq), p-톨루엔술폰산 일수화물(3.19 g, 16.79 mmol, 1.80 eq), 사이클로헥산(100 mL)을 첨가하고, 딘-스타크 트랩과 컨덴서를 설치하여 교반 및 환류하였다. 24시간 후, 상온으로 냉각하여 진공으로 농축하고, 염화메틸렌과 NaOH 수용액으로 추출한 후, 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하여 낮은 순도의 2-헥실옥틸 8-아미노옥타노에이트(2-hexyloctyl 8-aminooctanoate)를 얻었다. 추가적인 정제 없이, 250 mL 3-neck RBF에 앞서 얻은 2-헥실옥틸 8-아미노옥타노에이트, 염화메틸렌(100 mL), 트리에틸아민(2.08 g, 20.52 mmol, 2.20 eq)을 넣고 0 ℃로 냉각한 후, 아크릴로일 클로라이드(0.93 g, 10.26 mmol, 1.10 eq)를 한 방울씩 떨어뜨려 주입하였다. 반응기의 온도를 상온(20~25℃)으로 올려 교반하였다. 18시간 후, 반응기 안의 혼합물을 HCl 수용액으로 추출하고 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하고 에틸 아세테이트:헥산=1:1로 실리카 컬럼을 이용하여 정제하여 2-헥실옥틸 8-아크릴아미도옥타노에이트(2838.70 mg, 수율: 74 %)를 얻었다.8-Aminooctanoic acid (1.78 g, 11.19 mmol, 1.20 eq), 2-hexyloctan-1-ol (2.00 g, 9.33 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (3.19 g, 16.79 mmol, 1.80 eq), and cyclohexane (100 mL) were added to a 250 mL 3-neck RBF, and a Dean-Stark trap and a condenser were installed, followed by stirring and refluxing. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and NaOH aqueous solution. The organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to obtain low purity 2-hexyloctyl 8-aminooctanoate. Without further purification, the previously obtained 2-hexyloctyl 8-aminooctanoate, methylene chloride (100 mL), and triethylamine (2.08 g, 20.52 mmol, 2.20 eq) were added to a 250 mL 3-neck RBF, cooled to 0 °C, and acryloyl chloride (0.93 g, 10.26 mmol, 1.10 eq) was added dropwise. The temperature of the reactor was raised to room temperature (20–25 °C), and the mixture was stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl solution, and the organic layer was dried over Na 2 SO 4 and filtered. The residue was concentrated in vacuo and purified using a silica column with ethyl acetate:hexane = 1:1 to obtain 2-hexyloctyl 8-acrylamidooctanoate (2838.70 mg, yield: 74%).
1H-NMR (400 MHz, CDCl3) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.63 (d, 1H), 3.97 (d, 2H), 3.35 (q, 2H), 2.31 (t, 2H), 1.65 - 1.51 (m, 4H), 1.35 - 1.27 (m, 27H), 0.90 (t, 6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.63 (d, 1H), 3.97 (d, 2H), 3.35 (q, 2H), 2.31 (t, 2H), 1.65 - 1.51 (m, 4H), 1.35 - 1.27 (m, 27H), 0.90 (t, 6H)
3-3. 화학식 C의 화합물의 합성3-3. Synthesis of the compound of chemical formula C
100 mL 3-neck RBF에 2-헥실옥틸 8-아크릴아미도옥타노에이트(1130.14 mg, 2.76 mmol, 2.60 eq), tert-부틸 N-(2-아미노에틸)카바메이트(170.00 mg, 1.06 mmol, 1.00 eq), n-부탄올(11 mL)을 넣고 교반 및 환류하였다. 48 시간 후, 80℃에서 진공으로 농축하고 염화메틸렌:메탄올:수산화암모늄=15:1:0.1로 실리카 컬럼을 이용하여 정제하여 화학식 C의 화합물을 얻었다.A 100 mL 3-neck RBF was charged with 2-hexyloctyl 8-acrylamidooctanoate (1130.14 mg, 2.76 mmol, 2.60 eq), tert-butyl N-(2-aminoethyl)carbamate (170.00 mg, 1.06 mmol, 1.00 eq), and n-butanol (11 mL), stirred and refluxed. After 48 h, the mixture was concentrated in vacuo at 80 °C and purified using a silica column with methylene chloride:methanol:ammonium hydroxide = 15:1:0.1 to obtain the compound of formula C.
1H-NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 4.86 (s, 1H), 3.96 (d, 2H), 3.23 (q, 4H), 2.88 (t, 2H), 2.74 (t, 2H), 2.34 (t, 2H), 2.29 (t, 2H), 1.60-1.67 (m, 6H), 1.44-1.57 (m, 9H), 1.27-1.32 (m, 27H), 0.90 (t, 6H) 1 H-NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 4.86 (s, 1H), 3.96 (d, 2H), 3.23 (q, 4H), 2.88 (t, 2H), 2.74 (t, 2H), 2.34 (t, 2H), 2.29 (t, 2H), 1.60-1.67 (m, 6H), 1.44-1.57 (m, 9H), 1.27-1.32 (m, 27H), 0.90 (t, 6H)
실시예 4Example 4
4-1. 도 4에 나타낸 합성 개요에 따라 하기 화학식 D의 화합물을 제조하였다.4-1. A compound of the following chemical formula D was prepared according to the synthetic outline shown in Fig. 4.
[화학식 D][Chemical Formula D]
4-2. 2-헥실데실 6-아크릴아미도헥사노에이트(2-hexyldecyl 6-acrylamidohexanoate)의 합성4-2. Synthesis of 2-hexyldecyl 6-acrylamidohexanoate
500 mL 3-neck RBF에 6-아미노헥산산(3.25 g, 24.74 mmol, 1.20 eq), 2-헥실데칸-1-올(2-hexyldecan-1-ol)(5.00 g, 20.62 mmol, 1.00 eq), p-톨루엔술폰산 일수화물(7.06 g, 37.12 mmol, 1.80 eq), 사이클로헥산(150 mL)을 첨가하고, 딘-스타크 트랩과 컨덴서를 설치하여 교반 및 환류하였다. 24시간 후, 상온으로 냉각하여 진공으로 농축하고, 염화메틸렌과 NaOH 수용액으로 추출한 후, 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하여 낮은 순도의 2-헥실데실 6-아미노헥사노에이트(2-hexyldecyl 6-aminohexanoate)를 얻었다. 추가적인 정제 없이, 250 mL 3-neck RBF에 앞서 얻은 2-헥실데실 6-아미노헥사노에이트, 염화메틸렌(100 mL), 트리에틸아민(4.59 g, 45.36 mmol, 2.20 eq)을 넣고 0 ℃로 냉각한 후, 아크릴로일 클로라이드(2.05 g, 22.68 mmol, 1.10 eq)를 한 방울씩 떨어뜨려 주입하였다. 반응기의 온도를 상온(20~25℃)으로 올려 교반하였다. 18시간 후, 반응기 안의 혼합물을 3% HCl 수용액으로 추출하고 유기층을 Na2SO4로 건조하고 여과하였다. 여액은 진공으로 농축하고 에틸 아세테이트:헥산=1:1로 실리카 컬럼을 이용하여 정제하여 2-헥실데실 6-아크릴아미도헥사노에이트(6.01 g, 수율: 71 %)를 얻었다.A 500 mL 3-neck RBF was added 6-Aminohexanoic acid (3.25 g, 24.74 mmol, 1.20 eq), 2-hexyldecan-1-ol (5.00 g, 20.62 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (7.06 g, 37.12 mmol, 1.80 eq), and cyclohexane (150 mL), and a Dean-Stark trap and a condenser were installed, followed by stirring and refluxing. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and NaOH aqueous solution. The organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to obtain low purity 2-hexyldecyl 6-aminohexanoate. Without further purification, the previously obtained 2-hexyldecyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (4.59 g, 45.36 mmol, 2.20 eq) were added to a 250 mL 3-neck RBF, cooled to 0 °C, and acryloyl chloride (2.05 g, 22.68 mmol, 1.10 eq) was added dropwise. The temperature of the reactor was raised to room temperature (20–25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with 3% HCl aqueous solution, and the organic layer was dried over Na 2 SO 4 and filtered. The residue was concentrated in vacuo and purified using a silica column with ethyl acetate:hexane = 1:1 to obtain 2-hexyldecyl 6-acrylamidohexanoate (6.01 g, yield: 71%).
1H-NMR (400 MHz, CDCl3) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.64 (d, 1H), 3.97 (d, 2H), 3.36 (q, 2H), 2.33 (t, 2H), 1.68 - 1.54 (m, 5H), 1.41 - 1.30 (m, 28H), 0.90 (m, 6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 6.29 (d, 1H), 6.10 (m, 1H), 5.64 (d, 1H), 3.97 (d, 2H), 3.36 (q, 2H), 2.33 (t, 2H), 1.68 - 1.54 (m, 5H), 1.41 - 1.30 (m, 28H), 0.90 (m, 6H)
4-3. 화학식 D의 화합물의 합성4-3. Synthesis of the compound of chemical formula D
100 mL 3-neck RBF에 2-헥실데실 6-아크릴아미도헥사노에이트(2500 mg, 6.10 mmol, 3 eq), tert-부틸 N-(2-아미노에틸)카바메이트(325.92 mg, 2.03 mmol, 1.00 eq), n-부탄올(20 mL)을 넣고 교반 및 환류하였다. 96 시간 후, 80℃에서 진공으로 농축하고 염화메틸렌:메탄올:수산화암모늄=15:1:0.1로 실리카 컬럼을 이용하여 정제하여 화학식 D의 화합물을 얻었다.A 100 mL 3-neck RBF was charged with 2-hexyldecyl 6-acrylamidohexanoate (2500 mg, 6.10 mmol, 3 eq), tert-butyl N-(2-aminoethyl)carbamate (325.92 mg, 2.03 mmol, 1.00 eq), and n-butanol (20 mL), stirred and refluxed. After 96 h, the mixture was concentrated in vacuo at 80 °C, and purified using a silica column with methylene chloride:methanol:ammonium hydroxide = 15:1:0.1 to obtain the compound of formula D.
1H-NMR (400 MHz, CDCl3) δ 6.52 (t, 2H), 3.97 (d, 4H), 3.25 (q, 4H), 3.17 (br, 2H), 2.71 (t, 4H), 2.48 (t, 2H), 2.29 (m, 8H), 1.62 - 1.26 (m, 64H), 1.47 (s, 9H), 0.89 (t, 12H) 1 H-NMR (400 MHz, CDCl 3 ) δ 6.52 (t, 2H), 3.97 (d, 4H), 3.25 (q, 4H), 3.17 (br, 2H), 2.71 (t, 4H), 2.48 (t, 2H), 2.29 (m, 8H), 1.62 - 1.26 (m, 64H), 1.47 (s, 9H), 0.89 (t, 12H)
[약물 전달용 조성물의 제조예] [Preparation example of drug delivery composition ]
1. 원료 물질 준비1. Preparation of raw materials
하기 표에 나타낸 바에 따라, 제형 제조에 필요한 물질들을 각 희석 용매로 용해하여 필요 농도로 준비하였다. 녹일 때는 물질들을 상온화한 후 용매를 넣고 용해시켰다.According to the table below, the materials required for the formulation were dissolved in each dilution solvent and prepared at the required concentration. When dissolving, the materials were warmed to room temperature and then the solvent was added to dissolve them.
2. 원료 물질 혼합2. Mixing raw materials
NP ratio(지질의 아민기: mRNA의 포스페이트기)를 6에 맞추어 화학식 A의 화합물:DOPE:콜레스테롤:DMG-PEG=50:10:38.5:1.5의 비율에 따라 원료 물질들의 필요량을 취한 후 혼합하였다. 에탄올 층에는 모든 원료 물질의 합이 12.5 mM 이내로 존재하도록 에탄올을 추가하여 주고, 수상(aqueous phase)과 에탄올상(ethanol phase)은 3:1의 부피비를 유지하여 혼합하였다. 혼합 후 전체 에탄올 함량을 낮추기 위해 다음과 같이 버퍼 교환(buffer exchange)을 하였다: 혼합액을 Amicon-Ultra tube filter(Merk Millipore, UFC505096 또는 UFC805024, pore size: 50K 또는 100K, 부피 0.5 mL 또는 4 mL 또는 15 mL)를 사용하여 4,000 rpm에서 원심분리하여 농축한 다음, PBS로 희석한 후 원심분리하여 농축하는 과정을 반복하여 버퍼 교환을 하였다.The required amounts of raw materials were taken according to the ratio of compound of chemical formula A: DOPE: cholesterol: DMG-PEG = 50:10:38.5:1.5 and mixed to set the NP ratio (amine group of lipid: phosphate group of mRNA) to 6. Ethanol was added to the ethanol layer so that the sum of all raw materials was within 12.5 mM, and the aqueous phase and the ethanol phase were mixed while maintaining a volume ratio of 3:1. To lower the total ethanol content after mixing, buffer exchange was performed as follows: The mixed solution was centrifuged at 4,000 rpm using an Amicon-Ultra tube filter (Merk Millipore, UFC505096 or UFC805024, pore size: 50K or 100K, volume: 0.5 mL or 4 mL or 15 mL) to concentrate, then diluted with PBS and centrifuged to concentrate. This process was repeated to perform buffer exchange.
구체적인 공정 순서는 다음과 같다.The specific process sequence is as follows.
1) 멸균 튜브(Autoclaved tube) 두 개를 준비하였다(Tube (A), (B)).1) Two autoclaved tubes were prepared (Tube (A), (B)).
2) Tube (A)에 실험 조건에 따라 계산된 몰 수의 화학식 A 내지 C 각각의 화합물 및 DOPE, 콜레스테롤, DMG-PEG를 차례대로 첨가하고, 볼텍싱(vortexing)하여 섞어주었다.2) According to the experimental conditions, compounds of chemical formulas A to C and DOPE, cholesterol, and DMG-PEG were sequentially added to Tube (A) and mixed by vortexing.
3) 에탄올상(ethanol phase)에는 모든 원료 물질의 합이 12.5 mM 이내로 존재하도록, 필요시 에탄올을 추가하였다.3) Ethanol was added to the ethanol phase when necessary so that the sum of all raw materials was within 12.5 mM.
4) Tube (B)에는 mRNA와 20 mM 초산나트륨 완충액(sodium acetate buffer)(pH 4.6)(=3M sodium acetate buffer를 20 mM로 희석하고 1M HCl를 이용하여 pH 4.6으로 적정(titration)하여 준비된 것)를 섞어주었다. 그때 비율은 수상(aqueous phase)의 부피가 에탄올상(ethanol phase) 부피의 총 3배가 되도록 계산하여 첨가하였다. 4) In Tube (B), mRNA and 20 mM sodium acetate buffer (pH 4.6) (= prepared by diluting 3 M sodium acetate buffer to 20 mM and titrating to pH 4.6 with 1 M HCl) were mixed. The ratio was calculated so that the volume of the aqueous phase was three times the total volume of the ethanol phase and added.
5) Tube (A)와 Tube (B)의 혼합은 Microfluidics(Ignite, Precision Nanosystem) 기기를 이용하여 수행하였다. Microfluidics 작동 조건은 FRR(Flow Rate Ratio)이 C:R=3:1이었고, TRR(Total Flow Rate)이 12 mL/min이었다.5) Mixing of Tube (A) and Tube (B) was performed using a Microfluidics (Ignite, Precision Nanosystem) device. Microfluidics operating conditions were FRR (Flow Rate Ratio) of C:R=3:1 and TRR (Total Flow Rate) of 12 mL/min.
6) 5)단계의 결과 혼합액을, Amicon-Ultra tube filter(50K)를 사용하여 4,000 rpm에서 원심분리하여 농축한 다음, PBS로 희석 후 원심분리 농축하는 과정을 반복하여, 여분의 에탄올을 제거한 다음, 최종 x mg/mL(이론농도)로 농축하였다.6) The resulting mixture from step 5 was concentrated by centrifugation at 4,000 rpm using an Amicon-Ultra tube filter (50K), then diluted with PBS and centrifuged to concentrate. The process was repeated to remove excess ethanol, and then concentrated to a final x mg/mL (theoretical concentration).
3. 제형의 물성 평가3. Evaluation of physical properties of the formulation
1) 제조된 제형에 대하여, 입도분석기(Dynamic Light Scattering, DLS)를 통해 입자 특성(즉, 제타-평균 입자크기(Zeta-average), 다분산도(PDI) 및 제타-전위(Zeta-potential))을 확인하였으며, 그 결과를 하기 표1에 나타내었다.1) For the manufactured formulation, particle characteristics (i.e., zeta-average particle size, polydispersity index (PDI), and zeta-potential) were confirmed using a particle size analyzer (Dynamic Light Scattering, DLS), and the results are shown in Table 1 below.
2) 제조된 제형에 대하여, Ribo-green assay를 통하여 mRNA 봉입 효율(Encapsulation efficiency)을 확인하였으며, 그 결과를 하기 표 1에 나타내었다.2) For the manufactured formulation, mRNA encapsulation efficiency was confirmed through Ribo-green assay, and the results are shown in Table 1 below.
[표 1][Table 1]
Claims (9)
[화학식 1]
여기에서,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,
R3는 비치환된 알킬렌기이고,
R은 수소 원자(H) 또는 이고, 여기서 R4는 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고, R5는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고, *는 질소 원자에의 부착점(point of attachment)을 나타낸다.A lipid having a structure represented by the following chemical formula 1:
[Chemical Formula 1]
Here,
R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R 3 is an unsubstituted alkylene group,
R is a hydrogen atom (H) or , wherein R 4 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group, R 5 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group, and * represents a point of attachment to a nitrogen atom.
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C1-30 알킬기, 치환되거나 비치환된 C2-30 알케닐기, 또는 치환되거나 비치환된 C2-30 알키닐기이고,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C1-15 알킬렌기, 치환되거나 비치환된 C2-15 알케닐렌기, 또는 치환되거나 비치환된 C2-15 알키닐렌기이고,
R3는 비치환된 C2-9 알킬렌기인, 지질.In the first paragraph,
R 1 and R 4 are each independently a substituted or unsubstituted C 1-30 alkyl group, a substituted or unsubstituted C 2-30 alkenyl group, or a substituted or unsubstituted C 2-30 alkynyl group,
R 2 and R 5 are each independently a substituted or unsubstituted C 1-15 alkylene group, a substituted or unsubstituted C 2-15 alkenylene group, or a substituted or unsubstituted C 2-15 alkynylene group,
R 3 is an unsubstituted C 2-9 alkylene group, lipid.
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C1-20 알킬기, 치환되거나 비치환된 C2-20 알케닐기, 또는 치환되거나 비치환된 C2-20 알키닐기이고,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C1-12 알킬렌기, 치환되거나 비치환된 C2-12 알케닐렌기, 또는 치환되거나 비치환된 C2-12 알키닐렌기이고,
R3는 비치환된 C2-7 알킬렌기인, 지질.In the first paragraph,
R 1 and R 4 are each independently a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 2-20 alkenyl group, or a substituted or unsubstituted C 2-20 alkynyl group,
R 2 and R 5 are each independently a substituted or unsubstituted C 1-12 alkylene group, a substituted or unsubstituted C 2-12 alkenylene group, or a substituted or unsubstituted C 2-12 alkynylene group,
R 3 is an unsubstituted C 2-7 alkylene group, lipid.
R1 및 R4는 각각 독립적으로 치환되거나 비치환된 C5-20 알킬기, 치환되거나 비치환된 C5-20 알케닐기, 또는 치환되거나 비치환된 C5-20 알키닐기이고,
R2 및 R5는 각각 독립적으로 치환되거나 비치환된 C3-12 알킬렌기, 치환되거나 비치환된 C3-12 알케닐렌기, 또는 치환되거나 비치환된 C3-12 알키닐렌기이고,
R3는 비치환된 C2-5 알킬렌기인, 지질.In the first paragraph,
R 1 and R 4 are each independently a substituted or unsubstituted C 5-20 alkyl group, a substituted or unsubstituted C 5-20 alkenyl group, or a substituted or unsubstituted C 5-20 alkynyl group,
R 2 and R 5 are each independently a substituted or unsubstituted C 3-12 alkylene group, a substituted or unsubstituted C 3-12 alkenylene group, or a substituted or unsubstituted C 3-12 alkynylene group,
R 3 is an unsubstituted C 2-5 alkylene group, lipid.
In the first paragraph, a lipid having any one structure selected from the following chemical formulas A to L:
(2) 화학식 c의 화합물을 화학식 d의 화합물과 반응시켜 화학식 e의 화합물을 얻는 단계; 및
(3) 화학식 e의 화합물을 화학식 f의 화합물과 반응시켜 화학식 1-1의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법:
[화학식 a]
HOC(=O)-R2-NH2
[화학식 b]
R1-OH
[화학식 c]
R1-OC(=O)-R2-NH2
[화학식 d]
[화학식 e]
R1-OC(=O)-R2-NH-C(=O)-CH=CH2
[화학식 f]
tBu-OC(=O)-NH-R3-NH2
[화학식 1-1]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-NH-R3-NH-C(=O)O-tBu
상기에서,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,
R3는 비치환된 알킬렌기이고,
tBu는 tert-부틸기이고,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.(1) a step of reacting a compound of chemical formula a with a compound of chemical formula b to obtain a compound of chemical formula c;
(2) a step of reacting a compound of chemical formula c with a compound of chemical formula d to obtain a compound of chemical formula e; and
(3) A method for producing a lipid, comprising: a step of reacting a compound of chemical formula e with a compound of chemical formula f to obtain a compound of chemical formula 1-1;
[chemical formula a]
HOC(=O)-R 2 -NH 2
[chemical formula b]
R 1 -OH
[chemical formula c]
R 1 -OC(=O)-R 2 -NH 2
[chemical formula d]
[chemical formula e]
R 1 -OC(=O)-R 2 -NH-C(=O)-CH=CH 2
[chemical formula f]
tBu-OC(=O)-NH-R 3 -NH 2
[Chemical Formula 1-1]
R 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -NH-R 3 -NH-C(=O)O-tBu
In the above,
R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R 3 is an unsubstituted alkylene group,
tBu is tert-butyl group,
X is selected from the group consisting of F, CI, Br, and I.
(2) 화학식 c의 화합물을 화학식 d의 화합물과 반응시켜 화학식 e의 화합물을 얻는 단계; 및
(3) 화학식 e의 화합물을 화학식 f의 화합물과 반응시켜 화학식 1-2의 화합물을 얻는 단계;를 포함하는, 지질의 제조방법:
[화학식 a]
HOC(=O)-R2-NH2
[화학식 b]
R1-OH
[화학식 c]
R1-OC(=O)-R2-NH2
[화학식 d]
[화학식 e]
R1-OC(=O)-R2-NH-C(=O)-CH=CH2
[화학식 f]
tBu-OC(=O)-NH-R3-NH2
[화학식 1-2]
[R1-OC(=O)-R2-NH-C(=O)-CH2-CH2]2-N-R3-NH-C(=O)O-tBu
상기에서,
R1은 각각 독립적으로 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,
R2는 각각 독립적으로 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,
R3는 비치환된 알킬렌기이고,
tBu는 tert-부틸기이고,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.(1) a step of reacting a compound of chemical formula a with a compound of chemical formula b to obtain a compound of chemical formula c;
(2) a step of reacting a compound of chemical formula c with a compound of chemical formula d to obtain a compound of chemical formula e; and
(3) A method for producing a lipid, comprising: a step of reacting a compound of chemical formula e with a compound of chemical formula f to obtain a compound of chemical formula 1-2;
[chemical formula a]
HOC(=O)-R 2 -NH 2
[chemical formula b]
R 1 -OH
[chemical formula c]
R 1 -OC(=O)-R 2 -NH 2
[chemical formula d]
[chemical formula e]
R 1 -OC(=O)-R 2 -NH-C(=O)-CH=CH 2
[chemical formula f]
tBu-OC(=O)-NH-R 3 -NH 2
[Chemical Formula 1-2]
[R 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 ] 2 -NR 3 -NH-C(=O)O-tBu
In the above,
R 1 is each independently a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R 2 is each independently a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R 3 is an unsubstituted alkylene group,
tBu is tert-butyl group,
X is selected from the group consisting of F, CI, Br, and I.
[화학식 1-1]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-NH-R3-NH-C(=O)O-tBu
[화학식 g]
R4-OC(=O)-R5-NH-C(=O)-CH=CH2
[화학식 1-3]
R1-OC(=O)-R2-NH-C(=O)-CH2-CH2-N(A)-R3-NH-C(=O)O-tBu
상기에서,
R1은 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고,
R2는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,
R3는 비치환된 알킬렌기이고,
A는 -CH2-CH2-C(=O)-NH-R5-C(=O)O-R4이고, 여기서 R4는 치환되거나 비치환된 알킬기, 알케닐기 또는 알키닐기이고, R5는 치환되거나 비치환된 알킬렌기, 알케닐렌기 또는 알키닐렌기이고,
tBu는 tert-부틸기이고,
X는 F, CI, Br 및 I로 구성된 군으로부터 선택된다.A method for producing a lipid, comprising: a step of reacting a compound of chemical formula 1-1 obtained in claim 6 with a compound of chemical formula g to obtain a compound of chemical formula 1-3;
[Chemical Formula 1-1]
R 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -NH-R 3 -NH-C(=O)O-tBu
[chemical formula g]
R 4 -OC(=O)-R 5 -NH-C(=O)-CH=CH 2
[Chemical Formula 1-3]
R 1 -OC(=O)-R 2 -NH-C(=O)-CH 2 -CH 2 -N(A)-R 3 -NH-C(=O)O-tBu
In the above,
R 1 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group,
R 2 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
R 3 is an unsubstituted alkylene group,
A is -CH 2 -CH 2 -C(=O)-NH-R 5 -C(=O)OR 4 , where R 4 is a substituted or unsubstituted alkyl group, alkenyl group or alkynyl group, R 5 is a substituted or unsubstituted alkylene group, alkenylene group or alkynylene group,
tBu is tert-butyl group,
X is selected from the group consisting of F, CI, Br, and I.
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