CN106132431A - 具有靶向分子和两种不同药物的药物偶联物 - Google Patents
具有靶向分子和两种不同药物的药物偶联物 Download PDFInfo
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- CN106132431A CN106132431A CN201480068351.4A CN201480068351A CN106132431A CN 106132431 A CN106132431 A CN 106132431A CN 201480068351 A CN201480068351 A CN 201480068351A CN 106132431 A CN106132431 A CN 106132431A
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- drug conjugates
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- alkyl
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract
本申请公开了一种具有与单一靶向蛋白偶联的至少两种药物有效负载的改进ADC(抗体药物偶联物)类型组合物。更具体而言,本公开将第一药物偶联物连接到靶向蛋白的双半胱氨酸(Cys)残基上,并将具有不同药物的第二药物偶联物连接到该靶向蛋白的Lys残基上。
Description
技术领域
本公开提供了一种具有偶联到单一靶向蛋白的至少两种药物有效负载的改进ADC(抗体药物偶联物)类型组合物。更具体而言,本公开将第一药物偶联物连接到靶向蛋白的双半胱氨酸(Cys)残基上,并将具有不同药物的第二药物偶联物连接到该靶向蛋白的Lys残基上。
背景技术
抗体(或抗体片段)能够连接到药物有效负载上以形成免疫偶联物,称为抗体药物偶联物或ADC。抗体使得ADC与靶细胞结合。随后,ADC通常受到细胞内吞,而药物则得到释放,从而治疗细胞。因为靶定,副作用可以低于体系性给药的副作用。
发明内容
本公开提供了一种包括至少两种不同类型的药物的活性剂偶联物。第一种药物偶联到靶向蛋白Cys残基上的巯基(Cys残基彼此间隔4个氨基酸以内),例如在抗体铰链区,且第二种药物偶联到靶向蛋白的Lys侧链的氨基。
具体而言,本公开提供了一种包括式I结构的双药物偶联物
或其药学可接受的盐,
其中,
A为靶向部分;
每个D1可以独立选择,其中每个D1为活性剂;
每个L1是独立的包含至少一个N(氮)原子的连接子;
每个D2独立选择,其中每个D2包括活性剂;
每个L2是独立的连接子;
E-部分是任选取代的杂芳基或任选取代的杂环基;
每个L3是任选取代的C1-C6烷基,或每个L3为空;当所述L3为空时,所述硫直接连接到所述E-部分;
每个L4是任选取代的C1-C6烷基,或每个L4为空;当所述L4为空时,所述硫直接连接到所述E-部分;
m为1,2,3,4,5,6,7,8,9或10;和
n为1,2,3,4,5,6,7,8,9或10。
优选地,所述E-部分包括选自以下的片段:
和
L3为-(CH2)-;且L4为-(CH2)-。L3为空;且L4为空。
是或
L1包括-(CH2)n-,其中n可以是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,L1包括-(CH2CH2O)n-,其中n可以是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,L1包括Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB或PAB。在一些实施例中,L1包括肽,寡糖,-(CH2)n-,-(CH2CH2O)n-,Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB,PAB,或其组合。优选地,L1选自-(CH2)n-,-(CH2CH2O)n-,其中n是1-10的整数,肽,(其中X1是N(氮)或CH;Y1是N(氮)或CH;且p为0、1或2),或
L2包括-(CH2)n-,其中n可以是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,L2包括-(CH2CH2O)n-,其中n是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,L2包括Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB或PAB。在一些实施例中,L2包括肽,寡糖,-(CH2)n-,-(CH2CH2O)n-,Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB,PAB,或其组合。在一些实施例中,L2包括不可切割单元。在一些实施例中,该不可切割单元包括-(CH2)n-,其中n可以是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,该不可切割单元包括-(CH2CH2O)n-,其中n是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,L2包括可切割单元。优选地,该可切割单元包括肽。
所述A部分是抗体(mAB)或其片段。可选地,该A部分包括Cys工程抗体。在一些实施例中,所述A部分包括消除了至少一对重链间双硫键的抗体。在一些实施例中,所述A部分包括至少一个修饰的L-丙氨酸残基。在一些实施例中,所述A部分包括至少2个修饰的L-丙氨酸残基。在一些实施例中,至少一个L2包括-(CH2)n-,其中n可以是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,至少一个L2包括-(CH2CH2O)n-,其中n是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,至少一个L2包括Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB或PAB。在一些实施例中,至少一个L2包括肽、寡糖、-(CH2)n-,-(CH2CH2O)n-,Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB,PAB或其组合。
可选地,所述A部分包括至少2个修饰的L-丙氨酸残基。在一些实施例中,至少一个L2包括-(CH2)n-,其中n可以是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,至少一个L2包括-(CH2CH2O)n-,其中n是1,2,3,4,5,6,7,8,9,或10。在一些实施例中,至少一个L2包括Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB或PAB。在一些实施例中,至少一个L2包括肽、寡糖、-(CH2)n-,-(CH2CH2O)n-,Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB,PAB或其组合。
A包括至少一个修饰的正丁基L-α-氨基酸。在一些实施例中,A包括至少一个修饰的L-丙氨酸残基,其来自偶联前的肽的L-丙氨酸残基。在一些实施例中,A-NH共同包括至少一个修饰的L-丙氨酸残基。在一些实施例中,偶联前的肽的L-丙氨酸残基的侧链的末端氮提供了A-NH的NH。在一些实施例中,A包括提供了所述至少一个A-NH的偶联前的肽的L-丙氨酸残基的侧链的-(CH2)4-。在一些实施例中,A包括修饰的正丁基L-α-氨基酸残基。
附图说明
图1展示了与单K-锁或C-锁的偶联物相比,抗Her-2(A)双偶联物(K-锁+C-锁)(K-lock+C-lock)在乳腺癌细胞系中诱导的抗增殖效果的提高。A,SKBR-3(HER2 3+),B,HCC1954(HER23+),C,MCF-7(HER2+/-)均以单一偶联物或双偶联物处理3天。对于显示出50%细胞生长抑制的浓度,测定IC50。
图2展示了与单K-锁或C-锁的偶联物相比,抗Her-2(A)双偶联物(K-锁+C-锁)(K-lock+C-lock)在乳腺癌细胞系中诱导的抗增殖效果的提高。A,SKBR-3(HER2 3+),B,HCC1954(HER23+),C,MCF-7(HER2+/-)均以单一偶联物或双偶联物处理3天。图中展示了上述浓度下的细胞活性百分比并与单偶联物相比较。
图3展示了与单K-锁和单C-锁偶联物的组合相比,抗Her-2(A)双偶联物(K-锁+C-锁)(K-lock+C-lock)在乳腺癌细胞系中诱导的抗增殖效果的提高。A,SKBR-3(HER2 3+),B,HCC1954(HER2 3+),C,MCF-7(HER2+/-)均以单一偶联物或双偶联物处理3天。对于显示出50%细胞生长抑制的浓度,测定IC50。
具体实施方式
本公开提供了一类双药物改进ADC’s(抗体药物偶联物),其包括两种不同的药物(D1和D2),其中D1偶联物连接到靶向蛋白(优选为抗体或其片段)的Lys残基,亦称为“K-锁(K-Lock)”,而D2即第二种药物偶联物连接到该靶向蛋白上两个邻近的Cys残基,亦称为“C-锁(C-Lock)”。本公开满足了本领域一项长期存在的迫切需要,即能够使用单一靶向蛋白向靶细胞(例如癌症细胞)中递送两种不同的药物有效负载(D1和D2)。
如下表1展示了K-锁偶联物的结构,且如下表2展示了C-锁偶联物的结构。本公开基于以单一靶向蛋白同时实现C-锁和K-锁的能力。
表1.K-锁(Lys偶联物)化合物的结构
。
表2.C-锁(Cys偶联物)化合物的结构
如下表3提供了本公开中作为示例的双药物偶联物的列表,并展示了K-锁侧的D1药物和C-锁侧的D2药物。
表3.双偶联(K锁和C锁)ADCs列表
K锁(Lys)ID | C锁(Cys)ID | 双偶联ADC(本文中的名称) |
9 | 32 | A*-9-32 |
9 | 18 | A-9-18 |
9 | 38 | A-9-38 |
9 | 40 | A-9-40 |
3 | 17 | A-3-17 |
3 | 40 | A-3-40 |
3 | 37 | A-3-37 |
11 | 21 | A-11-21 |
11 | 26 | A-12-26 |
12 | 38 | A-12-38 |
10 | 38 | A-10-38 |
13 | 38 | A-13-38 |
13 | 21 | A-13-21 |
8 | 21 | A-8-21 |
10 | 21 | A-10-21 |
14 | 21 | A-14-21 |
8 | 26 | A-8-26 |
14 | 21 | A-14-21 |
14 | 27 | A-14-27 |
10 | 26 | A-10-26 |
12 | 39 | A-12-39 |
*A为抗HER2抗体。
双偶联ADC A-9-32的结构
双偶联ADC A-9-18的结构
双偶联ADC A-9-38的结构
双偶联ADC A-9-40的结构
双偶联ADC A-3-17的结构
双偶联ADC A-3-40的结构
双偶联ADC A-3-37的结构
双偶联ADC A-11-21的结构
双偶联ADC A-11-26的结构
双偶联ADC A-12-38的结构
双偶联ADC A-10-38的结构
双偶联ADC A-13-38的结构
双偶联ADC A-13-21的结构
双偶联ADC A-8-21的结构
双偶联ADC A-10-21的结构
双偶联ADC A-14-21的结构
双偶联ADC A-8-26的结构
双偶联ADC A-14-26的结构
双偶联ADC A-14-27的结构
双偶联ADC A-10-26的结构
双偶联ADC A-12-39的结构
通过使用两种不同的偶联方法,即第一偶联方法和第二偶联方法,偶联靶向蛋白以包括至少两个不同类型的药物。用于衍生具有有效负载的多肽的第一偶联方法,可以通过使用可经由迈克尔加成反应与抗体上的巯基反应的马来酰亚胺基或乙烯基部分来完成。游离巯基可通过将抗体的二硫键还原来形成。然而,该靶向蛋白(如抗体)的结构完整性在打开二硫键并将有效负载连接至外露的游离硫醇后受到损害。本申请所提供的组合物和方法,通过半胱氨酸残基提供偶联,不会降低结构稳定性。用于衍生具有有效负载的多肽的第二偶联方法,是通过与赖氨酸侧链形成酰胺键来完成的。由于大量具有类似反应活性的赖氨酸侧链胺的存在,此偶联策略可以产生复杂的异质混合物。本申请所提供的组合物和方法通过赖氨酸提供偶联,其中赖氨酸的增强选择性能够得到更少的异质混合物。将所述偶联方法标记为“第一”和“第二”方法,是为了便于讨论,而并不表明偶联的顺序。
术语“药学上可接受的盐”,是指保留了化合物的生物学有效性和性质的盐,且其不会在生物学或其它方面上不期望用于药物中。所公开的化合物能够凭借氨基和/或羧基或类似基团的存在来形成酸盐和/或碱盐。药学上可接受的酸加成盐可以通过无机酸和有机酸来形成。可以用于衍生盐的无机酸包括,例如,盐酸,氢溴酸,硫酸,硝酸,磷酸等。可以用于衍生盐的有机酸包括,例如,乙酸,丙酸,乙醇酸,丙酮酸,草酸,马来酸,丙二酸,琥珀酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,对甲苯磺酸,水杨酸等。药学上可接受的碱加成盐可以利用无机碱和有机碱来形成。可以用于衍生盐的无机碱包括,例如,钠,钾,锂,铵,钙,镁,铁,锌,铜,锰,铝等特别优选的是铵,钾,钠,钙和镁盐。可以用于衍生盐的有机碱包括,例如,伯、仲、叔胺,取代胺(包括天然存在的取代胺),环胺,碱性离子交换树脂等,具体地,例如异丙胺,三甲胺,二乙胺,三乙胺,三丙胺和乙醇胺。许多此类盐是本领域中已知的,如WO 87/05297中所述,(通过引用方式将其全文并入本申请)。
“Ca至Cb”或“Ca-b”中的“a”和“b”是指代指定基团中的碳原子数目的整数。亦即,该基团可含有从“a”到“b”(包含上下限)的碳原子。因此,例如,“C1至C4烷基”或“C1-4烷基”指的是具有1至4个碳原子的所有烷基,即CH3-,CH3CH2-,CH3CH2CH2-,(CH3)2CH-,CH3CH2CH2CH2-,CH3CH2CH(CH3)-和(CH3)3C-。
术语“卤素(halogen)”或“卤”是指氟,氯,溴,或碘。
“烷基(alkyl)”是指完全饱和的直链或支链烃链。该烷基可具有1~20个碳原子(每当在本申请中出现如“1至20”的数值范围时,其是指在给定范围内的各整数;例如,“1至20个碳原子”是指该烷基可由1个碳原子,2个碳原子,3个碳原子等,至多并包括20个碳原子组成,但是本定义也涵盖术语“烷基”没有指定数值范围的情形)。烷基也可以是具有1至9个碳原子的中等大小的烷基。烷基也可以是具有1至4个碳原子的低级烷基。该烷基可称为“C1-4烷基”或类似名称。举例而言,“C1-4烷基”表示烷基链中有一个至四个碳原子,即,该烷基链选自甲基,乙基,丙基,异丙基,正丁基,异丁基,仲丁基和叔丁基。典型的烷基包括但决不限于:甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,己基。
“烷氧基(alkoxy)”是指式-OR,其中R是如上述定义的烷基,例如“C1-9烷氧基”,包括但不限于甲氧基,乙氧基,正丙氧基,1-甲基乙氧基(异丙氧基),正丁氧基,异丁氧基,仲丁氧基和叔丁氧基。
“烷硫基(alkylthio)”是指式-SR,其中R是如上定义的烷基,例如“C1-9烷硫基”等,包括但不限于甲巯基,乙巯基,正丙基巯基,1-甲基乙基巯基(异丙基巯基),正丁基巯基,异丁基巯基,仲丁基巯基,叔丁基巯基。
“烯基(alkenyl)”是指含有一个或多个双键的直链或支链烃链。烯基可以具有2至20个碳原子,但是本定义还包括术语“烯基”没有指定数值范围的情形。烯基也可以是具有2至9个碳原子的中等大小的烯基。烯基也可以是具有2至4个碳原子的低级烯基。烯基可称为“C2-4烯基”或类似名称。仅作为举例说明,“C2-4烯基”表示烯基链有2-4个碳原子,亦即,烯基链选自乙烯基,丙烯-1-基,丙烯-2-基,丙烯-3-基,丁烯-1-基,丁烯-2-基,丁烯-3-基,丁烯-4-基,1-甲基-丙烯-1-基,2-甲基丙烯-1-基,1-乙基-乙烯-1-基,2-甲基-丙烯-3-基,丁-1,3-二烯基,丁-1,2,-二烯基和丁-1,2-二烯-4-基。典型的烯基包括,但绝不限于:乙烯基,丙烯基,丁烯基,戊烯基和己烯基。
“炔基(alkynyl)”是包含一个或多个三键的直链或支链烃链。炔基可以具有2至20个碳原子,但是本定义还包括术语“炔基”没有数值范围指定的情形。炔基也可以是具有2至9个碳原子的中等大小的炔基。炔基也可以是具有2至4个碳原子的低级炔基。炔基可称为“C2-4炔基”或类似名称。举例而言,“C2-4炔基”表示炔基链有2-4个碳原子,亦即,炔基链选自乙炔基,丙炔-1-基,丙炔-2-基,丁炔-1-基,丁炔-3-基,丁炔-4-基和2-丁炔基。炔基包括,例如,乙炔基,丙炔基,丁炔基,戊炔基和己炔基。
术语“芳族(aromatic)”是指具有共轭π电子体系的环或环体系,并且包括碳环芳基(例如苯基)和杂环芳基(例如,吡啶)。该术语包括单环或稠环多环基团,只要整个环体系是芳族即可。
“芳氧基(aryloxy)”和“芳硫基(arylthio)”是指RO-和RS-,其中R是如以上所定义的芳基,如“C6-10芳氧基”或“C6-10芳硫基”,如苯氧基。
“芳烷基(aralkyl)”或“芳基烷基(arylalkyl)”是通过作为取代基的亚烷基连接的芳基,例如“C7-14芳烷基”等,包括但不限于苄基,2-苯乙基,3-苯丙基和萘基。在一些情况下,该亚烷基是低级亚烷基(即,C1-4亚烷基)。
“杂芳基(heteroaryl)”是指在环骨架中含有一个或多个杂原子(即除碳以外的元素,包括但不限于,氮,氧和硫)的芳环或环体系。当杂芳基是一个环体系时,体系中的每个环均为芳族环。杂芳基可具有5-18个环成员(即,构成环骨架的原子(包括碳原子和杂原子)的数目),但是本定义还包括术语“杂芳基”没有数值范围指定的情形。在一些实施例中,杂芳基具有5至10个环成员或5至7个环成员。杂芳基可称为“5-7元杂芳基”、“5-10元杂芳基”或类似名称。杂芳环的示例包括呋喃基,噻吩基,酞嗪基,吡咯基,恶唑基,噻唑基,咪唑基,吡唑基,异恶唑基,异噻唑,***,噻二唑基,吡啶基,哒嗪基,嘧啶基,吡嗪基,三嗪基,喹啉基,异喹啉基,苯并咪唑基,苯并恶唑基,苯并噻唑基,吲哚基,异吲哚和苯并噻吩。
“杂芳烷基(heteroaralkyl)”或“杂芳基烷基(heteroarylalkyl)”是通过作为取代基的亚烷基连接的杂芳基。示例包括2-噻吩甲基,3-噻吩甲基,呋喃甲基,噻吩基,吡咯烷基,吡啶烷基,异恶唑烷基和咪唑基。在一些情况下,该亚烷基是低级亚烷基(即,C1-4亚烷基)。
“碳环基(carbocyclyl)”是指在环体系骨架中仅含有碳原子的非芳族环或环体系。当碳环基是环体系时,两个或更多个环可以连接在一起称为稠合的、桥连的或螺环的连接方式。
碳环基可具有任何饱和程度,只要环体系中至少一个环不是芳族的即可。因此,碳环基包括环烷基,环烯基和环炔基。碳环基团可以具有3至20个碳原子,但本定义还包括术语“碳环基”没有指定数值范围的情形。碳环基也可以是碳原子数为3~10的中等大小的碳环基。碳环基也可以是具有3至6个碳原子的碳环基。碳环基团可以称为“C3-6碳环基”或类似名称。碳环基环的示例包括,但不限于,环丙基,环丁基,环戊基,环己基,环己烯基,2,3-二氢茚,双环[2.2.2]辛基,金刚烷基和螺环[4.4]壬烷基。
“(碳环基)烷基((carbocyclyl)alkyl)”是通过作为取代基的亚烷基相连接的碳环基团,如“C4-10(碳环基)烷基”包括环丙基甲基,环丁基甲基,环丙基乙基,环丙基丁基,环丁基乙基,环丙基异丙基,环戊基甲基,环戊基乙基,环己基甲基,环己基乙基,环庚基甲基。在一些情况下,该亚烷基是低级亚烷基。
“环烷基(cycloalkyl)”是指完全饱和的碳环基环或环体系。其示例包括环丙基,环丁基,环戊基和环己基。
“环烯基(cycloalkenyl)”是指具有至少一个双键的碳环或环体系,其中该环体系中没有芳族环。其示例之一是环己烯基。
“杂环基(Heterocyclyl)”是指环骨架含有至少一个杂原子的非芳族环或环体系。杂环基可以通过稠合的、桥连的或螺环连接的方式接合。杂环基可具有提供饱和的任何程度,只要在环体系中至少一个环不是芳族环即可。所述杂原子可存在于该环体系中的非芳香环或芳香环中。所述杂环基可具有3至20个环成员(即,构成环骨架的原子的数目,包括碳原子和杂原子),但是本定义还包括术语“杂环基”没有指定数值范围的情形。所述杂环基还可以是具有3至10个环成员的中等大小的杂环基。所述杂环基还可以是具有3至6个环成员的杂环基。所述杂环基可以称为“3-6元杂环基”或类似名称。在优选的六元单环杂环基中,所述杂原子是选自O(氧),N(氮)或S(硫)中的一个至三个,而在优选的五元单环杂环基中,所述杂原子是选自O(氧),N(氮)或S(硫)中的一个至两个。杂环基环的示例包括:氮杂基,吖啶基,咔唑基,噌啉基,二氧戊环基,咪唑啉基,咪唑烷基,吗啉基,环氧乙烷基,氧杂环丁基,噻吩基,哌啶基,哌嗪基,二氧代哌嗪,吡咯烷基,吡咯烷酮基,吡咯烷酮基,4-哌啶酮基,吡唑啉基,吡唑烷基,1,3-二氧杂环己二烯,1,3-二恶烷基,1,4-二氧杂环己烯,1,4-二恶烷基,1,3-氧硫杂环己烷基,1,4-氧杂噻吩基,1,4-氧硫杂环己烷基,2H-1,2-恶嗪基,三恶烷基,六氢-1,3,5-三嗪,1,3-二恶茂基,1,3-二氧戊环基,1,3-二硫杂环戊烯基,1,3-二硫杂环戊烷基,异恶唑啉基,异恶唑烷基,恶唑啉基,恶唑烷基,恶唑烷酮基,噻唑啉基,噻唑烷基,1,3-氧硫环戊烷基,二氢吲哚基,异二氢吲哚,四氢呋喃基,四氢吡喃基,四氢噻吩基,四氢噻喃基,四氢-1,4-噻嗪基,硫代吗啉基,二氢苯并呋喃基,苯并咪唑烷基和四氢喹啉。
“(杂环)烷基((heterocyclyl)alky)”是通过作为取代基亚烷基连接的杂环基。其示例包括咪唑啉基甲基和吲哚基乙基。
“酰基(acyl)”是-C(=O)R,其中R是氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。其示例包括甲酰基,乙酰基,丙酰基,苯甲酰基和丙烯。
“O-羧基(O-carboxy)”基团是“-OC(=O)R”基团,其中R选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“C-羧基(C-carboxy)”基团是“-C(=O)OR”基团,其中R选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基,如本申请定义。非限制性示例之一包括羧基(即,-C(=O)OH)。
“氰基(cyano)”基团是“-CN”基团。
“氰酰基(cyanato)”基团是“-OCN”基团。
“异氰酸基(isocyanato)”基团是“-NCO”基团。
“氰硫基(thiocyanato)”基团是“-SCN”基团。
“异硫氰基(isothiocyanato)”基团是“-NCS”基团。
“亚磺酰基(sulfinyl)”基团是“-S(=O)R”基团,其中R选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“磺酰基(sulfonyl)”基团是“-SO2R”基,其中R选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“S-磺酰氨基(S-sulfonamido)”基团是"-SO2NRARB"基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
所谓“N-磺酰氨基(N-sulfonamido)”基团是"-N(RA)SO2RB"基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“O-氨基甲酰基(O-carbamyl)”基团是“-OC(=O)N RA RB”基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
所谓“N-氨基甲酰基(N-carbamyl)”基团是“-N(RA)C(=O)ORB”基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“O硫代氨基甲酰基(O-thiocarbamyl)”基团是“-OC(=S)NRARB”基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“脲(urea)”基团是“-N(RA)C(=O)N RA RB”,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
所谓“N-硫代氨基甲酰基(N-thiocarbamyl)”基团是“-N(RA)-C(=S)O RB”基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“C-酰胺基(C-amido)”基团是“-C(=O)N RA RB”基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“N-酰胺基(N-amido)”基团是“-N(RA)C(=O)RB”,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。
“氨基(amino)”基团是“-N RA RB”基团,其中RA和RB各自独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C3-7碳环基,C6-10芳基,5-10元杂芳基和5-10元杂环基。示例之一是自由氨基(-NH2)。
“氨基烷基(aminoalkyl)”基团是经由亚烷基连接的氨基。
“烷氧基(alkoxyalkyl)”基团是经由亚烷基连接的烷氧基,例如“C2-8烷氧基”。
取代基是从一个或多个氢原子置换为另一原子或基团的未取代母体基团衍生得来的。除非另有说明,否则当一个基团视为“被取代”时,是指该基团被一个或多个取代独立选自C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C7碳环基(被卤素,C1-C6烷基,C1-C6烷氧基,C6卤代烷基和C1-C6卤代烷氧基任选取代),C3-C7-碳环基-C1-C6-烷基(被卤素,C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基,和C1-C6卤代烷氧基任选取代),5-10元杂环基(被卤素,C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基,和C1-C6卤代烷氧基任选取代),5-10元杂环基-C1-C6-烷基(被卤素,C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基,和C1-C6卤代烷氧基任选取代),芳基(被卤素,C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基,和C1-C6卤代烷氧基任选取代),芳基(C1-C6)烷基(被卤素,C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基,和C1-C6卤代烷氧基任选取代),5-10元杂芳基(被卤素,C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基,和C1-C6卤代烷氧基任选取代),5-10元杂芳基(C1-C6)烷基(被卤素,C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基,和C1-C6卤代烷氧基任选取代),卤素,氰基,羟基,C1-C6烷氧基,C1-C6烷氧基(C1-C6)烷基(即,醚),芳氧基,巯基(氢硫基),卤代(C1-C6)烷基(例如,-CF3),卤代(C1-C6)烷氧基(例如,-OCF3),C1-C6烷硫基,芳硫基,氨基,氨基(C1-C6)烷基,硝基,O-氨基甲酰基,N-氨基甲酰基,O-硫代氨基甲酰基,N-硫代氨基甲酰基,C-酰氨基,N-酰氨基,S-磺酰氨基,N-磺酰氨基,C-羧基,O-羧基,酰基,氰酰基,异氰酸基,氰硫基,异硫氰基,亚磺酰基,磺酰基,和氧代(=O)。当一个基团被描述为“任选取代”时,该基团可以是被上述取代基取代。
只要取代基被描述为双自由基(di-radical)(即具有附着到分子的其余部分的两个点)时,应当理解,除非另有说明,否则该取代基可以通过任何取向的构型来连接。例如,描述为-AE-或的取代基包括该取代基取向为令A连接在该分子的最左侧连接点,以及A连接在该分子的最右侧连接点的情形。
这里使用的“对象”,是指人类或非人类哺乳动物,例如,狗,猫,小鼠,大鼠,牛,绵羊,猪,山羊,非人类灵长类动物或鸟,如鸡,以及任何其他脊椎动物或无脊椎动物。
定义
本申请中所用的一般有机简称的定义如下:
Ac 乙酰基
aq. 水性的
BOC或Boc:叔丁氧基羰基
BrOP 溴三(二甲氨基)鏻六氟磷酸盐
Bu 正丁基
℃ 温度,摄氏度
DCM 二氯甲烷
DEPC 焦碳酸二乙酯
DIC 二异丙基碳二亚胺
DIEA 二异丙基乙胺
DMA N,N’-二甲基甲酰胺
DMF N,N’-二甲基甲酰胺
EDC 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
Et 乙基
EtOAc 乙酸乙酯
Eq 当量
Fmoc 9-芴甲氧羰基
g 克
h 小时
HATU 2-(1H-四7-氮杂苯并***-1-基)-1,1-,3,3-四甲基铀六氟磷酸盐
ΗΟΒΤ N-羟基苯并***
HOSu N-羟基琥珀酰亚胺
HPLC 高效液相色谱法
LC/MS 液相色谱-质谱
Me 甲基
MeOH 甲醇
MeCN 乙腈
mL mL
MS 质谱
PAB 对-氨基苄基
RP-HPLC 反相HPLC
rt 室温
t-Bu 叔丁基
TEA 三乙胺
Tert,t 叔(tertiary)
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
μL 微升
一般合成方法中,由酸形成活性酯(例如NHS)。例如,可将酸溶解在DCM中,并根据需要加入DMF以帮助溶解。N-羟基琥珀酰亚胺(1.5当量),随后加入EDC.HCl(1.5当量)。将反应混合物在室温下搅拌1小时,直到大部分酸被消耗。该反应的进程通过RP-HPLC监测。然后用DCM稀释该混合物,并用柠檬酸(水溶液10%)和盐水洗涤。将有机层干燥并浓缩至干燥。可选地,粗产物通过RP-HPLC或硅胶柱色谱纯化。
所用的偶联方法、间隔物和连接子
一些实施例提供了通过间隔物或多功能连接子来偶联靶向分子的方法。在一些实施例中,该间隔物或多功能连接子可包括2-至5-原子的桥。在一些实施例中,该方法包括单步或连续偶联法。在一些实施例中,药物偶联物包括间隔物或多功能连接子。在一些实施例中,间隔物或多功能连接子可包括不可切割单元或可切割单元,例如肽。
功能和应用
一些实施例提供了治疗有需要的患者的方法,其包含将如本申请所公开和描述的活性剂偶联物向所述患者给药的方法。在一些实施例中,患者可能患有癌症,免疫疾病或糖尿病。
一些实施例提供了诊断或成像方法,其中包括将如本申请所公开和描述的活性剂偶联物向个体给药。
本公开的组合物
本公开的药学组合物具有式I的结构:
或其药学可接受的盐,
其中,
A为靶向蛋白;
每个D1是活性剂;
每个L1是独立的包含至少一个N(氮)原子的连接子;
每个D2是第二活性剂;
每个L2是独立的连接子;
E-部分是任选取代的杂芳基或任选取代的杂环基;
每个L3是任选取代的C1-C6烷基,或每个L3可以为空;当所述L3为空时,所述硫直接连接到所述E-部分;
每个L4是任选取代的C1-C6烷基,或每个L4可以为空;当所述L4为空时,所述硫直接连接到所述E-部分;
m和n是独立选自1-10的整数。
优选地,A选自单克隆抗体(mAb)和抗体片段。
D1和D2是不同的药物化合物,优选为抗癌药物或免疫调节剂。D1和D2的示例是微管蛋白结合剂,DNA烷化剂,HSP90抑制剂,DNA拓扑异构酶抑制剂,抗后生剂,HDAC抑制剂,抗代谢剂,蛋白酶体抑制剂,siRNA,反义DNA,埃坡霉素A,埃坡霉素B或紫杉醇。
L1可以包括间隔物或多功能连接子。L1可以包括间隔物和多功能连接子。在一些实施例中,L1可以包括多功能连接子。在一些实施例中,每个L1可以是连接子,其中所述连接子可以是在生物条件下可切割的或不可切割的。在一些实施例中,连接子可以是通过酶切割的。在一些实施例中,L1可包括连接子。
在一些实施例中,L2可以包括间隔物或多功能连接子。在一些实施例中,L2可以包括间隔物和多功能连接子。在一些实施例中,L2可以包括多功能连接子。在一些实施例中,每个L2可以是连接子,其中所述连接子可以是在生物条件下可切割的或不可切割的。在一些实施例中,连接子可以是通过酶切割的。在一些实施例中,L2可以包括连接子。
L2包括环状基团,其包括至少一个N(氮)原子。在一些实施例中,L2包括环状基团,其包括至少两个N(氮)原子。在一些实施例中,L2包括环状基团,其包括至少一个N(氮)原子和间隔物。
A包含至少一个修饰的L-丙氨酸残基。在一些实施例中,A包含至少两个修饰的L-丙氨酸残基。在一些实施例中,A包括连接到至少一个硫的至少一个修饰的L-丙氨酸残基。在一些实施例中,至少一个修饰的L-丙氨酸残基来自偶联前的肽的L-半胱氨酸残基。
A包括至少一个修饰的正丁基L-α-氨基酸。在一些实施例中,A包含来自偶联前的肽的L-赖氨酸残基的、至少一个修饰的L-赖氨酸残基。在一些实施例中,A-NH共同包括至少一个修饰的L-赖氨酸残基。在一些实施例中,偶联前的肽的L-赖氨酸残基的侧链的末端氮提供了式I的A-NH中的NH。在一些实施例中,A包括偶联前的肽的L-赖氨酸残基的提供了式I的至少一个A-NH的侧链的-(CH2)4-。在一些实施例中,A包括修饰的正丁基α-氨基酸残基。连接子可以是肽。
连接子可以包括寡糖。例如,连接子可以包括壳聚糖。在一些实施例中,L2可以包括连接子和-(CH2)n-,其中。n为1,2,3,4,5,6,7,8,9或10。在一些实施例中,L2可以包括连接子和-(CH2CH2O)n-,其中n为1,2,3,4,5,6,7,8,9或10。
连接子可以包括-(CH2)n-,其中n为1,2,3,4,5,6,7,8,9或10。
连接子可以包括-(CH2CH2O)n-,其中n为1,2,3,4,5,6,7,8,9或10。
连接子可以包括Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB,PAB等。
连接子可以包括肽,寡糖,-(CH2)n-,-(CH2CH2O)n-,Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB,PAB等的任意组合。
间隔物是肽,寡糖,-(CH2)n-,-(CH2CH2O)n-,Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu--Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB,PAB的任意组合。
包括4碳桥。
L3,L4和E部分的一部分包括4碳桥。
包括,
的S-连接部分包括修饰的L-丙氨酸残基,其中通过包含2-5个原子的桥连接到还原的二硫键的硫。例如,如所示的结构包括选自 和的片段。
的S-连接(硫-连接)部分包括修饰的L-丙氨酸残基。在一些实施例中,该的S-连接(硫-连接)部分包括修饰的L-丙氨酸残基,其中的修饰的L-丙氨酸部分来自偶联前的肽的L-丙氨酸残基。
结构部分是 或
E部分包括选自以下的片段:
和
L1可以包括或
活性剂可以选自微管蛋白粘合剂,DNA烷化剂,DNA嵌入剂,酶抑制剂,免疫调节剂,肽和核苷酸。
至少一个L1或L2包括-(CH2)n-,其中n是1,2,3,4,5,6,7,8,9或10。在一些实施例中,至少一个L1或L2包括-(CH2CH2O)n-,其中n是1,2,3,4,5,6,7,8,9或10。在一些实施例中,至少一个L1或L2包括Val-CIT-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB或PAB。在一些实施例中,至少一个L1或L2包括肽,寡糖,-(CH2)n-,-(CH2CH2O)n-,Val-Cit-PAB,Val-Ala-PAB,Val-Lys(Ac)-PAB,Phe-Lys-PAB,Phe-Lys(Ac)-PAB,D-Val-Leu-Lys,Gly-Gly-Arg,Ala-Ala-Asn-PAB,Ala-PAB或PAB。
靶向部分可以是抗体。在一些实施例中,靶向部分可以是单克隆抗体(mAb)。A部分包括人源化抗体。在一些实施例中,A部分包括嵌合抗体。在一些实施例中,A部分包括双特异性抗体。在一些实施例中,靶向部分可以是抗体片段,替代物或变体。
靶向部分可以是HuM195-AC-225,HuM195-BI-213,Anyara(naptumomabestafenatox;ABR-217620),AS1409,Zevalin(替伊莫单抗),BIIB015,BT-062,Neuradiab,CDX-1307,CROll-vcMMAE,曲妥单抗-DM1(R3502),Bexxar(托西莫单抗),IMGN242,IMGN388,IMGN901,131I-拉贝珠单抗,IMMU-102(90Y-依帕珠单抗),IMMU-107(90Y-clivatuzumabtetraxetan),MDX-1203,CAT-8015,EMD 273063(hul4.18-IL2),Tucotuzumabcelmoleukin(EMD 273066;huKS-IL2),188Re-PTI-6D2,Cotara,L19-IL2,Teleukin(F16-IL2),Tenarad(F16-131I),L19-11I,L19-TNF,PSMA-ADC,DI-Leul6-IL2,SAR3419,SGN-35或CMC544。在一些实施例中,该靶向部分可包括如下各项的抗体部分(或由其组成,或基本上由其组成):HuM195-AC-225,HuM195-BI-213,Anyara(naptumomab estafenatox;ABR-217620),AS1409,Zevalin(替伊莫单抗),BIIB015,BT-062,Neuradiab,CDX-1307,CROll-vcMMAE,曲妥单抗-DM1(R3502),Bexxar(托西莫单抗),IMGN242,IMGN388,IMGN901,131I-拉贝珠单抗,IMMU-102(90Y-依帕珠单抗),IMMU-107(90Y-clivatuzumab tetraxetan),MDX-1203,CAT-8015,EMD273063(hul4.18-IL2),Tucotuzumab celmoleukin(EMD 273066;huKS-IL2),188Re-PTI-6D2,Cotara,L19-IL2,Teleukin(F16-IL2),Tenarad(F16-131I),L19-11I,L19-TNF,PSMA-ADC,DI-Leul6-IL2,SAR3419,SGN-35或CMC544。
该靶向部分可以是Brentuximab vedotin,Trastuzumab emtansine,Inotuzumabozogamicin,Lorvotuzumab mertansine,Glembatumumab vedotin,SAR3419,Moxetumomabpasudotox,Moxetumomab pasudotox,AGS-16M8F,AGS-16M8F,BIIB-015,BT-062,IMGN-388,或IMGN-388。
该靶向部分可包括如下各项的抗体部分(或由其组成,或基本上由其组成):Brentuximab vedotin,Trastuzumab emtansine,Inotuzumab ozogamicin,Lorvotuzumabmertansine,Glembatumumab vedotin,SAR3419,Moxetumomab pasudotox,Moxetumomabpasudotox,AGS-16M8F,AGS-16M8F,BIIB-015,BT-062,IMGN-388,或IMGN-388。该靶向部分可包括如下各项(或由其组成,或基本上由其组成):Brentuximab,Inotuzumab,Gemtuzumab,Milatuzumab,Trastuzumab,Glembatumomab,Lorvotuzumab或Labestuzumab。
偶联方法I
方案I
方案I:G选自-F,-CI,-Br,-I,-N3,-OR,SR,-ONRR,RC(=O)O-和RSO2-O-;且R为任选取代的烷基,或任选取代的芳基。
通用偶联过程I-A:
向含0.5-50mg/mL I-A和0-30%的有机溶剂的pH6.0-9.0的缓冲液溶液中,以分批或连续流动的方式加入0.1-10当量的活化羧酸成分I-B。该反应在0-40℃下进行0.5-50小时,同时缓慢搅拌或摇动,通过HIC-HPLC监测。使用本领域现有方法,令生成的ADC粗产物经过必要的脱盐、缓冲液更换/配置和可选的纯化等下游步骤。该ADC产物I-C由HIC-HPLC,SEC,RP-HPLC和可选的LC-MS进行表征。
方案II
方案I:X选自-CI,-Br,-I和RSO2-O-;且R为任选取代的烷基,或任选取代的芳基。
通用偶联过程I-B:
向含0.5-50mg/mL ADC产物I-C的pH 5.0-9.0的某缓冲液(例如PBS)中,加入0.5~100当量还原剂(如TCEP和DTT),得到中间体I-D。该还原反应在0-40℃下进行0.5-40小时,同时缓慢搅拌或摇动,然后通过柱或超滤除去还原剂。向含0.5-50mg/mL中间体I-D和0-30%的有机共溶剂(例如DMA)的pH 5.0-9.0的某缓冲液中,加入0.5-10当量的活化药物连接子反应物I-E。该反应在0-40℃下进行0.5-40小时,同时缓慢搅拌或摇动,通过HIC-HPLC监测。使用本领域现有方法,令生成的ADC粗产物I-E经过必要的脱盐、缓冲液更换/配置和可选的纯化等下游步骤。最终的ADC产物I-E由HIC-HPLC,SEC,RP-HPLC和可选的LC-MS进行表征。
偶联方法II
方案III
通用偶联过程II-A
向含0.5-50mg/mL I-A的pH5.0-9.0的缓冲液(例如PBS)混合物中,加入0.5-100当量的还原剂如TCEP和DTT,以得到中间体II-A。该还原反应在0-40℃下进行0.5-40小时,同时缓慢搅拌或摇动,然后通过柱或超滤除去还原剂。
方案IV
方案IV:X选自-CI,-Br,-I和RSO2-O-;且R为任选取代的烷基,或任选取代的芳基。
通用偶联过程II-B:
向含0.5-50mg/mL中间体II-A和0-30%有机共溶剂(例如DMA)的pH 5.0-9.0的某缓冲液(例如PBS)中,加入0.5~10当量的活化药物连接子反应物I-E。该反应在0-40℃进行0.5-40小时,同时缓慢搅拌或摇动,通过HIC-HPLC监测进行。使用本领域现有方法,令生成的ADC粗产物I-E经过必要的脱盐、缓冲液更换/配置和可选的纯化等下游步骤。
向含0.5-50mg/mL II-B和0-30%有机溶剂的pH 6.0-9.0的缓冲液溶液中,以分批或连续流动的方式加入0.1-10当量的活化羧酸成分I-B。该反应在0-40℃下进行0.5-50小时,同时缓慢搅拌或摇动,通过HIC-HPLC监测。使用本领域现有方法,令生成的ADC粗产物I-F经过必要的脱盐、缓冲液更换/配置和可选的纯化等下游步骤。该ADC产物I-F由HIC-HPLC,SEC,RP-HPLC和可选的LC-MS进行表征。
活化羧酸成分I-B的示例包括:
其中G选自-F,-CI,-Br,-I,-N3,-OR,SR,-ONRR,RC(=O)O-和RSO2-O-;且R为任选取代的烷基,或任选取代的芳基。
活化药物连接子反应物I-E的示例为:
式I的化合物的示例:
实施例1
此实施例举例说明化合物3的合成。
向含化合物1(74mg,0.1mmol)的THF(5mL)的溶液中加入溴乙酸(70mg,5当量),接着加入NaHCO3饱和水溶液(2mL)。将混合物在室温下搅拌3小时,然后用1N盐酸酸化。用乙酸乙酯萃取该混合物,将有机层干燥并浓缩。粗产物通过RP-HPLC纯化,得到化合物2,其在冷冻干燥后为白色粉末(72mg,91%)。MS m/z 795.5[M+H]+。
将化合物2(72mg)转化成其相应的NHS酯(通用方法)。将NHS酯溶解于THF(2mL)中。添加含4-哌啶羧酸(60mg)的NaHCO3饱和水溶液(1mL),并将该混合物在室温下搅拌1小时。然后,用乙酸酸化该混合物,并浓缩至干燥。残余物通过RP-HPLC纯化,得到化合物3,为白色粉末(63mg)。MS m/z 906.6[M+H]+。
实施例2
此实施例举例说明化合物8的合成。
向含化合物4(95mg,0.2mmol)和化合物5(TFA盐,146mg,0.2mmol,其制备如WO2013/173392所述)的DMF(4mL)搅拌溶液中加入DIEA(0.14mL),随后加入HATU(80mg)。10分钟后,将哌啶(0.4mL)加入到该反应中,并将该混合物在室温下搅拌30分钟。浓缩该反应混合物,且残余物用RP-HPLC纯化,得到化合物6,为TFA盐(141mg,73%)。MS m/z 850.5[M+H]+。
将化合物6(141mg)和7(37mg)溶解在DMF(3mL)中。加入DIEA(0.1mL),随后加入HATU(57mg)。在室温下搅拌反应30分钟。加入1N NaOH水溶液(2mL),并将反应混合物在室温下搅拌2小时。将乙酸(0.5mL)加入到该反应中并浓缩混合物。残余物通过RP-HPLC纯化,得到化合物8,为白色粉末(115mg)。MS m/z 1061.5[M+H]+。
实施例3
表4
如WO2013/173392所述,制备化合物9,10,11,12,13,和14,其公开的内容通过引用方式并入本申请。
实施例4
向含化合物15(0.1mmol,其制备如WO 2013/173392所述,其公开内容通过援引方式并入本申请)的THF(3mL)溶液中加入含化合物16(0.15mmol,67mg)的乙腈/水(1/1,v/v,1mL)溶液,接着加入DIEA(50μL)。30分钟后,将反应物酸化并浓缩。将残余物通过反相HPLC纯化,得到化合物17,为白色固体(87mg)。MS m/z 1243.6[M+H]+。
实施例5
将化合物2(0.1mmol,80mg)和化合物16(0.1mmol,45mg)溶解于DCM/DMF(10/1,v/v,3mL)中。加入DIEA(20μL),随后加入DIC(25μL)。将混合物在室温下搅拌10分钟。令DCM蒸发,残余物通过反相HPLC纯化,得到化合物18,为白色粉末(66mg,53%)。MS m/z 1130.6[M+H]+。
实施例6
将化合物19(0.06mmol,36mg)和化合物20(0.05mmol,60mg,TFA盐)溶解于DCM/DMF(4/1,v/v,3mL)中。加入DIEA(25μL),随后加入DIC(15μL)。将混合物在室温下搅拌10分钟。将DCM蒸发,残余物通过反相HPLC纯化,得到化合物21,为白色粉末(41mg,49%)。MS m/z1572.8[M+H]+。
实施例7
向含化合物22(54mg,0.1mmol)的无水DMF(3mL)溶液中加入化合物23(80mg)和DIEA(20μL)。将混合物在室温下搅拌2小时。加入哌啶(40μL)。3小时后,在剧烈搅拌下将混合物滴加到100mL***中。收集沉淀的固体,并通过反相HPLC纯化,得到化合物24,为黄色固体(75mg)。MS m/z 947.3[M+H]+。
将化合物24(75mg)和化合物25(42mg)溶解于DCM/DMF(4/1,v/v,3mL)中。加入DIEA(20μL),随后加入由DIC(20μL)。将混合物在室温下搅拌20分钟。将DCM蒸发,残余物通过反相HPLC纯化,得到化合物26,为黄色粉末(48mg)。MS m/z 1447.5[M+H]+。
实施例8
利用如对化合物26所述的相同合成过程,从博莱霉素合成化合物26。MS m/z2320.8[M+H]+。
实施例9
化合物30的制备:向含化合物28(97mg,0.125mmol)的3mL DMF溶液中加入HATU(48mg,0.125mmol),DIEA(52mg,0.4mmol)和化合物29(100mg,0.125mmol)。1小时后,向混合物中加入哌啶(300μL),将混合物搅拌10分钟。然后蒸发该混合物并通过HPLC纯化,得到化合物30(83mg,50%)。MS m/z 1224.5(M+H)。
化合物32的制备:向含化合物30(26mg,0.074mmol)的1mL DCM溶液中加入DIC(46mg,0.037mmol)。10分钟后,加入含化合物31(41mg,0.031mmol)和DIEA(17μL)的DCM(2mL)溶液中,并将该混合物搅拌30分钟。在真空下蒸发溶剂,将残留物通过HPLC纯化,得到化合物32(30mg,63%)。MS m/z 1554.4(M+H)。
实施例10
化合物10的制备:
化合物35的制备:向含化合物33(64mg,0.077mmol)的3mLDMF溶液中加入34(97mg,0.077mmol),HOBt(5mg,0.04mmol)和DIEA(13mg,0.1mmol)。24小时后,用HPLC完成反应,并加入哌啶300μL。1小时后,将混合物通过HPLC纯化,得到化合物35(76mg,62%)。MS m/z1607.7(M+H)。
化合物37的制备:向含化合物36(31mg,0.09mmol)的1mL DCM溶液中加入DIC(60mg,0.045mmol)。10分钟后,加入含化合物35(77mg,0.045mmol)和DIEA(25μL)的2mL DCM溶液中,并将该混合物搅拌30分钟。在真空下蒸发溶剂,将残留物通过HPLC纯化,得到化合物37(60mg,69%)。MS m/z 1930.6(M+H)。
实施例11
化合物38和39的制备如WO 2013/173391所述,其公开内容通过引用方式并入本申请。
实施例12
使用如对化合物26所述的相同的过程,从化合物HTI-286合成化合物26。MS m/z1366.7[M+H]+。
实施例13
本实施例提供特定细胞中的体外测得的指定双药物偶联抗体的EC 50测定结果。
表5.1
表5.2
表5.3
表5.4
实施例14
本实施例提供了附图中提供的比较活性数据的说明。第一天,取特定的肿瘤细胞系,如SKBR-3,在96孔培养板(Corning)的100μL培养基中培养至20-30%汇合度。将细胞在CO2培养箱中37℃保温过夜。第二天,取双偶联ADC,如A-3-17,以19:60的比率连续稀释到培养基中,起始浓度为100nM。取5μL连续稀释偶联物加入到含有SKRB-3细胞的96孔板中。含双偶联物ADC(A-3-17)的SKBR-3细胞在37℃下保温72小时。随后根据厂商说明,使用细胞活性试剂盒(CelltitreGlo(Promega G-7573))在分析仪(SpectraMax L,来自Moleculardevice)上进行测定用双偶联物ADC(A-3-17)处理的肿瘤细胞具的活性。使用曲线拟合软件Graphpad Prism计算50%细胞生长抑制的IC50值。
图1展示了与单K-锁或C-锁的偶联物相比,抗Her-2(A)双偶联物(K-锁+C-锁)(K-lock+C-lock)在乳腺癌细胞系中诱导的抗增殖效果的提高。A,SKBR-3(HER2 3+),B,HCC1954(HER2 3+),C,MCF-7(HER2+/-)均以单一偶联物或双偶联物处理3天。对于显示出50%细胞生长抑制的浓度,测定IC50。
图2展示了与单K-锁或C-锁的偶联物相比,抗Her-2(A)双偶联物(K-锁+C-锁)(K-lock+C-lock)在乳腺癌细胞系中诱导的抗增殖效果的提高。A,SKBR-3(HER2 3+),B,HCC1954(HER2 3+),C,MCF-7(HER2+/-)均以单一偶联物或双偶联物处理3天。图中展示了上述浓度下的细胞活性百分比并与单偶联物相比较。
图3展示了与单K-锁和单C-锁偶联物的组合相比,抗Her-2(A)双偶联物(K-锁+C-锁)(K-lock+C-lock)在乳腺癌细胞系中诱导的抗增殖效果的提高。A,SKBR-3(HER2 3+),B,HCC1954(HER2 3+),C,MCF-7(HER2+/-)均以单一偶联物或双偶联物处理3天。对于显示出50%细胞生长抑制的浓度,测定IC50。
Claims (15)
1.包括式I结构的双药物偶联物
或其药学可接受的盐,
其中,
A为靶向部分;
每个D1独立选择,其中每个D1包括活性剂;
每个L1是独立的包含至少一个N(氮)原子的连接子;
每个D2独立选择,其中每个D2包括活性剂;
每个L2是独立的连接子;
E-部分是任选取代的杂芳基或任选取代的杂环基;
每个L3是任选取代的C1-C6烷基,或每个L3为空;当所述L3为空时,所述硫直接连接到所述E-部分;
每个L4是任选取代的C1-C6烷基,或每个L4为空;当所述L4为空时,所述硫直接连接到所述E-部分;
m为1,2,3,4,5,6,7,8,9或10;和
n为1,2,3,4,5,6,7,8,9或10。
2.根据权利要求1所述的双药物偶联物,其特征在于,所述E-部分包括选自以下的片段:
3.根据权利要求1所述的双药物偶联物,其特征在于,所述L3是-(CH2)-;且所述L4是-(CH2)-。
4.根据权利要求1所述的双药物偶联物,其特征在于,所述L3为空;且所述L4为空。
5.根据权利要求1所述的双药物偶联物,其特征在于,
是
6.根据权利要求1所述的双药物偶联物,其特征在于,L1包括
其中X1是N(氮)或CH;Y1是N(氮)或CH;且p是0,1或2。
7.根据权利要求6所述的双药物偶联物,其特征在于,L1包括
8.根据权利要求1所述的双药物偶联物,其特征在于,每个所述D1独立选自微管蛋白结合剂、DNA烷化剂、DNA嵌入剂、酶抑制剂、免疫调控剂、肽和核苷酸。
9.根据权利要求1所述的双药物偶联物,其特征在于,每个所述D2独立选自微管蛋白结合剂、DNA烷化剂、DNA嵌入剂、酶抑制剂、免疫调控剂、肽和核苷酸。
10.根据权利要求1所述的双药物偶联物,其特征在于,L1或L2包括-(CH2)n-,其中n是1,2,3,4,5,6,7,8,9或10。
11.根据权利要求1所述的双药物偶联物,其特征在于,L1或L2包括-(CH2CH2O)n,其中n是1,2,3,4,5,6,7,8,9或10。
12.根据权利要求1所述的双药物偶联物,其特征在于,所述A部分包括与L1的至少一个硫连接的至少一个修饰L-丙氨酸残基。
13.根据权利要求1所述的双药物偶联物,其特征在于,每个是
其中G是-NH-。
14.根据权利要求1所述的双药物偶联物,其特征在于,每个
是:
15.根据权利要求1所述的双药物偶联物,其特征在于,所述结构选自:
,
或其药学可接受的盐。
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CN113710277B (zh) * | 2021-07-19 | 2023-09-01 | 烟台迈百瑞国际生物医药股份有限公司 | 一种负载双毒素的抗体药物偶联物及其应用 |
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EP3057610A1 (en) | 2016-08-24 |
WO2015057876A8 (en) | 2016-11-10 |
RU2016134258A (ru) | 2018-02-28 |
SG11201604879QA (en) | 2016-07-28 |
US11987622B2 (en) | 2024-05-21 |
RU2016134258A3 (zh) | 2018-06-25 |
US20150105540A1 (en) | 2015-04-16 |
ZA201604375B (en) | 2019-04-24 |
EP3057610B1 (en) | 2021-09-22 |
AU2014337317A1 (en) | 2016-09-15 |
IL246218A0 (en) | 2016-11-30 |
US20210017274A1 (en) | 2021-01-21 |
US10836821B2 (en) | 2020-11-17 |
WO2015057876A1 (en) | 2015-04-23 |
EP3057610A4 (en) | 2017-07-05 |
CA2934030A1 (en) | 2015-04-23 |
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