Polymyxin derivatives, preparation method and application thereof
阅读说明：本技术 多粘菌素衍生物、其制备方法和应用 (Polymyxin derivatives, preparation method and application thereof ) 是由 李亚利 戈梅 饶敏 夏兴 黄亚妮 蔡晓龙 于 2019-03-12 设计创作，主要内容包括：本发明公开了通式(Ⅰ)所示的多粘菌素衍生物及其药学可接受的盐和溶剂合物：<Image he="425" wi="700" file="DDA0001992713500000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。本发明还提供了上述多粘菌素衍生物的药物组合物,制备方法和在制备预防或治疗细菌感染性疾病药物中的应用。本发明提供的多粘菌素衍生物具有良好的抗革兰氏阴性菌的抗菌活性,对于开发抗菌药物具有重要意义。(The invention discloses a polymyxin derivative shown as a general formula (I) and pharmaceutically acceptable salts and solvates thereof: . The invention also provides a pharmaceutical composition of the polymyxin derivative, a preparation method and application in preparing medicines for preventing or treating bacterial infectious diseases. The polymyxin derivative provided by the invention has good antibacterial activity against gram-negative bacteria, and has important significance for developing antibacterial drugs.)
1. Polymyxin derivatives of general formula (I) and pharmaceutically acceptable salts and solvates thereof:
wherein:
R1is CH (CH)3)2Or CH2C6H5；
n is 0 or 1;
when n is 0:
R2comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12A heteroaryl group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl radical-、-C(O)-、-NHC(O)-、-C(O)NH-、-OC(O)-、-C(O)O-、-S(O2)O-、-OS(O2)-；
R2、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halo substituted;
R6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group.
When n is 1:
R2is a compound of formula (I) in the formula (H),
R3is CH2SH、CH2CH2SCH3、CH2OH、CH(CH3)OH、CH2CONH2、CH2CH2CONH2、CH2C4H5N2、CH2C6H5OH、CH2C8H6N、CH2CH2CH2CH2NH2、CH2CH2NH2、CH2CH2CH2CH4N3，
R4Comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12A heteroaryl group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, -S (O)2)O-、-OS(O2)-；
R2、R3、R4、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halo substituted;
R6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group.
2. The polymyxin derivative of claim 1, wherein the pharmaceutically acceptable salt is a salt with an acid.
3. Polymyxin derivatives according to claim 2, wherein the acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulphonic acid, aspartic acid and glutamic acid.
4. Polymyxin derivatives according to claim 1, wherein the solvate is a hydrate, an ethanolate or an acetate.
5. A process for the preparation of a polymyxin derivative according to any of claims 1-4, comprising:
method (i), when n is 1, the general formula (, the synthetic route of the polymyxin derivative is:
；
wherein:
R1is CH (CH)3)2Or CH2C6H5，
R2Is a compound of formula (I) in the formula (H),
R3is CH2SH、CH2CH2SCH3、CH2OH、CH(CH3)OH、CH2CONH2、CH2CH2CONH2、CH2C4H5N2、CH2C6H5OH、CH2C8H6N、CH2CH2CH2CH2NH2、CH2CH2NH2、CH2CH2CH2CH4N3，
R4Comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12A heteroaryl group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, -S (O)2)O-、-OS(O2)-；
R2、R3、R4、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halo substituted;
R6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
method (ii), when n is 0, the synthesis route of the polymyxin derivative represented by the general formula (i) is:
；
alternatively, the first and second electrodes may be,
wherein:
R1is CH (CH)3)2Or CH2C6H5；
R2Comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12A heteroaryl group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, -S (O)2)O-、-OS(O2)-；
R2、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halogen substituted.
R6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group.
6. A pharmaceutical composition comprising a therapeutically effective amount of a polymyxin derivative of any of claims 1-4 or pharmaceutically acceptable salts and solvates thereof, and at least one pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable carrier is one or more of a diluent, an excipient, a binder, a filler, or a disintegrant.
8. Use of a polymyxin derivative according to any of claims 1-4 in the manufacture of a medicament for the prevention or treatment of bacterial infectious disease.
9. Use of a polymyxin derivative according to claim 8 in the preparation of a medicament for the prevention or treatment of infectious diseases caused by gram-negative bacteria.
10. Use of a polymyxin derivative according to claim 9 in the preparation of a medicament for the prevention or treatment of polymyxin resistant gram negative bacterial infectious disease.
11. The use of a polymyxin derivative according to claim 10 in the preparation of a medicament for the prevention or treatment of polymyxin-resistant acinetobacter baumannii infectious disease.
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a polymyxin derivative, and a preparation method and application thereof.
Background
In recent years, the number of cases of infection caused by gram-negative bacteria has increased, and many gram-negative bacteria have become resistant to a broad spectrum of antibiotics in clinical practice, and development of novel antibacterial agents against gram-negative resistant bacteria is urgent. Until now, polymyxin has a very good effect on the treatment of multidrug-resistant gram-negative bacterial infections, in particular on pseudomonas aeruginosa, acinetobacter baumannii and klebsiella pneumoniae, and thus, polymyxin is also called the last line of defense for the treatment of G-bacterial infections. Polymyxin is a group of cyclic peptide antibiotics consisting of A, B, C, D, E and the like produced by bacillus polymyxa, and finally only polymyxin B and polymyxin E (also called colistin) are clinically used due to good curative effect and relatively high safety. Polymyxin B is a sulfate preparation formed by more than 30 polypeptides, B1 and B2 are main parts of the polymyxin B, the polymyxin B is mainly administered in a parenteral form and is used for treating eye and ear diseases, most of the polymyxin B is a mesylate preparation, and the polymyxin B needs to be hydrolyzed into the polymyxin in vivo to play a role.
However, polymyxin has strong nephrotoxicity (incidence rate of 0-37%) and neurotoxicity (incidence rate of 0-7%) while sterilizing, and is dose-dependent, so that polymyxin drugs are limited to be clinically used in human in the 80 s of 20 th century and are only used as veterinary drugs. With the continuous emergence of drug resistance G-of gram-negative bacteria, people are prompted to develop polymyxin as a novel clinical drug for treating gram-negative bacteria again. Therefore, there is an urgent need to develop novel polymyxin antibiotics.
Disclosure of Invention
The inventor of the invention uses polymyxin as a starting compound and carries out chemical transformation on the polymyxin to obtain a series of improved polymyxin derivatives and pharmaceutically acceptable salts and solvates thereof. Tests prove that the polymyxin derivative has good bacteriostatic activity on gram-negative bacteria, and can be used for preparing medicaments for preventing or treating gram-negative bacteria infection.
The first object of the present invention is to provide polymyxin derivatives represented by the general formula (I) and pharmaceutically acceptable salts and solvates thereof:
wherein:
R1is CH (CH)3)2Or CH2C6H5；
n is 0 or 1;
when n is 0:
R2comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12A heteroaryl group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, -S (O)2)O-、 -OS(O2)-；
R2、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halo substituted; r6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenylradical-C5-12A heteroaryl group.
When n is 1:
R2is a compound of formula (I) in the formula (H),
R3is CH2SH、CH2CH2SCH3、CH2OH、CH(CH3)OH、CH2CONH2、CH2CH2CONH2、 CH2C4H5N2、CH2C6H5OH、CH2C8H6N、CH2CH2CH2CH2NH2、CH2CH2NH2、 CH2CH2CH2CH4N3，
R4Comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12Heteroaromatic compoundsA group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, -S (O)2)O-、 -OS(O2)-；
R2、R3、R4、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halo substituted;
R6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group.
According to a preferred technical scheme of the invention, the pharmaceutically acceptable salt is a salt formed by the polymyxin derivative shown in the general formula (I) and acid.
Preferably, the acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulphonic acid, aspartic acid or glutamic acid.
Preferably, in the solvate, the solvent does not interfere with the biological activity of the solute. By way of example, the solvent may be water, ethanol or acetic acid, and the solvation method is a method well known in the art. The solvate is hydrate, ethanol compound or acetic acid compound.
The second objective of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of the polymyxin derivative or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In the present invention, the pharmaceutically acceptable carrier refers to a pharmaceutical carrier that is conventional in the pharmaceutical field, such as diluents, excipients (e.g., water, etc.), binders (e.g., cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.), fillers (e.g., starch, etc.), and disintegrating agents (e.g., calcium carbonate, sodium bicarbonate). In addition, other adjuvants such as flavoring agents and sweeteners can also be added to the pharmaceutical composition.
The pharmaceutical composition of the present invention may be administered to a patient in need of treatment by intravenous injection, subcutaneous injection or oral administration. For oral administration, it can be prepared into conventional solid preparations such as tablet, powder or capsule; for injection, it can be prepared into injection. The various dosage forms of the pharmaceutical composition of the invention can be prepared by conventional methods in the medical field, wherein the content of the active ingredients is 0.1-99.5% (weight ratio). In the preparation, the weight content of the compound is 0.1-99.9%, and the preferable content is 0.5-90%.
The general dosage of the above pharmaceutical composition to be administered to a patient in need of treatment can be referred to the dosage of polymyxin used in the art.
A third object of the present invention is to provide a process for the preparation of a polymyxin derivative as described above, which comprises:
the synthesis route of the polymyxin derivative shown in the general formula (I) is as follows when n is 1:
(ii) a Wherein:
R1is CH (CH)3)2Or CH2C6H5，
R2Is a compound of formula (I) in the formula (H),
R3is CH2SH、CH2CH2SCH3、CH2OH、CH(CH3)OH、CH2CONH2、CH2CH2CONH2、 CH2C4H5N2、CH2C6H5OH、CH2C8H6N、CH2CH2CH2CH2NH2、CH2CH2NH2、 CH2CH2CH2CH4N3，
R4Comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12A heteroaryl group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, -S (O)2)O-、 -OS(O2)-；
R2、R3、R4、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halo substituted;
R6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group.
Method (ii), when n is 0, the synthesis route of the polymyxin derivative represented by the general formula (i) is:
(ii) a Alternatively, the first and second electrodes may be,
wherein:
R1is CH (CH)3)2Or CH2C6H5；
R2Comprises the following steps:
-Y-C7-14alkyl, -Y-C3-10Cycloalkyl, -Y-C2-10Heterocyclyl, -Y-C6-12Aryl, -Y-C5-12A heteroaryl group;
-Y-C1-7alkyl radical C3-10Cycloalkyl, -Y-C1-7Alkyl radical C2-10Heterocyclyl, -Y-C1-7Alkyl radical C6-12Aryl, -Y-C1-7Alkyl radical C5-12A heteroaryl group;
-Y-C3-10cycloalkyl radical C1-7Alkyl, -Y-C2-10Heterocyclyl radical C1-7Alkyl, -Y-C6-12Aryl radical C1-7Alkyl, -Y-C5-12Heteroaryl C1-7An alkyl group;
-Y-C1-7alkyl-O-C1-10Alkyl, -Y-C1-7alkyl-O-C3-10Cycloalkyl, -Y-C1-7alkyl-O-C2-10Heterocyclyl, -Y-C1-7alkyl-O-C6-12Aryl, -Y-C1-7alkyl-O-C5-12A heteroaryl group;
-Y-C1-7alkyl-NH-C1-10Alkyl, -Y-C1-7alkyl-NH-C3-10Cycloalkyl, -Y-C1-7alkyl-NH-C2-10Heterocyclyl, -Y-C1-7alkyl-NH-C6-12Aryl, -Y-C1-7alkyl-NH-C5-12A heteroaryl group;
y is a bond, -C (O) -;
x-is a bond, -C (O) -, -NHC (O) -, -OC (O) -, -CH2-or-SO2-；
R5Comprises the following steps:
-C3-10cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
-C1-10alkyl-Z-C1-10Alkyl, -C1-7alkyl-Z-C3-10Cycloalkyl, -C1-7alkyl-Z-C2-10Heterocyclyl radical, -C1-7alkyl-Z-C6-12Aryl radical, -C1-7alkyl-Z-C12-14Biphenyl, -C1-7alkyl-Z-C5-12A heteroaryl group;
-C3-10cycloalkyl-Z-C1-7Alkyl, -C2-10heterocyclyl-Z-C1-7Alkyl, -C6-12aryl-Z-C1-7Alkyl, -C12-14biphenyl-Z-C1-7Alkyl, -C5-12heteroaryl-Z-C1-7An alkyl group;
-C6-12-aryl-Z-C1-10Alkyl, -C6-12-aryl-Z-C3-10Cycloalkyl, -C6-12-aryl-Z-C2-10Heterocyclyl radical, -C6-12-aryl-Z-C6-12Aryl radical, -C6-12-aryl-Z-C12-14Biphenyl, -C6-12-aryl-Z-C5-12A heteroaryl group;
z is a covalent bond, -C1-3Alkyl-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, -S (O)2)O-、 -OS(O2)-；
R2、R5Each of which is optionally substituted by one or more-N (R)6)-L-R7Substituted, 0-3-OR8Substituted or halo substituted;
R6represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
and R is7represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group;
R8represents-H, -C1-10Alkyl, -C3-10Cycloalkyl, -C2-10Heterocyclyl radical, -C6-12Aryl radical, -C12-14Biphenyl, -C5-12A heteroaryl group.
In the above method, the preparation method of the compound II is described in detail in the preparation methods of the intermediate 1 and the intermediate 3.
The fourth purpose of the invention is to provide the application of the polymyxin derivative in preparing the medicines for treating bacterial infectious diseases.
According to a preferred embodiment of the present invention, there is provided the use of a polymyxin derivative as described above for the manufacture of a medicament for the treatment of infectious diseases caused by gram-negative bacteria.
Preferably, the polymyxin derivative is applied to preparation of a medicine for preventing or treating polymyxin-resistant gram-negative bacteria infectious diseases. I.e. the gram-negative bacterium is a polymyxin resistant gram-negative bacterium, such as: acinetobacter baumannii resistant to polymyxin.
A fifth object of the present invention is to provide a method for preventing or treating gram-negative bacterial infection, comprising administering a therapeutically effective amount of the above-mentioned polymyxin derivatives and pharmaceutically acceptable salts and solvates thereof to a subject in need thereof.
Compared with the prior art, the polymyxin derivative has the beneficial effects that:
the polymyxin derivative shown as the general formula (I) and pharmaceutically acceptable salts and solvates thereof have good antibacterial activity, especially gram-negative bacteria resistance activity, have equivalent or improved antibacterial activity to gram-negative bacteria compared with the existing polymyxin E or B, and can be applied to the preparation of medicines for treating bacterial infection and gram-negative bacteria infection; compared with polymyxin E, the polymyxin E has equivalent or improved antibacterial activity on drug-resistant gram-negative bacteria, and can be applied to preparation of drugs for preventing and treating drug-resistant bacterial infection and drug-resistant gram-negative bacterial infection. Therefore, the method has important significance for the development of new antibacterial drugs.
Detailed Description
The present invention will be further described with reference to the following specific examples. It should be understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.
In the present invention, the following abbreviations have the following meanings. Undefined abbreviations have their commonly accepted meaning, unless otherwise stated, all room temperatures refer to temperatures of 20 ℃ to 30 ℃.
PMB polymyxin B
PMBN polymyxin B nonapeptide
Boc-ON 2- (tert-butyloxycarbonyloxyiimino) -2-phenylacetonitrile
PME polymyxin E
DCM dichloromethane
EDCI 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride
HOBt 1-hydroxybenzotriazole
LiOH-H2OLithium hydroxide monohydrate
TFA trifluoroacetic acid
HATU 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
DIPEA N, N-diisopropylethylamine
MTBE methyl tert-butyl ether
PYBOP 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate
Minimum Inhibitory Concentration (MIC)
In the following examples, the concentrations of the elution solution and the prewash solution are in percent by volume, and the yields are molar yields.
In the following examples, HPLC monitoring conditions:
mobile phase: a.0.05% formic acid water B.0.05% formic acid acetonitrile
A chromatographic column: agilent Poroshell 120EC-C18(4.6 mm. times.150 mm, 2.7 μm)
Column temperature: 45 deg.C
Detection wavelength: 210, 240, 254, 280, 360nm
Analysis time: 50min
Flow rate: 0.7mL/min
HPLC gradient conditions are shown in table 1:
TABLE 1 HPLC gradient conditions
Time (min)
A％
B％
Flow rate (ml/min)
0
95
5
0.7
10
85
15
0.7
15
75
25
0.7
25
45
55
0.7
30
5
95
0.7
50
5
95
0.7
PSN column chromatography conditions were:
PSN column chromatography conditions of (I), polymyxin B nonapeptide (intermediate 1) and polymyxin E nonapeptide (intermediate 3):
(1) column volume: 1L of the compound. The sample loading liquid is an aqueous solution of a sample to be separated, and the sample loading volume (ml) is VSample loading＝20*mSample loading/g
(2) And washing 4 times of column volume after sample loading, and collecting the column volume by parts, wherein each bottle is 0.5 time of column volume.
(3) After the completion of the water washing, the column was washed with 10% acetonitrile acid (TFA 0.05%) for 3 column volumes and collected.
(4) And after the acid washing with 10% acetonitrile, washing with 20% acetonitrile for 3 times of column volume. And (6) merging and collecting. The column was then washed with 50% glycolic acid and finally equilibrated to neutral with water.
PSN column chromatography conditions for (di), tetra- (Boc) polymyxin B nonapeptide (intermediate 2) and tetra- (Boc) polymyxin E nonapeptide (intermediate 4):
the column volume is 1L. The sample loading liquid is the aqueous solution of the sample to be separated, and the sample loading volume VSample loading＝20*mSample loading/g. After the sample is loaded, 50% methanol water is firstly used for washing 4 times of column volume, the column volume is combined and collected, then 70% methanol water is used for fractional collection, one bottle is collected every 0.5 time of column volume, the column volume is washed for 4 times, then 75% methanol water is used for elution, fractional collection is carried out, the column volume is washed for 4 times of column volume, finally 85% methanol water is used for washing for twice of column volume, and the column volume is combined and collected.
The invention provides a polymyxin derivative shown as a general formula (I) and pharmaceutically acceptable salts and solvates thereof:
the structures of specific compounds of the general formula (I) referred to in the following examples are shown in Table 2.
TABLE 2 Structure of the respective Compounds
The compounds in table 2 are prepared below by way of a number of specific examples, as examples.
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