CN115784972A - Ethylene diamine derivative and preparation method and application thereof - Google Patents
Ethylene diamine derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an ethylenediamine derivative and a preparation method and application thereof. The structural formula of the ethylenediamine derivative is shown as a formula I. The compound can be prepared by artificial synthesis, has broad-spectrum anti-tumor effect, can prolong life cycle of tumor patients, and improve life quality of tumor patients. The compound has stable drug effect, low toxicity and easy acceptance by human bodies, can be applied to the treatment of most cancers, and has certain advantages compared with the current anti-tumor drugs on the market.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an ethylenediamine derivative, and a preparation method and application thereof.
Background
Bradykinin (BK) has been found to be an important growth factor in many cancers, and it can promote neovascularization by stimulating secretion of vascular endothelial growth factor and can also stimulate cancer cell migration and invasion by activating Matrix Metalloproteinase (MMP) active enzymes.
The action of BK on the body is effected by binding to the B1 receptor (B1R) and the B2 receptor (B2R) on the cell membrane. Both B1R and B2R are G protein-coupled receptors. The research on cancer finds that: B1R is not only abnormally up-regulated in malignant prostate tumor, but also can stimulate the activation of macrophage and dendritic cell in tumor microenvironment; B2R is not only overexpressed in human brain gliomas, but is also detected in stomach, duodenum, prostate, lung, and liver cancers.
The end result of BK binding to either the B1 or B2 receptor is the stimulation of phospholipase C-beta (PLC-. Beta.) via the Gq subunit in the G protein-coupled receptor family, leading to inositol triphosphate (IP 3) hydrolysis and intracellular Ca 2+ And inhibit Adenylate Cyclase (AC) activation of mitogen-activated protein kinase pathway (MAPK) by G protein subunit G α -i to promote cancer cell proliferation migration and invasion. Among them, the MAPK pathway is involved in P38, proto-oncogene N-terminal kinase (JNK) and ERK.
Based on the target, a series of inhibitors have been developed, such as compounds PL-AC-15, PL-AC-202, and the like. Wherein PL-AC-15 is an amino acid derivative developed by Jiangsu pley pharmaceutical biotechnology company (see Chinese patent CN 107382827B), and has good antitumor effect. PL-AC-202 is a compound obtained by further structural optimization and modification of PL-AC-15 by Jiangsu pley pharmaceutical biotechnology limited (see Chinese patent application No. 202010386293.7), and a compound with better anti-tumor effect is obtained by further structural modification.
Disclosure of Invention
An object of the present invention is to provide a class of ethylenediamine derivatives and pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof).
The structural formula of the ethylenediamine derivative provided by the invention is shown as the following formula I:
wherein R is 1 Selected from any one of the following: c 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl.
R 1 The hydrogen above may be optionally substituted with one or more of the following substituents: halogen, C 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl, -CN, -NO 2 、-CF 2 H、-CF 2 OH、-CF 3 、-OCF 3 、-CR 1 R 2 R 3 、-OR 1 、-O(C＝O)R 1 、-O(C＝O)OR 1 、-O(C＝O)NR 2 R 3 、-(C＝O)R 1 、-(C＝O)OR 1 、-(C＝O)NR 2 R 3 、-SR 1 、-(S＝O) m R 1 、-NR 2 R 3 、-NR 4 (C＝O)R 1 、-NR 4 C(＝O)NR 2 R 3 、-NR 4 C(＝O)OR 1 、-NR 4 S(＝O) m NR 2 R 3 、-NR 4 S(＝O) m OR 1 or-NR 4 S(＝O) m R 1 Or R is 1 Groups of upper adjacent atoms may combine to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclics, and 5-12 membered heteroaryl ring groups;
wherein R is 1 、R 2 、R 3 、R 4 Can be independently selected from hydrogen, halogen or any of the following groups: c 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl, or R bound to the same nitrogen atom 1 、R 2 、R 3 、R 4 Any two of which may be combined together with the nitrogen to which they are bound to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl group, optionally containing 1 to 3 additional heteroatoms selected from N, 0 and S, or R bound to the same carbon atom 1 、R 2 、R 3 Any two of which may be combined to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and R 1 、R 2 、R 3 、R 4 Each hydrogen in (1) is optionally substituted by R 5 Substituted, or R 1 、R 2 、R 3 、R 4 Wherein two hydrogen atoms on the same carbon atom are optionally oxo substituents.
R 5 Can be independently selected from the following groups: hydrogen, halogen, C 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl; -CN, -NO 2 、-OH、-NH 2 Partially or fully halogenated C 1-5 Alkyl, -C (= O) (CH) 2 ) n CH 3 、-C(＝O)O(CH 2 ) n CH 3 、-C(＝O)OH、-C(＝O)N[(CH 2 ) n CH 3 ] 2 、-C(＝O)NH 2 、-C(＝O)NH(CH 2 ) n CH 3 、-NH(CH 2 ) n CH 3 、-N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)NH(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)NH 2 、-N(CH 2 ) n CH 3 C(＝O)O(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)OH、-NHC(＝O)(CH 2 ) n CH 3 、-NHC(＝O)NH(CH 2 ) n CH 3 、-NHC(＝O)N[(CH 2 ) n CH 3 ] 2 、-NHC(＝O)NH 2 、-NHC(＝O)O(CH 2 ) n CH 3 ,-NHC(＝O)OH,-N(CH 2 ) n CH 3 S(＝O) m (CH 2 ) n CH 3 、-NHS(＝O) m (CH 2 ) n CH 3 、-O(CH 2 ) n CH 3 、＝O、-OC(＝O)(CH 2 ) n CH 3 、OC(＝O)O(CH 2 ) n CH 3 、-OC(＝O)N[(CH 2 ) n CH 3 ] 2 、-OC(＝O)NH(CH 2 ) n CH 3 、-OC(＝O)NH 2 、-S(＝O) m (CH2) n CH 3 、-OS(＝O) m (CH 2 ) n CH 3 、-S(＝O) m NH(CH 2 ) n CH 3 、-S(＝O) m N[(CH 2 ) n CH 3 ] 2 ；
M is selected from 1 or 2;
the n is 1,2,3,4 or 5.
R 2 Selected from any one of the following groups: h, halogen, C 1-10 Alkyl, oxy C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl, oxy C 5-14 Aryl, nitro radicals C 6-14 Aryl, nitrogen radical C 5-14 Heteroaryl, 5-14 membered heteroaryl.
R 2 The hydrogen above may be optionally substituted with one or more of the following substituents: halogen, -CN, -NO 2 、-CF 2 H、-CF 2 OH、-CF 3 、-OCF 3 、-CR 6 R 7 R 8 、-OR 6 、-O(C＝O)R 6 、-O(C＝O)OR 6 、-O(C＝O)NR 7 R 8 、-(C＝O)R 6 、-(C＝O)OR 6 、-(C＝O)NR 7 R 8 、-SR 6 、-(S＝O)R 6 、-S(＝O) 2 R 6 、-NR 7 R 8 、-NR 9 (C＝O)R 6 、-NR 9 C(＝O)NR 7 R 8 、-NR 9 C(＝O)OR 6 、-NR 9 S(＝O) m NR 7 R 8 、-NR 9 S(＝O) m OR 6 or-NR 9 S(＝O) m R 6 Or R is 2 Groups of upper adjacent atoms may combine to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclic group and 5-12 membered heteroaromatic ring;
wherein R is 6 、R 7 、R 8 、R 9 May be hydrogen or optionally selected from C 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 An heteroaryl group, a 5-14 membered heteroaryl group, or any two of R1, R2, R3, R4 bound to the same nitrogen atom may be combined together with the nitrogen to which they are bound to form a 3-12 membered heterocyclic group or a 5-12 membered heteroaryl group, optionally containing 1 to 3 additional heteroatoms selected from N, 0 and S; or R bound to the same carbon atom 6 、R 7 、R 8 R 9 Any two of which may be combined to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and R 6 、R 7 、R 8 Each hydrogen in (1) is optionally substituted by R 10 Substituted, or R 6 、R 7 、R 8 、R 9 Wherein two hydrogen atoms on the same carbon atom are optionally oxo substituents.
R 10 Can be independently selected from: hydrogen, halogen, C 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl, -CN, -NO 2 、-OH、-NH 2 Partially or fully halogenated C 1-5 Alkyl, -C (= O) (CH) 2 ) n CH 3 、-C(＝O)O(CH 2 ) n CH 3 、-C(＝O)OH、-C(＝O)N[(CH 2 ) n CH 3 ] 2 、-C(＝O)NH 2 、-C(＝O)NH(CH 2 ) n CH 3 、-NH(CH 2 ) n CH 3 、-N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)NH(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)NH 2 、-N(CH 2 ) n CH 3 C(＝O)O(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)OH、-NHC(＝O)(CH 2 ) n CH 3 、-NHC(＝O)NH(CH 2 ) n CH 3 、-NHC(＝O)N[(CH 2 ) n CH 3 ] 2 、-NHC(＝O)NH 2 、-NHC(＝O)O(CH 2 ) n CH 3 ,-NHC(＝O)OH,-N(CH 2 ) n CH 3 S(＝O) m (CH 2 ) n CH 3 、-NHS(＝O) m (CH 2 ) n CH 3 、-O(CH 2 ) n CH 3 、＝O、-OC(＝O)(CH 2 ) n CH 3 、OC(＝O)O(CH 2 ) n CH 3 、-OC(＝O)N[(CH 2 ) n CH 3 ] 2 、-OC(＝O)NH(CH 2 ) n CH 3 、-OC(＝O)NH 2 、-S(＝O)m(CH 2 ) n CH 3 、-OS(＝O)m(CH 2 ) n CH 3 、-S(＝O) m NH(CH 2 ) n CH 3 、-S(＝O) m N[(CH 2 ) n CH 3 ] 2 ；
M is selected from 1 or 2;
the n is 1,2,3,4 or 5.
W represents a bond or a group selected from any of the following: c 1-8 Alkylene (e.g. -CH) 2 CH 2 -)，C 2-8 Alkenylene (e.g. -CH) 2 ＝CH-CH 2 -),C 2-8 Alkynylene (e.g. -C.ident.C-CH) 2 -)，C 3-8 Cycloalkylene, 3-8 membered heterocyclylene, oxy C 1-8 Alkylene, -O-, -NH-, amino C 1-8 Alkylene, or any of the above groups wherein one or more hydrogens are replaced with halogen, and hydrogen is optionally replaced with R 11 Substituted radicals as described above, wherein R 11 Is as defined for R 1 。
Said C is 3-8 Cycloalkylene groups, including but not limited to the following groups:
the 3-8 membered heterocyclylene group includes, but is not limited to, the following groups:
said oxy group C 1-8 Alkylene groups, such as: -OCH 2 -,-CH 2 O-,
Said amino group C 1-8 Alkylene groups, such as: -NHCH 2 -，-CH 2 NH-，-NCH 3 CH 2 -,-CH 2 CH 3 N-,
X represents a chemical bond or any group selected from: c 1-8 Alkylene (e.g. -CH) 2 -，-CH 2 CH 2 -，-CHCH 3 CH 2 -, -O-, oxy C 1-8 Alkylene (e.g.: OCH) 2 -,-CH 2 O-), -NH-, amino C 1-8 Alkylene (e.g.: NHCH) 2 -，-CH 2 NH-，-NCH 3 CH 2 -, mercapto group C 1-8 Alkylene (e.g.: SCH) 2 -,-CH 2 S-), oxidizing mercapto group C 1-8 Alkylene (such as-S (= O) CH 2 -,-CH 2 S(＝O) 2 -)，-S(＝O)NH-,-S(＝O) 2 NH-, or the above groups wherein one or more of any of the hydrogens on X is replaced with a halogen, and any of the hydrogens on X is replaced with R 12 Substituted as described above. Wherein R is 12 Is as defined for R 1 。
Preferred R 1 Selected from any one of the following: c 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-7 Cycloalkyl (e.g., cyclohexyl), phenyl, phenoxy, fluorenyl, pyridyl, substituted pyridyl, and R 1 Hydrogen on being optionally substituted by R 13 A substituted radical in which R 13 Definition of (A) and R 10 The same;
preferred R 2 Selected from any one of the following groups: h, halogen, phenyl, biphenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, and R 2 Hydrogen of any above is substituted by R 14 A substituted radical in which R 14 Definition of (A) and R 10 The same is that:
preferably W represents a bond or a group selected from any of: c 1-4 Alkylene radical, C 2-6 Alkenylene, -OCH 2 -，-CH 2 O-；
Preferably X represents a bond or a group selected from any of: -CH 2 -，-CH 2 CH 2 -, oxy C 1-4 An alkylene group, which is a cyclic alkylene group,
further, R in formula I 1 Associating W groups includes, but is not limited to, the following fragments:
x in combination with R in the formula I 2 Including but not limited to the following fragments:
in some embodiments, the ethylenediamine derivative of the present invention can be represented by the following structures, but is not limited to the following structures (all the structures of the compounds are shown in table 1):
TABLE 1 list of ethylenediamine derivatives of the invention
The term "alkyl" as used herein refers to a group consisting of only carbon and hydrogen atoms, and having no unsaturation (e.g., double bonds, triple bonds, or rings), which encompasses a wide variety of possible geometric and stereoisomeric groups. This group is connected to the rest of the molecule by a single bond. By way of non-limiting examples of alkyl groups, mention may be made of the following linear or branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven further isomers thereof, n-hexyl and sixteen further isomers thereof, n-heptyl and various isomers thereof, n-octyl and various isomers thereof, n-nonyl and various isomers thereof, and n-decyl and various isomers thereof.
The term "cycloalkyl" as used herein refers to a saturated non-aromatic ring system consisting of at least 3 carbon atoms, which may be monocyclic, bicyclic, polycyclic, fused, bridged, or spiro. As non-limiting examples of cycloalkyl groups, the following groups may be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; and fused, bridged or spiro ring groups formed from two or more of the above-mentioned monocyclic rings via a common side and a common carbon atom.
The term "aryl" as used herein, alone or as part of an "arylalkyl" refers to a monocyclic, bicyclic, and tricyclic carbocyclic ring system containing a total of 6 to 14 membered rings, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 membered rings and only one attachment point is attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g. aromatic rings may include phenyl, naphthyl, anthracenyl.
The term "heteroaryl" as used herein refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which may be monocyclic, bicyclic, polycyclic wherein bicyclic and polycyclic may be formed from a single ring by single bond linkages or fused. As non-limiting examples of heteroaryl groups, the following groups may be cited: oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, coumarinyl, pyrazolopyridinyl, pyridopyridazinyl, pyrrolopyridyl, imidazopyridinyl, pyrazolopyridazinyl; and a group formed by the above-mentioned heteroaryl group by a single bond connection or a fusion connection.
The compounds of the present invention may also be used in the form of their pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof).
The invention also aims to provide a preparation method of the ethylenediamine derivative shown in the formula I.
The synthetic route of the ethylenediamine derivative compound shown in the formula I provided by the invention is shown as follows:
the preparation method comprises the following steps: r is to be 1 W-COOH by oxalyl chloride [ (COCl) 2 )]Activating, and reacting with intermediate 1 or intermediate 2 at room temperature to obtain the final product of formula I.
R in the intermediate 1 is-X-R 2 Wherein X is as defined for formula I (excluding X as-OCH) 2 -case (c) of R in said intermediate 1 2 Is as defined in formula I.
In the intermediate 2, Y represents that hydrogen in the benzene ring connected with Y is substituted by one or more R 15 A group obtained by substitution, wherein R 15 Is as defined for R in formula I 1 。
Specifically, the synthetic route of the intermediate 1 is as follows:
the specific preparation method of the intermediate 1 comprises the following steps: naBH under catalysis of Lewis acid 4 Reducing carboxylic acid 1 to obtain compound 2; oxidizing compound 2 under NaBr, naClO and TEMPO conditions to obtain compound 3; then 4-amino-2,2,6,6-tetramethylpiperidine in NaBH (OAc) 3 Reducing the amino group under the conditions of (1) to obtain a compound 4; deprotection of compound 4 via TFA in DCM affords intermediate 1.
The synthetic route of the intermediate 2 is shown as follows:
the preparation method of the intermediate 2 comprises the following steps: phenol 5 and bromide in K 2 CO 3 Carrying out a substitution reaction under the conditions of (1) to obtain a compound 6; in MeOH/THF/H 2 In the O solution, hydrolyzing the compound 6 by NaOH to obtain a compound 7; in NaBH 4 Under the conditions of (1), the compound 7 is reduced to obtain a compound 8; oxidizing the compound 8 by NaBr, TEMPO and NaClO to obtain a compound 9; carrying out reductive amination reaction on the compound 9 and 4-amino-2,2,6,6-tetramethylpiperidine to obtain a compound 10; deprotection of compound 10 via TFA affords intermediate 2.
Still another object of the present invention is to provide the use of the ethylenediamine derivative represented by formula I or a pharmaceutically acceptable salt, ester, solvate or isomer (including a stereoisomer, an enantiomer, a tautomer or a mixture thereof) thereof.
The application provided by the invention comprises the following aspects: 1) The application of the ethylenediamine derivative shown in the formula I or pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof) thereof in preparing a medicament for preventing and/or treating cancer; 2) The application of the ethylenediamine derivative shown in the formula I or pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof) thereof in preparing a medicament for inhibiting cancer cell proliferation.
Such cancers include various cancers known in the art (solid or non-solid), including but not limited to: liver cancer, lung cancer, and prostate cancer.
The cancer cells include liver cancer cells (such as Bel-7402 cells, hepG-2 cells, SK-hep1 cells), lung cancer cells (such as A549 cells, H460 cells, H1299 cells, H292 cells), and prostate cancer cells (such as PC-3 cells).
The invention also discloses a medicament for preventing and/or treating cancer, which is prepared by using the ethylenediamine derivative shown in the formula I or pharmaceutically acceptable salts, esters, solvates or isomers (including stereoisomers, enantiomers, tautomers or mixtures thereof) thereof as an active ingredient.
The tripeptide compound shown in the formula I is a brand new compound obtained by de novo design. The compounds of the invention are bradykinin receptor antagonists, which inhibit the growth and invasion of tumor cells by inhibiting the binding of bradykinin and its receptor, and further inhibit the occurrence of tumors. The compounds with similar structures may have the same action mechanism, and understanding of the action mechanisms of different compounds is helpful for fully understanding the clinical application prospect and possible problems of the compounds and the analogues thereof in the invention, so that the research and development are more targeted.
Detailed Description
The present invention is described below with reference to specific embodiments, but the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The structural formulae of the PL-AC-15 compounds referred to in the examples below are as follows:
the details of the preparation are shown in Chinese patent CN107382827B.
The structural formula of the PL-AC-202 compounds referred to in the examples below is shown below:
the details of the preparation are shown in Chinese patent CN113620862A.
1. Preparation and characterization of the Compounds
Example 1: (S, E) -N- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -4-phenyl-3-enamide (Cpd 001)
Intermediate 16 (corresponding to Y =2,6-dichloro in intermediate 2) was prepared as follows:
1) Compound 5 (47.8g, 170mmol) was dissolved in acetonitrile, and potassium carbonate (48.4g, 350mmol) was added thereto, followed by stirring for 10 minutes, further addition of 2,6-dichlorobenzyl bromide (33.6 g, 140mmol) and reaction at 80 ℃ for 15 hours. After completion of the reaction of compound 5 (EA/PE =1/5,v/v) as shown by TLC, the system was spin-dried, 300mL of water-containing white insoluble material was added, and a white solid was obtained by suction filtration to give compound 11 (45 g).
2) Compound 11 (35.0 g, 79mmol) was dissolved in tetrahydrofuran and methanol (350 mL:350mL, v/v), an aqueous solution of sodium hydroxide was slowly added thereto, and the reaction was carried out at room temperature for 15 hours. After the completion of the reaction of compound 11 was shown by TLC (EA/PE =1/5,v/v), the system was spin dried, an appropriate amount of water was added, the system pH was adjusted to 3-4 with dilute hydrochloric acid, and a white solid was obtained by suction filtration as compound 12 (23 g, yield 68.4%).
3) Compound 12 (21.3g, 50mmol) is dissolved in methanol, cooled to 0-5 ℃ and NiCl is added with stirring 2 .6H 2 O (11.9g, 50mmol) and then NaBH is added in portions 4 (7.6g, 200mmol), after incubation for 1 hour or more after addition, complete reaction of compound 12 was shown by TLC (EA/PE =1/3,v/v). Directly filtering the system to obtain a gray black filtrate, adding a saturated sodium bicarbonate solution into the filtrate, and adjusting the pH value of the system to 7-8. Extraction with ethyl acetate was performed, and the organic phase was dried to give a pale yellow oil, which was purified by column chromatography (EA/PE =1/5,v/v) to give compound 13 (9.4 g, 45.6% yield)
4) Compound 13 (8.5g, 20mmol) was dissolved in isopropyl acetate, and sodium bromide (206mg, 22mmol) and TEMPO (31.3mg, 0.2mmol) were added, and the mixture was cooled to-5 to 5 ℃ and an aqueous solution of sodium hypochlorite (2.2g, 30mmol) adjusted to pH 9 to 10 with sodium hydrogencarbonate was added dropwise. After about 1 hour after the end of the dropping, the reaction was shown to be complete by TLC (EA/PE =1/3,v/v). The reaction was brought to room temperature and quenched by the addition of 10% sodium sulfite solution and extracted with ethyl acetate to give 14 as a pale yellow oil after drying the organic phase (6.2 g, 75.2% yield).
5) Dissolving compound 14 (14.0g, 34mmol) in dichloromethane, adding 4-amino-2,2,6,6-tetramethylpiperidine (5.3g, 34mmol), cooling to about 0 deg.C, adding NaBH (OAc) in portions 3 (14.4 g, 68mmol), after the addition was completed, the reaction was slowly returned to room temperature for 15 hours. After completion of the reaction as shown by TLC (EA/PE =1/3,v/v), saturated sodium bicarbonate solution was added, the pH of the system was adjusted to 7-8, and extracted with dichloromethane, and the organic phase was dried to give 15 as a pale yellow oil (15.8 g, yield 84.3%).
6) Compound 15 (15.0 g, 27mmol) was dissolved in 500mL of dichloromethane, cooled to 0-5 deg.C, 100mL of TFA was added dropwise, stirred at room temperature for 30 minutes after completion of addition, and allowed to react at room temperature for 3 hours. After the reaction was complete as shown by TLC (methanol/dichloromethane =1/10, v/v), the system was directly spin dried, saturated sodium bicarbonate solution was added, the pH of the system was adjusted to 7-8, and extracted with ethyl acetate, and after drying the spin-dried organic phase, purification was performed by column chromatography (methanol/dichloromethane =1/20, v/v) to give intermediate 16 (4.3 g, yield 36.4%) as a pale red-brown clear oil.
1) Compound 17 (0.73g, 4.5 mmol) was dissolved in 10mL of dichloromethane, 3 drops of DMF were added dropwise, cooled to 0-5 deg.C, oxalyl chloride (1.14g, 9mmol) was added dropwise, after completion of the addition, stirring was carried out for 20 minutes under constant temperature, and after 5 hours of reaction at room temperature, the system was dried by spinning to obtain intermediate 18.
2) Dissolving the intermediate 18 (0.81g, 4.5 mmol) in 10mL of dichloromethane, adding triethylamine, cooling to 0-5 ℃, slowly dripping 10mL of dichloromethane solution of the product (intermediate 16,2.03g,4.5 mmol), keeping the temperature for 30 minutes after dripping, and returning to room temperature for reaction for 10 hours. The reaction was shown to be complete by TLC (methanol/dichloromethane =1/10,v/v). The reaction was washed with water, the organic phase was dried and spin dried and purified by column chromatography (methanol/dichloromethane =1/15, v/v) to give the product Cpd001 (S, E) -N- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -4-phenyl-3-enamide (530 mg, yield 19.4%).
Structure confirmation data: 1 H NMR(400MHz,DMSO-d 6 )δ8.12(s,2H),7.74(d,J＝8.2Hz,1H),7.59–7.53(m,2H),7.47(dd,J＝8.9,7.1Hz,1H),7.39(d,J＝7.2Hz,2H),7.36–7.28(m,2H),7.26–7.16(m,1H),7.19–7.12(m,2H),6.96–6.88(m,2H),6.44(d,J＝15.9Hz,1H),6.28(dt,J＝15.8,7.0Hz,1H),5.20–5.08(m,2H),3.95(s,1H),3.30(s,1H),3.11(s,1H),3.00(d,J＝7.1Hz,2H),2.94(s,1H),2.78(dd,J＝13.8,5.3Hz,1H),2.61(t,J＝7.0Hz,3H),1.85(t,J＝16.1Hz,2H),1.34–1.21(m,13H),1.13(d,J＝12.2Hz,2H).MS m/z:608.2(M+H).
other compounds of formula I were prepared following the procedure for the preparation of example 1 (Cpd 001) (rac) above using the corresponding intermediates and carboxylic acid.
Example 2: (S) -N- ((S) -1- ([ 1,1 '-biphenyl ] -4-yl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -2- (2-fluoro- [1,1' -biphenyl ] -4-yl) propanamide (Cpd 002)
1 H NMR(400MHz,CDCl 3 )δ7.58–7.29(m,13H),7.20(d,J＝7.9Hz,2H),7.16–7.08(m,2H),6.26(s,1H),4.24(d,J＝7.0Hz,1H),3.61(q,J＝7.1Hz,1H),3.48(s,2H),2.92(dd,J＝13.7,6.7Hz,1H),2.81(dd,J＝13.8,7.1Hz,1H),2.69(s,1H),1.78(d,J＝13.1Hz,1H),1.65(d,J＝13.1Hz,1H),1.52–1.44(m,7H),1.40(d,J＝8.3Hz,6H),1.33(s,3H),1.25(t,J＝3.5Hz,1H),0.86(s,1H),0.07(s,1H).MS m/z:592.4(M+H).
Example 3: (S) -2- (2-fluoro- [1,1' -biphenyl ] -4-yl) -N- ((S) -1-phenyl-3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) propanamide (Cpd 003)
1 H NMR(400MHz,DMSO-d 6 )δ7.83(d,J＝8.4Hz,1H),7.57–7.45(m,4H),7.47–7.34(m,2H),7.15–7.04(m,5H),7.02(dd,J＝7.3,2.2Hz,2H),3.93(d,J＝6.3Hz,1H),3.62(q,J＝7.0Hz,1H),2.86–2.74(m,2H),2.57(dd,J＝13.4,7.6Hz,3H),1.70(t,J＝13.9Hz,2H),1.32(d,J＝7.0Hz,3H),1.28–1.21(m,2H),1.15(s,6H),1.08(s,6H),1.04(s,0H),0.89–0.82(m,3H).MS m/z:592.4(M+H).
Example 4: (S) -N- ((S) -1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -2- (2-fluoro- [1,1' -biphenyl ] -4-yl) propanamide (Cpd 004)
1 H NMR(400MHz,DMSO-d 6 )δ7.85(d,J＝8.7Hz,1H),7.60–7.49(m,4H),7.53–7.42(m,4H),7.46–7.35(m,1H),7.27–7.19(m,2H),7.18–7.11(m,2H),7.01–6.92(m,2H),5.18(s,2H),3.95(d,J＝7.1Hz,1H),3.63(q,J＝7.0Hz,1H),3.29(s,1H),2.83(s,1H),2.79(dd,J＝13.7,5.3Hz,1H),2.66–2.56(m,2H),2.53(s,1H),1.82–1.73(m,1H),1.58(d,J＝13.1Hz,1H),1.30–1.24(m,6H),1.23(d,J＝16.0Hz,10H),1.03(s,2H).MS m/z:690.3(M+H).
Example 5: (S) -N- ((S) -1- (4-chlorophenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -2- (2-fluoro- [1,1' -biphenyl ] -4-yl) propanamide (Cpd 005)
1 H NMR(400MHz,DMSO-d 6 )δ7.85(dd,J＝12.4,8.6Hz,1H),7.58–7.29(m,10H),7.31(s,1H),7.25–7.17(m,3H),7.14–6.99(m,3H),3.95(s,2H),3.60(dd,J＝7.2,3.9Hz,1H),2.82(dt,J＝11.8,5.7Hz,2H),2.70(s,1H),2.67–2.53(m,3H),2.05–1.95(m,1H),1.72(t,J＝15.9Hz,1H),1.61(d,J＝12.4Hz,1H),1.50–1.41(m,1H),1.31(d,J＝7.5Hz,3H),1.29–1.21(m,8H),1.17(s,4H),1.10(d,J＝5.8Hz,6H),1.05(s,4H),1.00(s,3H),0.85(t,J＝6.6Hz,1H),0.75(s,2H).MS m/z:550.25(M+H).
Example 6: (9H-fluoren-9-yl) methyl- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) carbamate (Cpd 006)
1 H NMR(400MHz,DMSO-d 6 )δ7.88(t,J＝8.6Hz,3H),7.64(t,J＝7.7Hz,2H),7.55(d,J＝7.4Hz,2H),7.52–7.27(m,5H),7.19(d,J＝8.7Hz,1H),7.14(d,J＝8.3Hz,2H),6.93(d,J＝8.0Hz,2H),5.22–5.09(m,2H),4.27(dd,J＝8.6,4.7Hz,1H),4.22–4.12(m,2H),3.65(d,J＝6.5Hz,1H),2.86(s,1H),2.78(dd,J＝13.6,5.2Hz,1H),2.59(s,12H),1.98(s,1H),1.76(t,J＝12.3Hz,2H),1.47(s,1H),1.32–1.17(m,22H),1.01(s,4H),0.95(dd,J＝13.8,6.6Hz,1H).MS m/z:686.25(M+H).
Example 7: (S) -N- (1- ([ 1,1' -biphenyl ] -4-yl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -3,3-dimethylbutylamine (Cpd 007)
1 H NMR(400MHz,DMSO-d 6 )δ8.17(s,1H),7.69–7.56(m,3H),7.59–7.53(m,3H),7.45(dd,J＝8.3,7.0Hz,2H),7.34(t,J＝7.4Hz,1H),7.30(d,J＝8.1Hz,2H),4.05(s,1H),3.30(s,2H),2.95(s,2H),2.88(dd,J＝13.8,5.5Hz,1H),2.65(dd,J＝13.8,8.3Hz,1H),2.60(d,J＝6.2Hz,2H),1.93–1.82(m,4H),1.41–1.30(m,12H),1.24(s,1H),1.16(s,1H),1.12(d,J＝11.7Hz,1H),0.87(s,9H).MS m/z:464.3(M+H).
Example 8: (S) -N- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -3,3-dimethylbutylamine (Cpd 008)
1 H NMR(400MHz,DMSO-d 6 )δ8.17(s,1H),7.59–7.54(m,2H),7.53(s,1H),7.47(dd,J＝8.9,7.1Hz,1H),7.15(d,J＝8.6Hz,2H),6.99–6.92(m,2H),5.18(s,2H),4.06–3.97(m,1H),3.30(s,1H),2.97(s,1H),2.78(dd,J＝13.9,5.6Hz,1H),2.61–2.52(m,3H),1.96–1.82(m,4H),1.37–1.31(m,11H),1.28–1.17(m,1H),1.20–1.12(m,1H),0.87(s,8H).MS m/z:562.45(M+H).
Example 9: n- ((S) -1- ([ 1,1' -biphenyl ] -4-yl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -2-cyclohexylbutylamine (Cpd 009)
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.68–7.51(m,6H),7.44(t,J＝7.6Hz,2H),7.32(ddd,J＝18.0,7.7,1.9Hz,4H),4.12(s,1H),2.98(d,J＝12.6Hz,1H),2.90(dt,J＝20.0,7.0Hz,1H),2.70–2.54(m,4H),1.87(s,2H),1.77–1.65(m,1H),1.65–1.49(m,2H),1.33(t,J＝7.4Hz,17H),1.27–1.21(m,2H),1.10(t,J＝14.2Hz,5H),0.96–0.87(m,1H),0.87–0.74(m,1H),0.73(d,J＝7.3Hz,1H),0.62(t,J＝12.6Hz,1H),0.47(t,J＝7.3Hz,2H).MS m/z:518.55(M+H).
Example 10: 2-cyclohexyl-N- ((S) -1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) butanamide (Cpd 010)
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.59–7.50(m,3H),7.47(dd,J＝9.0,7.1Hz,1H),7.15(d,J＝8.5Hz,2H),6.97–6.90(m,2H),5.15(s,2H),4.06(s,1H),2.95(s,1H),2.85(dd,J＝13.8,4.5Hz,1H),2.58(d,J＝6.3Hz,2H),1.86(t,J＝14.0Hz,2H),1.73–1.55(m,3H),1.49(d,J＝9.2Hz,2H),1.40(d,J＝7.7Hz,1H),1.36–1.21(m,14H),1.14(s,7H),1.04(d,J＝12.0Hz,1H),0.95(dd,J＝10.9,7.9Hz,1H),0.74(t,J＝7.3Hz,3H),0.65–0.55(m,1H).MS m/z:618.25(M+H).
Example 11: (S, E) -N- (1- ([ 1,1' -biphenyl ] -4-yl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -4-phenyl-3-enamide (Cpd 011)
1 H NMR(400MHz,DMSO-d 6 )δ8.18(s,1H),7.79(d,J＝8.5Hz,1H),7.60–7.49(m,4H),7.43(dd,J＝8.3,6.9Hz,2H),7.41–7.29(m,3H),7.33–7.23(m,4H),7.26–7.17(m,1H),6.41(d,J＝15.9Hz,1H),6.24(dt,J＝15.8,7.0Hz,1H),4.04–3.98(m,1H),3.07–2.92(m,2H),2.95(s,1H),2.90(dd,J＝13.7,5.2Hz,1H),2.72–2.58(m,3H),1.87(ddd,J＝21.3,13.0,3.3Hz,2H),1.35–1.21(m,13H),1.14(q,J＝11.8Hz,2H).MS m/z:510.45(M+H).
Example 12: (S) -N- (1- ([ 1,1' -biphenyl ] -4-yl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -2-chloronicotinamide (Cpd 012)
1 H NMR(400MHz,DMSO-d 6 )δ8.52–8.42(m,2H),7.70(dd,J＝7.6,2.0Hz,1H),7.66(dd,J＝7.2,1.8Hz,2H),7.63–7.58(m,2H),7.52–7.42(m,3H),7.36(d,J＝7.8Hz,3H),4.26–4.16(m,1H),2.98(dd,J＝13.7,5.5Hz,2H),2.90(s,0H),2.77(dd,J＝13.7,8.4Hz,1H),2.73(s,1H),2.72(s,1H),1.85(s,2H),1.30–1.21(m,14H),1.06(s,3H).MS m/z:505.3(M+H).
Example 13: (S) -2-chloro-N- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) nicotinamide (Cpd 013)
1 H NMR(400MHz,DMSO-d 6 )δ8.49–8.40(m,2H),8.32(s,1H),7.69(dd,J＝7.5,2.0Hz,1H),7.57(d,J＝8.0Hz,2H),7.48(ddd,J＝9.0,6.0,4.0Hz,2H),7.21(d,J＝8.2Hz,2H),7.00(d,J＝8.5Hz,2H),5.20(s,2H),4.15(d,J＝7.7Hz,1H),3.30(s,1H),3.01(s,1H),2.93–2.83(m,1H),2.69(dt,J＝13.7,9.1Hz,3H),2.03–1.85(m,2H),1.35(dd,J＝7.9,2.7Hz,11H),1.28–1.17(m,2H),1.14(d,J＝13.1Hz,1H).MS m/z:605.35(M+H).
Example 14: (S) -N- (1- ([ 1,1' -biphenyl ] -4-yl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) cinnamamide (Cpd 014)
1 H NMR(400MHz,DMSO-d 6 )δ8.03(d,J＝8.3Hz,1H),7.79(s,4H),7.69–7.61(m,2H),7.56(dd,J＝18.4,7.5Hz,4H),7.51–7.29(m,9H),6.63(d,J＝15.8Hz,1H),4.14(dt,J＝8.1,5.3Hz,1H),2.96(dd,J＝13.9,5.8Hz,2H),2.76(dd,J＝13.8,8.0Hz,1H),2.68(d,J＝6.2Hz,2H),2.58(s,0H),1.88(t,J＝11.2Hz,2H),1.33–1.21(m,13H),1.12(d,J＝11.3Hz,2H).MS m/z:496.35(M+H).
Example 15: (S) -N- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) cinnamamide (Cpd 015)
1 H NMR(400MHz,DMSO-d 6 )δ7.97(d,J＝8.4Hz,1H),7.62–7.51(m,4H),7.50–7.34(m,5H),7.22–7.15(m,2H),7.01–6.94(m,2H),6.62(d,J＝15.8Hz,1H),5.18(s,2H),4.08(q,J＝6.7Hz,1H),2.97(s,1H),2.85(dd,J＝13.8,5.7Hz,1H),2.67(dd,J＝13.5,7.4Hz,3H),1.97–1.84(m,2H),1.33(d,J＝7.9Hz,11H),1.24(d,J＝3.4Hz,1H),1.16(q,J＝11.7Hz,2H).MS m/z:594.25(M+H).
Example 16: (S) -N- (1- ([ 1,1' -biphenyl ] -4-yl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) -2,2-bis (4-chlorophenoxy) acetamide (Cpd 016)
1 H NMR(400MHz,DMSO-d 6 )δ8.41(d,J＝8.7Hz,1H),7.64(d,J＝7.6Hz,2H),7.56(d,J＝7.9Hz,2H),7.46(t,J＝7.6Hz,2H),7.39–7.25(m,8H),7.04–6.92(m,5H),6.17(s,1H),4.09(d,J＝8.3Hz,1H),2.98–2.89(m,2H),2.77(dd,J＝13.8,8.9Hz,1H),2.68(d,J＝6.4Hz,2H),1.87(d,J＝13.3Hz,1H),1.77(d,J＝13.8Hz,1H),1.61(s,1H),1.32(d,J＝6.6Hz,6H),1.30(s,6H),1.25(d,J＝8.7Hz,1H),1.13(q,J＝11.3,10.8Hz,2H).MS m/z:660.15(M+H).
Example 17: (S) -2,2-bis (4-chlorophenoxy) -N- (1- (4- ((2,6-dichlorobenzyl) oxy) phenyl) -3- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) propan-2-yl) acetamide (Cpd 017)
1 H NMR(400MHz,DMSO-d 6 )δ8.33(d,J＝8.7Hz,1H),7.56(d,J＝8.0Hz,2H),7.51–7.43(m,1H),7.35(t,J＝9.1Hz,4H),7.16(d,J＝8.2Hz,2H),7.05–6.93(m,7H),6.16(s,1H),5.20(s,2H),4.01(q,J＝7.3Hz,1H),2.91(s,2H),2.83(dd,J＝13.7,5.1Hz,1H),2.67(dd,J＝23.6,7.6Hz,3H),1.85(d,J＝13.4Hz,1H),1.76(d,J＝13.0Hz,1H),1.35–1.27(m,12H),1.24(s,1H),1.21–1.03(m,2H).MS m/z:760.35(M+H).
2. Biological Activity assay for Compounds of the invention
Example 18 in vitro antitumor Activity test of the Compounds of the examples
Selecting human tumor cell line 5, culturing in RPMI-1640 (Gibco Co.) or DMEM (Gibco Co.) or GMEM/F12 culture medium containing 10% inactivated fetal calf serum, 100U/ml penicillin and 100U/ml streptomycin(Gibco Co.) at 37 ℃ with 5% CO 2 Culturing in an incubator. Cells in logarithmic growth phase were seeded in 96-well plates (100. Mu.l/well, 2X 10) using MTT method 4 Individual cells) while setting blank wells. After overnight incubation in the incubator, 100. Mu.l of drug (final concentration 25. Mu.M fold-rate dilution to 0.39. Mu.M, total 7 drug concentrations) was added to the control wells, and 3 duplicate wells were added to each drug concentration. After 48 hours of incubation, the supernatant was discarded, and after two washes with PBS, 100. Mu.l of MTT (5 mg/ml) was added to each well for an additional 2 hours. Measuring absorbance (A) with microplate reader 492nm Value), the inhibition rate of the drug on the tumor cells was calculated.
Calculation of Compound IC on tumor cells Using GraphPad software 50 The value is obtained. The results of the in vitro activity of the compounds of the three examples are shown in Table 2, and the inhibition rate of the compounds on different cancer cells is equivalent to that of PL-AC-15 and PL-AC-202, and is superior to that of cisplatin.
TABLE 2 in vitro antitumor Activity of the Compounds of the examples IC 50 (μM)
EXAMPLE 19 in vivo antitumor Effect test of example Compound (Cpd 014)
In vivo efficacy evaluation model was constructed using BALB/c nude mice, and 0.15mL of tumor cell suspension (A549 lung cancer cells, 2X 10 cells) was subcutaneously inoculated to the right forelimb axilla of each mouse 7 Pieces/ml). The cells to be inoculated grow into 300mm tumor 3 At that time, administration is started. Intraperitoneal administration (20 mg/kg) was performed on day 22 after inoculation, 1 time/2 days for 10 times, and on day 2 after the last administration, tumor-bearing mice were all sacrificed, tumor weights were weighed, and tumor inhibition rates were calculated. Experimental results show that the in vivo tumor inhibition rate of the compound Cpd014 is higher than that of PL-AC-202 and docetaxel.
Table 3 results of antitumor activity of the compounds of examples in vivo
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A compound having a structural formula as shown in formula I or a pharmaceutically acceptable salt, ester, solvate or isomer thereof:
wherein, R is 1 Selected from any one of the following groups: c 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl;
R 1 the hydrogens on the chain may be optionally substituted with one or more of the following substituents: halogen, C 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl, -CN, -NO 2 、-CF 2 H、-CF 2 OH、-CF 3 、-OCF 3 、-CR 1 R 2 R 3 、-OR 1 、-O(C＝O)R 1 、-O(C＝O)OR 1 、-O(C＝O)NR 2 R 3 、-(C＝O)R 1 、-(C＝O)OR 1 、-(C＝O)NR 2 R 3 、-SR 1 、-(S＝O) m R 1 、-NR 2 R 3 、-NR 4 (C＝O)R 1 、-NR 4 C(＝O)NR 2 R 3 、-NR 4 C(＝O)OR 1 、-NR 4 S(＝O) m NR 2 R 3 、-NR 4 S(＝O) m OR 1 or-NR 4 S(＝O) m R 1 Or R is 1 Groups of upper adjacent atoms may combine to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclics, and 5-12 membered heteroaryl ring groups;
wherein R is 1 、R 2 、R 3 、R 4 Independently selected from hydrogen, halogen or any of the following groups: c 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl, or R bound to the same nitrogen atom 1 、R 2 、R 3 、R 4 Any two of which may be combined together with the nitrogen to which they are bound to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl group, optionally containing 1 to 3 additional heteroatoms selected from N, 0 and S, or R bound to the same carbon atom 1 、R 2 、R 3 Any two of which may be combined to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and R 1 、R 2 、R 3 、R 4 Each hydrogen in (1) is optionally substituted by R 5 Substituted, or R 1 、R 2 、R 3 、R 4 Wherein two hydrogen atoms on the same carbon atom are optionally oxo substituents;
R 5 independently selected from the following groups: hydrogen, halogen, C 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Aryl, nitro radicals C 6-14 Aryl or nitro radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl; -CN, -NO 2 、-OH、-NH 2 Partially or fully halogenated C 1-5 Alkyl, -C (= O) (CH) 2 ) n CH 3 、-C(＝O)O(CH 2 ) n CH 3 、-C(＝O)OH、-C(＝O)N[(CH 2 ) n CH 3 ] 2 、-C(＝O)NH 2 、-C(＝O)NH(CH 2 ) n CH 3 、-NH(CH 2 ) n CH 3 、-N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)NH(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)NH 2 、-N(CH 2 ) n CH 3 C(＝O)O(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)OH、-NHC(＝O)(CH 2 ) n CH 3 、-NHC(＝O)NH(CH 2 ) n CH 3 、-NHC(＝O)N[(CH 2 ) n CH 3 ] 2 、-NHC(＝O)NH 2 、-NHC(＝O)O(CH 2 ) n CH 3 ,-NHC(＝O)OH,-N(CH 2 ) n CH 3 S(＝O) m (CH 2 ) n CH 3 、-NHS(＝O) m (CH 2 ) n CH 3 、-O(CH 2 ) n CH 3 、＝O、-OC(＝O)(CH 2 ) n CH 3 、OC(＝O)O(CH 2 ) n CH 3 、-OC(＝O)N[(CH 2 ) n CH 3 ] 2 、-OC(＝O)NH(CH 2 ) n CH 3 、-OC(＝O)NH 2 、-S(＝O) m (CH2) n CH 3 、-OS(＝O) m (CH 2 ) n CH 3 、-S(＝O) m NH(CH 2 ) n CH 3 、-S(＝O) m N[(CH 2 ) n CH 3 ] 2 ；
M is selected from 1 or 2
N is 1,2,3,4 or 5;
R 2 selected from any one of the following groups: h, halogenElement, C 1-10 Alkyl, oxy C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl, oxy C 5-14 Aryl, nitro radicals C 6-14 Aryl, nitrogen radical C 5-14 Heteroaryl, 5-14 membered heteroaryl;
R 2 the hydrogen above may be optionally substituted with one or more of the following substituents: halogen, -CN, -NO 2 、-CF 2 H、-CF 2 OH、-CF 3 、-OCF 3 、-CR 6 R 7 R 8 、-OR 6 、-O(C＝O)R 6 、-O(C＝O)OR 6 、-O(C＝O)NR 7 R 8 、-(C＝O)R 6 、-(C＝O)OR 6 、-(C＝O)NR 7 R 8 、-SR 6 、-(S＝O)R 6 、-S(＝O) 2 R 6 、-NR 7 R 8 、-NR 9 (C＝O)R 6 、-NR 9 C(＝O)NR 7 R 8 、-NR 9 C(＝O)OR 6 、-NR 9 S(＝O) m NR 7 R 8 、-NR 9 S(＝O) m OR 6 or-NR 9 S(＝O) m R 6 Or R is 2 Groups of upper adjacent atoms may combine to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclic group and 5-12 membered heteroaromatic ring;
wherein R is 6 、R 7 、R 8 、R 9 Independently selected from hydrogen or any of the following groups: c 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 An heteroaryl group, a 5-14 membered heteroaryl group, or any two of R1, R2, R3, R4 bound to the same nitrogen atom may be combined together with the nitrogen to which they are bound to form a 3-12 membered heterocyclic group or a 5-12 membered heteroaryl group, optionally containing 1 to 3 additional heteroatoms selected from N, 0 and S; or R bound to the same carbon atom 6 、R 7 、R 8 R 9 Any two of which may be combined to form C 3-12 Cycloalkyl radical, C 6-12 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; and R 6 、R 7 、R 8 Each hydrogen in (1) is optionally substituted by R 10 Substituted, or R 6 、R 7 、R 8 、R 9 Wherein two hydrogen atoms on the same carbon atom are optionally oxo substituents.
R 10 Independently selected from: hydrogen, halogen, C 1-10 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, oxy C 6-14 Aryl or oxy radicals C 5-14 Heteroaryl, nitro C 6-14 Aryl or nitrogen radicals C 5-14 Heteroaryl, 5-14 membered heteroaryl, -CN, -NO 2 、-OH、-NH 2 Partially or fully halogenated C 1-5 Alkyl, -C (= O) (CH) 2 ) n CH 3 、-C(＝O)O(CH 2 ) n CH 3 、-C(＝O)OH、-C(＝O)N[(CH 2 ) n CH 3 ] 2 、-C(＝O)NH 2 、-C(＝O)NH(CH 2 ) n CH 3 、-NH(CH 2 ) n CH 3 、-N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)NH(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)N[(CH 2 ) n CH 3 ] 2 、-N(CH 2 ) n CH 3 C(＝O)NH 2 、-N(CH 2 ) n CH 3 C(＝O)O(CH 2 ) n CH 3 、-N(CH 2 ) n CH 3 C(＝O)OH、-NHC(＝O)(CH 2 ) n CH 3 、-NHC(＝O)NH(CH 2 ) n CH 3 、-NHC(＝O)N[(CH 2 ) n CH 3 ] 2 、-NHC(＝O)NH 2 、-NHC(＝O)O(CH 2 ) n CH 3 ,-NHC(＝O)OH,-N(CH 2 ) n CH 3 S(＝O) m (CH 2 ) n CH 3 、-NHS(＝O) m (CH 2 ) n CH 3 、-O(CH 2 ) n CH 3 、＝O、-OC(＝O)(CH 2 ) n CH 3 、OC(＝O)O(CH 2 ) n CH 3 、-OC(＝O)N[(CH 2 ) n CH 3 ] 2 、-OC(＝O)NH(CH 2 ) n CH 3 、-OC(＝O)NH 2 、-S(＝O)m(CH 2 ) n CH 3 、-OS(＝O)m(CH 2 ) n CH 3 、-S(＝O) m NH(CH 2 ) n CH 3 、-S(＝O) m N[(CH 2 ) n CH 3 ] 2 ；
M is selected from 1 or 2;
n is 1,2,3,4 or 5;
w represents a bond or a group selected from any of the following: c 1-8 Alkylene radical, C 2-8 Alkenylene radical, C 2-8 Alkynylene, C 3-8 Cycloalkylene, 3-8 membered heterocyclylene, oxy C 1-8 Alkylene, -O-, -NH-, amino C 1-8 Alkylene, or any of the above groups wherein one or more hydrogens are replaced with halogen, and hydrogen is optionally replaced with R 11 Substituted radicals as described above, wherein R 11 Is as defined for R 1 ；
X represents a bond or a group selected from any one of: c 1-8 Alkylene, -O-, oxy C 1-8 Alkylene, -NH-, amino C 1-8 Alkylene, mercapto C 1-8 Alkylene, mercapto oxides C 1-8 Alkylene, -S (= O) NH-, -S (= O) 2 NH-, or the above groups in which any one or more hydrogens on X are replaced with a halogen, and the hydrogen on X is optionally replaced with R 12 Substituted radicals as described above, wherein R 12 Is as defined for R 1 。
2. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, solvate or isomer thereof, wherein:
the above-mentionedR 1 Selected from any one of the following: c 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-7 Cycloalkyl, phenyl, phenoxy, fluorenyl, pyridyl, substituted pyridyl, and R 1 Hydrogen of (A) optionally substituted by R 13 A substituted radical in which R 13 Is defined as in claim 1 10 The same;
R 2 selected from any one of the following groups: h, halogen, phenyl, biphenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, and R 2 Hydrogen of any above is substituted by R 14 A substituted radical in which R 14 Is defined as in claim 1 10 The same is that:
w represents a bond or any group selected from: c 1-4 Alkylene radical, C 2-6 Alkenylene, -OCH 2 -，-CH 2 O-；
X represents a bond or a group selected from any one of: -CH 2 -，-CH 2 CH 2 -, oxy C 1-4 An alkylene group.
3. The compound according to claim 2, or a pharmaceutically acceptable salt, ester, solvate or isomer thereof, wherein:
in the formula I, R 1 Associating W groups includes, but is not limited to, the following fragments:
in the formula I, X is combined with R 2 Including but not limited to the following fragments:
4. the compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester, solvate, or isomer thereof, wherein: the compound shown in the formula I is selected from any one of the following compounds:
5. a process for the preparation of a compound of formula I as claimed in any one of claims 1 to 4, comprising the steps of:
r is to be 1 Activating W-COOH by oxalyl chloride, and reacting with the intermediate 1 or the intermediate 2 at room temperature to obtain a corresponding final product shown in formula I;
the R is 1 R in-W-COOH 1 W is as defined in formula I in claim 1;
r in the intermediate 1 is-X-R 2 Wherein X is as defined for formula I, except that X is-OCH 2 (ii) the condition of (a); r in the intermediate 1 2 Is as defined in formula I in claim 1;
in the intermediate 2, Y represents that hydrogen in the benzene ring connected with Y is substituted by one or more R 15 A group obtained by substitution, wherein R 15 Is as defined in claim 1, wherein R is in formula I 1 。
6. The method of claim 5, wherein: the synthetic route of the intermediate 1 is shown as follows:
the preparation method comprises the following steps: in NaBH 4 Reducing carboxylic acid 1 under conditions to provide compound 2; oxidizing compound 2 under NaClO and TEMPO conditions to provide compound 3; then mixing with 1,1,2,2-4 methyl-4-aminopiperidine in NaBH 4 Reducing the amino group under the conditions of (1) to obtain a compound 4; deprotection of compound 4 via TFA in DCM provides intermediate 1;
wherein R in the compounds 1-4 is as defined for intermediate 1;
the synthetic route of the intermediate 2 is shown as follows:
the preparation method of the intermediate 2 comprises the following steps: carboxylic acid 5 and 2,6 dichloro-benzyl bromide in K 2 CO 3 Carrying out a substitution reaction under the conditions of (1) to obtain a compound 6; in MeOH/THF/H 2 Hydrolyzing the compound 6 with NaOH under the condition of O to obtain a compound 7; in NaBH 4 Reducing the compound 7 under the condition of (1) to obtain a compound 8, and then carrying out oxidation reaction on the compound 8 with TEMPO and NaClO to obtain a compound 9; carrying out reductive amination reaction on the compound 9 and 1,1,2,2-4 methyl-4-aminopiperidine to obtain a compound 10; deprotection of the compound 10 using TFA in DCM solvent provided intermediate 2.
7. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, solvate or isomer thereof, for the manufacture of a medicament for the prevention and/or treatment of cancer or for the manufacture of a medicament for inhibiting cancer cell proliferation.
8. Use according to claim 7, characterized in that: the cancer is solid cancer or non-solid cancer, including liver cancer, lung cancer and prostatic cancer;
the cancer cells comprise liver cancer cells, lung cancer cells and prostate cancer cells.
9. A medicament or pharmaceutical composition for the prevention and/or treatment of cancer, characterized in that: the medicament or pharmaceutical composition comprising an effective amount of a compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt, ester, solvate or isomer thereof.
10. The medicament or pharmaceutical composition of claim 8, wherein: the cancer is solid cancer or non-solid cancer, including liver cancer, lung cancer, breast cancer, prostatic cancer, pancreatic cancer, colon cancer, cervical cancer, gastric cancer, melanoma or human osteosarcoma.
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