CN115477684A - Substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor, preparation method and application - Google Patents
Substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor, preparation method and application Download PDFInfo
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Abstract
The invention discloses a substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor, a preparation method and application thereofThe compound has a structure as shown in the general formula (I):
Description
Technical Field
The invention relates to a substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor, and a preparation method, a pharmaceutical composition and a medical application thereof, and belongs to the technical field of medicines.
Background
Apoptosis, also known as Programmed Cell Death (PCD), is a type of conserved evolutionary and highly regulated death process that is an important protection mechanism for multicellular organisms. It can eliminate the cells without function, harm, mutation and damage in animal body, protect them from the influence of uncontrolled cell growth and proliferation caused by DNA mutation, and play an important role in maintaining body's homeostasis and embryo's growth and development. The escape of apoptosis is a mark of malignant tumor, and is one of the reasons for tumorigenesis, tumor development and drug resistance to various conventional antitumor drug treatments. The research shows that the apoptosis mainly has two apoptosis paths, namely a death receptor mediated exogenous apoptosis path and a mitochondria mediated endogenous apoptosis path. To date, restoration of normal apoptosis of tumor cells by acting on key regulators in the apoptotic pathway has become a very promising anti-tumor strategy.
Research has shown that the B cell lymphoma/leukemia-2 (B-cell leukemia/lymphoma-2, bcl-2) protein family is a key regulator of apoptosis and plays an important role in the endogenous pathway mediated by mitochondria. The Bcl-2 protein families can be classified into three major groups according to their functions and structures: (1) Anti-apoptotic proteins such as Bcl-2, bcl-xL, mcl-1, and the like; (2) multidomain proapoptotic proteins such as Bax, bak; (3) Pro-apoptotic BH3-only proteins such as Bad, bim, noxa, and the like. When cells generate an endogenous apoptosis pathway, the BH3-only protein activates Bax and Bak to be adsorbed on the outer membrane of mitochondria, and apoptosis promoting factors such as cytochrome c and Smac protein are released into the cells by changing the permeability of the outer membrane, so that the cysteine aspartase is activated to cause the apoptosis. And the anti-apoptosis proteins Bcl-2, bcl-xL and Mcl-1 can form hetero-oligomers with pro-apoptosis proteins Bad, bim, bax, bak and the like to inhibit the activities of the pro-apoptosis proteins, thereby achieving the effect of avoiding apoptosis. The research finds that the anti-apoptosis proteins Bcl-2, bcl-xL and Mcl-1 are highly expressed in various malignant tumor cells (breast cancer, prostatic cancer, lymph cancer, leukemia and the like), and are closely related to the occurrence and recurrence of related tumors and the drug resistance of chemotherapeutic drugs. Therefore, the development of small molecule inhibitors to antagonize the activity of anti-apoptotic Bcl-2 proteins has become a hot spot in the development of current anti-tumor drugs.
Over the past decades, a number of small molecule anti-apoptotic Bcl-2 protein inhibitors of novel structure have been reported in succession and have shown good anti-tumor activity. In particular, the first selective Bcl-2 inhibitor Venetocalax/ABT-199 was approved by the U.S. Food and Drug Administration (FDA) for marketing, and was highly encouraging drug workers to treat chronic lymphocytic leukemia patients with 17p chromosome deletions. However, ABT-199 binds to Mcl-1 poorly and is not ideal for inducing apoptosis in certain hematological disorders and solid tumor cells that depend on Mcl-1 for survival. Aiming at the clinical reality problem, the search for a novel small-molecule inhibitor targeting Mcl-1 becomes a research subject with great challenge and great application value in the current tumor (especially malignant tumor) treatment field.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor and a preparation method of the compound.
The invention further provides a pharmaceutical composition and medical application of the compound.
The technical scheme of the invention is as follows:
1. substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor
A substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor is a compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof.
In the general formula (I), R 1 Is alkyl, aryl, heteroaryl; r is 1 Preferably optionally substituted C1-C10 alkyl, C3-C10 cycloalkyl, C5-C15 aryl, and mono-heterocyclic aryl containing 5 or 6 ring atoms, or bis-heterocyclic aryl having 8 to 15 ring atoms, the heterocyclic aryl containing 1-4 heteroatoms independently selected from O, S, N or oxidized S or N; the carbon atom or the nitrogen atom is a connecting point of a heteroaromatic ring structure, and the heteroaromatic ring structure is stable;
in the general formula (I), R 2 Is isopropyl or-A-R 4 ；
Wherein A is CH 2 NH, O, S atom, preferably CH 2 ；R 4 Is optionally substituted aryl, heteroaryl; r 4 Preferably optionally substituted C5-C15 aryl, and mono-heterocyclic aryl containing 5 or 6 ring atoms, or bis-heterocyclic aryl having 8 to 15 ring atoms, the heterocyclic aryl containing 1-4 heteroatoms independently selected from O, S, N or oxidized S or N; the carbon atom or the nitrogen atom is a connecting point of a heteroaromatic ring structure, and the heteroaromatic ring structure is stable;
in the general formula (I), R 3 Is optionally substituted aryl, heteroaryl; r is 3 Preferably optionally substituted C5-C15 aryl, and mono-heterocyclic aryl containing 5 or 6 ring atoms, or bis-heterocyclic aryl having 8 to 15 ring atoms, the heterocyclic aryl containing 1-4 heteroatoms independently selected from O, S, N or oxidized S or N; the carbon atom or the nitrogen atom is a connecting point of a heteroaromatic ring structure, and the heteroaromatic ring structure is stable;
the group or substituent is selected from the group consisting of hydroxy, halogen, nitro, cyano, guanidino, carboxy, haloC 1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, aralkoxy, heteroaryl of 5-10 ring atoms containing 1-2 heteroatoms, 1-3 of the above groups or substituents being attached at any accessible position to produce a stable compound.
According to a preferred embodiment of the invention, in the general formula (I),
R 1 is haloC 1-C6 alkyl, C3-C8 cycloalkyl, an aromatic group Ar, -NH-R linked to a morpholine group, piperazine group, substituted or unsubstituted with 1-2 hydroxy, halogen, nitro, cyano substituents 5 (ii) a Ar is phenyl or naphthalene containing 1 substituent or no substituentA group, pyridyl, pyridazinyl, pyrazinyl, indolizinyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl, benzothiazolyl, thienyl, benzo [ b ] b]Thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furyl, benzofuryl and indolyl; r 5 C1-C6 alkyl substituted or unsubstituted with 1-2 hydroxy, halogen, nitro, cyano substituents, and the above aromatic group Ar to which C1-C3 alkylene is attached; the substituent is hydroxyl, halogen, nitryl, cyano, guanidyl, carboxyl, haloC 1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C5-C10 aryl, and heteroaryl containing 1-2 heteroatoms and having 5-10 ring atoms;
R 2 is isopropyl or-CH 2 -R 4 ；R 4 Is 3-indolyl and phenyl, naphthyl, pyridyl, pyridazinyl, pyrazinyl, indolizinyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl, benzothiazolyl, thienyl, benzo [ b ] b, which may be substituted or unsubstituted by 1-2 substituents]Thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furyl, benzofuryl and indolyl; the substituent is hydroxyl, halogen, nitryl, cyano, guanidyl, carboxyl, haloC 1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C5-C10 aryl, substituted aralkyloxy, heteroaryl containing 1-2 heteroatoms and having 5-10 ring atoms;
R 3 is an aromatic group Ar, -NH-R connected with a morpholine group and a piperazine group which are substituted or not substituted by 1-2 hydroxyl, halogen, nitro and cyano substituents 5 (ii) a Ar is phenyl, naphthyl, pyridyl, pyridazinyl, pyrazinyl, indolizinyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl, benzothiazolyl, thienyl, benzo [ b ] b]Thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furyl, benzofuryl and indolyl; r4 is 1-2 hydroxy, halogen,Nitro, cyano-substituted or unsubstituted C1-C6 alkyl, and C1-C3 alkylene-linked aromatic group Ar as described above; the substituent is hydroxyl, halogen, nitryl, cyano, guanidyl, carboxyl, haloC 1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 naphthenic base, C5-C10 aryl, and heteroaryl with 5-10 ring atoms containing 1-2 heteroatoms;
according to the invention, it is further preferred that the compound of the above general formula (I) is one of the following:
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (A1)
(S) -N- (4-Methylbenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3-phenylpropanamide (A2)
(S) -N- (4-Chlorosulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (A3)
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (A4)
(S) -N- (4-Methylbenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3-phenylpropanamide (A5)
(S) -N- (4-Chlorosulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3-phenylpropanamide (A6)
(S) -N- (3-Nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (A7)
(S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A8)
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A9)
(S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A10)
(S) -N- (3-Nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A11)
(S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A12)
(S) -N- (4-Chlorosulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A13)
(S) -N- (4-Methylbenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A14)
(S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (A15)
(S) -N- (4-Nitrophenylsulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (A16)
(S) -N- (4-Nitrophenylsulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (A17)
(S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (benzyloxy) phenyl) propionamide (A18)
(S) -N- (3-Nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (benzyloxy) phenyl) propanamide (A19)
(S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (4-nitrobenzyloxy) phenyl) propanamide (A20)
The above compounds are preferred, and the following numbers in parentheses are numbers corresponding to the structures of the compounds in the following schemes and table 1.
Detailed Description
The terms and definitions used herein have the following meanings:
"aryl" means an aromatic hydrocarbon containing a ring system, such as phenyl or naphthyl, optionally fused with a cycloalkyl group, preferably having 5 to 7 ring atoms, more preferably having 5 to 6 ring atoms. Preferred aryl groups contain 5 to 15 carbon atoms.
"heteroaryl" is an aromatic heterocycle, which may be a monocyclic or bicyclic group. They contain one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2 heteroatoms independently selected from O, S and N. Heteroaryl groups include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tricyclic nitrogen. The carbon or nitrogen atom is the point of attachment to the heteroaromatic ring structure, thereby maintaining a stable aromatic ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, indolizinyl, benzo [ b ] thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furyl, benzofuryl, and indolyl.
"arylalkyl" refers to a C1-C6 alkylene-linked aryl group.
"heteroarylalkyl" refers to a C1-C6 alkylene-linked heteroaryl.
"arylalkenyl" refers to a C2-C6 alkenyl-linked aryl group.
"heteroarylalkenyl" refers to a C2-C6 alkenyl-linked heteroaryl.
"Alkyl (Alkyl)", alone or in combination, refers to a group derived from an alkane, containing from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, if not specifically indicated. Which is a straight or branched chain alkyl group and includes straight or branched chain alkyl groups containing or interrupted by cycloalkyl moieties. Straight or branched alkyl groups are attached at any accessible site (available point) to produce stable compounds. Examples include, but are not limited to, 4- (isopropyl) -cyclohexylethyl or 2-methyl-cyclopropylpentyl. In many embodiments, alkyl is a straight or branched alkyl group containing 1 to 15 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.
An "alkylene" is a divalent alkane-derived radical of carbon atoms, straight or branched, in which two hydrogen atoms are removed from the same carbon atom or different carbon atoms. Examples of alkylene groups include, but are not limited to, -CH 2 -、-CH 2 CH 2 -and-CH 2 CH(CH 3 )-。
"Alkenyl" means, alone or in combination, a straight or branched chain hydrocarbon containing from 2 to 6, preferably from 2 to 4, carbon atoms and containing from 1 to 2, preferably one, carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl.
"cycloalkyl" is a substituted or unsubstituted, saturated or unsaturated cyclic group containing carbon atoms and/or one or more heteroatoms. The rings may be monocyclic or fused, bridged or spiro ring systems. The number of ring atoms in each ring is 3 to 8, more preferably 3 to 6, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like.
"alkoxy" means the group-O-alkyl.
"halogen", alone or in combination, means all halogens, i.e. chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).
By "pharmaceutically acceptable salt" is meant a therapeutically effective and non-toxic salt form of the compound of formula (I). It may form an anionic salt from any acidic group (e.g. carboxyl) or a cationic salt from any basic group (e.g. amino). Many such salts are known in the art. A cationic salt formed on any acidic group (e.g., a carboxyl group), or an anionic salt formed on any basic group (e.g., an amino group). Many of these salts are known in the art, such as cationic salts including salts of alkali metals (e.g., sodium and potassium) and alkaline earth metals (e.g., magnesium and calcium) and organic salts (e.g., ammonium salts). Anionic salts may also be conveniently obtained by treating the basic form of I with the corresponding acid, such acids including inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropanoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, phenylmethanesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexylsulfinic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like. These salts are well known to the skilled artisan and the skilled artisan can prepare any of the salts provided by the knowledge in the art. In addition, the skilled artisan may select one salt and select another salt depending on solubility, stability, ease of formulation, and the like. The determination and optimization of these salts is within the experience of the skilled artisan.
"stereoisomers" as used herein defines all possible stereoisomeric forms of the compounds of the invention or physiological derivatives thereof. Unless otherwise indicated, the chemical designation of the compounds of the invention includes mixtures of all possible stereochemical forms, which mixtures comprise all diastereomers and enantiomers of the basic structural molecule, as well as the substantially pure individual isomeric forms of the compounds of the invention, i.e. containing less than 10%, preferably less than 5%, in particular less than 2%, most preferably less than 1% of other isomers. Various stereoisomeric forms of the peptoid compounds of the present invention are expressly included within the scope of the present invention.
The compounds of general formula (I) may also exist in other protected forms or derivatives, which are obvious to a person skilled in the art and which are intended to be included within the scope of the present invention.
The substituents described above may themselves be substituted by one or more substituents. Such substituents include those listed in C.Hansch and A.Leo, scientific Constants for Correlation Analysis in Chemistry and Biology (1979). Preferred substituents include alkyl, alkenyl, alkoxy, hydroxy, oxy, nitro, amino, aminoalkyl (e.g., aminomethyl, and the like), cyano, halogen, carboxy, carbonylalkoxy (e.g., carbonylethoxy, and the like), thio, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolyl, and the like), imino, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
"pharmaceutical composition" refers to a preparation containing a therapeutically significant amount of an active agent, which is prepared in a form suitable for administration to a patient. Thus, the preparation does not contain such an amount of any component or components that a properly cautious medical practitioner finds the preparation unsuitable for administration to an ordinary subject. In many cases, such pharmaceutical compositions are sterile preparations.
The room temperature is the environmental temperature of the experimental operation and is controlled within the range of 10-30 ℃.
2. Preparation method of substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor
The preparation process of substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor includes the following steps: taking thiazolidine-2,4-diketone as a starting material, firstly carrying out Knoevenagel condensation reaction with formaldehyde with different substitutions to generate intermediates 1a-1c, then carrying out nucleophilic substitution reaction on 3-site N of the thiazolidine and methyl bromoacetate, and removing methyl ester under an acidic condition to generate key intermediates 2a-2c; in addition, the amino acids 3a-3e with different substitutions and the benzene sulfonamide with different substitutions are subjected to amide condensation reaction to generate key intermediates 4a-4k; and finally, removing Boc protection from the key intermediates 4a-4k in hydrogen chloride gas saturated ethyl acetate, and then performing amide condensation reaction with another key intermediate 2a-2c under the action of N-methylmorpholine and isobutyl chloroformate by using a mixed anhydride method to obtain target compounds A1-A20.
The synthetic route is as follows:
wherein R is 1 -R 3 Is as defined above for formula (I);
reagents and conditions: a) Refluxing different substituted formaldehyde, piperidine and ethanol; b) Refluxing methyl bromoacetate, potassium carbonate and acetone; refluxing glacial acetic acid and concentrated hydrochloric acid; c) 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIEA), dichloromethane, ice bath-room temperature; d) Hydrogen chloride saturated ethyl acetate solution at room temperature; n-methylmorpholine, isobutyl chloroformate, tetrahydrofuran, -20 ℃ to room temperature.
The structural formula of the target compound in the synthetic route is shown in the following table 1:
the specific procedures for the compounds described in the structural formulae of the target compounds of Table 1 will be illustrated in detail in the examples.
The skilled person can vary the above steps to increase the yield, and can determine the synthetic route according to the basic knowledge in the art, such as choice of reactants, solvents and temperature, and can increase the yield by using various conventional protecting groups to avoid side reactions. These conventional protection methods can be found, for example, in T.Greene, protecting Groups in Organic Synthesis.
3. Application of substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor
The invention also provides application of the series of compounds in preparing medicaments for preventing or treating related mammal diseases caused by abnormal expression of Mcl-1 protein. The mammal diseases related to the abnormal expression of the Mcl-1 protein comprise cancer, neurodegenerative diseases, virus infection, inflammation, leukemia, malaria, diabetes and the like.
In addition, the present invention also includes a pharmaceutical composition suitable for oral administration to a mammal comprising any of the compounds of formula (I) above, and a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.
In addition, the present invention also includes a pharmaceutical composition suitable for parenteral administration to a mammal comprising a compound of any of the above general formulae (I) and II, and a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.
Assays for both inhibitory and cellular activity were performed to evaluate the biological activity of the compounds in vitro.
In the in vitro enzyme inhibition experiment, a fluorescence polarization experiment determination method is utilized, in a specific measurement system, 5-FAM labeled Bid-BH3 polypeptide is adopted as a fluorescence labeled molecule, the molecule can be specifically combined with Mcl-1 protein, and the dissociation constant (K) of the molecule is d ) The combination of the two results in higher polarization values around 30-60 nM. If the tested target compound can be combined with the target protein, the Bid is competitively inhibited from being combined with the protein, so that the polarization value is reduced, a quantity-effect curve of competitive combination of the target compound is obtained, and finally the inhibition constant K is calculated i 。
The cell activity of the compound is tested by using an MTT detection method, a tumor cell suspension (a myeloma cell strain KM3 and a non-small cell lung cancer H1299) and a normal liver cell strain LO2 are respectively inoculated in a 96-well plate, a culture medium containing the compound with different concentrations is added into each well, after incubation, MTT staining is carried out, after incubation is continued, the absorbance OD value of each well is measured at 570nm on an enzyme labeling instrument, and the cell growth inhibition rate is calculated, so that the activity of the compound is determined.
In vitro enzyme inhibition experiments show that most of the compounds in the invention have stronger inhibitory activity to Mcl-1 protein, wherein the activities of the compounds A1, A8, A9 and the like are equivalent to that of a positive control drug UMI-77, and the inhibitory activity of the compound A10 to the Mcl-1 protein is higher than that of the positive control drug UMI-77. Meanwhile, in an in vitro anti-tumor cell proliferation test, the compounds A1, A8, A9 and A10 have better inhibitory activity on a myeloma cell strain KM3, are equivalent to a positive control drug AT-101, have a great development prospect, and can be used for guiding the discovery of a novel Mcl-1 protein inhibitor.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Example 1.5 Synthesis of- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione (1 a)
Thiazolidine-2,4-dione (1.17g, 10mmol) was slowly added to anhydrous ethanol (80 mL), and after stirring and dissolving at room temperature, piperidine (0.8mL, 8mmol) and 4' -chloro-biphenyl-4-carbaldehyde (2.27g, 10.5mmol) were added successively. The reaction was then refluxed overnight in an oil bath. After cooling to room temperature, 200mL of distilled water was added, and then 2mL of glacial acetic acid was slowly added dropwise, followed by stirring at room temperature for 30min. The precipitate was collected by filtration, washed with water, dried in vacuo and the resulting solid was recrystallized from methanol to give 2.23g of a yellow crystalline solid 1a in 71% yield, mp:93-94 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.65(s,1H),7.85(d,J＝8.5Hz,3H),7.77(d,J＝8.5Hz,2H),7.69(d,J＝8.0Hz,2H),7.55(d,J＝8.5Hz,2H).
Synthesis of 2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetic acid (2 a)
Compound 1a (2.21g, 7mmol) was dissolved in 100mL of anhydrous acetone, followed by the addition of potassium carbonate (1.93g, 14mmol) and methyl bromoacetate (1.3mL, 14mmol). The reaction was transferred to an oil bath and stirred at reflux overnight. After cooling to room temperature, the filtrate was filtered off, dried by spinning and recrystallized from methanol to give 1.54g of a yellow solid with a yield of 59%. 1.24g was dissolved in 18mL of glacial acetic acid, after which 4.5mL of concentrated HCl was added and the reaction was transferred to an oil bath. After refluxing for 4h, the reaction was cooled overnight. The precipitate was collected by filtration, washed with water and dried in vacuo to give 1.12g of Compound 2a as a yellow solid in 94% yield, mp:100-101 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ13.43(s,1H),8.04(s,1H),7.89(d,J＝8.5Hz,2H),7.80-7.74(m,4H),7.56(d,J＝8.5Hz,2H),4.41(s,2H).
Synthesis of (S) -tert-butyl (1- (3-nitro-4-chlorobenzenesulfonamido) -1-oxo-3-phenylpropan-2-yl) carbamate (4 a)
N-Boc-L-phenylalanine 3a (1.33g, 5 mmol) was dissolved in 30mL of anhydrous dichloromethane under ice-bath conditions, followed by the sequential addition of DIEA (1.75mL, 10 mmol) and HATU (2.29g, 6 mmol). After stirring for 30min, 3-nitro-4-chlorobenzenesulfonamide (1.3g, 1.1mmol) was added. The ice bath was removed, stirred at room temperature overnight and the solvent was spin dried. Then extracting with ethyl acetate2 times, the ethyl acetate layers were combined and washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and spin-drying, separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1-6:1) gave 1.96g of white solid 4a in 81% yield, mp:118-119 ℃. 1 H NMR(500MHz,CDCl 3 -d 6 ),δ10.22(s,1H),8.45(s,1H),8.17-8.25(m,1H),7.72(d,J＝8.5Hz,1H),7.20-7.19(m,3H),7.03(d,J＝4.5Hz,2H),5.16(s,1H),4.38(s,1H),3.04-3.00(m,1H),2.93-2.89(m,1H),1.38(s,9H).
Synthesis of (S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (LJB-II-20) (A1)
One of the key intermediates 4a (0.58g, 1.2mmol) was dissolved in 20mL of a hydrogen chloride gas saturated solution in ethyl acetate, which was filtered and dried after stirring overnight at room temperature, and this hydrochloride intermediate was collected for use. Another key intermediate 2a (0.37g, 1mmol) was dissolved in 20mL of anhydrous tetrahydrofuran and stirred at-20 ℃. N-methylmorpholine (0.24mL, 2.2 mmol) and isobutyl chloroformate (0.2mL, 1.5 mmol) were added every 10min. After stirring for 1h, the intermediate hydrochloride salt was added and allowed to warm slowly to room temperature and stirred overnight. The reaction solvent was spin-dried, then an appropriate amount of ethyl acetate was added and transferred to a separatory funnel, washed 2 times with 1mol/L hydrochloric acid solution and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered and spin-dried, and purified and separated by column chromatography (petroleum ether: ethyl acetate = 1:1-1:2) to obtain 0.11g of pale yellow solid A1, yield: 14% and mp:208-209 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ8.37(s,1H),8.18(s,1H),8.05-8.00(m,2H),7.89-7.84(m,3H),7.81-7.74(m,4H),7.57(d,J＝7.5Hz,2H),7.12(s.3H),6.99(s,2H),4.32-4.27(m,3H),2.97(d,J＝8.5Hz,1H),2.83(d,J＝6.0Hz,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ166.80,165.18,164.14,146.47,140.59,137.56,133.17,132.62,132.21,131.52,130.85,129.30,129.03,128.58,127.65,127.42,125.92,124.48,121.08,56.17,43.26,37.61.
EXAMPLE 2 Synthesis of (S) -N- (4-methylbenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (A2)
Intermediates and target compounds were prepared as in example 1. The yield is 20%, mp is 228-229 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.44(s,1H),8.66(d,J＝7.0Hz,1H),7.99(s,1H),7.88(d,J＝8.0Hz,2H),7.79-7.73(m,6H),7.56(d,J＝8.0Hz,2H),7.43(d,J＝7.5Hz,2H),7.21-7.11(m,5H),4.52(d,J＝5.5Hz,1H),4.30-4.20(m,2H),2.94-2.91(m,1H),2.73-2.69(m,1H),2.41(s,3H). 13 C NMR(125MHz,DMSO-d 6 ),δ170.35,167.22,165.57,165.53,144.75,141.15,138.04,136.78,133.69,133.24,132.69,131.36,130.01,129.66,129.53,129.07,128.58,128.04,127.93,127.02,121.49,54.94,43.61,37.15,21.58.
EXAMPLE 3 Synthesis of (S) -N- (4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3-phenylpropanamide (A3)
Intermediates and target compounds were prepared as in example 1. The yield is 26 percent, and the mp is 238-239 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.63(s,1H),8.70(d,J＝7.5Hz,1H),7.80(s,1H),7.90-7.87(m,4H),7.80(d,J＝8.0Hz,2H),7.75-7.69(m,4H),7.57(d,J＝8.5Hz,2H),7.21-7.11(m,5H),4.52-4.49(m,1H),4.31-4.22(m,2H),2.94-2.90(m,1H),2.76-2.72(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ170.59,167.24,165.61,165.58,141.15,139.20,138.25,138.04,136.68,133.70,133.27,132.69,131.37,130.00,129.75,129.65,129.53,129.07,128.58,127.92,127.06,121.48,55.03,43.60,37.02.
EXAMPLE 4 Synthesis of (S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (A4)
Intermediates and the preparation of the target compounds are carried out as in example 1. The yield is 25%, mp 195-196 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ8.40(s,1H),8.33(s,1H),8.07(d,J＝7.5Hz,1H),7.99(s,1H),7.92(d,J＝8.0Hz,1H)),7.86(d,J＝8.0Hz,2H),7.73(d,J＝8.6Hz,2H),7.67(d,J＝8.0Hz,2H)),7.32(d,J＝7.5Hz,2H),7.14-7.03(m,5H),4.31-4.23(m,3H),2.97-2.93(m,1H),2.82-2.78(m,1H),2.36(s,3H). 13 CNMR(125MHz,DMSO-d 6 ),δ170.81,170.21,167.25,165.58,165.55,144.61,141.16,139.77,138.05,136.27,133.69,133.24,132.70,131.90,131.39,129.95,129.54,129.10,128.04,127.95,121.50,120.29,54.74,43.65,36.53,21.59.
EXAMPLE 5 Synthesis of (S) -N- (4-methylbenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3-phenylpropanamide (A5)
Intermediates and target compounds were prepared as in example 1. The yield is 45%, mp:251-252 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.46(s,1H),8.66(s,1H),7.99(s,1H),7.85-7.66(m,8H)),7.43-7.11(m,9H),4.51(s,1H),4.26(d,J＝11.5Hz,2H),2.93-2.91(m,1H),2.73-2.70(m,1H),2.41(s,3H),2.36(s,3H). 13 C NMR(125MHz,DMSO-d 6 ),δ170.35,167.29,165.61,165.56,144.77,142.53,138.33,136.78,136.67,136.32,133.45,132.04,131.36,130.19,130.02,129.67,128.59,128.05,127.66,127.14,127.04,120.97,54.93,43.60,37.14,21.58,21.21.
EXAMPLE 6 Synthesis of (S) -N- (4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (A6)
Intermediates and target compounds were prepared as in example 1. The yield is 26%, mp 222-223 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.61(s,1H),8.50(d,J＝5.5Hz,1H),7.93(s,1H),7.81-7.80(m,4H),7.70-7.66(m,4H),7.60(d,J＝8.5Hz,2H),7.45-7.42(m,2H),7.37-7.34(m,1H),7.12-7.01(m,5H),4.41-4.37(m,1H),4.24-4.15(m,2H),2.88-2.84(m,1H),2.71-2.66(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ171.22,167.28,165.62,165.41,142.57,139.26,136.98,133.37,132.38,131.34,129.91,129.68,129.57,129.47,128.77,128.50,127.97,127.31,126.93,121.26,55.32,43.65,37.23.
EXAMPLE 7 Synthesis of (S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3-phenylpropanamide (A7)
Intermediates and target compounds were prepared as in example 1. The yield was 22%, mp:232-233 ℃ 1H NMR (500MHz, DMSO-d) 6 ),δ8.70(d,J＝6.5Hz,1H),8.49(d,J＝2.5Hz,1H),8.12(dd,J 1 ＝2.0Hz,J 2 ＝8.5Hz,1H),8.02-8.00(m,2H),7.89(d,J＝8.5Hz,2H),7.77-7.74(m,4H),7.52(t,J＝7.5Hz,2H),7.44-7.41(m,1H),7.20-7.19(m,3H),7.12-7.11(m,2H),4.51-4.46(m,1H),4.30-4.23(m,2H),2.96-2.92(m,1H),2.82-2.77(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ171.22,167.29,165.67,165.62,147.51,142.58,139.54,139.26,136.65,133.40,132.87,132.38,131.37,131.14,129.68,129.59,128.79,128.54,128.00,127.33,127.05,125.61,121.23,55.24,43.57,36.94.
EXAMPLE 8 Synthesis of (S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A8)
Intermediates and the preparation of the target compounds are carried out as in example 1. The yield is 36%, mp is 198-199 deg.C. 1 H NMR(500MHz,DMSO-d 6 ),δ8.49(s,1H),8.36(d,J＝8.5Hz,2H),8.08(d,J＝9.0Hz,2H),8.00(s,1H),7.89(d,J＝8.0Hz,2H),7.80(d,J＝8.5Hz,2H),7.75(d,J＝8.0Hz,2H),7.57(d,J＝8.5Hz,2H),7.35(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),4.38(d,J＝6.0Hz,1H),4.26(s,2H),2.95-2.91(m,1H),2.79-2.75(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ167.27,165.61,165.23,149.80,141.13,138.03,136.84,133.68,133.21,132.69,131.96,131.36,131.26,129.52,129.38,129.07,127.91,124.26,121.49,120.06,55.66,43.71,36.85.
EXAMPLE 9 Synthesis of (S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A9)
Intermediates and target compounds were prepared as in example 1. The yield is 37%, mp is 232-233 deg.C. 1 H NMR(500MHz,DMSO-d 6 ),δ8.44(s,1H),8.09(d,J＝8.5Hz,1H),8.00(s,1H),7.94-7.88(m,4H),7.80(d,J＝8.5Hz,2H),7.76(d,J＝8.5Hz,2H),7.57(d,J＝8.5Hz,2H),7.33(d,J＝8.5Hz,2H),7.01(d,J＝8.0Hz,2H),4.35-4.34(m,1H),4.27(s,2H),2.95-2.91(m,1H),2.80-2.76(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ166.72,165.07,164.77,146.74,140.60,140.56,137.51,136.17,133.15,133.07,132.67,132.64,132.26,132.17,131.43,130.82,130.68,128.97,128.51,127.36,124.83,120.96,119.64,55.08,43.20,36.25.
EXAMPLE 10 Synthesis of (S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propanamide (A10)
Intermediates and target compounds were prepared as in example 1. The yield is 39%, mp is 211-212 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.87(s,1H),8.72(d,J＝7.0Hz,1H),8.42(d,J＝8.5Hz,2H),8.13(d,J＝8.5Hz,2H),7.98(s,1H),7.86(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),7.11(d,J＝8.0Hz,2H),4.50(dd,J 1 ＝7.5Hz,J 2 ＝14.0Hz,1H),4.25(s,2H),2.93-2.90(m,1H),2.77-2.73(m,1H),2.36(s,3H). 13 C NMR(125MHz,DMSO-d 6 ),δ170.93,167.29,165.69,165.60,150.59,142.53,138.32,136.31,136.22,133.47,132.01,131.90,131.45,131.35,130.18,129.68,127.63,127.12,124.78,120.91,120.36,55.00,43.57,36.30,21.21.
EXAMPLE 11 Synthesis of (S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A11)
Intermediates and target compounds were prepared as in example 1. The yield is 17%, mp is 178-179 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ8.40(s,1H),8.24(s,1H),8.06-8.01(m,2H),7.94-7.87(m,3H),7.77-7.74(m,4H),7.52-7.50(m,2H),7.44-7.41(m,1H),7.30(d,J＝7.0Hz,2H),6.97(d,J＝7.0Hz,2H),4.28(s,3H),2.95-2.92(m,1H),2.81-2.77(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ173.59,166.97,165.17,164.63,146.51,143.42,142.02,138.59,136.48,132.86,132.17,131.84,131.69,131.42,130.82,130.56,129.09,128.28,128.11,127.37,126.71,124.48,120.64,119.41,55.68,43.16,36.64.
EXAMPLE 12 Synthesis of (S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A12)
Intermediate and target compound preparation methodThe procedure is as in example 1. The yield is 22%, mp is 184-185 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.79(s,1H),8.73(d,J＝7.5Hz,1H),8.42(d,J＝9.0Hz,2H),8.13(d,J＝8.5Hz,2H),7.99(s,1H),7.89(d,J＝8.5Hz,2H),7.77-7.74(m,4H),7.53(t,J＝7.5Hz,2H),7.44-7.37(m,3H),7.11(d,J＝8.5Hz,2H),4.50-4.46(m,1H),4.25(s,2H),2.93-2.90(m,1H),2.77-2.73(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ170.80,167.27,165.71,165.59,150.68,142.61,139.26,136.18,133.41,132.36,131.89,131.46,131.35,129.69,129.58,128.77,127.98,127.32,124.81,121.22,120.37,54.95,43.59,36.27.
EXAMPLE 13 Synthesis of (S) -N- (4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A13)
Intermediates and target compounds were prepared as in example 1. The yield is 55%, mp is 174-175 deg.C. 1 H NMR(500MHz,DMSO-d 6 ),δ12.62(s,1H),8.70(d,J＝7.5Hz,1H),8.01(s,1H),7.89-7.84(m,4H),7.77-7.74(m,4H),7.71(d,J＝8.5Hz,2H)7.53(t,J＝7.5Hz,2H),7.44-7.38(m,3H),7.08(d,J＝8.5Hz,2H),4.51(dd,J 1 ＝8.0,J 2 ＝13.5Hz,1H),4.29-4.22(m,2H),2.91-2.87(m,1H),2.74-2.69(m,1H). 13 CNMR(125MHz,DMSO-d 6 ),δ169.81,166.80,165.20,165.10,142.08,138.80,138.74,137.60,135.61,132.91,131.85,131.38,130.93,130.87,129.51,129.27,129.09,128.28,127.48,126.82,120.72,119.89,54.24,43.10,36.20.
EXAMPLE 14 Synthesis of (S) -N- (4-methylbenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (A14)
Intermediates and the preparation of the target compounds are carried out as in example 1. The yield is 18 percent, and mp is 182-183 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ12.43(s,1H),8.68(d,J＝6.5Hz,1H),8.00(s,1H),7.89(d,J＝7.0Hz,2H),7.77-7.75(m,6H),7.51-7-37(m,7H),7.07(d,J＝7.0Hz,2H),4.51(s,1H),4.29-4.22(m,2H),2.90-2.88(m,1H),2.71-2.67(m,1H),2.42(s,3H). 13 C NMR(125MHz,DMSO-d 6 ),δ169.61,166.79,165.10,144.26,142.08,138.74,136.16,135.71,132.88,131.85,131.38,130.91,130.86,129.49,129.08,128.28,127.55,127.48,126.82,120.73,119.82,54.18,43.13,36.00,21.09.
EXAMPLE 15 Synthesis of (S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (A15)
Intermediates and target compounds were prepared as in example 1. The yield is 15%, mp is 189-190 ℃. 1 H NMR(500MHz,DMSO-d 6 ),δ8.67(d,J＝6.5Hz,1H),8.41(d,J＝8.5Hz,1H),8.14-8.10(m,1H),8.00-7.97(m,1H),7.89-7.85(m,2H),7.80-7.73(m,4H),7.60-7.55(m,4H),7.41-7.37(m,2H),7.16(d,J＝8.0Hz,1H),7.06(d,J＝8.0Hz,2H),6.94-6.81(m,3H),5.06-5.01(m,2H),4.44(d,J＝7.0Hz,1H),4.25(s,2H),2.88-2.84(m,1H),2.73-2.68(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ166.74,165.09,164.91,156.79,140.64,140.60,137.53,136.60,136.56,133.18,132.76,132.73,132.17,131.29,130.86,130.25,129.66,129.03,128.57,127.41,124.06,120.94,120.84,114.34,68.24,55.18,43.13,35.85.
EXAMPLE 16 Synthesis of (S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (A16)
Intermediates and target compounds were prepared as in example 1. The yield is 36%, mp is 183-184 deg.C. 1 H NMR(400MHz,DMSO-d 6 ),δ8.68(d,J＝7.2Hz,1H),8.39(d,J＝8.8Hz,2H),8.10(d,J＝8.8Hz,2H),7.95(s,1H),7.84(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),7.65(d,J＝8.0Hz,2H),7.58(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),7.30(d,J＝8.0Hz,2H),7.04(d,J＝8.4Hz,2H),6.83(d,J＝8.0Hz,2H),5.02(s,2H),4.44-4.38(m,1H),4.22(s,2H),2.86-2.81(m,1H),2.70-2.64(m,1H),2.33(s,3H). 13 C NMR(100MHz,DMSO-d 6 ),δ170.58,166.79,165.16,165.11,156.87,150.15,148.34,142.03,137.83,136.59,135.81,132.97,131.51,131.30,130.86,130.23,129.69,129.19,128.42,127.15,126.64,124.31,120.85,120.42,114.42,68.25,54.87,43.05,35.60,20.71.
EXAMPLE 17 Synthesis of (S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (A17)
Intermediates and target compounds were prepared as in example 1. The yield is 31 percent, and mp is 155-156 ℃. 1 H NMR(400MHz,DMSO-d 6 ),δ12.86(s,1H),8.52(s,1H),8.35(d,J＝8.8Hz,2H),8.06(d,J＝8.4Hz,2H),7.96(s,1H),7.85(d,J＝8.0Hz,2H),7.74-7.69(m,4H),7.57(d,J＝8.4Hz,2H),7.49(t,J＝7.6Hz,2H),7.41-7.36(m,3H),7.00(d,J＝8.4Hz,2H),6.79(d,J＝8.4Hz,2H),5.00(s,2H),4.34-4.31(m,1H),4.22(s,2H),2.86-2.81(m,1H),2.70-2.64(m,1H). 13 C NMR(100MHz,DMSO-d 6 ),δ171.06,167.23,165.66,165.58,157.16,150.68,147.43,145.61,141.18,138.04,133.70,133.27,132.67,131.38,130.81,129.70,129.54,129.22,129.09,128.61,127.94,124.84,124.07,121.44,114.97,68.41,55.36,43.57,36.10.
EXAMPLE 18 Synthesis of (S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (benzyloxy) phenyl) propionamide (A18)
Intermediates and target compounds were prepared as in example 1. The yield is 34%, mp:188-189 ℃. 1 H NMR(400MHz,DMSO-d 6 ),δ12.86(s,1H),8.72(s,1H),8.42(d,J＝7.2Hz,2H),8.13(d,J＝7.2Hz,2H),8.00(s,1H),7.89-7.75(m,6H),7.51-7.34(m,8H),7.07(d,J＝6.4Hz,2H),6.86(d,J＝6.0Hz,2H),5.06(s,2H),4.45(s,1H),4.26(s,2H),2.87-2.85(m,1H),2.73-2.68(m,1H). 13 C NMR(125MHz,DMSO-d 6 ),δ167.26,165.63,165.24,157.01,147.41,147.28,145.66,141.13,138.04,133.69,133.20,132.81,132.71,131.36,130.86,129.75,129.53,129.08,128.57,127.93,125.40,124.07,121.52,114.75,68.39,55.97,43.71,36.57.
EXAMPLE 19 Synthesis of (S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (benzyloxy) phenyl) propionamide (A19)
Intermediates and target compounds were prepared as in example 1. The yield is 24%, mp is 216-217 ℃. 1 H NMR(400MHz,DMSO-d 6 ),δ12.86(s,1H),8.73(d,J＝6.8Hz,1H),8.53(d,J＝2.0Hz,1H),8.14-8.12(m,1H),8.03-8.00(m,2H),7.89(d,J＝8.4Hz,2H),7.77-7.73(m,4H),7.53-7.34(m,8H),7.05(d,J＝8.4Hz,2H),6.86(d,J＝8.4Hz,2H),5.06(s,2H),4.48(dd,J 1 ＝7.2Hz,J 2 ＝13.6Hz,1H),4.28(s,2H),2.90-2.86(m,1H),2.75-2.70(m,1H). 13 C NMR(100MHz,DMSO-d 6 ),δ171.10,167.29,165.71,165.62,157.64,147.53,142.59,139.26,137.60,133.46,133.40,132.87,132.38,131.36,131.32,130.74,129.59,128.90,128.78,128.66,128.27,128.12,127.99,127.32,125.69,121.25,114.84,69.61,55.40,43.58,36.10.
EXAMPLE 20 Synthesis of (S) -N- (4-Nitrophenylsulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (4-nitrobenzyloxy) phenyl) propionamide (A20)
Intermediates and the preparation of the target compounds are carried out as in example 1. The yield is 50%, mp is 205-206 ℃. 1 H NMR(400MHz,DMSO-d 6 ),δ12.88(s,1H),8.47(s,1H),8.37(d,J＝8.8Hz,2H),8.28(d,J＝8.8Hz,2H),8.09(d,J＝8.8Hz,2H),7.99(s,1H),7.89(d,J＝8.4Hz,2H),7.77-7.70(m,6H),7.53-7.49(m,2H),7.45-7.41(m,1H),7.04(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),5.23(s,2H),4.36-4.21(m,3H),2.92-2.87(m,1H),2.75-2.70(m,1H). 13 C NMR(100MHz,DMSO-d 6 ),δ167.30,165.65,165.20,156.98,149.83,147.41,145.67,142.56,139.24,133.34,132.36,131.34,130.85,129.92,129.58,129.41,128.78,128.57,127.96,127.31,124.31,124.06,121.23,114.82,68.39,56.03,43.70,36.62.
Evaluation of target Compound Activity
EXAMPLE 1 test for Mcl-1 protein inhibition by the Compound of interest (In vitro)
Experimental reagent:
Bid-BH3 polypeptide with N-terminal fluorescently labeled by 5-FAM
(5-FAM-QEDIIRNIARHLAQVGDSMDRSIPPG) in 1 x PBS;
test buffer: 1 × PBS;
correction solution: 1nM fluoroescein, 10mM NaOH;
an experimental instrument:
TECAN Genios Pro type multifunctional microplate reader.
The experimental steps are as follows:
(1) And adding the target protein and the small molecular compound to be detected into the test buffer solution, uniformly mixing, and incubating for 30min at room temperature in a dark place. Then adding fluorescence labeled Bid BH3 polypeptide to ensure that the total volume of each solution is 200 mu L, uniformly mixing, and incubating for 20min at room temperature in a dark place.
(2) 60 μ L of each of the above-mentioned solution and the calibration solution was transferred to a black 384-well plate (three sets of plates in parallel), and fluorescence polarization was immediately detected on a microplate reader at 485nm as an excitation wavelength and 535nm as an emission wavelength, and the fluorescence polarization value of the calibration solution was set to 20mP.
(3) All compounds were first screened initially at three typical concentrations (1. Mu.M, 10. Mu.M, 50. Mu.M), each compound was assayed in duplicate in 3 wells on the same plate, and the results of the polarization values were averaged. And (4) calculating the inhibition rate according to the measurement results of the negative control, the positive control and the polarization value of the tested compound. The concentration of the target protein usually adopted in the determination is 300-500 nM, the fluorescence labeling polypeptide adopts 5-FAM-Bid-BH3 polypeptide, and the positive compound adopts AT-101. If the test result shows that the compound has an inhibition rate of more than 50% at a concentration of 50 mu M and the inhibition rate shows obvious dose-dependent relationship at three concentrations tested, the compound is considered to have specific binding with the target protein, and a more accurate IC (integrated circuit) needs to be further determined 50 Numerical values.
(4) The complete binding curve was determined at 7 different concentrations (1nM, 10nM,100nM, 1. Mu.M, 10. Mu.M, 50. Mu.M, 100. Mu.M) for compounds showing significant activity in the primary screen. Each compound was subjected to 3 replicate wells on the same plate and the results of the polarization measurements were averaged. Data were processed and plotted using GraphPad Prism software to obtain the IC of the compound 50 The value is obtained.
(5) Based on the total concentration of protein, total concentration of fluorescent polypeptide, dissociation constant of protein-polypeptide complex, and IC of the test compound used in the measurement 50 Values, competitive inhibition constant K for test compounds, using the calculation methods described in the literature i (Nikolovska-Coleska,Z.；et al.Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization.Anal Biochem.2004,332,261-273).
The results are shown in Table 2.
TABLE 2 in vitro inhibition test results of target compound on Mcl-1 protein
a The values in the table are the average of the results of three experiments and it can be seen that most compounds show inhibitory activity at sub-micromolar levels against Mcl-1. When the amino acid is phenylalanine or 4-bromophenylalanine and the sulfonamide moiety is 4-chloro-3-nitrobenzenesulfonamide or 4-nitrobenzenesulfonamide, the compounds have better inhibitory activity on Mcl-1 protein, such as compounds A1, A4, A8, A9, A10 and A11. Among them, the inhibitory activity of the compounds A1, A4, A8, A9 and A11 on Mcl-1 was comparable to that of the positive drug UMI-77. In addition, the compound A10 with the highest activity shows the inhibitory activity higher than that of a positive control drug, and has important significance for further developing Mcl-1 protein inhibitors with higher activity and preparing drugs for preventing and treating related mammal diseases caused by abnormal expression of Mcl-1 protein.
EXAMPLE 2 Activity test for inhibition of cell proliferation by target Compound (In vitro)
From these, 4 compounds with better enzymatic activity were selected for the activity test of inhibiting cancer cell proliferation in vitro, and the results are shown in table 3.
Description of terms:
myeloma cell line KM3, non-small cell lung cancer H1299 and normal liver cell line LO2.
IC 50 : half inhibitory concentration.
Materials:
KM3, H1299, LO2, MTT,10% fetal calf serum and 96-well plate
The method comprises the following steps:
the cell culture cell strain is cultured by a conventional method. Cells in logarithmic growth phase were used for all experiments.
Cell growth assay (MTT method) cell suspension was adjusted to 5X 10 4 /mL (suspension cells adjusted to 10) 5 mL), seeded in 96-well plates (100 μ L/well), 2000-5000 cells/well, respectively. After plating for 4h, 100 μ L of medium containing different concentrations of compounds was added to each well, three replicates per concentration were set, and wells with no cells were read as blank, wells with no cells added as compound blank wells, and UMI-77 as compound positive control. At 37 ℃ C, 5% CO 2 The culture medium is incubated for 48h, 10. Mu.L of 0.5% MTT staining solution is added to each well, and the incubation is continued. After 4h, centrifuge at 2500rpm for 30min, discard the medium in the plate well, add 150. Mu.L DMSO per well, shake at 37 ℃ for 5-10min. Measuring the absorbance OD value of each hole at 570nm on a microplate reader, and calculating the cell growth inhibition rate according to the following formula:
TABLE 3 antitumor cell proliferation test results of Compounds A1, A8, A9 and A10
a The values in the table are the average of three tests, and the values after "+ -" indicate the standard deviation
In-vitro antiproliferative activity experiments of KM3 and H1299 tumor cells and a normal liver cell strain LO2 are carried out on 4 compounds with better enzyme activity. Test data show that 4 tested target compounds have inhibitory effect on two tumor cells, especially KM3 cells. Meanwhile, these 4 compounds had little effect on the growth of normal cells. And the inhibitory activity of the compounds on KM3 cells is equivalent to that of positive control UMI-77, which shows that the substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor has good development prospect, can carry out deep activity research, and develops more active compounds for preparing medicaments for preventing and treating related mammal diseases caused by abnormal expression of Mcl-1 protein.
Claims (11)
1. A substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor is a compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof:
in the general formula (I),
R 1 is an aromatic group Ar connected by 1-2 hydroxyl groups, halogen, nitro-substituted or unsubstituted morpholine groups and piperazine groups; ar is selected from phenyl, naphthyl and indolyl;
R 2 is isopropyl or-A-R 4 (ii) a Wherein R is 4 Is phenyl containing 1-2 substituent groups or unsubstituted, wherein the substituent groups are hydroxyl, halogen, nitro, cyano, guanidino and carboxyl;
R 3 is an aromatic group Ar connected by 1-2 hydroxyl groups, halogen, nitro or unsubstituted morpholine groups and piperazine groups; ar is selected from phenyl, naphthyl and indolyl.
2. The substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitor is characterized by being one of the following compounds:
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (LJB-II-20) (A1);
(S) -N- (4-methylbenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (LJB-II-28) (A2);
(S) -N- (4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (LJB-II-30) (A3);
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (LJB-III-10) (A4);
(S) -N- (4-methylbenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (LJB-III-12) (A5);
(S) -N- (4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (DX-I-4) (A6);
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3-phenylpropanamide (DX-I-6) (A7);
(S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propanamide (LJB-II-44) (A8);
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (LJB-II-45) (A9);
(S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (LJB-II-41) (a 10);
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (DX-I-10) (a 11);
(S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (DX-I-19) (a 12);
(S) -N- (4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4-bromophenyl) propionamide (DX-I-21) (a 13);
(S) -N- (4-methylbenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4-bromophenyl) propionamide (DX-I-22) (a 14);
(S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (DX-I-20) (a 15);
(S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- ((4 '-methyl- [1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (LJB-III-27) (a 16);
(S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-dione-3-yl) acetamido) -3- (4- (4-bromobenzyloxy) phenyl) propionamide (DX-I-36) (a 17);
(S) -N- (4-nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (benzyloxy) phenyl) propionamide (DX-I-39) (a 18);
(S) -N- (3-nitro-4-chlorobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (benzyloxy) phenyl) propionamide (LJB-III-43) (a 19);
(S) -N- (4-Nitrobenzenesulfonyl) -2- (2- (5- (([ 1,1' -biphenyl ] -4-yl) methylene) -thiazolidine-2,4-diketo-3-yl) acetamido) -3- (4- (4-nitrobenzyloxy) phenyl) propanamide (LJB-III-45) (A20).
3. The process for preparing a substituted 3-thiazolidine-2,4-dione Mcl-1 protein inhibitor according to claim 1 or 2, comprising the steps of:
the method comprises the following steps: taking thiazolidine-2,4-diketone as a starting material, and carrying out Knoevenagel condensation reaction with different substituted formaldehyde to generate intermediates 1a-1c;
step two: nucleophilic substitution reaction is carried out on the 3-site N of the thiazolidine of the intermediate 1a-1c and methyl bromoacetate, and the methyl ester is removed under the acidic condition to generate a key intermediate 2a-2c;
step three: carrying out amide condensation reaction on different substituted amino acids 3a-3e and different substituted benzene sulfonamides to generate key intermediates 4a-4k;
step four: the key intermediates 4a-4k are subjected to Boc protection removal in hydrogen chloride gas saturated ethyl acetate, and then are subjected to amide condensation reaction with another key intermediate 2a-2c under the action of N-methylmorpholine and isobutyl chloroformate by using a mixed anhydride method to obtain target compounds A1-A20, namely substituted 3-thiazolidine-2,4-diketone Mcl-1 protein inhibitors;
wherein R is 1 -R 3 The definition of (A) is as described in the above general formula (I).
4. The method for preparing the substituted 3-thiazolidine-2,4-dione Mcl-1 protein inhibitor according to claim 3, wherein the method comprises the following steps: reagents and conditions a: different substituted formaldehydes, piperidine, ethanol, reflux.
5. The method of preparing a substituted 3-thiazolidine-2,4-dione Mcl-1 protein inhibitor according to claim 3, wherein the substituted 3-thiazolidine-2,4-dione Mcl-1 protein inhibitor comprises: reagents and conditions b: i. refluxing methyl bromoacetate, potassium carbonate and acetone; glacial acetic acid, concentrated hydrochloric acid, reflux.
6. The method for preparing the substituted 3-thiazolidine-2,4-dione Mcl-1 protein inhibitor according to claim 3, wherein the method comprises the following steps: reagents and conditions c:2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIEA), dichloromethane, ice bath-room temperature.
7. The method for preparing the substituted 3-thiazolidine-2,4-dione Mcl-1 protein inhibitor according to claim 3, wherein the method comprises the following steps: reagents and conditions d: i. hydrogen chloride saturated ethyl acetate solution, room temperature; n-methylmorpholine, isobutyl chloroformate, tetrahydrofuran, from-20 ℃ to room temperature.
8. Use of a compound according to any one of claims 1-2 for the manufacture of a medicament for the prophylaxis or treatment of a disease in a mammal associated with abnormal Mcl-1 protein expression.
9. The use according to claim 8, wherein the mammalian diseases associated with the abnormal expression of Mcl-1 protein include cancer, neurodegenerative diseases, viral infections, inflammation, leukemia, malaria and diabetes.
10. A pharmaceutical composition suitable for oral administration to a mammal comprising a compound of any one of claims 1-2 and one or more pharmaceutically acceptable carriers or excipients.
11. A pharmaceutical composition suitable for parenteral administration to a mammal comprising a compound of any one of claims 1-2 and one or more pharmaceutically acceptable carriers or excipients.
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