CN106565823B - Eph receptor small molecule inhibitor and preparation method thereof - Google Patents
Eph receptor small molecule inhibitor and preparation method thereof Download PDFInfo
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- CN106565823B CN106565823B CN201610994909.2A CN201610994909A CN106565823B CN 106565823 B CN106565823 B CN 106565823B CN 201610994909 A CN201610994909 A CN 201610994909A CN 106565823 B CN106565823 B CN 106565823B
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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Abstract
The invention discloses an Eph receptor small molecule inhibitor compound or an isomer, a diastereoisomer, an enantiomer, a meso body, a racemate, a mixture form thereof or a medical salt thereof, which has the following structural general formula:
selectively acts on the extracellular binding region of Eph receptor and ephrin ligand, and can be used for treating nervous system diseases and vascular system diseases of mammals and inhibiting the occurrence and development of tumor diseases. The invention also discloses a preparation method of the Eph receptor small molecule inhibitor compound, and the preparation method is simple to operate and good in reproducibility.
Description
Technical Field
The invention relates to the field of tyrosine kinase inhibition, in particular to a receptor tyrosine kinase Eph (erythropoietin-producing liver cell receptor) small molecule inhibitor compound, and provides the Eph receptor small molecule inhibitor compound or isomers, diastereomers, enantiomers, meso-forms, racemic forms and mixture forms thereof, or pharmaceutically acceptable salts thereof, and a method for preparing the compound.
Background
The Eph receptor family is the largest known family of receptor tyrosine kinases (RPTK). The Eph receptor family is divided into EphA receptor subfamily and EphB receptor subfamily according to differences in sequence homology, structure, expression and ligand binding properties, and the ligand is named Ephrin. The EphA receptor subfamily comprises 10 members EphA1-EphA10, and the EphB receptor subfamily comprises 6 members EphB1-EphB 6. 9 EphA receptors bind to 5A-class ephrin ligands, and 5 EphB receptors bind to 3B-class ephrin. Eph receptor is a membrane-bound glycoprotein whose structure includes an extracellular ligand-binding domain, an intracellular tyrosine kinase active domain, and a transmembrane domain composed of hydrophobic amino acids connecting these two domains. The extracellular domain of the Eph receptor subfamily consists of an N-terminal globular domain, a cysteine-rich region and two fibronectin type III repeats. The intracellular region of the Eph receptor subfamily contains the receptor tyrosine kinase domain. The receptor forms polymer after being combined with corresponding ligand, so that the conformation of the receptor is changed, tyrosine kinase in cytoplasm is activated, autophosphorylation is caused, downstream substrate protein molecules are activated through connecting protein, and signals are transmitted step by step.
EphA and EphB receptor tyrosine kinases, as well as their ligands ephrin-A and ephrin-B, play important physiopathological roles in different histiocytes. Therefore, the development of molecules that modulate the activity of the Eph/ephrin protein complex can be used as molecular probes for studying the Eph/ephrin complex system and as chemical drugs for treating various related diseases, which can inhibit the metastasis and angiogenesis of tumor cells or promote the neural development of the damaged nervous system (regeneration of nerve cells). The role of the Eph/ephrin protein complex in stem cell proliferation and differentiation can also be exploited as a regenerative drug. In addition, molecules that interfere with the interaction of the Eph/ephrin protein complex may also be used in antiviral therapy.
At present, Eph kinase inhibitors acting on intracellular tyrosine kinase domains have been reported in the literature, but as competitive inhibitors of Adenosine Triphosphate (ATP) binding to tyrosine kinases, these inhibitors also act on other kinase family proteins and do not act selectively on Eph kinase proteins. Therefore, the development of a small molecule inhibitor which targets the extracellular binding region of Eph receptor and ephrin ligand thereof rather than the intracellular tyrosine kinase region is of great significance for treating nervous system diseases, vascular system diseases and inhibiting the occurrence and development of tumors.
Disclosure of Invention
In order to solve the above technical problems, the present invention provides a compound which is a small molecule inhibitor of Eph receptor selectively acting on Eph kinase protein or its isomers, diastereomers, enantiomers, meso forms, racemic forms and mixtures thereof, or its pharmaceutically acceptable salts, and a method for preparing such a compound.
The invention provides an Eph receptor small molecule inhibitor compound or isomers, diastereomers, enantiomers, meso-forms, racemic forms, mixtures thereof, or pharmaceutically acceptable salts thereof, which has the following general structural formula:
in formula I:
is a single bond or is free of such a single bond;
R1the group is selected from hydroxy, amino, -O (R)2)、-NH(R2) or-N (R)2)(R3)；
The L group is selected from-O-, -S (O)2-、-C(O)N(R2)-、-N(R2)C(O)-、-C(S)N(R2)-、-N(R2)C(S)-、-C(O)2-、-OC(O)-、-S(O)2N(R2)-、-N(R2)S(O)2-or without such a group;
x is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or the absence of such a group;
the Y group is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or no such group;
the A group is aryl, heteroaryl, alkenyl, alkynyl, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl or free of such groups;
the B group is aryl, heteroaryl, arylalkyl, haloalkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl or free of such groups;
R2and R3The radicals are identical or different and are each: alkyl, alkenyl, alkynyl, haloalkyl, cycloalkylHeteroalkyl, heterocycloalkyl, aryl, heteroaryl;
the R is1Group, said L group, said X group, said Y group, said A group, said B group, said R group2Group and said R3Any of which may be optionally substituted with one or more substituents independently selected from the group consisting of: H. halogen, ═ O, ═ S, -CF3、-OCF3Cyano, nitro, alkenyl, alkynyl, alkyl, haloalkenyl, haloalkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkoxy, carboxy, acyl, sulfonyl, amino, -C (O) OR4、-OC(O)R4、-COR4、-NHS(O)mR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-OC(O)NR5R6、-OC(O)R5R6、-SH、-SR5Substituted;
m is 1 or 2;
R4selected from aryl, heteroaryl, alkenyl, alkynyl, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl, optionally further substituted with one or more substituents selected from halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, acyl;
R5or R6Each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkenyl, alkynyl, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl, wherein said aryl, heteroaryl, alkenyl, alkynyl, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl is optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, acyl;
the halogen is fluorine, chlorine, bromine or iodine;
the alkyl group is C1-C16A linear or branched aliphatic hydrocarbon group;
the heteroalkyl group is a straight-chain or branched-chain alkyl-containing group and at least contains one or more heteroatoms, and the heteroatoms are S, O or N atoms;
the cycloalkyl is a saturated or partially saturated monocyclic, fused or spiro carbocyclic ring;
the heterocycloalkyl group is a cycloalkyl group containing at least one heteroatom;
the aryl group is an optionally substituted monocyclic, fused polycyclic or aromatic carbocyclic ring containing 5 to 12 carbon atoms;
the heteroaryl group is an optionally substituted aromatic ring-containing group having one or more heteroatoms in the ring atoms of the aromatic ring.
As a refinement of the invention, the X group is alkyl or cycloalkyl, the Y group is alkyl or aryl, the a group is selected from:
R7the group is H, the group B is
R8The groups may be optionally substituted with one or more substituents independently selected from the group consisting of: H. halogen, ═ O, ═ S, -CF3、-OCF3Cyano, nitro, alkenyl, alkynyl, alkyl, haloalkenyl, haloalkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkoxy, carboxy, acyl, sulfonyl, heteroaryl, alkoxy, sulfonyl, alkoxy,amino group, -C (O) OR4、-OC(O)R4、-COR4、-NHS(O)mR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-OC(O)NR5R6、-OC(O)R5R6、-SH、-SR5Wherein m and R are4、R5、R6As previously described.
The invention discloses a pharmaceutical composition, which comprises the compound and a pharmaceutically acceptable carrier, diluent or excipient.
As an improvement of the invention, the Eph receptor small molecule inhibitor compound or the isomer, diastereomer, enantiomer, mesomer, racemate or mixture form thereof, or the medical salt compound thereof is a selective Eph receptor small molecule inhibitor and acts on the extracellular binding area of Eph receptor and ephrin ligand.
As an improvement of the present invention, the compound acts on the extracellular binding region of Eph receptor and ephrin ligand, and is used for treating nervous system diseases, vascular system diseases or inhibiting the occurrence and development of tumor diseases in mammals.
The invention also provides a preparation method of the Eph receptor small molecule inhibitor compound or isomers, diastereomers, enantiomers, meso-forms, racemic forms and mixtures thereof, or medicinal salts thereof, which comprises the following steps:
carrying out palladium-catalyzed coupling reaction on the compound of the formula 1 and the compound of the formula 2 to obtain a compound of a formula 3; hydrolyzing the compound of formula 3 under alkaline conditions to obtain a compound of formula 4; condensing the compound of formula 4 with the compound of formula 5 under the condition of a condensing agent to obtain a compound of formula 6; coupling arginine with a protecting group with resin under the condition of a condensing agent to obtain a compound shown in a formula 9; the compound of formula 9 is coupled stepwise by a solid phase reaction to give a compound of formula 14;
wherein R is7And R8Is as defined above；
Condensing agents include, but are not limited to, N, N '-diisopropylcarbodiimide, N, N' -dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-tetramethylhexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
The invention has the following beneficial effects:
the Eph receptor small molecule inhibitor compound provided by the invention or the isomer, diastereomer, enantiomer, mesomer, racemate and mixture form thereof, or the medical salt thereof can selectively act on the extracellular binding region of the Eph receptor and ephrin ligand, and is used for treating nervous system diseases and vascular system diseases of mammals and inhibiting the occurrence and development of tumor diseases. The method is simple to operate and good in reproducibility.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a graph showing the inhibition of Hela cell activity by test compounds at various concentrations according to the present invention;
FIG. 2 is a graph comparing the inhibition of K562 cell activity by test compounds at different concentrations provided by the present invention.
Detailed Description
In order that those skilled in the art will more clearly understand and practice the present invention, reference is made to the following specific embodiments.
Example (b):
1) in the examples below, all temperatures are given in degrees celsius unless otherwise indicated.
2) Various starting materials and reagents are commercially available. Suppliers include, but are not limited to, AlfaAesar, Prodword et al. Unless otherwise indicated, commercial starting materials and reagents were used without further purification.
3) The glassware is oven dried and/or heat dried. Thin Layer Chromatography (TLC) using silica gel plates of 0.15-0.2mm size, analytical thin layer chromatography and development with appropriate solvent ratio (v/v). The column chromatography generally uses 200-300 mesh silica gel as a carrier.
4)1HNMR spectra were obtained using a Bruker instrument (400MHz) and chemical shifts are expressed in ppm. Chloroform was used as a reference standard (7.25ppm) or tetramethylsilane internal standard (0.00 ppm). Other solvents commonly used for NMR may also be used as necessary.1The HNMR can be expressed by s-singlet, d-doublet, t-triplet, m-multiplet, br-broadened, dd doublet of doublet, and dt doublet of triplet. If a coupling constant is provided, it is in Hz.
5) The mass spectrum is measured by an MS instrument, and the ionization mode can be ESI or APCI.
6) The following examples are merely illustrative of the synthesis of specific compounds of the invention. But there is no limitation on the synthesis method. The compounds not shown in the examples can be prepared by selecting appropriate starting materials and adjusting reaction conditions slightly appropriately and universally as necessary by the same synthetic route and synthetic method as described below.
The synthetic route for 5- (4-acetylphenyl) -N- (3-adamantyl-1-carboxamide) -1- ((1-amino-5-guanidino-1-oxopentan-2-yl) amino) -1-oxopropan-2-yl) furan-2-carboxamide is shown in Scheme 1.
A process for the preparation of 5- (4-acetylphenyl) -N- (3-adamantyl-1-amide) -1- ((1-amino-5-guanidino-1-oxopentan-2-yl) amino) -1-oxopropan-2-yl) furan-2-amide, the following steps being carried out in sequence:
adding compound 1(5g, 0.025mol), compound 2(12.6g, 0.1mol), potassium acetate (4.9g, 0.05mol), palladium acetate (56mg, 0.0025mol) and DMAC (80mL) into a 250mL round-bottom flask, reacting the obtained solution at 130 ℃ for 6 hours under the protection of nitrogen, adding 80mL of water into the reaction solution after the reaction solution is cooled to room temperature, extracting with diethyl ether (100mL × 2), washing the organic phase with saturated sodium chloride solution (50mL × 2) in turn, concentrating the filtrate, distilling, and carrying out silica gel column chromatography [ V (petroleum ether): V (ethyl acetate) ═ 10: 1)]Compound 3(3.7g) was obtained.1HNMR(400MHz,CDCl3,ppm):8.05-8.03(d,1H),7.91-7.89(d,1H),7.30-7.29(d,1H),6.91-6.90(d,1H),3.96(s,3H),2.66(s,3H)。
Compound 3(3.7g, 0.015mol), tetrahydrofuran (40mL), water (10mL), and lithium hydroxide (1.85g, 0.045mol) were added to a 250mL round bottom flask and the reaction was stirred at room temperature for 1.5 hours. After the reaction, the pH of the reaction solution was adjusted to 2-3 with 1mol/L aqueous hydrochloric acid, extracted with ethyl acetate (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude compound 4 (3.5g) which was used directly in the next reaction.
To a 250mL round bottom flask were added compound 4(2g, 8.7mmol), compound 5(2.97g, 8.7mmol), HATU (4.96g, 13.05mmol), HOBt (1.76g, 13.05mmol), and tetrahydrofuran (30 mL). The resulting solution was cooled to 5-10 deg.C and DIEA (3.36g, 26.1mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 80mL of water, followed by extraction with ethyl acetate (100mL × 2), washing of the organic phase with a saturated sodium chloride solution, concentration distillation, and silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 1:1] gave compound 6(4.1 g).
To a 250mL round bottom flask was added compound 6(552mg, 1mmol), tetrahydrofuran (10mL), water (3 mL). The temperature of the obtained solution is reduced to 5-10 ℃, lithium hydroxide (41mg, 2mmol) is added, and the reaction is stirred for 15 minutes at 5-10 ℃. After the reaction was completed, the reaction solution was adjusted to pH 2-3 with 1mol/L aqueous hydrochloric acid, extracted with ethyl acetate (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude compound 7 (550mg), which was used directly in the next reaction.
714mg of Rinkamide-MBHA resin with substitution degree of 0.28mmol/g, i.e. compound 8, is weighed into a solid phase reactor, DCM is added for swelling for 30min, and then 20% PIP/DMF solution is added for deprotection for 2 times, the first time is 5min, and the second time is 20 min. Washed with DCM and DMF several times and then dried by suction. Fmoc-Arg (Pbf) -OH (648mg,1mmol), HOBt (135mg,1mmol), DIC (126mg,1mmol), DMF (6mL) were added to the solid phase reactor and reacted at room temperature for 2 h. The resin is washed and drained to obtain Fmoc-Arg (Pbf) -Rinkamide-MBHA resin, namely a compound 9.
Adding 20% PIP/DMF solution into the solid phase reactor, reacting for 20+5min to remove Fmoc protecting group, washing with DCM and DMF for 3 times respectively to obtain NH2-arg (pbf) -RinkAmide-MBHA resin, compound 10.
To a solid phase reactor was added compound 7(540mg,1mmol), HOBt (135mg,1mmol), DIC (126mg,1mmol), DMF (6mL) and reacted at room temperature for 2 h. The coupling completion degree is detected by using a Kaiser test, and the next reaction is carried out after the detection is passed. And washing the resin and draining to obtain the compound 11.
And adding 20% PIP/DMF solution into the solid phase reactor to react for 20+5min to remove the Fmoc protecting group, and washing with DCM and DMF for 3 times respectively to obtain a compound 12.
To the solid phase reactor was added 1-adamantanecarboxylic acid (144mg,0.8mmol), HOBt (108mg,0.8mmol), DIC (101mg,0.8mmol), DMF (6mL) and reacted at room temperature for 2 h. The coupling completion degree is detected by using a Kaiser test, and the next reaction is carried out after the detection is passed. And washing the resin and draining to obtain the compound 13.
To the solid phase reactor, 8mL of a frozen lysate (volume ratio: trifluoroacetic acid/diphenyl sulfide/water: 95:2.5:2.5) was added, and the reaction was carried out at room temperature for 2 hours. After the cleavage reaction is finished, the resin is filtered, the resin is washed by trifluoroacetic acid and dichloromethane, the filtrate and the washing liquid are combined, and rotary evaporation is carried out for concentration. 10mL of frozen ether solution was added to precipitate a white precipitate, which was centrifuged and dried in vacuo to give 105mg of crude peptide. The crude peptide was purified using preparative HPLC and the liquid obtained from the preparation was lyophilized to give compound 14. MS (M/z) 634.2932[ M + H]+,1HNMR(400MHz,DMSO,ppm):8.10(m,4H),7.84(m,1H),7.46–7.10(m,3H),4.46(s,1H),4.19(s,1H),3.10(s,3H),2.63(s,3H),1.92(m,3H),1.77(m,6H),1.62(m,10H)。
Biological Activity assay
Collecting 5000 Hela cells or 1 × 104After plating K562 cells in a 96-well plate, test compounds of different concentrations were added, and 3 multiple wells were set for each group. At 37 ℃ with 5% CO2Incubate at concentration for 72 hours, remove and add MTS for testing. Adding CellTiter
AQueousSingle solution reagent, 20. mu.L/well, in CO2Incubate for 3h in the incubator, and then measure the absorbance (OD) of each well at 490nm using a microplate reader. Activity data are expressed as inhibition. The inhibitory effect of the test compounds on the activity of Hela cells at different concentrations is shown in FIG. 1, and the inhibitory effect of the test compounds at different concentrations on the activity of K562 cells is shown in FIG. 2. The results of inhibition of some of the tested compounds are detailed in table 1.
The inhibition rate calculation formula is as follows:
cell viability (%) ═ (T)OD-BOD)/(COD-BOD)
Cell inhibition (%) (1-cell viability value) × 100%
Wherein, TOD、BOD、CODThe absorbance mean values of the administration group, the blank group and the control group are shown, respectively.
Table 1 compounds of formula (i) and their biological activity
The 4 compounds in table 1 were synthesized according to the methods shown in the examples.
As shown in Table 1, the concentration of NI-E-00003 was 1 × 10-4mol·L-1Has relatively good inhibition effect on Hela cells and K562 cells.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (4)
1. An Eph receptor small molecule inhibitor compound or a pharmaceutically acceptable salt thereof, having the structural formula:
alternatively, the first and second electrodes may be,
alternatively, the first and second electrodes may be,
alternatively, the first and second electrodes may be,
2. use of a small molecule inhibitor compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease of the vascular system or inhibiting the occurrence and progression of a neoplastic disease.
3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
4. A method of making the Eph receptor small molecule inhibitor compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
carrying out palladium-catalyzed coupling reaction on the compound of the formula 1 and the compound of the formula 2 to obtain a compound of a formula 3; hydrolyzing the compound of formula 3 under alkaline conditions to obtain a compound of formula 4; condensing the compound of formula 4 with the compound of formula 5 under the condition of a condensing agent to obtain a compound of formula 6; coupling arginine with a protecting group with resin under the condition of a condensing agent to obtain a compound shown in a formula 9; the compound of formula 9 is coupled stepwise by a solid phase reaction to give a compound of formula 14; wherein R is an acetyl or cyano group;
condensing agents include, but are not limited to, N, N '-diisopropylcarbodiimide, N, N' -dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-tetramethylhexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
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| WO2006066955A1 (en) * | 2004-12-22 | 2006-06-29 | Bayer Schering Pharma Aktiengesellschaft | Quinoline derivative, use and production thereof, and drug containing the same |
| CN1860103A (en) * | 2003-09-22 | 2006-11-08 | S*Bio私人有限公司 | Benzimidazole derivates: preparation and pharmaceutical applications |
| CN101087788A (en) * | 2004-12-22 | 2007-12-12 | 拜耳先灵医药股份有限公司 | Quinoline derivative, its use, production and pharmaceutical agents containing the latter |
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| WO2006066955A1 (en) * | 2004-12-22 | 2006-06-29 | Bayer Schering Pharma Aktiengesellschaft | Quinoline derivative, use and production thereof, and drug containing the same |
| CN101087788A (en) * | 2004-12-22 | 2007-12-12 | 拜耳先灵医药股份有限公司 | Quinoline derivative, its use, production and pharmaceutical agents containing the latter |
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