An antitumor compound

Abstract

This invention belongs to the field of medicinal chemistry and relates to an antitumor compound. Specifically, this invention provides an antitumor compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug, or metabolite thereof, which exhibits good antitumor activity.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to an antitumor compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemic mixture, prodrug or metabolite thereof, pharmaceutical compositions comprising the same, and their uses. Background Technology

[0002] Cancer is a malignant disease with extremely high incidence and mortality rates worldwide, and relatively poor treatment outcomes. Globally, anti-tumor drugs have become the largest therapeutic area in the pharmaceutical market. Currently, commonly used anti-tumor drugs include cytotoxic drugs, hormone drugs, molecularly targeted therapies, biological response modifiers, tumor differentiation inducers, tumor angiogenesis inhibitors, and adjuvant therapies for cancer.

[0003] In 2020, breast cancer became the most common cancer worldwide, followed by lung cancer, which is the leading cause of cancer death globally. Colorectal cancer was the third most common cancer, and its mortality rate was second only to lung cancer. Therefore, the discovery and development of anti-tumor drugs has always been a key focus of research for scientists worldwide, and a major health and survival problem urgently needing to be solved.

[0004] Currently, antitumor drugs are characterized by high toxicity and low selectivity. Therefore, the discovery and development of novel compounds with higher activity, better selectivity, and lower toxicity is of great significance. Summary of the Invention

[0005] This invention is based on the scientific hypothesis that "cancer is an internal sore" and "treating cancer starts with treating the sore." Starting from the structures of a series of anti-inflammatory drugs or lead compounds, approximately 30,000 compounds were designed and synthesized. Through extensive research, a series of novel small molecule compounds with structures shown in Formula I were optimized and screened for synthesis. Surprisingly, they all exhibited high antitumor activity, good selectivity, and low toxicity. These compounds, or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, racemates, prodrugs, or metabolites, and their pharmaceutical compositions, can be used to treat and / or prevent cancers such as lung cancer, breast cancer, colon cancer, and melanoma.

[0006] This invention provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug, or metabolite thereof:

[0007]

[0008] in,

[0009] R1, R2, R3, R4, and R5 are each independently selected from: -R8, -O-R8;

[0010] R6 is selected from: -R8, -R9, -(CH2) n -R9, where n is an integer from 1 to 4;

[0011] R7 is selected from: -R8, halogen;

[0012] R8 is selected from: -H, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 3-8 cycloalkyl, -C 3-8 Cycloalkenyl;

[0013] R9 is selected from: -6 to 14 aryl, -5 to 14 heterocyclic, and -5 to 14 heteroaryl, and is optionally decorated with one or more -OH or -C groups. 1-4 Alkyl substitution.

[0014] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which can be a straight-chain or branched group.

[0015] The term "alkenyl" refers to an alkyl group as defined above that contains at least one carbon-carbon double bond, and can be a straight-chain or branched group.

[0016] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent.

[0017] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.

[0018] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0019] The term "aryl" refers to a cyclic aromatic group whose ring atom is a carbon atom, including monocyclic aryl and fused-ring aryl. Monocyclic aryl refers to a completely unsaturated aryl group, while fused-ring aryl refers to a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms, with at least one ring being a completely unsaturated aromatic ring.

[0020] The term "heterocyclic group" refers to a saturated or unsaturated non-aromatic group consisting of 1 to 3 rings and containing 1, 2, 3 or 4 heteroatoms (N, O or S).

[0021] The term "heteroaryl" refers to an aromatic ring structure, including monocyclic heteroaryl and fused-ring heteroaryl. At least one of the ring atoms is a heteroatom (N, O, or S), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur.

[0022] Preferably, in Formula I, R6 is selected from: -R9, -(CH2) n -R9, where n is an integer from 1 to 4; more preferably from: -(CH2) n-R9, where n is an integer from 1 to 2; further preferred from: -CH2-R9 (e.g., benzyl).

[0023] Preferably, in Formula I, R7 is selected from: halogens; more preferably from: -F, -Cl, -Br; and even more preferably from: -F.

[0024] Preferably, in Formula I, R8 is selected from: -H, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 3-6 cycloalkyl, -C 3-6 Cycloalkenyl; more preferably from: -H, -C 1-6 Alkyl, -C 2-6 Alkenyl group.

[0025] Preferably, in Formula I, R9 is selected from: -6 to 10 aryl, -5 to 10 heterocyclic, -5 to 10 heteroaryl; more preferably from: -6 to 8 aryl; and even more preferably from: phenyl.

[0026] Preferably, in Formula I, at least one of R1, R2, R3, R4, and R5 is selected from: -R8, -O-R8; wherein R8 is selected from: -C 1-8 Alkyl, -C 2-8 alkenyl, -C 3-8 cycloalkyl, -C 3-8 Cycloalkenyl; more preferably from: -C 1-6 Alkyl, -C 2-6 alkenyl, -C 3-6 cycloalkyl, -C 3-6 Cycloalkenyl.

[0027] Preferably, in Formula I, R1, R3, and R5 are each independently selected from: -H, -OH, -OC 1-6 Alkyl, -OC 2-6 Alkenyl group.

[0028] Preferably, in formula I, R2 and R4 are each independently selected from: -H, -OC 1-3 Alkyl, -C 2-6 Alkenyl group.

[0029] Preferably, in Formula I, R1, R3 and R5 are each independently selected from: -H, -OH, -O-CH3, -O-CH2CH=CH2, -O-CH2CH=C(CH3)2, -O-(CH2)5CH3, -O-(CH2)3CH3.

[0030] Preferably, in Formula I, R2 and R4 are each independently selected from: -H, -OCH3, -CH2CH=CH2, -CH2CH=C(CH3)2.

[0031] Preferably, in Formula I, R2 is selected from: -CH2CH=CH2, -CH2CH=C(CH3)2.

[0032] In some specific embodiments, the compounds of Formula I and their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, racemates, prodrugs, or metabolites described in this invention are selected from:

[0033]

[0034]

[0035] This invention also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemic mixture, prodrug, or metabolite thereof, comprising the following steps:

[0036]

[0037] Compound A reacts with an alcohol to form the corresponding ester, compound B; compound B reacts with halogenated R6 to form compound C; compound C reacts with hydrazine hydrate to give compound D; compound D undergoes a condensation reaction with compound E to give compound I. The definitions of R1, R2, R3, R4, R5, R6, R7, R8, and R9 are the same as described above.

[0038] Compound A is commercially available. Compound C is obtained from commercially available benzaldehyde compounds via substitution and optional rearrangement reactions.

[0039] In another aspect, the present invention also provides a pharmaceutical composition comprising at least one compound of formula I of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug, or metabolite thereof, and one or more pharmaceutically acceptable carriers.

[0040] In another aspect of the present invention, the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemic mixture, prodrug or metabolite, or pharmaceutical composition thereof proposed in the present invention is used for the prevention and / or treatment of cancer, primarily lung cancer, breast cancer, colon cancer, and melanoma.

[0041] The compounds of this invention exhibit strong tumor cell inhibitory activity, along with significant selectivity, low cytotoxicity against normal cells, and low toxicity. These compounds possess antitumor activity, low toxicity, high selectivity, and are synthesized using a mild and simple method, making them suitable for industrial production. Detailed Implementation

[0042] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified in the following embodiments, test methods performed under conventional conditions for such reactions are generally performed. The terminology used in this invention is for descriptive purposes only and not for limiting specific embodiments. Unless otherwise specified in the context, all technical and scientific terms used in this invention are intended to have the same meaning as commonly understood by those skilled in the art. The technical intent used in this invention refers to technology commonly understood in the art, including variations or equivalent substitutions of technology that are obvious to those skilled in the art.

[0043] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0044] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance. 1 H-NMR and 13 The determination was made by C-NMR. The NMR spectrometer used was an Agilent DD2 600 MH NMR spectrometer. The solvents used for determination were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterated dimethyl sulfoxide (DMSO-d6). The internal standard was tetramethylsilane (TMS).

[0045] The abbreviations used in the nuclear magnetic resonance (NMR) data in the following examples have the following meanings:

[0046] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift, chemical shift (δ) values ​​are given in parts per million (ppm).

[0047] Example 1: Preparation of Compound 7

[0048]

[0049] Step 1: Synthesis of Intermediate 1

[0050] Weigh 25.0 g of SM1, dissolve it in anhydrous ethanol and stir well. Add 37.5 g of concentrated sulfuric acid, heat to reflux and react. After the reaction is complete, cool to room temperature, add 50 ml of water, and add 80.0 g of potassium carbonate in portions while stirring. Stir for 1 hour, keeping the pH above 8. Filter, collect the filtrate and evaporate to dryness under reduced pressure. Add 150 ml of water to the concentrated solution, stir well, extract with ethyl acetate, retain the aqueous phase, extract twice with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to give 4.03 g of off-white solid, with a yield of 14.82%.

[0051] Step 2: Synthesis of Intermediate 2

[0052] Weigh 2.0 g of intermediate 1, add 15 ml of dichloromethane, stir to dissolve, add 700.5 mg of triethylamine, add 1.20 g of benzyl bromide, stir to react at room temperature, after the reaction is complete, wash twice with 10 ml of water, collect the dichloromethane layer, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to give 2.02 g of off-white solid, yield: 80.19%.

[0053] Step 3: Synthesis of Intermediate 3

[0054] Weigh 2.0 g of intermediate 2, add 30 ml of anhydrous ethanol, stir to dissolve, add 4 ml of hydrazine hydrate, reflux the reaction, after the reaction is complete, cool to room temperature, filter, and give 1.53 g of off-white solid, yield: 79.03%.

[0055] Step 4: Synthesis of Compound 7

[0056] Weigh 100 mg (1.0 eq) of intermediate 3, add 5 ml of anhydrous ethanol, heat and stir to dissolve, add 53.9 mg (1.2 eq) of 2-isopentenoxybenzaldehyde, reflux the reaction, and after the reaction is complete, allow it to cool to room temperature naturally. A solid precipitates out, filter and wash three times with 2 ml of ethanol each time. Dry the filter cake to give 97.1 mg of white solid, yield 69.03%.

[0057] 1H NMR (600MHz, CDCl3) δ13.21(s,1H),8.83(d,J=2.8Hz,1H),8.67-8.64(m,1H),8.19(d,J=6.6Hz,1H),8.07(d,J=11.7Hz,1H),7.3 5(t,J=5.0Hz,5H),7.29(s,1H),6.97(d,J=8.3Hz,1H),6.89(d,J=7.6Hz,1H),6.81(d,J=6.2Hz,1H),5.51(d,J=7.8Hz,1H),4.58- 4.53(m,2H),4.35-4.27(m,2H),3.61(s,2H),3.31(d,J=6.0Hz,4H),2.69(d,J =6.2Hz, 4H), 1.83 (d, J = 3.4Hz, 3H), 1.75 (d, J = 3.5Hz, 3H), 1.61-1.53 ​​(m, 3H).

[0058] 13 C NMR(150MHz, CDCl3)δ175.32(175.30),161.90,157.75,154.40(152.74),147.20, 145.66(145.59),144.57,138.04,137.93,136,70,131.39,129.32,128.51,127.49,127.45,123.14, 122.36(122.31),120.75,119.87,113.19(113.04),112.21,111.18,103.85(103.82),65.51,63.10, 52.91, 50.25, 50.22, 49.48, 25.94, 18.39, 14.60.

[0059] Example 2 Preparation of Compound 22

[0060]

[0061] Step 1: Synthesis of Intermediate 1

[0062] The synthesis steps are the same as those for intermediate 1 in Example 1.

[0063] Step 2: Synthesis of Intermediate 2

[0064] The synthesis steps are the same as those for intermediate 2 in Example 1.

[0065] Step 3: Synthesis of Intermediate 3

[0066] The synthesis steps are the same as those for intermediate 3 in Example 1.

[0067] Step 4: Synthesis of Compound 22

[0068] Weigh intermediate 3 (109.47 mg, 1.0 eq), add anhydrous ethanol, stir well, add 3-allyl-4-allyloxybenzaldehyde (89.1 mg, 1.5 eq), reflux the reaction, and allow it to cool to room temperature after the reaction is complete. A solid precipitates out, is filtered and washed three times with 2 ml of anhydrous ethanol each time, and dried to obtain 123.4 mg of solid, with a yield of 78.55%.

[0069] 1 H NMR (600MHz, CDCl3) δ13.18(s,1H),8.80(s,1H),8.15(s,1H),8.07(d,J=13.2Hz, 1H),7.70(d,J=2.2Hz,1H),7.56(dd,J=8.5,2.2Hz,1H),7.27-7.37(m,5H),6.84(d,J=8.5H z,1H),6.80(d,J=6.8Hz,1H),6.10-5.94(m,2H),5.47-5.26(m,2H),5.10-5.02(m,2H),4.58 (dt,J=5.0,1.7Hz,2H),4.30(q,J=7.3Hz,2H),3.60(s,2H),3.44(dd,J=6.6,1 .6Hz,2H),3.30(t,J=4.9Hz,4H),2.68(t,J=4.9Hz,4H),1.55(t,J=7.2Hz,3H).

[0070] 13 C NMR(150MHz, CDCl3)δ175.10(175.09),161.66,158.10,154.19(152.53),148.39, 146.90,145.48(145.41),137.70,136.46,133.05,129.39,129.16,129.13,128.34,127.85,127.29, 126.64,122.14(122.09),117.20,115.69,113.02(112.87),111.29,110.87,103.67(103.65),68.75, 62.92, 52.71, 50.04, 50.01, 49.34, 34.48, 14.44.

[0071] The inventors also synthesized the following compounds using a similar synthesis method to that of Examples 1 and 2.

[0072] Table 1. Structural formulas and data analysis of the compounds of this invention.

[0073]

[0074]

[0075]

[0076]

[0077]

[0078] Example 3 In vitro activity study

[0079] The compounds of this invention exhibit inhibitory activity against human non-small cell lung cancer cells (A549), human breast cancer cells (MCF-7), human melanoma cells (A375), and human colon cancer cells (HCT-116).

[0080] (1) Test method: The MTT assay was used to study the inhibitory effect of the compound on cancer cell proliferation.

[0081] (2) Instruments and reagents are shown in Table 2 and Table 3.

[0082] Table 2 Reagent List

[0083]

[0084] Table 3. List of Instruments

[0085]

[0086] (3) Compound preparation

[0087] The compound was dissolved in DSMO and stored at room temperature under nitrogen atmosphere for later use. The sample in DSMO was then serially diluted with culture medium to the required concentration.

[0088] (4) Test methods

[0089] The specific steps are as follows: human non-small cell lung cancer cells (A549), human breast cancer cells (MCF-7), human melanoma cells (A375), and human colon cancer cells (HCT-116) are cultured in DMEM medium containing 10% FBS (penicillin and streptomycin are both 100kU / L) in a 37°C constant temperature incubator with 5% CO2. When the cells grow to 80-90% confluence on the plate, they are passaged, and the medium is replaced with fresh medium every 24 hours.

[0090] A549, MCF-7, HCT-116, and A375 cells were cultured at 37°C in a 5% CO2 incubator until the logarithmic growth phase. Cells were seeded into 96-well plates at a density of 4000 cells / well. After 24 hours, the plates were divided into a blank control group (NC), a positive control group (2 μM), and a test compound group (2 μM). After 48 hours of culture, 20 μL of MTT solution (5 mg / mL) was added to each well. -1 Continue culturing for 4 hours, carefully aspirate the culture medium, add 150 μL of DMSO solution to each well, and shake for 10 min to completely dissolve. Measure the absorbance (OD) of each well at 490 nm using a microplate reader and calculate the cell inhibition rate. In this example, the inhibitory activity of the compound of the present invention against cancer cells was determined, as shown in Table 4 below.

[0091] Table 4. Inhibitory activity data of the compounds of this invention against cancer cells (48h)

[0092]

[0093] Note: The inhibition rate is negative for "\".

[0094] As can be seen from the results in Table 4, compounds 7, 13, 14, 21, 22, and 28 exhibited good inhibitory activity in the study of their inhibitory effects on A549 cells.

[0095] In studies on the inhibitory effects on MCF-7 cells, compounds 1, 5, 7, 14-24, and 28 of this invention showed significant antitumor effects, with compounds 17 and 21 exhibiting the best anti-breast cancer effects.

[0096] In studies on the inhibitory effects on HCT116 cells, compounds 2, 6, 15, 17, 21, 26, and 27 of this invention exhibited good inhibitory activity.

[0097] In studies on the inhibitory effects on A375 cells, compounds 7, 11, 13, 17, 21, and 27 of this invention exhibited good inhibitory activity.

[0098] Based on the above description of the invention, those skilled in the art can fully apply the present invention, and all modifications based on the same principles or similar modifications should be considered to be included within the scope of the present invention.

Claims

1. The following compounds with antitumor activity or their pharmaceutically acceptable salts, 、 or 。 2. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the preparation of a medicament for the prevention and / or treatment of cancer.

4. Use according to claim 3, wherein, The cancer in question is lung cancer, breast cancer, colon cancer, or melanoma.

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